Chemistry of α-oxoesters: a powerful tool for the synthesis of heterocycles.

Review pubs.acs.org/CR

Chemistry of α‑Oxoesters: A Powerful Tool for the Synthesis of Heterocycles Bagher Eftekhari-Sis*,† and Maryam Zirak‡ †

Department of Chemistry, University of Maragheh, Maragheh 55181-83111, Iran Department of Chemistry, Payame Noor University, Iran

‡

S Supporting Information *

4.6. Dioxolanes 4.7. Hydropyrans and Pyrans 4.8. Chromanes and Chromenes 4.9. Isochromanes and Isochromenes 4.10. Dioxanes 4.11. Oxepins 5. Synthesis of N,O-Heterocycles 5.1. Isoxazoles 5.2. Oxazoles 5.3. Oxazines 5.4. Oxazepines 6. Synthesis of N,S- and N,Se-Heterocycles 6.1. Thiazoles 6.2. Thiazines 6.3. Thiazepines 6.4. Selenazoles 7. Synthesis of S-, S,O-, and Si,O-Heterocycles 7.1. Thiophenes 7.2. Thiopyrans 7.3. Oxathiolanes 7.4. 1,4-Oxathianes 7.5. Dioxasilocine 8. Conclusion Associated Content Supporting Information Author Information Corresponding Author Notes Biographies Acknowledgments References

CONTENTS 1. Introduction 2. Synthesis of α-Oxoesters 3. Synthesis of N-Heterocycles 3.1. Aziridines and Azirines 3.2. β-Lactams 3.3. Pyrrolidines and Pyrrolines 3.4. Pyrroles 3.5. Pyrazoles 3.6. Imidazoles 3.7. Triazoles 3.8. Indoles 3.9. Pyrrolizidines and Pyrrolizines 3.10. Indolizidines and Indolizines 3.11. Imidazopyridines 3.12. Piperidines 3.13. Tetrahydro- and Dihydropyridines 3.14. Pyridines 3.15. Fused Pyridines and Naphthyridines 3.16. Quinolines 3.17. Isoquinolines 3.18. β-Carbolines 3.19. Pyridazines 3.20. Pyrimidines 3.21. Pyrazines 3.22. Quinoxalines 3.23. Triazines 3.24. Azepines and Diazepines 3.25. Miscellaneous N-Heterocycles 4. Synthesis of O-Heterocycles 4.1. Oxiranes 4.2. Oxetanes and β-Lactones 4.3. Tetrahydrofurans 4.4. Dihydrofurans 4.5. Furans © 2014 American Chemical Society

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1. INTRODUCTION Heterocycles are an important class of organic compounds accounting for nearly one-third of the past decade’s publications, which are in the field of heterocyclic chemistry. In fact, two-thirds of organic compounds are heterocyclic compounds. Heterocycles are vastly distributed in natural products, as more than 84 natural products possessing heterocyclic structural units were isolated and structurally elucidated during 2013, such as penicillactone A, B, and C,1 gymnocin-A2,2 oxalicumone A, B, and C,3 illihenlactone A, B, Received: August 4, 2014 Published: November 25, 2014 151

dx.doi.org/10.1021/cr5004216 | Chem. Rev. 2015, 115, 151−264

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Figure 1. Reactivity portrait of the important types of α-oxoesters.

portrait of the important types of α-oxoesters, glyoxalates, pyruvates, and α,β-unsaturated α-oxoesters is illustrated in Figure 1, indicating the reactive positions of these scaffolds, incorporated in the synthesis of various types of heterocycles. There is a growing number of published papers on αoxoesters in organic synthesis, as about three-quarters of papers, which will be reviewed, were published in the past decade. Figure 2 shows the strong increase of the research in

C, D, E, and F,4 sartorypyrone A and B,5 dichapetalin N, O, P, Q, R, and S,6 trichiliton G and H,7 stemona-lactam S,8 pancrimatine A, B, and C,9 meloscine N-oxide,10 etc. Moreover, they are present in most important molecules of life such as DNA, RNA, chlorophyll, and heme. Also, they have been frequently found as a key structural unit in a wide variety of drugs, most vitamins, synthetic pharmaceuticals, and agrochemicals. Most heterocycles exhibit biological activity, including antitumor, anti-HIV, antibiotic, antidepressant, antiinflammatory, antiviral, antidiabetic, antimalarial, antimicrobial, antibacterial, antifungal, herbicidal, fungicidal, and insecticidal activities. Additionally, they have important applications in organic synthesis as organocatalysts, synthetic intermediates, chiral auxiliaries, and metal ligands in asymmetric catalysis. Therefore, the development of new efficient methods to synthesize heterocycles is of considerable interest. In continuing our research on heterocycles and α-keto aldehydes chemistry, we have recently published a review article entitled “Arylglyoxals in Synthesis of Heterocyclic Compounds” in Chemical Reviews,11 and during the reviewing process of our manuscript, one of the reviewers suggested the addition of another section about the synthesis of heterocycles using αketoesters, with structure similar to that of α-keto aldehydes. Further studies on the α-oxoesters revealed that many types of heterocyclic compounds with different heteroatoms were synthesized starting from α-oxoesters. So this encouraged us to write another review on the synthesis of heterocyclic compounds starting with α-oxoesters. Because the main purpose of this Review is to show the application of α-oxoesters to synthesize heterocycles, not only simple α-oxoesters, such as glyoxalates and pyruvates, are reviewed, but also conjugate pyruvates, benzoylpuruvates, and cyclic α-oxoesters are included. Thanks to the reactive carbonyl functionality, α-oxoesters are susceptible for many kinds of reactions, and all types of reactions, such as Paal−Knorr reaction, Dieckmann cyclization, Fischer indole synthesis, Pfitzinger-type condensation, [2 + 2]-, [4 + 2]-, [3 + 2]-, and 1,3-dipolar cycloaddition reactions, Pictet−Spengler reaction, Friedländer synthesis, and any sequences of other reactions such as tandem 1,4-conjugate addition-cyclization, aldol condensation-cyclization, aza-Wittig-reductive cyclization, Baylis−Hillman-cyclization, cascade arylation-cyclization, Michael addition-hemiketalization reactions, etc., which led to the construction of heterocyclic compounds, are reviewed. The reactions occurred at different sites of α-oxoesters, leading to heterocyclic systems with a variety of ring sizes. The reactivity

Figure 2. Number of papers dealing with the synthesis of heterocycles starting from α-oxoesters appearing in the literature.

the field that led, in about 15 years, to more than 450 references reporting the synthesis of heterocycles starting from αoxoesters. This Review has the aim of covering the literature up to the end of May 2014, showing the distribution of publications involving use of α-oxoesters for preparation of heterocycles, which was elaborated using the Web of Science, Google Scholar, ACS Publications, Wiley Online Library, Science Direct, RSC Publishing, Thieme Chemistry, and other sites with the keywords α-ketoester, α-keto ester, α-oxo and 2oxo ester, glyoxalate, pyruvate, 2-oxoacetate, and benzoyl formate and from a selection of papers related to the synthesis of heterocyclic compounds starting with α-oxoesters and related derivatives, such as acetals, imines, oximes, hydrazone, etc. This Review begins by describing the methods for the preparation of various α-oxoesters, followed by the use of them to synthesize heterocycles in the arrangement of N-, O-, N,O-, N,S-, S-, and S,O-heterocycles in the ring size order of three-, four-, five-, six-, and seven-membered heterocycles. However, there are some review articles about special derivatives of αoxoesters or similar structures, “arylidene pyruvic acids”,12 “(E)2-oxo-3-butenoates”,13a and “benzoylpyruvates”,13b but to the 152


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Table 1. Synthesis of α-Oxoestersa

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Table 1. continued

a

See also ref 46.

(entry 3).18 Carbonylation of aryl iodide using 70 atm initial pressure of CO catalyzed with PdCl2(Cy3)2 in the presence of alcohols and Et3N in DCM at 70 °C afforded arylglyoxalates in 22−69% yields (entry 4).19 Also, arylglyoxalates were prepared via the rearrangement of aromatic cyanohydrin carbonate esters, prepared by the reaction of aromatic aldehydes, ethyl chloroformate, aq KCN, and benzyltrimethylammonium chloride in DCM. Rearrangement occurred using LDA in THF at −78 °C for 1 h and then at room temperature overnight, to give (het)arylglyoxalates in 60−76% yields (entry 5).20 The synthesis of a variety of substituted arylglyoxalates was achieved by reactions of functionalized aryllithiums with dialkyl oxalates using a flow microreactor in 63−95% yields (entry 6).21 Oxidative esterification of 2,2-dibromo-1-(het)arylethanones by sequential treatment with DMSO and an alcohol was developed by Raghunadh et al. Reactions were performed by heating a solution of 2,2-dibromo-1-(het)arylethanones in DMSO at 70−75 °C for 14−16 h, and then cooled to room temperature and treated with an alcohol for 1− 2 h, to afford corresponding arylglyoxalate derivatives in 35− 76% yields (entry 7).22 Also, direct conversion of ethylbenzenes to arylglyoxalates was reported by irradiation of a mixture of ethylbenzenes in EtOAc and 48% aq HBr in the presence of O2 using 22 W fluorescent lamps, for 20 h, at 40 °C. Reactions

best of our knowledge, there are no reviews and book chapters in the field of α-oxoesters in heterocycles synthesis.

2. SYNTHESIS OF α-OXOESTERS Various procedures were reported for the synthesis of αoxoester derivatives. Some methods with reaction conditions and synthesized α-oxoesters are summarized in Table 1. Alkyl glyoxalates, as the simplest α-oxoesters, are conveniently prepared by oxidative cleavage of tartrate esters,14 or ozonolysis of a double bond of the corresponding maleate or fumarate esters (entry 1).15 Also, ethyl glyoxalate was prepared in 72% yield by electrochemical oxidation of ethyl cyanoacetate.16 Aromatic α-ketoesters, arylglyoxalates, are prepared by a variety of methods, such as Friedel−Crafts acylation, oxidative dehydrogenative coupling of alcohols and α-carbonyl aldehydes, oxidations of aryl acetylene, oxidative esterification of 2,2-dibromo-1-(het)arylethanones, etc. Friedel−Crafts reaction of substituted aromatic compounds with ethyl oxalyl chloride was developed using AlCl3 under solvent-free conditions to give the corresponding arylglyoxalates in 80−91% yields (entry 2).17 Rhodium-catalyzed reaction of ethyl cyanoformate with arylboronic acids in the presence of H3BO3 in dioxane, at room temperature for 30 min, and then at 60 °C for 3 h, led to the corresponding ethyl arylglyoxalates in 46−87% yields 154


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azirinomycin, (−)-(E)-dysidazirine, (Z)-dysidazirine, (+)-(Z)antazirine, and (+)-(E)-antazirine. Thermolysis or photolysis of vinyl azides, ring contraction of isoxazoles, additions of carbenes to nitriles or nitrenes to acetylenes, and Neber rearrangement are among the most useful methods for the synthesis of azirine derivatives. The synthesis of aziridine carboxylates 2 was reported by reaction of primary amines (2 equiv) with vinyl triflates of αketoesters 1 in dry DMF or acetonitrile under an Ar atmosphere. The reactions were completed in 24 h, and the corresponding aziridines 2 were obtained in 59−89% yields with 1/2 to 2/1 cis/trans selectivity. When binucleophilic amines such as ethanolamine or ethylenediamine were used as amine component, in addition to aziridines 4, corresponding fused bicyclic aziridine lactone or lactam 3 was obtained as the major product by aziridination and then lactone or lactam ring closure with carboxylate group in 24% or 60% yield, respectively. α-Ketoesters were converted to the corresponding vinyl triflates 1 using Tf2O in the presence of an equimolar amount of DIPEA in dry DCM under an Ar atmosphere at 0 °C (Scheme 1).47

occurred via tribromoacetophenone derivatives as reaction intermediate (entry 8).23 Moreover, ozonolysis of ethyl 2-aryl3-hydroxyacrylates24 and NaBr-induced hydrolysis of benzoyl cyanides in the presence of H2SO4 followed by treatment with MeOH25 are other approaches for the preparation of aromatic α-ketoesters. Rh2(OAc)4-catalyzed reaction of aryl diazoacetates with H2O and DEAD in refluxing toluene (entry 9),26 and oxidation of aryl diazoacetates with dimethyldioxirane, generated in situ from acetone and oxone (entry 10),27 are also used for the preparation of arylglyoxalates. Zhang and Jiao developed an efficient aerobic oxidative dehydrogenative coupling of alcohols and arylglyoxals to afford arylglyoxalates using CuBr in the presence of pyridine in toluene at 90 °C, in 42−88% yields (entry 11).28 One-pot oxidation of acetophenone derivatives using SeO2 in pyridine at 100 °C, followed by esterification, led to aromatic α-ketoesters in 71−80% yields (entry 12).29 Nef reaction of 2-aryl-2-nitroacetates using TBAF, MeI, and KF in THF proved to generate aromatic α-ketoesters in 51−86% yields (entry 13).30 Various derivatives of pyruvate and also aromatic α-ketoesters were prepared by oxidation of αhydroxy esters (entry 14),31 ozonolysis of Morita−Baylis− Hillman adducts (entry 15), 3 2 and [(triphenyl)phosphynyliden]-3-oxoalkanenitriles,33 oxidation of alkyne derivatives (entry 16),34 oxidative reaction of α-allyl-βketoesters with Mn(OAc)3·2H2O,35 decyanation of α-cyanoα-hydroxy esters (entry 17),36 and α-cyano-α-amino esters,37 epoxy-carbonyl rearrangement of α-chloroglycidates,38 reaction of Grignard reagent with 1-[N-(ethoxyoxalyl)-N-methylamino]3-methylimidazolium iodide (entry 18),39 or with methyl oxalyl chloride (entry 19),40 reaction of benzylamine immobilized polymer with nitroolefinic esters, via enamino esters, generated by removing nitrous acid, using a continuous flow reactor (entry 20),41 two-carbon homologation of aldehydes by Horner−Emmons reaction of trichloro-t-butyloxy carbonate (TCBOC) protected phosphonoglycolate ester with aldehydes, followed by Zn-dust induced reductive elimination of TCBOC protecting group (entry 21),42 photoinduced alcoholysis of the trichloroacetate group,43 and oxidative hydrolysis of 2ethoxycarbonyl-l,3-dithian with NBS.44 CuBr-Promoted hydroacylation of arylacetylenes with ethyl glyoxalate in the presence of morpholine in refluxing dioxane led to the formation of α,βunsaturated α-oxoesters in 56−82% yields (entry 22).45

Scheme 1. Synthesis of Aziridine Carboxylates 2a

a 1

R = H, 3-XC6H4 (X = H, NO2); R2 = H, Me, n-Bu, 4-XBn (X = H, Cl, MeO), (R)-PhCH(Me); 2, 59−89%, cis/trans = 1/2−2/1; X = O; 3, 24%; 4, R3 = H, 11%; X = NH; 3, 60%; 4, R3 = Ac, 28%.

Williams et al.48 reported the TfOH-catalyzed aza-Darzens reaction between methyl or t-butyl glyoxalate imines and ethyl diazoacetate to afford aziridines 5 in 86−89% yields, with >95/ 5 syn selectivity. The reactions were carried out by preparation of glyoxalate imines through the reaction of methyl or t-butyl glyoxalate with diphenylmethyl amine in the presence of 4 Å MS or MgSO4 in DCM at 25 °C, respectively, and then conversion to aziridines 5 by treatment with ethyl diazoacetate (1.2 equiv) in the presence of TfOH (0.25 equiv) in propionitrile at −78 °C for 6 h (Scheme 2). Aziridination reaction of α-imino esters with diazo compounds catalyzed by the different chiral ligands/Cu(I) complexes was also developed to afford corresponding aziridines in 24−66% yields. Reactions were performed in THF, DCM, or toluene by 5−10% catalyst loading.49 Chloroaziridines 6,7 were prepared via carbene addition to ethyl glyoxalate imines. Chlorocarbenes were in situ generated from CHCl3 using KOt-Bu as a base or from DCM and n-BuLi. Reactions were conducted by addition of KOt-Bu (2 equiv) and CHCl3 (2 equiv) to a solution of α-iminoesters in n-hexane at −20 to −30 °C and stirring for 3 h at the same temperature and then for 5 h at room temperature, giving aziridines 6 in 50−

3. SYNTHESIS OF N-HETEROCYCLES 3.1. Aziridines and Azirines

The aziridine moiety is found in the structure of many natural products and alkaloids, such as mitomycin, albomitomycin A and C, ficellomycin, porfiromycin, azicemicin A and B, azinomycin A, maduropeptin, madurastatin A1 and B1, and miraziridine A, which exhibit a broad range of biological activities. Moreover, thanks to the high strain and reactivity of the three-membered ring, aziridines are versatile synthetic intermediates to synthesize N-containing compounds including functionalized α- and β-amino acids, β-amino alcohols, βlactams, alkaloids, and other heterocyclic compounds, via ringopening and ring-expansion reactions. Therefore, a variety of methods were developed for the preparation of aziridines such as aziridination by carbene transfer to imines and the nitrene or nitrene equivalents transfer to olefins, ring-closure of amino alcohols, aminolysis of epoxides, and aza-Darzens reactions. Additionally, there are many natural products possessing an azirine structural motif with antibiotic activity, such as 155


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The synthesis of 2H-azirines 14 was reported by Patonay et al.52 in three steps, starting from ethyl pyruvate and phenacyl azides 10. Treatment of phenacyl azides 10 with ethyl pyruvate in dry THF in the presence of DBU at 0 °C for 5−27 h gave ethyl 4-aryl-3-azido-2-hydroxy-2-methyl-4-oxobutanoates 11, which were transformed into corresponding vinyl azides 12 when reacted with mesyl chloride in dry pyridine at room temperature for 40−91 h. The overall yields for two steps are 36−51%. Conversion of vinyl azides 12 to 2H-azirines 14 was performed by refluxing in toluene for 1 h in 33−70% yields. Vinyl nitrene 13 was proposed as a reaction intermediate, which gave 14 by migration of the π-electrons of the double bond to the electron-deficient nitrene (Scheme 5).

Scheme 2. Synthesis of Aziridines 5 via Aza-Darzens Reactiona

a

R = Me, t-Bu; 86−89%, syn/anti = >95/5.

56% yields, or by addition of a hexane solution of n-BuLi to DCM in dry THF/ether at below −90 °C under N 2 atmosphere, followed by treatment with a solution of PMPimine of ethyl glyoxalate in dry ether and stirring for 5 min at the same temperature, then for 10 min at −78 °C, leading to aziridine 7 in 50% yield (Scheme 3).50

Scheme 5. Synthesis of 2H-Azirines 14 via Vinyl Nitrene Intermediate 13a

Scheme 3. Synthesis of Chloroaziridines 6,7 via Carbenoid Additiona

a

Ar = XC6H4 (X = H, 4-F, 4-Cl, 3-MeO, 4-MeO, 4-Ph); 12, 36−51%; 14, 33−70%.

a

R = Ph, PMP; 6, 50−56%; 7, 50%.

3.2. β-Lactams

β-Lactam antibiotics are a broad class of antibiotics, containing a β-lactam ring in their structures, such as penicillin, amoxicillin, cephalosporins, monobactams, and carbapenems. Also, βlactams have applications as synthons for the synthesis of many types of biologically active compounds. Staudinger [2 + 2] cycloaddition reaction between ketenes and imines is one of the most important routes to the preparation of β-lactams. Palomo et al.53 developed a method to synthesize 3alkylaspartates 16 via β-lactams. β-Lactams 15a were prepared as syn isomer by [2 + 2] cycloaddition reaction of in situ generated ketenes with imine, derived from methyl glyoxalate and di-p-anisylmethylamine, in refluxing benzene or DCM in the presence of Et3N for 12−14 h. Obtained β-lactams 15a were converted to corresponding aspartates 16 with further reactions. In another work, Palomo et al.54 conducted the [2 + 2] cycloaddition reaction between α-imino ester, prepared from methyl glyoxalate and bis(trimethylsilyl)methylamine, and acyl chlorides in the presence of Et3N in benzene or DCM to give β-lactams 15b in 80−98% yields as only cis isomer. The βlactams 15b (R2 = phthalimide) underwent further reactions to synthesize oxacephalosporin 17, which exhibit antibacterial activity (Scheme 6). Enantioselective [2 + 2] cycloaddition reactions of an α-imino ester with in situ generated ketenes were also reported using benzoylquinine in the presence of proton sponge55a or C2-symmetric bis(cyclophane) ligand/ Al(III)55b in toluene at −78 °C to afford corresponding βlactams in 36−65% yields, with 95−99% ee, and 25/1 to >99/1 dr.

51

Li et al. developed a method for transformation of nitroaldol products 8 of the reaction of α-ketoesters with CH3NO2 to enantiomerically enriched aziridines 9 with 91% ee. Cinchona alkaloid derivatives I-1-catalyzed enantioselective nitroaldol addition of CH3NO2 to α-ketoesters was performed in DCM at −20 °C in 89−96% yields with 95% ee. Conversion of nitroaldol products 8 into corresponding aziridines 9 was conducted in three steps as shown in Scheme 4. Scheme 4. Conversion of Nitroaldol Products 8 into Aziridines 9a

a

R = Me, Ph; 8, 89−96%, 95% ee; 9, 71−80%, 91% ee. 156


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Scheme 6. Synthesis of β-Lactams 15 via [2 + 2] Cycloaddition Reactiona

A three-component reaction of alkylhydroxylamines, glyoxalates, and bicyclopropylidene 21 to give 3-spirocyclopropanated 2-azetidinones 25 was developed by Zanobini et al.58 Reactions were performed using equimolar amounts of alkylhydroxylamines and glyoxalates, and 0.5 equiv of 21 in the presence of NaOAc (1 equiv) in EtOH under heating at 80 °C in MW oven for 15−120 min, leading to 3-spirocyclopropanated 2-azetidinones 25 in 53−78% yields. The conversion could be explained by 1,3-dipolar cycloaddition reaction of bicyclopropylidene 21 with nitrones 22, in situ generated from alkylhydroxylamines and alkyl glyoxalates, to form isoxazolidine 23, which underwent fragmentation to 25 and ethylene via intermediates 24 (Scheme 9).

a

15a, R1 = PMP; R2 = Me, Et, i-Pr, Ph, Bn, CH(SiMe2Ph)Ph; 15b, R1 = TMS; R2 = Et, PhS, phthalimide; 80−98%.

Scheme 9. Synthesis of 3-Spirocyclopropanated 2Azetidinones 25a

Also, β-lactam containing pentafluorosulfanylmethyl substituent 18 was synthesized via Staudinger cycloaddition between ketimine, derived from MgSO4-mediated condensation of ethyl pentafluorosulfanylpyruvate with 3 equiv of pmethoxyaniline in DCM, and benzyloxyketene in only 8% yield. Reaction was conducted by in situ generation of benzyloxyketene using benzyloxyacetyl chloride in the presence of Et3N in DCM, followed by addition of a solution of ketimine in DCM and stirring at room temperature for overnight (Scheme 7).56 Scheme 7. Synthesis of β-Lactam Containing Pentafluorosulfanylmethyl Substituent 18

a 1

R = t-Bu, Bn, PMP; R2 = Me, Et; 53−78%.

One example of conversion of nitroaldol product 8 to βlactam 26 was performed by reduction of nitro group using H2 (1 atm) in the presence of Raney Ni in EtOH, followed by treatment with i-PrMgCl in dry THF at room temperature for 19 h, in 38% yield over two steps (Scheme 10, see also Scheme 4).51 Scheme 10. Conversion of Nitroaldol Product 8 to β-Lactam 26

Photolysis of cyclohexyl benzoylformate in the presence of various imines was studied by Aoyama et al.57 Reactions were carried out in dry benzene at 80 °C for 3 h, which gave corresponding β-lactams 20 in 27−77% yields. First, hydroxyphenylketene 19 was in situ generated by photolysis of cyclohexyl benzoylformate, and then underwent [2 + 2] cycloaddition reaction with imines to afford β-lactams 20 (Scheme 8).

3.3. Pyrrolidines and Pyrrolines

Pyrrolidines and pyrrolines are important classes of heterocycles found in numerous natural and non-natural products, such as kaitocephalin, bioxalomycin β1, enalapril, captopril, ramipril, radicamine A, nakadomarin A, manzamine A, (+)-castanospermine, and (+)-casuarine, with a wide range of biological activities. Also, they are found in the structure of many pharmaceuticals, and have applications as organocatalysts, chiral ligands in asymmetric synthesis, and building blocks in organic synthesis. [3 + 2]-Cycloadditions, Pd-catalyzed carboamination reactions, intramolecular cyclization of epoxy and halogenated sulfones under basic conditions, intramolecular carbolithiation of homoallylic amines, Brønsted acid-catalyzed intramolecular hydroamination of alkenylamines, and ring-closing metathesis of bis-allylic amines are among the most used approaches for the synthesis of pyrrolidine and pyrroline derivatives.

Scheme 8. Synthesis of β-Lactams 20 via Photolysis of Cyclohexyl Benzoylformate in the Presence of Iminesa

a

R = Et, i-Pr, t-Bu, Bn, 4-ClBn, 4-MeBn; Ar = 4-XC6H4 (X = H, Cl, Me, MeO, CN); 27−77%. 157


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Cu(OTf)2-Catalyzed three-component reaction of aromatic amines, ethyl glyoxalate, and cyclobutanols 27 bearing dihydropyrrolyl or pyranyl moieties was reported by Zhang et al.59 The reactions were carried out by slow addition of 27 to a solution of ethyl glyoxalate, aniline derivatives, Cu(OTf)2 (2 mol %), and 5 Å MS in acetone or THF at room temperature for 1 h. Pyrrolidines 28 were obtained in 52−83% yields with low diastereoselectivity (Scheme 11).

Scheme 12. Synthesis of N-Sulfonylamidines 34 via Brook Rearrangementa

Scheme 11. Three-Component Synthesis of Pyrrolidines 28a

a 1

R = Bn, t-Bu; R2 = Et, XC6H4 (X = H, 4-Cl, 4-Br, 4-Me, 2-MeO, 3MeO, 4-MeO), 3,5-(OCH2O)C6H3, 1-naphthyl, 2-furyl, 2-thienyl, Ph(CH2)2, styryl; Ar = XC6H4 (X = H, 4-Me, 4-MeO); 59−91%; dr = >20/1; 94−99% ee.

a

n = 1, R = H, X = NTs, Ar = 4-Br-3-NO2C6H3; 83% (only 28a); n = 2, R = TBS, X = O, Ar = 3-XC6H4 (X = NO2, CF3), 4-Br-3-NO2C6H3; 52−72%, 28a/28b = ∼1/1.

cyclization occurred, and pyrrolidine-2-ones 43 were obtained in 62−68% yields. When an enantiomeric form 44 was used, pyrrolidine-2-one 45 was obtained in 70% yield (Scheme 14).62 The synthesis of N-benzyloxy-α-methylene-L-pyroglutamic acid 48 was reported via PTSA-catalyzed cyclization of Nbenzyloxy derivative 47, which was prepared by allylation of the glyoxalate oxime using t-butyl ester-substituted allylzinc reagent 46 in THF at −78 °C for 0.5 h, followed by hydrolysis of tbutyl ester moieties with TFA in DCM (Scheme 15).63 The synthesis of pyrrolidine moiety of acromelic acid 55 was reported by Ouchi et al.64 via conjugate addition of nitroalkene 49 with α-ketoester 50 using 5 mol % Ni(OAc)2−diamine catalyst II in DME at −10 °C within 48 h, to give 51 in 88% yield, followed by reduction of nitro group with H2 in the presence of Raney Ni in MeOH at 75 °C, leading to ketimine 52 by in situ cyclocondensation of amine with ketone moiety, which underwent in situ reduction to the corresponding pyrrolidine structure 53. Hydrogenolysis of diphenylmethyl (Dpm) moiety followed by esterification using SOCl2 and MeOH at room temperature for 20 h afforded pyrrolidine 54 in 63% yield, for three steps (Scheme 16). Three-component tandem 1,4-conjugate addition−cyclization reaction of diazoacetophenones 56 with anilines and β,γunsaturated α-oxoesters was described by Zhang et al.65 to synthesize 2-hydroxypyrrolidine-2-carboxylate derivatives 57. Reactions were carried out by addition of diazoacetophenones 56 (1.8 equiv) to a solution of Rh2(OAc)4 (1 mol %), anilines (1.8 equiv), and β,γ-unsaturated α-oxoesters (1 mmol) in DCM at 40 °C, over 1 h. 2-Hydroxypyrrolidine-2-carboxylates 57 were obtained in 45−84% yields with 87/13−96/4 (syn/anti) diastereoselectivity (Scheme 17). Zhu et al.66 developed a methodology similar to the preparation of pyrroline derivatives 59 via one-pot, threecomponent tandem reaction of diazo compounds 58 with anilines and β,γ-unsaturated α-oxoesters. Tandem 1,4-conjugate addition−cyclization reaction between diazo compounds, anilines, and β,γ-unsaturated α-oxoesters was carried out using 1 mol % Rh2(OAc)4 as catalyst in toluene at 45 °C for 1 h, leading to 2-hydroxypyrrolidines, which underwent one-pot dehydration to pyrroline derivatives 59, when heated in the

Yao and Lu60 reported an efficient method for the synthesis of cyclic N-sulfonylamidines 34 via three-component coupling reaction of sulfonylimidates 29, silyl glyoxylates, and N-tbutanesulfinyl aldimines 30. Reactions were performed by addition of (R)-t-butanesulfinyl aldimine 30 and silyl glyoxylate to a solution of LiHMDS-induced metalated sulfonylimidate 31 in THF at −78 °C, and stirring at the same temperature for 5 h, which afforded cyclic N-sulfonylamidines 34 in 59−91% isolated yields, with excellent diastereoselectivity (>20/1) and enantioselectivity (94−99% ee). The proposed reaction mechanism involved the nucleophilic addition of lithium azaenolates 31, derived from sulfonylimidates 29, to silyl glyoxylates and then Brook rearrangement to enolates 32, which underwent addition to 30. Cyclic N-sulfonylamidines 34 were produced by nitrogen-induced cyclization and subsequent desulfinylation by nucleophilic attack of ethoxide (Scheme 12). Synthesis of pyrrolidine ring of pyrrolizidine alkaloids, isotussilagine 38a, tussilagine 38b, and (2)-petasinecine 41, was conducted starting with α-oxoesters, methyl pyruvate, or ethyl glyoxalate, based on an aldol condensation−deprotection−cyclization sequence. Aldol condensation of 35 with methyl pyruvate or ethyl glyoxalate was performed using LDA, which gave aldol products 36 as two separable diastereoisomers. Deprotection of benzyl moieties on nitrogen by Pd/C-catalyzed hydrogenation provided pyrrolidinones 37 and 39 in 85% yield. Pyrrolidinones 37a and 37b were converted to isotussilagine 38a and tussilagine 38b, respectively, via Mitsunobu reaction using PBu3−ADDP [1,1′-(azodicarbonyl)diperidine], followed by reduction with BH3−THF complex, and then treating with K2CO3 in MeOH at room temperature for 1 day. (−)-Petasinecine 41 was synthesized from 39 in five steps via synthetic intermediate 40 as outlined in Scheme 13.61 A similar procedure was applied to synthesize polyfunctional pyrrolidine-2-ones 43 starting with 42 and ethyl glyoxalate. Aldol reactions were carried out by addition of ethyl glyoxalate to a mixture of 42 and trimethyl borate in THF at −78 °C and maintained at the same temperature for 1 h. By reduction of benzyl moieties using H2 in the presence of Pd/C in MeOH, 158


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Scheme 13. Synthesis of Pyrrolizidine Alkaloids, Isotussilagine 38a, Tussilagine 38b, and (−)-Petasinecine 41a

a

36a,a′, R1 = R2 = R3 = Me; a, 51%; a′, 31%; 36b, R1 = R3 = Et, R2 = H, 75%.

Scheme 14. Synthesis of Polyfunctional Pyrrolidine-2-ones 43 and 45a

a

Scheme 16. Synthesis of Pyrrolidine Moiety of Acromelic Acid 55a

R = Me, n-Pr, n-Hept; 43, 62−68%.

Scheme 15. PTSA-Catalyzed Synthesis of α-Methylene Pyrrolidin-2-one 48

a

Ar = 2-MeO-6-MeO2C-pyridin-3-yl.

presence of citric acid monohydrate (20 mol %) in toluene under reflux conditions for 3−4 h, by azeotropic removal of 159


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(trimethylsilyl)methanamine in dry DCM or toluene in the presence of MgSO4 or 4 Å MS at room temperature. Obtained α-silylimines 70 were treated with different dipolarophiles in the presence of [Cu(CH3CN)4]PF6 and III-1 in toluene or THF at room temperature to 60 °C. Reactions were completed in 3−12 h, and the corresponding pyrrolidine carboxylates 71,72 were obtained in 48−99% yields, with 55−99% ee. Also, pyrrolidine spirolactones 74,75 were prepared by a similar procedure starting from α-silylimine 73, in 76−88% yields, with 81−99% ee (Scheme 20). 1,3-Dipolar cycloaddition reaction of phenylvinylsulfone with azomethine ylide, in situ generated from ethyl N-[(R)-1-phenylethyl]glycinecarboxylate and ethyl glyoxalate, was reported in refluxing toluene by azeotropic removal of water yielding the corresponding pyrrolidine in 67% yield.69a Also, the one-pot 1,3-dipolar cycloaddition reaction of the (R)-N-(1-phenylethyl)-substituted glycine ester with ethyl glyoxalate and N-methylmaleimide for the preparation of enantiomerically pure proline derivative was reported.69b N-Substituted 3-hydroxy-2-pyrrolidinones 79 were synthesized via reductive photocyclization of N-substituted γ-aminoα-keto esters 77, in which irradiation was performed in DCM at 20 °C for 14 h. The proposed reaction mechanism involves the generation of diradical 78, which underwent cyclization within hydrogen transfer from the alcohol group of the ester leading to reduction of ketone group along with construction of 3hydroxy-2-pyrrolidinone structure 79. Starting γ-amino-α-keto esters were prepared by reaction of β-amino acids 76 with Ph3PCHCN in the presence of EDC and DMAP in DCM at 0 °C for 18 h, followed by ozonolysis in the presence of MeOH in DCM at −78 °C for 1 h (Scheme 21).70 Raup et al.71 developed an NHC/Lewis acid-catalyzed synthesis of pyrrolidine-2-ones 82 through reaction of α,βunsaturated aldehyde 80 with hydrazones 81, derived from ethyl glyoxalate. Reactions were carried out by addition of unsaturated aldehyde 80 (1.5 equiv) and then 1,5,7triazabicyclo[4.4.0]dec-5-ene (TBD) (10 mol %) to a solution of hydrazone 81, NHC IV-1 (5 mol %), and Mg(Ot-Bu)2 (5 mol %) in THF and heating at 60 °C for 24 h. Pyrrolidine-2ones 82 were obtained in 60−85% yields, with 5/1−12/1 diastereoselectivity and 85−98% ee. With hydrazones derived from aromatic aldehydes such as benzaldehyde, reaction did not occur (Scheme 22). By treatment of ethyl glyoxalate with anilines and αangelicalactone 83 in a multicomponent reaction in the presence of Sc(OTf)3 in CH3CN at room temperature for 12 h, N-arylpyrrolidin-2-ones 85 were obtained in 11−31% yields, as two stereoisomers trans and cis. Yields refer to isolated products after MCR-recyclization using SOCl2 in pyridineepimerization using TFA sequences. In the proposed reaction mechanism, Mannich-type reaction of 83 occurred with in situ generated glyoxalate imine to give intermediate 84, and then lactamization took place by nucleophilic addition of nitrogen at the activated carbonyl group (Scheme 23).72 Recently, Alonso et al.73 described a methodology based on Wittig reaction between ethyl glyoxalate and conjugated phosphorylated ylides 88, in situ generated via [2 + 2]cycloaddition-cycloreversion of phosphazenes 86 with alkyne phosphonates 87, to produce a new series of pyrrolidine-2-ones 91. The Wittig reaction of 88 with ethyl glyoxalate was performed in CHCl3 at room temperature under a N2 atmosphere for 12−24 h, affording the corresponding 1azadienes 89 in 65−80% yields. By treatment of 89 with NaBH4 in EtOH at room temperature for 1−2 h, β-

Scheme 17. Synthesis of 2-Hydroxypyrrolidine-2-carboxylate Derivatives 57a

a

Ar1 = 4-XC6H4 (X = H, Cl, Br, MeO), 2-furyl; Ar2 = XC6H4 (X = H, 4-F, 4-Cl, 3-Br, 3-Me, 4-Me, 4-MeO), 2-thienyl; Ar3 = XC6H4 (X = H, 4-F, 4-Cl, 3-Br, 4-Br, 4-Me, 4-CF3, 4-NO2); 45−84%.

produced water. Pyrrolines 59 were obtained in 41−84% yields, with low diastereoselectivity (Scheme 18). Scheme 18. Synthesis of Pyrrolines 59 via 1,4-Conjugate Addition−Cyclization−Dehydration Sequencesa

a

R = Me, t-Bu; Ar1 = XC6H4 (X = H, 3-Cl, 4-Br, 4-MeO); Ar2 = XC6H4 (X = H, 4-F, 4-Cl, 3-Br, 3-Me, 4-Me, 4-MeO, 4-NO2), 2thienyl; Ar3 = 4-XC6H4 (X = H, F, Br, MeO, NO2); 41−84%, cis/trans = 12/88−71/29.

Harwood et al.67 reported the 1,3-dipolar cycloaddition reaction of the azomethine ylide, in situ derived from the condensation of 5-(S)-phenylmorpholin-2-one 60 with ethyl glyoxalate, with various dipolarophiles. Reactions were conducted using ethyl glyoxalate trimer either by azeotropic removal of water in the presence of MS in refluxing toluene (A) or in the presence of MgBr2·OEt2 in THF at room temperature (B). In the case of dimethyl maleate and fumarate, only stereoisomer 61 and 62 were obtained under both reaction conditions, respectively, while N-methyl and phenyl maleimide led to corresponding cycloadducts as two stereoisomers 63,64a and 63,64b. Catalytic hydrogenation of cycloadducts 61−63 using Pearlman’s catalyst in the presence of TFA in MeOH resulted in pyrrolidine-2-carboxylic acids 66−68 in 75−90% yields. When methyl acetylene carboxylate was used as a dipolarophile, cycloaddition reaction led to pyrroline 65, which underwent dehydrogenation with palladium on charcoal in refluxing ethyl acetate to give the corresponding pyrrole 69 in quantitative yield (Scheme 19). An efficient catalytic asymmetric protocol for 1,3-dipolar cycloaddition of α-silylimines 70, derived from α-oxoesters, and activated olefins catalyzed with Cu(I) and DTBM-Segphos ligand III-1 to produce pyrrolidine carboxylates 71,72 was reported by Hernández-Toribio et al.68 α-Silylimines 70 were prepared by stirring a mixture of an α-oxoester and 160


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Scheme 19. Synthesis of Pyrrolidine-2-carboxylic Acids via 1,3-Dipolar Cycloaddition Reaction

Scheme 21. Synthesis of N-Substituted 3-Hydroxy-2pyrrolidinones 79 via Reductive Photocyclizationa

Scheme 20. Synthesis of Pyrrolidines 71,72 and Pyrrolidine Spirolactones 74,75 by 1,3-Dipolar Cycloaddition of αSilylimines 70 and 73a

a

R = H, CO2t-Bu; X = Boc, Z-Gly, Z-Ala, Boc-Gly, Boc-Pro; 46−91%.

By treatment of β,γ-unsaturated α-iminoester 93 with NaBH4 in THF at 25 °C, ethyl 5-oxopyrrolidine-2-carboxylate 94 was obtained in 73% yield. Starting β,γ-unsaturated α-iminoester 93 was generated by aza-Wittig reaction of β,γ-unsaturated αoxoester 92 with in situ formed phosphazene in DCM at room temperature for 30 min (Scheme 25).74 Trimethyl 3-phenyl-3,4-dihydro-2H-pyrrole-2,2,5-tricarboxylate 96 was synthesized in 83% yield, by treatment of α(methylsulfonyloxyimino)ester 95 with DBU (1.5 equiv) in DCM at 0 °C for 15 min. α-(Methylsulfonyloxyimino)ester 95 was prepared by reaction of corresponding α-ketoester with hydroxyl amine hydrochloride in water in the presence of Na2CO3 at room temperature for 4 h, followed by treatment of obtained oxime with methansulfonyl chloride (1.5 equiv) in DCM in the presence of Et3N (2 equiv) at 0 °C for 30 min (Scheme 26).75 Luo et al.76 reported Pd(II)-catalyzed cascade cyclization of ethyl glyoxalate with amines to produce 2,5-dihydropyrrol-2one derivatives 97. Reactions were carried out by addition of

a 1

R = H, Me, i-Bu, allylCH2, Ph(CH2)2, XC6H4 (X = H, 4-F, 4-Cl, 4CN, 3-Me, 4-Me, 4-MeO), 2-naphthyl; 71, 45−80%, 81−98% ee; R1 = Me, Ph(CH2)2; R2 = Me, Et; R3 = H, CO2Me; R4 = H, SO2Ph; 72, 48−89%, 55−99% ee; 74, 88%, 99% ee; 75, 76%, 81% ee.

aminophosphonates 90 were obtained in 35−82% yields as a mixture of diastereoisomers syn and anti. Diastereomeric mixture β-aminophosphonates 90 were transformed into pyrrolidine-2-ones 91 by ring closure using NaH in THF at room temperature for 3−36 h. Pyrrolidine-2-ones 91 were obtained in 70−90% yields as only trans diastereomer (Scheme 24). 161


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Scheme 22. NHC/Lewis Acid-Catalyzed Synthesis of Pyrrolidine-2-ones 82a

Scheme 25. Synthesis of Ethyl 5-Oxopyrrolidine-2carboxylate

Scheme 26. Synthesis of Trimethyl 3-Phenyl-3,4-dihydro2H-pyrrole-2,2,5-tricarboxylate

a

R = n-Pr, c-Hex, (CH2)3OTBDPS, XC6H4 (X = H, 2-Cl, 3-Cl, 4-Cl, 4-Br, 4-Me, 4-MeO, 4-MeO2C), 2-naphthyl, 2-furyl; Ar = XC6H4 (X = H, 4-F, 4-Cl, 4-Br, 4-MeO), 2-furyl; 60−85%, dr = 5/1−12/1, 85− 98% ee.

Scheme 23. Synthesis of N-Arylpyrrolidin-2-ones 83 via MCRa

Pd(TFA)2 (5 mol %) and anhydrous Na2SO4 to a solution of amines and ethyl glyoxalate (2 equiv) in toluene under Ar atmosphere and heating at 70 °C for 11−48 h. In the proposed reaction mechanism, in situ generated Pd(0) was inserted into H−Csp2 of ethyl glyoxalate via oxidative addition, followed by insertion of in situ produced α-iminoester, giving intermediate 98, and then reductive elimination, and intermediate 99 was produced, which underwent reduction and then lost a molecule of water to give enamine intermediate 100. By cross-coupling of enamine 100 with α-iminoester and then cyclization, pyrroline2-one derivatives 97 were obtained in 34−74% yields (Scheme 27). In the case of strongly electron-withdrawing-substituted aniline, 4-nitroaniline, reaction did not occur.

a

Ar = XC6H4 (X = 4-Cl, 4-Br, 4-Me, 4-MeO, 2-NO2); 11−31% (after recyclization-epimerization), trans/cis = 9/1.

Scheme 24. Synthesis of Pyrrolidine-2-ones 91 via Wittig Reactiona

Scheme 27. Pd(II)-Catalyzed Cascade Cyclization of Ethyl Glyoxalate with Amines to 2,5-Dihydropyrrol-2-one Derivatives 97a

a R = c-Pr, c-Bu, Bn, XC6H4 (X = H, 3-F, 4-F, 3-Cl, 4-Cl, 4-Br, 3-Me, 4Me, 4-Et, 4-MeO, 4-EtO, 4-Ac, 3-EtO2C, 4-EtO2C, 4-NHAc), 3,5Me2C6H3; 34−74%.

a

PR13 = PMe3, PPh3, PMe2Ph; R2 = CF3, CF2H, C2F5; Ar = 4-XC6H4 (X = Me, MeO, NO2); 70−90%. 162


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One-pot three-component reaction of methyl pyruvates, aldehydes, and amines yielding 3-hydroxy-1,5-dihydro-2Hpyrrol-2-ones 101 was reported by Ryabukhin et al.77 Reactions were carried out either by addition of TMSCl to a solution of a pyruvate, an aldehyde, and an amine in DMF and heating for 2−8 h or by refluxing a mixture of a pyruvate, an amine, and an aldehyde in AcOH for 2−8 h. About 114 examples of pyrrolin2-ones 101 were synthesized by this procedure in 11−93% yields (Scheme 28a). Similar methodology was applied by

Scheme 29. Synthesis of 1-(2-Oxopyrrolin-1-yl)-2-(2oxopiperazin-1-yl)ethanes 103a

Scheme 28. Synthesis of 3-Hydroxy-1,5-dihydro-2H-pyrrol2-ones 101 and 2-Oxopyrroline-3-carboxylates 102a

a

Ar = XC6H4 (X = H, 4-F, 4-Cl, 4-Me, 4-i-Pr, 4-t-Bu, 4-MeO, 4-NO2), 3,4-(MeO)2C6H3, 4-OH-3-MeOC6H3; 35−37%.

Scheme 30. Synthesis of Dihydrochromeno[2,3-c]pyrrole3,9-diones 105a

a

101: R1 = qunoline-2-yl, Ac, i-PrCO, c-PrCO, Ar′CO (Ar′ = Ph, 2ClC6H4, 4-ClC6H4, 2-furyl, 2-thienyl); Ar = XC6H4 (X = H, 4-Cl, 4MeO, 4-EtO, 4-CO2H), 3-thienyl, 1-methylpyrazole-4-yl, 1-methylpyrazole-5-yl; R2 = 30 different aliphatic (cyclic and acyclic), aromatic and heteroaromatic−NH2; 11−93%.77 102: Ar = XC6H4 (X = H, 4-Cl, 4-Br, 2-OH, 3-OH, 4-OH, 4-Me, 4-MeO, 3-CO2H, 4-NO2, 4-Me2N, 4allylO), 2-thienyl, 2-furyl; R3 = H, Me, allyl, c-Hex, Bn, PMB, XC6H4 (X = 4-Cl, 4-NO2), 3,4,5-(MeO)3C6H2; 15−79%.79 a

Ar = XC6H4 (X = H, 4-Cl, 4-MeO, 4-NO2), 3,4-(MeO)2C6H3; R2N = Me2N, Et2N, O(CH2CH2)2N; n = 2,3; 104, 69−94%; 105, 49−82%.

different research groups using various reaction conditions, such as refluxing dioxane,78a and AcOH,78b,c or in EtOH,78d−h dioxane,78i−k and THF at room temperature.78l Similar protocol was developed to synthesize 2-oxopyrroline-3-carboxylate derivatives 102 via condensation reaction of sodium diethyl oxaloacetate with amines and aldehydes. Reactions were conducted in refluxing EtOH for 1 h, and afforded 2oxopyrroline-3-carboxylates 102 in 15−79% yields (Scheme 28b).79 When methyl benzoylpyruvate was reacted with aromatic aldehydes and diethylenetriamine as amine component, 1-(2oxopyrrolin-1-yl)-2-(2-oxopiperazin-1-yl)ethanes 103 were obtained in 35−37% yields, where pyrrolinone and piperazinone moieties were formed simultaneously. Reactions were carried out by addition of methyl benzoylpyruvate (2 equiv) to a solution of diethylenetriamine and an aromatic aldehyde in dioxane and standing at room temperature for 24 h (Scheme 29).80 Treatment of methyl o-hydroxybenzoylpyruvate with N,Ndimethylethylenediamine and aromatic aldehydes in dry MeOH under reflux conditions, in a similar manner, yielded corresponding 3-hydroxy-4-(2-hydroxyphenyl)pyrrolin-2-ones 104, which were converted to dihydrochromeno[2,3-c]pyrrole-3,9-diones 105 in 49−82% yields, when heated in glacial AcOH under reflux conditions for 1 h (Scheme 30).81 Vydzhak et al.82 described the synthesis of dihydropyrano[2,3-c]pyrrole-4,7-dione derivatives 108 in two steps starting from methyl (E)-6-phenyl-2,4-dioxohex-5-enoate 106. By refluxing a solution of an equimolar amount of 106, aromatic aldehyde, and 2-aminothiazole in glacial AcOH, pyrroline-2ones 107 were obtained in 42−45% yields. Dihydropyrano[2,3-

c]pyrrole-4,7-dione derivatives 108 were obtained in 42−47% yields, when 107 was heated in the presence of a catalytic amount of I2 in DMSO under reflux conditions for 30 min (Scheme 31). 5-Benzyl-3-(2-ethoxyethoxy)-1H-pyrrol-2(5H)-one 111b was prepared via Emmons−Horner reaction of dimethylphosphite with methyl glyoxalate hydrate. The reaction was carried out in benzene under N2 atmosphere with removal of water using Dean−Stark apparatus, followed by reaction with ethyl Scheme 31. Synthesis of Dihydropyrano[2,3-c]pyrrole-4,7dione Derivatives 108a

a

163

Ar = XC6H4 (X = H, 4-Cl); 107, 42−45%; 108, 42−47%. dx.doi.org/10.1021/cr5004216 | Chem. Rev. 2015, 115, 151−264

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Scheme 33. Synthesis of 3-Aminopyrrolin-2-onesa

vinyl ether in the presence of p-TSA to give ethoxyethyl protected phosphonoacetate 109 in 60% yield. By reaction of (D,L)-Cbz-phenylalaninal with lithiated phosphonoacetate 109 using LDA in THF at −40 °C, followed by removing of Cbzprotecting group by hydrogenation with hydrogen in the presence of 10% Pd/C in ethanol at atmospheric pressure, pyrroline-2-one 111b was obtained. The noncyclized product 110 was also formed in lower yield (Scheme 32).83 Scheme 32. Synthesis of 5-Benzyl-3-(2-ethoxyethoxy)-1Hpyrrol-2(5H)-one 111ba

a 1 R = Me, 4-NO2C6H4, 2-furyl, CO2Et; R2 = 4-XC6H4 (X = Cl, Me, MeO), L-PhCH(Me); 69−88%; three-component: 73−80%.

a

of enamines 115 with ethyl trifluoropyruvate. Reactions were conducted by stirring a mixture of enamine 115, ethyl trifluoropyruvate (2 equiv), cinchona alkaloid (10 mol %), and Ti(OiPr)4 (10 mol %) in DCM at room temperature for several hours, and then refluxing using 1,2-dichloroethane as a cosolvent. 3-Hydroxypyrroline-2-one derivatives 116 were provided in 58−99% yields, as two enantiomers (S)-116 and (R)-116 with 54−93% and 54−89% ee, respectively (Scheme 34).

110,111 = 70%, 111a,b/110 = 85/15.

Palacios et al.84 developed an efficient synthesis of 3aminopyrrolin-2-ones 114 by the addition of 2 equiv of amine to β,γ-unsaturated α-oxoesters. Reactions were carried out by refluxing a solution of β,γ-unsaturated α-oxoesters (5 mmol), amine (2 equiv), Ti(OEt)4 (2 equiv), and a drop of H2SO4 in DCM for 2 h. 3-Aminopyrrolin-2-ones 114 were obtained in 69−88% yields. In the proposed reaction mechanism, 1azadiene 112, in situ generated by condensation of amine with ketone group, underwent conjugate addition with second amine molecule to yield γ-amino α-enamino ester 113, which was transformed into the corresponding 3-aminopyrrolin-2-ones 114 by nucleophilic addition of nitrogen to ester group and removal of a molecule of EtOH. Also, three-component reaction of ethyl pyruvate (5 mmol), an aldehyde (1 equiv), and an amine (2 equiv) was carried out in the presence of a catalytic amount of H2SO4 in DCM at room temperature for 48 h, which led to 3-aminopyrrolin-2-ones 114 in 73−80% yields (Scheme 33). Similar methodology was also reported by refluxing a solution of β,γ-unsaturated α-oxoesters with anilines (2 equiv) in DCM for 4−9 h, which afforded the corresponding 3-aminopyrrolin-2-ones in 64−92% yields.85a Three-component approach was also developed by different research groups using fluorous imine-1,1′-bis(carbothioate) in the presence of Na2SO4 in CH3CN at room temperature,85b thiourea or phosphoric acid organocatalyst in the presence of Na2SO4 in toluene at room temperature,85c and FeCl3−SiO2 under solvent-free conditions under heating at 100 °C.85d Also, a similar manner was developed for the reaction of methyl pyruvate with aniline, in which methyl pyruvate was incorporated in the reaction also as oxo component.85e Ogawa et al.86 described the enantioselective synthesis of 3hydroxypyrroline-2-one derivatives 116 via cinchona alkaloids/ Ti(OiPr)4-catalyzed tandem condensation−cyclization reaction

Scheme 34. Synthesis of 3-Hydroxypyrroline-2-ones 116 via Tandem Condensation−Cyclization Reactiona

R = H, Me; R1−R1 = (CH2)n, n = 3, 4, 5; R2 = CHPh2, 9-fluorenyl, CH2−10-anthracenyl, 3,4-(MeO)2C6H3(CH2)2; X = CH2, O; 58− 99%; (S)-116, 54−93% ee; (R)-116, 54−89% ee. a 1

Basavaiah et al.87a described a facile methodology for the synthesis of 3,4-disubstituted maleimides 118−119 using Baylis−Hillman (BH) adducts 117, derived through the coupling of α-oxoesters with acrylonitrile. By treatment of BH adducts 117 with benzene in the presence of methanesulfonic acid (3 equiv) at reflux conditions, desired maleimides 118 were obtained in 55−79% yields, via Friedel− Crafts reaction, selective hydrolysis, and cyclization sequences. BH adducts 117 were prepared by reaction of α-oxoesters with acrylonitrile (2 equiv) in the presence of DABCO (30 mol %) at room temperature (Scheme 35).88 BH adducts 117 were converted to the corresponding 3-(alkylcarbonyloxy)methyl maleimides 119 in 52−65% yields, when reacted with 164


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maleimides, which exhibit glycogen synthase kinase-3β (GSK3β) inhibitory activity.91 Also, there are other reports on similar methodology.92 By treatment of 2-methoxyphenylglyoxalate 124 with 2,3,6trifluorophenylacetamide 125 under similar conditions, the expected bisarylmaleimide was not obtained, but instead the tricyclic derivative 129 and 2-hydroxyaryl-substituted bisarylmaleimide 128, where the 2-fluoro substituent has been displaced by a hydroxy group, were formed in 30% and 8% yields, respectively. In the proposed reaction mechanism, intermediate dianion 126, in situ generated under basic condition, underwent the displacement of the o-fluoro substituent by the hydroxy anion in an SNAr process to give cis-tricyclic ring system 129 via protonation of 127, which could be converted to o-hydroxy maleimide 128 under the reaction conditions by deprotonation of the bridgehead methine proton followed by β-elimination (Scheme 37).93

Scheme 35. Synthesis of 3,4-Disubstituted Maleimides 118,119 via BH Adducts 117a

Scheme 37. Synthesis of Tricyclic Derivative 129 and 2Hydroxyaryl-Substituted Bisarylmaleimide 128

a

118, R1 = Me, Et, n-Pr, XC6H4 (X = H, 4-Cl, 4-Br, 2-Me, 3-Me, 4-Me, 2-MeO, 3-MeO, 4-MeO, 4-EtO); 54−79%; 119, R1 = Me, XC6H4 (X = H, 2-Me, 3-Me, 4-Me, 3-MeO); R2 = Me, Et; 52−65%.

carboxylic acid in the presence of FeCl3 under reflux conditions for 5 h (Scheme 35).87b The reaction of arylglyoxalates with acetamides 120 yielding maleimides 121 was reported by Faul et al.89a The reactions were carried out by addition of KOt-Bu to a mixture of glyoxalate and acetamide 120 in THF at 0 °C and afforded the corresponding maleimides 121 in 67−99% yields. When an aliphatic α-ketoester, ethyl isopropylglyoxylate, was used, corresponding maleimide was obtained in very low yield (8%). The same procedure was applied to synthesize bisindolylmaleimide 122 by condensation of indole-3-acetamide with methyl indolyl-3-glyoxylate.89b Bisindolylmaleimide 122 was converted to indolocarbazole 123, staurosporine aglycon 16, in 47% yield by a three-step oxidative cyclization/ reduction sequence (Scheme 36).90 In another report, a similar procedure was developed for the synthesis of 3-aryl-4-pyrrolylScheme 36. Synthesis of Maleimides 121a Natural product maleimide farinomalein 133a, possessing fungicidal activity, was synthesized starting from ethyl 3-methyl2-oxobutyrate via Horner−Wadsworth−Emmons (HWE) reaction. 2-Oxobutyrate underwent HWE reaction with triethylphosphonoacetate 130 using NaH in THF at 0−50 °C for 1 h to produce diester 131 in 80% yield, which was hydrolyzed to the corresponding cis-diacid 132 in 96% yield, when treated with 2 N LiOH in THF at room temperature. cisDiacid 132 was converted into maleimide farinomalein 133a in two steps, by reacting with TFAA at room temperature followed by reaction with β-alanine in refluxing AcOH. Also, farinomalein analogues 133b were formed through reaction with different amino acids (Scheme 38).94 Treatment of 5-aryl-2,3-dihydrofuran-2,3-diones, a cyclic αoxoester, with enamino amide 134 in dry toluene under reflux conditions afforded pyrrolidine-2,4-diones 136 in 83−88% yields. The reaction proceeded by nucleophilic addition of enamine to ester group and then enamine regeneration to give intermediate 135, which underwent cyclocondensation of nitrogen of amide with ketone to provide pyrrolidine-2,4diones 136 with removal of a molecule of water (Scheme 39).95

a R = Me, Et; Ar1 = Ph, 2-furyl, 2-thienyl, 3-indolyl, N-methyl-3indolyl; Ar2 = 4-XC6H4 (X = H, Br, MeO), 1-naphthyl, 3-benzo[b]thienyl, 3-indolyl, N-methyl-3-indolyl; 67−99%.

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Scheme 38. Synthesis of Farinomalein 133a

Scheme 41. Synthesis of Pyrrole-2,3-diones 139 and 2Hydroxypyrrol-3-ones 141a

a 139, R = Me, Et; Ar = 4-MeC6H4, 3,4-(MeO)2C6H3; 47−68%; 141, Ar 1 = Ph, PMP; Ar 2 = PMP, styryl; NR 2 = NMe 2 , 2,4(NO2)2C6H3NH; 52−57%.

a 133a, R = (CH2)2CO2H; 60%; 133b, R = L-CHR′CO2H (R′ = H, iPr, CH2i-Pr, Bn); 41−64%.

temperature for 1 h, 2-(1-amino-4-aroyl-2-hydroxy-3-oxo-2,3dihydro-1H-pyrrol-2-yl)acetates 141 were obtained in 52−57% yields (Scheme 41b).98

Scheme 39. Synthesis of Pyrrolidine-2,4-diones 136a

3.4. Pyrroles

a

The development of new strategies for the synthesis of substituted pyrroles is of interest due to their occurrence in the structure of many bioactive and natural products, such as atorvastatin, porphobilinogen, verrucarin E, pyrrolnitrin antibiotic, coumermycin A1, clorobiocin, polycitone A and B, pyrrolomycin B, etc. Also, pyrrole moieties are present in the structure of some molecules of life such as heme and chlorophyll a, and in many molecules of medicine. Many methods have been developed for pyrrole synthesis, including Knorr, Paal−Knorr, and Hantzsch syntheses, hydroamination of 1,4- and 1,5-diynes, intramolecular cyclization of 3-alkyne1,2-diols and 1-amino-3-alkyn-2-ols, Schmidt reaction of homopropargyl azides, and 1,3-dipolar cycloaddition reactions. Lin et al.99 developed a one-pot multicomponent reaction of primary amines, ethyl glyoxalate, and 2-bromoacetophenones affording pyrrol-3-carboxylates 142. Reactions were carried out in the presence of pyridine (5 equiv) in refluxing acetonitrile for 12 h. In the plausible reaction mechanism, aziridinium bromide 144 was formed by nucleophilic addition of pyridinium ylide 143, formed from reaction of 2-bromoacetophenones with pyridine followed by deprotonation, to in situ generated αimino ester from amine and ethyl glyoxylate, and then an intramolecular nucleophilic substitution. Next, 144 was attacked by another molecule 143 to form pyridinium salt 145, which underwent an elimination of pyridine to give enamino ketone 146, followed by an intramolecular cyclocondensation and dehydration to afford pyrroles 142 in 28− 70% yields (Scheme 42). Synthesis of ethyl 3,5-diaryl-1H-pyrrole-2-carboxylates 148 from α,δ-diketoesters 147 was reported by Aginagalde et al.100 via Paal−Knorr reaction using microwave irradiation. α,δDiketoesters 147 were prepared by the Nef oxidation of 2nitro-4-oxoesters, obtained from reaction of α,β-unsaturated ketones with ethyl nitroacetate in the presence of Et3N at 75 °C. The Nef oxidation was carried out with NaOMe/MeOH under acidic conditions, to yield α,δ-dioxoesters 147 in 62− 84% yields (Scheme 43). Ethyl 4-ethyl-2-tosyl-1H-pyrrole-3-carboxylate 149, as a synthetic intermediate for the preparation of the D-ring of 5Za15Ea-biliverdin 150, was synthesized in three steps starting from Henry reaction of ethyl glyoxalate with 1-nitropropane

R = H, OMe; Ar = 4-XC6H4 (X = H, Cl, Me); 83−88%.

Pyrrol-2,3-diones 138 was synthesized by reaction of 4ethoxycarbonyl-2,3-furandione with arylisocyanates at 70 °C. First, a seven-membered ring system 137 was generated as an intermediate, which underwent decarboxylation at the same temperature to produce the corresponding pyrrol-2,3-diones 138 in 75−85% yields (Scheme 40).96 Scheme 40. Synthesis of Pyrrol-2,3-diones 138a

a

Ar = 4-XC6H4 (X = H, Cl, Me); 75−85%.

Also, pyrrole-2,3-dione derivatives 139 were prepared in 47− 68% yields, by reaction of 4-aroyl-5-aryl-furan-2,3-diones with N,N-dialkylurea derivatives. Reactions were conducted in benzene under reflux conditions for 4−6 h (Scheme 41a).97 By treatment of 2-(4-aroyl-3-oxofuran-2(3H)-ylidene)acetate 140 with hydrazine derivatives in dry benzene at room 166


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Scheme 42. Synthesis of Pyrrol-3-carboxylates 142a

Pyrrole 152, an intermediate for the synthesis of BMS690514, was prepared in multisteps initiated by alkylation of sodium diethyl oxalacetate with bromohydrazone 151 in toluene in the presence of AcOH at 20 °C for 5−6 h, followed by one-pot cyclodehydration by addition of p-TsOH under heating at 40−45 °C for 4−6 h, to give 152. The yield for two steps is 78% (Scheme 45).102 Scheme 45. Synthesis of Pyrrole 152

a

R = n-Bu, c-Hex, Bn, 4-XC6H4 (X = H, Cl, Br, Me, MeO); Ar = 4XC6H4 (X = H, Cl, Br, Me); 28−70%.

Scheme 43. Synthesis of Pyrrole-2-carboxylates 148 via Paal−Knorr Reactiona A similar approach was developed by Migliara et al.103a to synthesize pyrrolo[2,1-f ]-1,2,4-triazine derivatives 156. By treatment of sodium salt of α-oxoesters with chloroacetone semicarbazone 153 in absolute EtOH or MeOH at room temperature for 2−3 h, alkylation products 154 were obtained in 65−70% yields, which were converted into pyrroles 155 in 70% yields, when subjected to HCl in EtOH or MeOH at room temperature for 3 h. Refluxing a solution of 155 in EtOH in the presence of 2% NaOH for 2 h led to pyrrolo[2,1-f ]-1,2,4triazines 156 in 60% yields. However, treatment of 154 with HCl at room temperature for 24 h, and then refluxing for 1 h, resulted in the formation of 3H-imidazo[1,5-b]pyridazine-5,7(6H)diones 157 in 60−80% yields (Scheme 46).103b

a

Ar1 = 4-XC6H4 (X = F, OH, MeO), 3-thienyl; Ar2 = 4-XC6H4 (X = H, F); R = H, Bn, 3,5-(MeO)2C6H3; 57−97%.

(1.2 equiv) using 0.2 equiv of Et3N in refluxing toluene for 5 min, then at room temperature for 3 h, followed by acetylation of obtained nitro alcohol with Ac2O (1.5 equiv) in the presence of DMAP (0.2 equiv) at 0 °C to room temperature for 4 h. By treatment of acetylated nitro alcohol product with tosylmethyl isocyanide (TosMIC, 1 equiv) and DBU (2 equiv) in CH3CN, at −40 °C, and then room temperature for 4 h, 149 was obtained in 50% overall yield (Scheme 44).101

Scheme 46. Synthesis of Pyrrolo[2,1-f ]-1,2,4-triazines 156 and 3H-Imidazo[1,5-b]pyridazine-5,7-(6H)diones 157a

Scheme 44. Synthesis of Ethyl 4-Ethyl-2-tosyl-1H-pyrrole-3carboxylate 149

a 1

R = Ph, OEt; R2 = Me, Et; R3 = Me; 154, 65−70%; 155, 70%; 156, 60%;103a R1 = Me, Ph, EtO; R2 = Me, Et; R3 = Ph; 157, 60−80%.103b 167


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Quiclet-Sire et al.104 have reported radical reaction between N-ethylsulfonylenamide 158 and α-xanthyl ketones 159 to give pyrrole-2-carboxylates 162. N-Ethylsulfonylenamide 158 was prepared by reaction of ethyl pyruvate with ethanesulfonamide in the presence of POCl3 in anhydrous acetonitrile under reflux conditions for 4 h, and then reacted with xanthate 159 using AIBN (2.5 mol %) in a mixture of heptane and chlorobenzene (5/1: v/v) under reflux conditions and argon atmosphere. Ethyl radical, generated by action of initiator on enesulfonamide 158 followed by loss of SO2, reacted with xanthate 159 by addition−fragmentation to produce acetonyl radical 160 by removal of diethyl xanthate. By addition of radical 160 to enesulfonamide 158, α-imino ester 161 was generated, which underwent ring closure to the pyrrole 162 (Scheme 47).

3.5. Pyrazoles

Pyrazole and pyrazoline derivatives have received great attention because of their interesting biological activities, such as antibacterial, antiviral, antidiabetic, antitubercular, antitumor, anti-inflammatory, and antidepressant activities. They are present in a number of natural products, including withasomnine and 4-hydroxywithasomnine, pyrazofurine, formycin A and B, oxoformycin B, nostocine A, fluviol, and 3-nnonylpyrazole. Also, they are used in supramolecular and polymer chemistry, in organic synthesis as ligands, in the food industry, and as cosmetic colorings. Condensation of hydrazines with 1,3-dicarbonyl compounds or their 1,3dielectrophilic equivalents and 1,3-dipolar cycloaddition reactions are among the most used approaches for construction of pyrazoles moieties. Intramolecular 1,3-dipolar cycloaddition reaction of azomethine imine 171, in situ derived from the reaction of dihydropyrrole α-ketoester 170 with 2,2,2-trichloroethyl carbazate, was carried out in refluxing xylene to prepare triazacyclopenta[cd]pentalene diester 172, possessing pyrazolidine moiety. When dihydropyrrole α-oxoesters 170 were treated with thiosemicarbazide in AcOH at 70 °C for 24 h, tetracyclic imidazopyrazolidines 174 were obtained in 49−95% yields via the corresponding cycloadducts 173 (Scheme 49).106 Also, reaction of α-ketoester 175 with monosubstituted hydrazines was investigated, which gave 2-substituted octahydrocyclopenta[c]pyrazole-3,6a-dicarboxylates 176 by in situ generation of azomethine imine followed by intramolecular 1,3-dipolar cycloaddition reaction. Reactions were conducted in EtOH at 100 °C for 18−60 h, and cyclopenta[c]pyrazolidines 176 were obtained in 56−92% yields. Reaction with thiosemicarbazide (1.1 equiv) in EtOH at 100 °C for 60 h led to the corresponding cyclopentapyrazolidine 176, which was transformed into tricyclic thiohydantoin 177 in 90% yield by further heating at 135 °C for additional 24 h. By heating of a solution of 175 and thiosemicarbazide in the presence of citric acid in EtOH or t-BuOH, tricyclic thiohydantoin 177 was obtained directly in 89% or 93% yield, respectively (Scheme 50).107 The synthesis of ethyl 1-oxohexahydropyrazolo[1,2-c][1,3,4]oxadiazine-6-carboxylate derivatives 181 was reported by 1,3dipolar cycloaddition reaction between azomethine imine ylides 180, derived from cycloreversion of oxadiazolidine 179, and different dipolarophiles. By reaction of carbazate 178 with ethyl glyoxalate (4 equiv) in the presence of MgBr2·OEt2 in THF at 65 °C for 7 h, oxadiazolidine 179 was prepared, which underwent cycloreversion/1,3-dipolar cycloaddition reactions, when treated with dipolarophiles in toluene at 70−80 °C for 3−12 days, to give cycloadducts 181 in 48−84% yields with 32−94% de (Scheme 51).108 Synthesis of pyrazoline-3-carboxylates 185 was reported by 1,3-dipolar cycloaddition reaction between dipolarophiles and nitrile imine 184, generated by chlorination of hydrazone of ethyl glyoxalate 182 and then in situ treatment with KHCO3 or K2CO3. Hydrazone 182 was prepared from EtOAc using NCS in the presence of benzylhydrazine dihydrochloride at 60 °C for 1 h or from ethyl 2-chloro-2-ethoxyacetate by addition to a solution of benzylhydrazine dihydrochloride in water/dioxane and stirring for 1 h. 1,3-Dipolar cycloaddition reactions were carried out by chlorination of hydrazone 182 using either NCS or t-BuOCl in EtOAc at 60 or 0 °C for 1 h, respectively, followed by treatment of obtained intermediate 183 with dipolarophile in the presence of KHCO3 or K2CO3 and a few

Scheme 47. Synthesis of Pyrrole-2-carboxylates 162a

a 1 R = Me, XC6H4 (X = 4-F, 4-Cl, 4-MeO, 2-EtO2C), 2-furyl; R2 = H, Me; R1−R2 = (CH2)4; 50−81%.

The synthesis of polycyclic pyrrole-2-carboxylates 167 was reported via CuBr2-catalyzed multicomponent Mannich reaction of N-benzylallylamine, ethyl glyoxalate, and terminal alkynes followed by iridium-catalyzed cycloisomerization/ Diels−Alder cycloaddition/dehydrogenation sequence. Reactions were carried out with each 1 equiv of N-benzylallylamine, ethyl glyoxalate, and an alkyne in the presence of 10 mol % CuBr2 and 4 Å MS in toluene at room temperature for 24 h to afford enynes 163a. Cycloisomerizations were carried out with crude enynes 163a and 1.1 equiv of a dienophile in the presence of 3 mol % [IrCl(cod)]2 and AcOH in toluene under either reflux condition for 24 h or microwave heating (150 °C) for 0.5 h, and occurred via diene intermediate 164, which transformed to 167 by DA reaction with dienophile to give 166, followed by in situ dehydrogenation. When enyne 163a (R = n-Bu), obtained from reaction of N-benzylallylamine, ethyl glyoxalate, and hexyne, was subjected to cycloisomerization using [IrCl(cod)]2 and AcOH in the absence of dienophile, pyrrole 165 was obtained in 39% overall yield for two steps. When enynes 163b and 163c, prepared via Mannich coupling of ethyl glyoxalate, hexyne, and N-benzylhexa-2,4-dienylamine and N-benzyl-2-cyclopropylallylamine, respectively, were heated under MW irradiation in toluene in the presence of Rh catalyst, corresponding cycloadducts 168 and 169 were formed in 64% and 46% yields, respectively (Scheme 48).105 168


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Scheme 48. Synthesis of Polycyclic Pyrrole-2-carboxylates 167a

a 1

R = n-Bu, MeOCH2, MeO(CH2)3, Cl(CH2)3, MeO2C(CH2)3, Ph, Fc; X = NPh, O, o-phenylene; 167, reflux, 35−74%; MW, 29−68%.

Scheme 49. Synthesis of Triazacyclopenta[cd]pentalenes 172 and Tetracyclic Imidazopyrazolidines 174a

a

172, X = H; R = Cbz; 86%; 174, X = H, OTBDMS; R = Cbz, SO2CH2CH2TMS; 49−95%.

drops of water at 45−70 °C for 16−22 h. Pyrazoline-3carboxylates 185 were obtained in 25−86% yields (Scheme 52).109 Methyl 4-(2-nitrophenyl)-2-oxobut-3-enoates 186 were subjected with anhydrous hydrazine in refluxing absolute EtOH, to synthesize methyl 5-(2-nitrophenyl)-4,5-dihydro1H-pyrazole-3-carboxylates 187 in 40−90% yields, which were converted to methyl 5-oxo-1,5,6,10b-tetrahydropyrazolo[1,5c]quinazoline-2-carboxylates 188 in two steps by reduction of nitro group using H2 (30 psi) in the presence of PtO2 in EtOAc or EtOH for 12 h, followed by treatment with triphosgene and Et3N in dry THF at room temperature for 30 min (Scheme 53).110 Hanzlowsky and co-workers111 described the synthesis of pyrazole-5-carboxylates 190 or pyrazole-3,4-dicarboxylates 192, by reaction of hydrazine derivatives with ethyl 3-[(E)-

Scheme 50. Synthesis of Cyclopenta[c]pyrazolidines 176 and Tricyclic Thiohydantoin 177a

a

Ac, Bz, Cbz, Troc, 3-pyridylcarbonyl, C(S)NH2; 176, 56−92%.

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Scheme 51. Synthesis of 1-Oxohexahydropyrazolo[1,2c][1,3,4]oxadiazine-6-carboxylates 181a

Scheme 53. Synthesis of Methyl 4,5-Dihydro-1H-pyrazole-3carboxylates 187a

a

187, R = 4-Cl, 5-Cl, 4,5-Cl2; 40−90%.

drazine dihydrochloride was investigated in AcOH under reflux conditions, in which 1-methyl-pyrazole-3-carboxylate 194 was obtained in 43% yield by formation of dihydropyrazole 193 as reaction intermediate and underwent aromatization by removing a MeOH molecule (Scheme 54). 4-Acylpyrazole-5carboxylates were prepared in 73−94% yields by the similar condensation reaction of ethyl 3-acyl-4-(dimethylamino)-2oxobut-3-enoate with hydrazine derivatives in EtOH.112 The synthesis of N-(2,4-dichlorophenyl)pyrazole-3-carboxylates 196 was reported by Machado et al.113 through reaction of 2,4-dichlorophenylhydrazine hydrochloride with ethyl 4methoxy (or 4-hydroxy)-2-oxobut-3-enoate 195. Reactions were carried out using a solution of 195 and hydrazine (1.1 equiv) in EtOH either by sonication for 10−12 min or by refluxing for 2.5−3 h. The corresponding pyrazole-3-carboxylates 196 were isolated in 71−92% yields (Scheme 55). Ethyl pyrazole-3-carboxylate derivatives 200 were prepared by reaction of hydrazones of enolizable ketones 197 with diethyl oxalate in 31−72% yields. Reactions were carried out by in situ generation of dianion of hydrazone 197 using n-BuLi in THF at −78 °C, followed by addition of 1.1 equiv of ethyl glyoxalate at the same temperature, and then warming to 20 °C. The solvent was evaporated after 16 h, and the residue was treated with p-TsOH in toluene under reflux conditions for 8 h. Reactions proceeded through γ-hydrazones of α,γ-dioxoesters 198, which underwent intramolecular nucleophilic addition to give 199 as a reaction intermediate (Scheme 56).114 The reaction of the 2,5-anhydroallose 201 with ethyl triphenylphosphoranylidene pyruvate at 90 °C for 2 days gave both diastereoisomers 203 via internal Michael addition of α,β-unsaturated α-ketoester 202. By condensation of the isomeric mixture 203a and 203b with ethyl hydrazinoacetate hydrochloride, corresponding isomeric hydrazones 204 were obtained, which underwent Dieckmann cyclization to furnish an isomeric mixture of 4-hydroxy pyrazole derivatives 205, when treated with NaOMe in MeOH under reflux conditions for 3 h (Scheme 57).115 Similar Dieckmann condensation of αketoester 2-carboalkoxymethylhydrazones was reported by Farkaš et al.116 to synthesize corresponding 3-substituted 4hydroxypyrezole-5-carboxylates in 39−85% yields. Reactions were conducted using NaOEt in refluxing EtOH for 2 h. The starting hydrazones were prepared by treatment of α-oxoesters with hydrazinoacetate derivatives. 1H,4H-Benzo[e,f ]-s-indaceno[2,3-d]pyrazoles 208 were synthesized when hydrazine precursors were heated with ethyl 9oxo-9H-benzo[e,f ]-s-indaceno-8-glyoxalate 207 in EtOH or

R = R4 = H, R2 = R3 = CO2Me; 84%, 70% de; R1 = R4 = H, R2−R3 = CON(Ph)CO; 73%, 49% de; R2 = R4 = H, R1 = R3 = CO2Me; 71%, 32% de; R1 = R3 = H, R2 = CO2Me, R4 = Me; 71%, 18% de; R1 = R2 = R3 = H, R4 = 4-XC6H4 (X = H, MeO, MeO2C); 48−65%, 85−94% de.

a 1

Scheme 52. Synthesis of Pyrazoline-3-carboxylates 185a

R = Bu, CH2OH, COMe, CO2Et, CN, Ph; R2 = H, Ph; R1−R2 = (CH2)4; 25−86%.

a 1

(d imet hylamino)meth ylid ene]p yruvate 18 9 o r 3[(dimethylamino)methylidene]-2-oxosuccinate 191, which was prepared by reaction of ethyl pyruvate with N,Ndimethylformamide diethyl acetal (DMFDEA) in DCM at room temperature for 2 h, or reaction of sodium salt of diethyl 2-oxosuccinate with DMFDEA in anhydrous ethanol at room temperature for 30 min, followed by addition of AcOH and stirring at room temperature for 24 h, respectively. Cyclocondensation reactions of 189 and 191 with hydrazine derivatives were carried out in the presence of conc HCl (∼1 equiv) in MeOH or EtOH at room temperature to 60 °C for 2−24 h. In the case of the reaction of heteroarylhydrazines with 189, the corresponding 5-hydroxypyrazolin-5-carboxylates were isolated, which transformed into the corresponding pyrazole-5carboxylates 190 when heated in AcOH under reflux conditions. Also, the reaction of 189 with 1,2-dimethylhy170


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Scheme 54. Synthesis of Pyrazole-5-carboxylates 190 and Pyrazole-3,4-dicarboxylates 192a

a

R = H, 4-XC6H4 (X = H, NO2), pyridazine and pyrimidine hetaryls; 190, 9−88%; 192, 29−89%.

glacial AcOH under reflux conditions. Reactions proceeded in 5−8 h and afforded the corresponding indaceno[2,3-d]pyrazoles 208 in 40−44% yields. Starting glyoxalate 207 was prepared by reaction of tetrahydro-9H-benzo[e,f ]-s-indacen-9one 206 with diethyl oxalate in the presence of NaOEt in benzene at room temperature (Scheme 58a).117a Similar methodology was used to synthesize pyrazole-3-carboxylates 210 fused to thiopyrane ring by condensation of corresponding oxo-glyoxalate 209 with hydrazine derivatives in AcOH under reflux conditions (Scheme 58b).118 By reaction of N-benzylpiperidin-4-ones with diethyl oxalate mediated with NaOEt in EtOH at −10 °C, then warmed to room temperature, corresponding Claisen products were in situ generated, which in treatment with hydrazine hydrate (1.1 equiv) and AcOH (3 equiv) transformed into unexpected tetrahydropyrazolo[1,5-c]pyrimidines 215. In the proposed reaction mechanism, hydrazone 211 cyclized to tautomer of pyrazole 212 (213), which underwent retro-Mannich reaction that resulted in the formation of iminium ion 214 along with ring opening, followed by cyclization to 215, by addition of nitrogen of pyrazole to iminium ion 214. In addition to 215, minor amounts of the corresponding pyrazolopyridines 213 were also obtained. In the case of 1-benzylazepan-4-one, the major product is expected to be pyrazoles 217 (70% yield), which is obtained as two isomers in 40/30 ratio of a/b, with unexpected tetrahydro-4H-pyrazolo[1,5-c][1,3]diazepine 218 in only 8% yield, whereas 1-benzylpyrrolidin-3-one led to expected pyrazole 216 in 50% yield (Scheme 59).119

Scheme 55. Synthesis of N-(2,4-Dichlorophenyl)pyrazole-3carboxylates 196a

a 1

R = nPr, XC6H4 (X = H, 4-F, 4-Cl, 4-Br, 4-Me, 4-MeO, 4-NO2), 2furyl; R2 = H; R1−R2 = (CH2)n, n = 3, 4, 5, 6; 71−92%.

Scheme 56. Synthesis of Ethyl Pyrazole-3-carboxylate Derivatives 200a

a 1 R = n-Pr, i-Pr, XC6H4 (X = H, 4-F, 4-Cl, 2-Me, 3-Me, 4-Me, 2-MeO, 4-MeO), 1-naphthyl, 2-naphthyl; R2 = H, Me; R1−R2 = (CH2)n, n = 4, 5, 6, 10; 31−72%.

Scheme 57. Synthesis of 4-Hydroxy Pyrazole Derivative 205

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activities. Also, they have been found in biomolecules, including biotin, the essential amino acid histidine, histamine, and in pharmaceuticals such as cimetidine and losartan. However, there are many reports on the synthesis of imidazole derivatives in the literature, and the development of new methods is of interest. Phosphine-catalyzed annulation of glyoxalate imines to imidazolidin-4-ones 219 was reported by treatment of glyoxalate imines with methyl vinyl ketone (MVK) (1.5 equiv) in the presence of Ph2PMe (30 mol %) and 4 Å MS in CH3CN at 20 °C. However, MVK did not incorporate in the structure of the final imidazolidine product; the addition of MVK is essential to induce the formation of imidazolidine moiety. As in the absence of MVK, noncyclic compound 220 was obtained as a major product. Reactions were completed in 36−48 h, and corresponding imidazolidin-4-ones 219 were obtained in 29−81% yields (Scheme 60).120

Scheme 58. Synthesis of Fused Pyrazole-3-carboxylates 208 and 210a

Scheme 60. Phosphine-Catalyzed Annulation of Glyoxalate Imines to Imidazolidin-4-ones 219a

a

208, R = H, X = OH; R = (CO)NH2, (CS)NH2, X = Cl; 40−44%; 210, W = Y = S, X = CH2−S, Z = CH2, R = H, Ph, 55−60%; W = X = CHCH, Y = CH2, Z = S, R = H, Me, Ph, 50%; W = CHCH, X = S−CH2, Y = S, Z = CH2, R = Me, Ph, 52−79%. a

Ar = XC6H4 (X = H, 3-F, 4-F, 4-Cl, 3-Br, 4-Br, 3-Me, 3-CF3, 4-CF3); 29−81%.

3.6. Imidazoles

Imidazoles are one of the most important five-membered heterocyclic compounds due to their occurrence in a number of natural products and alkaloids, such as oroidin, hymenidine, girolline, styloguanidine, axinellamine A, axinelline A, dragmacidine E and F, and ageliferin, with a wide range of biological

Multicomponent one-pot synthesis of imidazoline 225 was reported via 1,3-dipolar cycloaddition reaction between 4methyl-2-phenyloxazol-5(4H)-one 221 and in situ generated

Scheme 59. Synthesis of Unexpected Tetrahydropyrazolo[1,5-c]pyrimidines 215a

a

R = R1 = H; 213, 19%; 215, 43%; R = Me, R1 = H; 213, minor; 215, 37%; R = H, R1−R1 = CH2COCH2; 213, minor; 215, 31%. 172


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glyoxalate imine. Reaction was carried out by addition of 221 and TMSCl in a solution of ethyl glyoxalate and 4-fluoroaniline in DCM under N2 atmosphere and refluxing for 6 h. The corresponding imidazoline 225 was obtained in 72% yield. In the proposed reaction mechanism, 1,3-dipolar component 222, generated by N-silylation followed by deprotonation of oxazoline, underwent 1,3-dipolar cycloaddition with glyoxalate imine to give 223, which afforded the imidazole 225 by rearrangement to 224 and desilylation (Scheme 61).121

Scheme 62. Synthesis of Hydantoin and Thiohydantoin 227 via TMSN3−Ugi/RNCX Cyclization Reactionsa

Scheme 61. Synthesis of Imidazoline 225 via 1,3-Dipolar Cycloaddition Reaction

a 1

R = n-Bu, i-Bu, c-Pr, CH2CH2OMe, PhCH2CH2, Ph, 3,4(MeO)2C6H3CH2; R2 = n-Bu, t-Bu, Bn, 4-FC6H4, 2-Cl-6-MeC6H3, 2,6-Me2C6H3; R3 = H, Et, XC6H4 (X = H, 4-F, 4-Br, 3-Me, 4-EtO); X = O, S; 226, 21−60%; 227, 25−99%.

Scheme 63. Synthesis of Coumarin-4-yl-Substituted Imidazolin-2,5-diones and 2-Thioxoimidazolin-5-ones 230a

Recently, Medda et al.122 reported the construction of hydantoin and thiohydantoin scaffolds 227 via a TMSN3−Ugi/ RNCX cyclization reactions sequence. Ethyl 2-(tetrazol-5-yl)-2(alkylamino)acetates 226, obtained by TMSN3−Ugi reaction between glyoxalate imines, in situ generated from ethyl glyoxalate and amines, TMSN3, and isocyanides in CF3CH2OH at room temperature, were transformed into the corresponding hydantoins or thiohydantoins 227 when treated with isocyanate or isothiocyanate in dry EtOH under a N2 atmosphere at room temperature for 2−36 h or under MW irradiation for 1.5−2 h. TMSN3−Ugi products 226 and hydantoins or thiohydantoins 227 were obtained in 21−60% and 25−99% yields, respectively (Scheme 62). Coumarin-4-yl-substituted imidazolin-2,5-diones and 2-thioxoimidazolin-5-ones 230 were synthesized by condensation of ethyl coumarin-4-yl-glyoxalates 229 with urea and thiourea in 56−60% and 55−58% yields, respectively. Reactions were carried out in refluxing AcOH for 3−10 h. The starting ethyl coumarin-4-yl-glyoxalates 229 were obtained by oxidation of the corresponding ethyl coumarin-4-yl-acetates 228 using SeO2 in refluxing xylene in 80−86% yields (Scheme 63).123 Matsuda et al.124 developed a methodology for the construction of imidazoline-4-one structure 231 through α(N-trimethylsilyl)imino esters, which was obtained by reaction of α-oxoesters with LiHMDS in THF followed by addition of TMSCl. By treatment of α-(N-trimethylsilyl)imino esters with MeOH, dimerization occurred to give imidazoline-4-ones 231

R −R2 = (CH)4, R3 = H; R1 = H, R2−R3 = (CH)4; R1 = R3 = H, R2 = OH; X = O, S; 55−60%.

a 1

via desilylated α-imino ester, in 50−87% yields. Reactions were carried out at room temperature or 50−60 °C for 1 h. Alkylation of obtained imidazoline-4-ones 231a was investigated using various alkyl halides in the presence of KOH in dry DMSO at room temperature, and depending on alkylating agent, N-alkylation (232) or O-alkylation (233) occurred. In the case of α-branched alkyl halides, O-alkylation was observed (Scheme 64). Groarke et al.125 have reported the reaction between glyoxal of N-Cbz-L-valine 234 and methyl glyoxalate in the presence of NH4OAc in MeOH under reflux conditions to give the corresponding imidazol-2-carboxylate 235 (Scheme 65). Bukhryakov et al.126 reported the synthesis of benzimidazole 237 by reaction of o-phenylenediamine 236 with ethyl glyoxalate in the presence of I2 in EtOH at room temperature for 12 h. Benzimidazole 237 was obtained in 82% yield, and could be converted into pyrazino[1,2-a]benzimidazole-1,3dione 238 in two steps (Scheme 66). 3.7. Triazoles

Because of their wide range of uses in biological science, material chemistry, medicinal chemistry, and agrochemicals, 173


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Scheme 67. Synthesis of cis-Triazoline 239a

Scheme 64. Synthesis of Imidazoline-4-ones 231 via Dimerization of α-(N-TMS)imino Estersa

a

231, R1 = Ph, t-Bu; R2 = Me, Et; 50−87%; X = Cl, Br, I; 232, R3 = Me, Et, Bn; 63−88%; 233, R3 = i-Pr, c-Hex; 50−80%.

a

Scheme 65. Synthesis of Imidazol-2-carboxylate 235

82%, 239/240 = 26/2.4; 239, 95% ee.

[1,2,3]Triazolo[1,5-a]quinoxalin-4(5H)-ones 242 were obtained in 53−74% yields (Scheme 68). Scheme 68. Synthesis of 1H-1,2,3-Triazole-5-carboxylates 241 and [1,2,3]Triazolo[1,5-a]quinoxalin-4(5H)-ones 242a

Scheme 66. Synthesis of Benzimidazole 237

a 1 R = H, F, Cl, CF3; R2 = PhCO, 2-furylCO, CO2Et; 241, 17−28%; 242, 53−74%.

1,2,3-triazoles have become one of the most important heterocycles in current chemistry research. Thermal 1,3-dipolar cycloaddition of azides with alkynes is one of the most attractive ways to prepare 1,2,3-triazole moieties. The reaction of glyoxalate imine with CF3CHN2 was investigated by Chai et al.127 to produce aziridine moiety. The reaction was carried out by adding a solution of chiral phosphoric acid V-1 and MgSO4 in CH3CN to a solution of glyoxalate imine and in situ generated CF3CHN2 in toluene, and stirring at room temperature for 6−12 h. In contrast to the expected aziridine, reaction led to cis-triazoline 239 as the major product, and aziridine 240 was obtained only in very low yield, as determined by 19F NMR analysis of the crude reaction mixture (Scheme 67). Biagi et al.128 developed the 1,3-dipolar cycloaddition reaction between 2-nitrophenylazide and sodium salt of substituted ethyl pyruvates to furnish ethyl 1-(2-nitrophenyl)1H-1,2,3-triazole-5-carboxylates 241. Reactions were conducted in anhydrous THF at 50−60 °C for 7 h, and gave corresponding triazoles 241 in 17−28% yields, which were converted to [1,2,3]triazolo[1,5-a]quinoxalin-4(5H)-ones 242 when hydrogenated in the presence of Pd/C or Ni-Raney in EtOH or EtOH/water at room temperature, respectively.

3.8. Indoles

Indole moieties are present in the structure of a number of biologically important molecules, such as tryptophan, tryptamine, serotonin, melatonin, brassinin, lysergic acid diethylamide, indol-3-ylacetic acid, and vincristine, and in pharmacologically active compounds, such as delavirdine as anti-HIV, apaziquone as anticancer, oxypertine as antipsychotic, and Arbidol as antiviral, pindolol as antihypertensive, oglufanide as immunomodulator, etc. Fischer, Batcho−Leimgruber, Reissert, Hegedus, Bischler, Gassman, Japp−Klingemann, Buchwald, Bucherer, Larock, Bartoli, Castro, Hemetsberger, Madelung, and Nenitzescu indole synthesis are among the most used approaches for the construction of indole derivatives. One example of 3-phenylindolines, ethyl 3-phenyl-Npivaloylindoline-2-carboxylate 245, was synthesized by Mitsunobu cyclodehydration reaction of ethyl 3-(2-aminophenyl)-2hydroxy-3-phenylpropanoate 244 with PBu3 (2.5 equiv) and DEAD (2.5 equiv) in CH3CN at room temperature during 6 h. 244 was prepared from reaction of o-benzyl-N-pivaloylaniline 243 with ethyl glyoxalate (2.5 equiv) mediated by (−)-sparteine (2.2 equiv) and n-BuLi (2.2 equiv) in MTBE at −78 °C 174


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for 20 min. The overall yield for two steps is 67% (Scheme 69).129

Scheme 71. Synthesis of Ethyl 6-Azaindole-2-carboxylate 250

Scheme 69. Synthesis of Ethyl 3-Phenyl-N-pivaloylindoline2-carboxylate 245

leneamino-3-methoxy-5-methylpyridazine 1-oxide 251 with diethyl oxalate in the presence of KOEt in ether under Ar atmosphere for 5 h (Scheme 72).132a Similar manner was applied for the synthesis of ethyl pyrrolo[3,2-c]pyridazine-6carboxylate 2-oxide in 77% yield.132b Scheme 72. Synthesis of Pyrrolo[2,3-d]pyridazine-2carboxylate 5-Oxide 254

By treatment of lithiated N-BOC-3,4-difluoroaniline with ethyl bromopyruvate, unexpected ethyl 4,5-difluoroindole-3carboxylate 247 was obtained in 26% yield. Reaction was carried out by in situ generation of lithiated N-BOC-3,4difluoroaniline from reaction of N-BOC-3,4-difluoroaniline 246 with t-BuLi in anhydrous THF at −78 °C, then by addition of ethyl bromopyruvate and stirring at 0 °C for 2 h, which afforded intermediate 247 via alkylation of lithiated C2 with ketone group of pyruvate. Intermediate 247 was converted to indole-3-carboxylate 248, when heated in the presence of TFA in xylene under reflux conditions (Scheme 70).130 Scheme 70. Synthesis of Indole-3-carboxylate 248

Polyfunctionalized N-hydroxyindoles 258 were synthesized by nucleophilic additions to α,β-unsaturated nitrones 257, which were in situ generated by reduction of nitro-α,βunsaturated ketoesters 255 and then intramolecular condensation of N-hydroxylamines 256 (route b). Reactions were carried out by addition of a nucleophile (5.0 equiv) and a nitro ketoester 255 (1.0 equiv) to a solution of SnCl2·2H2O (2.2−2.5 equiv) and 4 Å MS in DME at 25 °C, and then heating to 40− 45 °C for 1−72 h in the absence of light. The scope of the reaction was studied using various O−, S−, N−, and C− nucleophiles such as alcohols, thiols, amines, silyl enol ethers, silanes, and stannanes. In addition to corresponding Nhydroxyindoles 258, N-hydroxyindol-3-yl ketoester 259 was produced in 11−20% yields as a byproduct, via an intramolecular aza-Michael addition followed by oxidation/aromatization (route a). Starting nitro-α,β-unsaturated ketoesters 255 were prepared by reaction of the corresponding nitrotoluene with excess dimethyl oxalate in the presence of NaH in DMF at 0−25 °C, followed by exposure with Eschenmoser’s salt in the presence of NaH in THF at the same temperature (Scheme 73).133 3-Aryl-3-hydroxyoxindole derivatives 262 were prepared by cascade enantioselective arylation-cyclization of benzyl 2-(Bocaminophenyl)-2-oxoacetate 260. The arylation step was

6-Azaindole-2-carboxylate, ethyl 1H-pyrrolo[2,3-c]pyridine2-carboxylate 250, was prepared via modified Reissert indole synthesis. By reaction of 3-nitro-4-picoline with diethyl oxalate using KOEt as a base in dry ether, ethyl 3-(3-nitro-4pyridy1)pyruvate 249 was produced, which was transformed into 6-azaindole-2-carboxylate 250 by reduction of nitro group using H2(g) in the presence of Pd/C (5%) in AcOH at room temperature, in 44% yield. 6-Azaindole-2-carboxylate 250 could be converted to 6-azaindole by hydrolysis of ester using NaOH followed by decarboxylation under heating at 370 °C (Scheme 71).131 By heating potassium enolate of ethyl 4-ethoxymethyleneamino-3-methoxy-5-pyridazinylpyruvate 1-oxide 252 in DMF at 100 °C for 1 h, ethyl 7-methoxypyrrolo[2,3-d]pyridazine-3glyoxalate 5-oxide 253 was obtained in 90% yield. When the reaction was performed in the presence of HCl (5%) in DMF at 40 °C for 17 h, ethyl 7-methoxypyrrolo[2,3-d]pyridazine-2carboxylate 5-oxide 254 was obtained in 84% yield. Potassium enolate 252 was prepared by reaction of ethyl 4-ethoxymethy175


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Scheme 73. Synthesis of Polyfunctionalized N-Hydroxyindoles 258a

a 1

R = H, F, CN; R2 = H, F; R3 = H, F, Br, CH2OSEM; Nu = O−nucleophiles−ROH (R = Et, n-Hex, c-Hex, Bn), 37−87%; S−nucleophiles−RSH (R = n-Hex, c-Hex, Bn, Ph), 54−75%; N−nucleophiles−RR′NH [R = Ph and R′ = H, R−R′ = O(CH2CH2)2], 18−27%; C−nucleophiles−silyl enol ethers (13 examples), 22−75%; silanes and stannanes (10 examples), 20−61%; and also phenol and 2,6-(MeO)2phenol, 31−40%.

performed by reaction of 260 with 2 equiv of arylboronic acid in toluene at 60 °C using [Rh(COE)2Cl]2 (1.5 mol %), chiral ligand VI (3.3 mol %), and 1.0 equiv of DIEA, to form (R)benzyl 2-(Boc-aminophenyl)-2-hydroxy-2-phenylacetate 261 in 65−73% yields with 93−98% ee. Obtained 261 was converted to the corresponding 3-aryl-3-hydroxyoxindoles 262 in 95− 99% yields, with 93−98% ee, by reacting with TFA in DCM at room temperature for 30 min followed by treatment with NaH (2 equiv) in THF at room temperature (Scheme 74).134

Scheme 75. Synthesis of Indole-2-carboxylate 263 by Oxidative Cyclization

nicotinic acid (20 mol %) in toluene at 100 or 110 °C for 24 or 48 h. In the proposed reaction mechanism, reaction of TBHP with coordination product (264) of Cu(II) with aniline and ethyl glyoxalate led to free radical 265, which attached to the ortho-position of anilines affording o-acylation product 267 by subsequent rearomatization of 266 through hydrogen abstraction by in situ generated t-BuO radical. Finally, o-acylated anilines 267 underwent lactamization by intramolecular nucleophilic attack of the NH to the ester to produce the corresponding isatins 268 in 36−65% yields (Scheme 76). The synthesis of 3-aminoindole-2-carboxylates 271 was reported by Sorensen et al.137 via Ugi reaction between isocyanides and imines, derived from ethyl glyoxalate, in the presence of triflyl phosphoramide as an acid. Reactions were carried out by addition of an isocyanide (1.5 equiv) and triflyl phosphoramide (1.1 equiv) to a solution of a glyoxalate imine in DCM at 23 °C for 2 h, to afford the corresponding 3aminoindole-2-carboxylates 271 in 12−72% yields. The proposed reaction mechanism involves the nucleophilic addition of isocyanide to iminium ion, followed by intramolecular Houben−Hoesch reaction of electron-rich aromatic ring with generated nitrilium ion 269 to furnish ketamine derivative 270, which underwent tautomerization to 3-aminoindole-2-carboxylates 271 (Scheme 77). Fischer indole synthesis of pyruvates was extensively used for construction of indole-2-carboxylate scaffolds. In this context, Sudhakara et al.138 reported a one-pot procedure for the synthesis of indole-2-carboxylates 273 via in situ generation of the hydrazones 272 by reaction of arylhydrazines with ethyl pyruvate in the presence of Bi(NO3)3, followed by Fischer indolization in the presence of polyphosphoric acid (PPA). Reactions were carried out by refluxing a mixture of arylhydrazine hydrochloride and ethyl pyruvate in MeOH in

Scheme 74. Synthesis of 3-Aryl-3-hydroxyoxindoles 262 by Cascade Arylation-Cyclizationa

a

R = H, Cl; Ar = Ph, 4-MeOC6H4, 1-naphthyl; 261, 65−73%, 93−98% ee; 262, 95−99%, 93−98% ee.

Wei et al.135 described the synthesis of 5-methoxyindole-2carboxylate 263 by one-pot oxidative cyclization of in situ generated imine from reaction of ethyl pyruvate and panisidine. Oxidative cyclization reaction was conducted using Pd(OAc)2 (20 mol %) in the presence of Cu(OAc)2 (3 equiv) in DMSO at 40 °C for 24 h. The 5-methoxyindole-2carboxylate 263 was obtained in 41% yield (Scheme 75). Fu et al.136 described the Cu(II)/TBHP-induced oxidativecyclization of secondary anilines with ethyl glyoxalate to give indoline-2,3-diones, isatins 268. Reactions were carried out by heating a solution of secondary aniline, ethyl glyoxalate (2 equiv), Cu(OAc)2 (10 mol %), TBHP (1.5 equiv), and 176


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Scheme 76. Synthesis of Isatins 268 via Cu(II)/TBHP-Induced Oxidative-Cyclization Reactiona

R = H, 5-Cl, 4-Me, 5-Me, 6-Me, 4,5-(CH)4; R2 = Me, i-Pr, n-Bu, n-Pent, c-Hex, XC6H4 (X = H, 2-Cl, 3-Cl, 4-Cl, 4-Me, 3-CF3); R1−R2 = 7CH2CH2CH2; 36−65%. a 1

by Fischer indolization in ethyl esters of polyphosphoric acid (PPAEE) at 80 °C for 20 min.140 Also, p-TSOH in refluxing dry benzene141 and ethanolic HCl at room temperature142 was performed for the Fischer indolization of aryl hydrazones of ethyl pyruvates. Similarly, ethyl benz[g]indole-2-carboxylate and ethyl benz[e]indole-2-carboxylate have been synthesized by Fischer indolization of 1- and 2-naphthylhydrazones of ethyl pyruvate, respectively.143 Wagaw et al.144 reported the synthesis of ethyl 4,6-dimethylindole-2-carboxylate by reaction of ethyl pyruvate with N-(3,5-dimethylphenyl)benzophenone hydrazone in the presence of p-TSOH in toluene at 80 °C. Reaction proceeded by hydrolysis of benzophenone hydrazone, followed by Fischer indolization of generated 3,5-dimethylphenylhydrazine with ethyl pyruvate to produce corresponding indole-2carboxylate in 68% yield. Neat PPE at room temperature145 and PPA under heating conditions146 were also used for Fischer indole synthesis. Also, Fischer indolization of diaryl hydrazones of ethyl pyruvate 274 was investigated using ethanolic HCl at room temperature, which afforded the corresponding indole-2carboxylates 275 in 44.8−78% yields as a mixture of two Naryl (275a) and N-aryl′ (275b) indoles, in which indolization occurs predominantly at the more electron-rich arene ring (Scheme 79).147 When 2-(2-methoxyphenyl)hydrazone of ethyl pyruvate 276 was treated with HCl in EtOH or ZnCl2 in AcOH, abnormal

Scheme 77. Synthesis of 3-Aminoindole-2-carboxylates 271 via Ugi Reactiona

a 1

R = H, 6-MeO, 6-MeS, 5,6-(MeO)2, 5,6-(CH2OCH2), 4,5-(CH)4; R2 = t-Bu, c-Hex, 4-MeOC6H4, (S)-(Me)CHC6H5; 12−72%.

the presence of Bi(NO3)3 (20 mol %) and PPA for 0.4−3 h. The reactions afforded the corresponding indole-2-carboxylates 273 in 80−90% yields (Scheme 78). A similar procedure was Scheme 78. Synthesis of Indole-2-carboxylates 273 via Fischer Indolizationa

Scheme 79. Fischer Indolization of Diaryl Hydrazones of Ethyl Pyruvates 274a

a

R = H, 5-F, 4-Cl, 6-Cl, 5-Br, 6-Br, 5-NO2, 6-NO2, 7-NO2, 4-F-5-NO2; 80−90%.

applied to synthesize indole moiety of seco-duocarmycin SA, a highly potent cytostatic agent, by treatment of the 2-methoxy4-nitrophenyl hydrazone of methyl pyruvate with PPA in xylene at 120 °C for 18 h. The corresponding indole-2-carboxylate was obtained in 64% yield.139 Ethyl 5-phenyl indole-2-carboxylate was synthesized by reaction of biphenyl hydrazine hydrochloride with ethyl pyruvate in the presence of AcOH in a mixture of EtOH/water at room temperature for 2 h, followed

a 1

R = OMe, R2 = H, 44.8%, a/b = 42.5/2.3; R1 = H, R2 = OMe, 60%, a/b = 43/17; R1 = CO2Et, R2 = H, 78%, a/b = 11/67. 177


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Scheme 80. Abnormal Fischer Indolization of o-Methoxy-Substituted Phenylhydrazone of Ethyl Pyruvate 276

1,8-diamine 285 with methyl trifluoromethyl pyruvate in dry Et2O at room temperature for 36 h. Hemiaminal 287 was generated rapidly, which underwent intramolecular rearrangement to o-C-alkylation product 288 that subsequently transformed into indolinone 289 in 44% yield. Indolinone 289 was converted to tetrahydroindolo[1,7a,7,6-c,d,e]quinazolin-3-one 290 in 81% yield, when treated with acetone in the presence of MgSO4 for 16 days (Scheme 82).150

Fischer indolization took place to give ethyl 6-chloro- and 6ethoxyindole-2-carboxylates 281a and 281b or ethyl 5chloroindole-2-carboxylate 282, together with a small amount of the expected ethyl 7-methoxyindole-2-carboxylate 278, respectively. The proposed reaction mechanism involves the Cope-type reaction of ene-hydrazine 277 through the methoxysubstituted ortho position rather than the normal unsubstituted one, then formation of intermediate cation 280 by cyclization via removal of an ammonia molecule from 279, which underwent addition of chloride anion or ethanol molecule and loss of methanol to furnish abnormal Fischer indolization products 281 (Scheme 80).147,148 In some cases, the studied arylhydrazones of ethyl pyruvate were prepared by Japp− Klingemann reaction. Similarly, when (1-methoxy-2-naphthyl)hydrazone of methyl pyruvate 283 was treated with ethanolic HCl, abnormal Fischer indolization products, 5-chloro-3H-benz[e]indole-2-carboxylate 284a and ethyl 1-chloro-3H-benz[e]indole-2-carboxylat 284b, were obtained in 74.6% and 2.2% yields, respectively, whereas the normal Fisher indolization product, ethyl 9-methoxy-1Hbenz[f ]indole-2-carboxylate 285, was not produced (Scheme 81).149 9-Amino-3-hydroxy-3-(trifluoromethyl)-1,3-dihydrobenzo[g]indol-2-one 289 was prepared by reaction of naphthalene-

Scheme 82. Synthesis of Dihydrobenzo[g]indol-2-one 289

Scheme 81. Abnormal Fischer Indolization of (1-Methoxy-2naphthyl)hydrazone of Methyl Pyruvate 283a There is one report on the synthesis of indazole moiety starting from α-keto esters in the literature, in which ethyl 1phenylindazole-3-carboxylate 293 was synthesized by oxidation of phenylhydrazone of ethyl benzoylformate 291 with Pb(OAc)4, followed by cyclization of obtained azoacetate 292 using BF3·OEt2 in ether under heating on the water bath for 20 min. The yield of two steps is 74% (Scheme 83).151 3.9. Pyrrolizidines and Pyrrolizines

a

Pyrrolizidine alkaloids, such as (−)-alexine, (+)-australine, (+)-7-epiaustraline, retronecine, platynecine, indicine N-oxide, hyacinthacines A1, A2, and A3, uniflorine A, and casuarine, constitute a large class of naturally occurring compounds, and

284a, R1 = Cl, R2 = H, 74.6%; 284b, R1 = H, R2 = Cl, 2.2%. 178


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pyrrolizidine derivatives 298 in 50−76% yields with excellent diastereoselectivity toward endo-cycloadducts (Scheme 85).

Scheme 83. Synthesis of Ethyl 1-Phenylindazole-3carboxylate 293

Scheme 85. Synthesis of Pyrrolizidine Derivatives 298 via 1,3-Dipolar Cycloaddition Reactiona

are found in a great variety of plant species spread throughout the world. They have glycosidase inhibitory, antiviral, anticancer, antidiabetic, and antiobesity activities. Additionally, pyrrolizine derivatives have potent cytostatic effects and are useful for the development of antitumor and antiviral agents. Consequently, the achievement of new routes for the synthesis of pyrrolizidine and pyrrolizine rings has gained great interest in synthetic and medicinal chemistry. 1,3-Dipolar cycloaddition reaction of ethyl pyruvate with βnitrostyrene and L-proline was developed to synthesize substituted pyrrolizidine 296 in a one-pot three-component manner. Reaction was carried out in i-PrOH at room temperature to give pyrrolizidine 296 in 90% yield with 9/1 regioselectivity. The proposed reaction mechanism involves the in situ generation of azomethine ylide 295 from reaction of Lproline with ethyl pyruvate followed by decarboxylation of 294, which was converted to pyrrolizidine 296 in treatment with βnitrostyrene under 1,3-dipolar cycloaddition reaction (Scheme 84).152

a

Ar = XC6H4 (X = H, 4-F, 3-Cl, 4-Cl, 3-Br, 4-Br, 2-Me, 3-Me, 4-Me, 3MeO, 4-MeO, 4-CN, 4-NO2); R = Me, Et, i-Pr; 50−76%.

An approach was developed to synthesize 3-hydroxy-1-aryl2,3-dihydro-1H-pyrrolizine-3-carboxylates 300 by 1,4-addition of pyrrole (2 equiv) to β,γ-unsaturated α-oxoesters mediated by Cu(OTf)2 (10 mol %) in THF at room temperature to afford corresponding Friedel−Crafts products 299 in 43−83% yields, which, by heating in CCl4 under reflux conditions for 6 h, converted to the pyrrolizine-3-carboxylate derivatives 300. The yields of 300 were not reported (Scheme 86).154 Scheme 86. Synthesis of 3-Hydroxy-1-aryl-2,3-dihydro-1Hpyrrolizine-3-carboxylates 300a

Scheme 84. Synthesis of Pyrrolizidine 296 via 1,3-Dipolar Cycloaddition Reaction

a

Ar = XC6H4 (X = H, 4-F, 4-Cl, 4-Br, 4-Me, 2-MeO, 4-MeO, 4-NO2).

Chiral N-triflyl phosphoramide V-2-catalyzed Friedel−Crafts alkylation of 4,7-dihydroindole with β,γ-unsaturated αoxoesters followed by oxidation with p-benzoquinone to construction of pyrrolo[1,2-a]indoles 302 was described by Mi et al.155 Reactions were carried out by addition of β,γunsaturated α-ketoester to a solution of 4,7-dihydroindole, Ntriflyl phosphoramide V-2 (5 mol %), and 5 Å MS in toluene under argon atmosphere at −78 °C to give Friedel−Crafts products 301. p-Benzoquinone-induced oxidation of Friedel− Crafts products 301 was conducted in CH3CN at room temperature to afford corresponding pyrrolo[1,2-a]indoles 302 in 48−87% yields with moderate diastereoselectivity (Scheme 87a). The synthesis of similar pyrrolo[1,2-a]indole structural motifs 303 was reported via Cu(OTf)2/chiral bis(oxazoline) ligand VII-1-catalyzed enantioselective Friedel−Crafts alkylation/N-hemiacetalization cascade reactions between β,γ-unsaturated α-oxoesters and indoles. Reactions were carried out in toluene at 0 °C for 8−48 h, and the corresponding pyrrolo[1,2a]indoles 303 were obtained in 67−97% yields with 56/44− 97/3 diastereoselectivity. Also, substituted indoles worked well under similar reaction conditions (Scheme 87b).156a

Recently, Kang et al.153 reported a tandem cycloaddition between proline and β,γ-unsaturated α-oxoesters. Reactions were carried out by heating a solution of racemic proline (0.5 equiv) and β,γ-unsaturated α-oxoesters in CH3CN at 80 °C for 12−24 h. In the proposed reaction mechanism, unsaturated azomethine ylide 297, in situ generated by condensation of proline with one molecule of β,γ-unsaturated α-oxoesters and then decarboxylation, underwent cycloaddition reaction with another molecule of β,γ-unsaturated α-oxoesters to afford 179


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Scheme 87. Synthesis of Pyrrolo[1,2-a]indoles 302,303a

a 302, Ar = XC6H4 (X = H, 3-Br, 4-Br, 4-Cl, 3-NO2, 4-MeO), 3,4-(OCH2O)C6H3, 2-furyl, 2-thienyl, 1-naphthyl, 2-naphthyl; 48−87%; 46/54−75/25 dr; 303, R1 = H, 5-F, 6-F, 5-Cl, 6-Cl, 5-Br, 4-Me, 5-Me, 6-Me, 5-MeO, 5-BnO; R2 = Me, Et, i-Pr, Bn, c-Hex, Ph, CH2CO2Me, (CH2)2OTBS, (CH2)2NPhth; R3 = n-Pr, c-Hex, (MeO)2CH, CO2Et, PhCHCH, 2-thienyl, XC6H4 (X = H, 2-F, 4-F, 3-Br, 4-Br, 4-Cl, 4-Me, 4-MeO); R4 = Me, Et, Bn, i-Pr; 67−97%; dr = 56/44−97/3.

Lee and co-worker157 described the primary amine I-2catalyzed cascade aza-Michael−aldol reactions of α,β-unsaturated ketones with 2-(1H-pyrrol-2-yl)-2-oxoacetates to synthesize pyrrolizines 304. Reactions were performed by treatment of α,β-unsaturated ketone with pyrroleyl-2-oxoacetates in the presence of cinchona-based primary amine catalyst I-2 (20 mol %) and Ph3CCO2H (40 mol %) in toluene at 0 °C or room temperature for 24 or 48 h. The corresponding pyrrolizines 304 were obtained in 63−92% yields, with 90−95% ee and >20/1 diastereoselectivity (Scheme 88).

terase V inhibitors. Consequently, there has been an ongoing interest in the synthesis of indolizidine and indolizine heterocycles. Ethyl 2-hydroxy-3-oxohexahydroindolizine-1-carboxylate 305a was synthesized by condensation of 2,3,4,5-tetrahydropyridine (2,3,4,5-THP) with diethyl oxaloacetate or ethyl 3-tbutoxycarbonyl-2-oxopropionate in ether−EtOH−benzene solution under refluxing conditions for 3 h, in 48% yield. Acidic hydrolysis of 305a with refluxing HCl (10%) followed by decarboxylation afforded 8,9-dioxo-1-azabicyclo[4.3.0]nonane 307 in 60% yield. 2,3,4,5-THP was prepared by reaction of piperidine with NCS followed by treatment of obtained 2chloropiperidine with KOH. From reaction of 2,3,4,5-THP with diethyl methyloxalacetate under similar conditions, 7ethoxycarbonyl-7-methyl-8,9-dioxo-1-azabicyclo[4.3.0]nonane 306 was obtained in 13% yield, which was transformed into 308 in 74% yield, when hydrolyzed using HCl (10%) (Scheme 89).158 Similar methodology was developed to prepare ethyl 6hydroxy-5-oxo-2,3,5,7-tetrahydro-1H-pyrrolizine-7-carboxylate 305b.159 Mao et al.160 developed an approach for the synthesis of polysubstituted indolizines 314 via four-component reaction of ethyl glyoxalate, phenacyl bromide (2.2 equiv), and pyridine (2.5 equiv) in the presence of Na2CO3 in refluxing CH3CN for 16 h. In the proposed reaction mechanism, ethyl glyoxalate underwent nucleophilic addition with pyridinium ylide 309, in situ generated by reaction of pyridine with phenacyl bromide followed by deprotonation, to produce intermediate 310, which was transformed into reactive alkene 311 by removing a pyridine molecule. 1,3-Dipolar cycloaddition reaction of 311 with another pyridinium ylide 309, followed by removal of a molecule of water from 312, afforded the intermediate 313, which underwent oxidation by O2 to give indolizines 314 in 55−89% yields. Also, 1-bromo-2-butanone, an aliphatic αbromo ketone, was also investigated under the same reaction conditions, and the desired product was obtained in 32% yield (Scheme 90).

Scheme 88. Synthesis of Pyrrolizines 304 via Cascade AzaMichael−Aldol Reactionsa

a 1

R = Cl, Br, I; R2 = Cl, Br, I; R3 = Me, n-Bu, i-Bu, (CH2)2Ph, (CH2)2OTBS, (CH2)2OBn, (CH2)2SBn, (CH2)2Oallyl, (CH2)2−2furyl, CH2N(Boc)Cbz; 63−92%; ee = 90−95%; dr = >20/1.

3.10. Indolizidines and Indolizines

Indolizidine alkaloids, such as (−)-indolizidine 167B, indolizidine 209D, tashiromine, (−)-steviamine, (−)-tylophorine, and (−)-elaeokanine C, are one of the most important class of natural products, known for their wide range of pharmaceutical applications. Additionally, some compounds possessing indolizine moiety have been reported as histamine H3 receptor antagonists, leukotriene synthesis inhibitors, and phosphodies180


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Scheme 89. Synthesis of Hexahydroindolizine-1-carboxylates 305a and 306a

Scheme 91. Synthesis of 1H-Pyrazolo[3,4-e]indolizine-5carboxylates 317a

a

n = 1, 2; R1 = H, Me; R2 = Et, t-Bu; 305a, n = 2, R2 = Et, t-Bu; 305b, n = 1, R2 = Et. a

By intramolecular cyclization of pyrryl-2-oxoacetate derivatives 316 using K2CO3 (2.2 equiv) in DMF at 100 °C during 4 h, 1H-pyrazolo[3,4-e]indolizine-5-carboxylates 317 were formed in 32−53% yields, which were transformed into pyrazolo[3,4-e]pyrrolo[3,4-g]indolizine-4,6(1H,5H)-diones 318 possessing glycogen synthase kinase-3 inhibitatory activity, when treated with TFA and H2SO4 at room temperature for 2 h, in 29−31% yields. Starting pyrryl-2-oxoacetates 316 were synthesized from reaction of [(1H-pyrrol-1-yl)-1H-pyrazol-4yl]acetonitriles 315 with 2-chloro-2-oxoacetate (6 equiv) in refluxing toluene in 98−99% yields (Scheme 91).161 Modified von Miller−Plöchl reaction was developed for the synthesis of 5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carboxylates 321 and 322, from reaction of in situ generated anion of 1,2,3,4-tetrahydroisoquinoline-1-carbonitrile 319 with benzylidenepyruvate, to give intermediate 320, which was transformed into 322 by elimination of HCN and a molecule of water, when heated in EtOH in the presence of AcOH. By treatment of the obtained product with Br2 in DCM at room temperature, the corresponding bromo-pyrrolo[2,1-a]isoquinoline-3-carboxylate 321 was obtained in 12% yield (Scheme 92).162 1-Benzoyl-2-hydroxy-8,9-dimethoxy-3,5,6,10btetrahydropyrrolo[2,1-a]isoquinolin-3-one 325 was prepared from reaction of 5-phenyl-2,3-dihydrofuran-2,3-dione with 6,7dimethoxy-3,4-dihydroisoquinoline 323 in anhydrous dioxane at 20−22 °C for 12 h. The conversion could be explained by generation of zwitterion 324 via ring opening of 2,3dihydrofuran-2,3-dione by nucleophilic addition of N atom of

Ar = 2,4-Cl2C6H3, 4-Cl-2-MeC6H3; 317, 32−53%; 318, 29−31%.

Scheme 92. Synthesis of 5,6-Dihydropyrrolo[2,1a]isoquinoline-3-carboxylates 321 and 322

Scheme 90. Four-Component Synthesis of Indolizines 314a

R = H, R1−R1 = (CH)4; R2 = Et, XC6H4 (X = H, 4-Cl, 4-Br, 4-Me, 3-MeO); 32−89%.

a 1

181


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Scheme 94. Synthesis of Pyrroloquinazolines 331a

dihydroisoquinoline 323, which underwent cyclization with subsequent enolization to 325, which was oxidized to 1benzoyl-8,9-dimethoxy-2,3,5,6-tetrahydropyrrolo[2,1-a]isoquinoline-2,3-dione 326 when heated in EtOH in 24% overall yield (Scheme 93).163 Scheme 93. Synthesis of 1-Benzoyl-2hydroxytetrahydropyrrolo[2,1-a]isoquinolin-3-one 325

R = Me, Et, n-Bu, t-Bu, Ph; R2 = H, Me, n-Bu, (Me)2, Ph; R1−R2 = (CH2)3, (CH2)4, CH(Me)CH2CH2CH2; 331, 28−89.3%; 332, 0− 24%. a 1

The synthesis of pyrroloquinazolines 331 was reported by annulation of 2-(aminomethyl)aniline, methyl 3,3,3-trifluoropyruvate, and various carbonyl compounds. The addition adduct 327 was first generated as the reaction intermediate, which converted to enamine 328 in reaction with carbonyl compounds. Enamine 328 underwent rearrangement to give imine 329 that transformed into cyclic aminal 330, which finally afforded the corresponding thermodynamically stable linearly annulated tricyclic pyrroloquinazolines 331. Reactions were carried out in ether or dioxane at room temperature or 100 °C for 1−200 h. In addition to 331, angularly annulated tricyclic pyrroloquinazolines 332 were isolated as byproducts in low yields (Scheme 94).164 1,3-Dipolar cycloaddition reaction of in situ generated azomethine ylides, derived from condensation of glyoxalate with cyclic α-amino esters 333−335, with N-methyl maleimide was developed by Grigg et al.165 Reaction of (+)-menthyl glyoxalate, N-methyl maleimide, and 333 or 334 was performed in DMF under heating condition at 110−120 °C for 15−18 h, and cycloadducts pyrrolo-isoquinoline 336 or indolizino-indole 337 were obtained in 73% (336a/336b = 5/1) or 71% (337a/ 337b = 3.5/1) yields, respectively. Moreover, reactions of methyl glyoxalate with N-methyl maleimide and cyclic α-amino esters 333−334 and 335 were carried out in refluxing CH3CN for 15−16 h and DMF at 120 °C for 12 h, respectively. The yields of the corresponding cycloadducts 336, 337, and 338 were 71%, 68%, and 68%, respectively (Scheme 95). Zhang et al.166 developed the 1,6-annulation reaction of azomethine ylide 340, derived from reaction of methyl (indol3-yl)pyruvate 339 with proline, to construct one example of indolizino-indole moiety 341. Reaction was carried out using 2 equiv of proline in refluxing xylene for 1.75 h, and the corresponding indolizino-indole 341 was obtained in 52% yield as a mixture of two stereoisomers with 75/25 diastereoselectivity (Scheme 96).

Treatment of 2-ethoxycarbonylmethylidenecyclohexanone 343 with 3-hydroxy-4-methoxyphenethylamine in t-BuOH under heating conditions for 24 h afforded erythrinanone 344. Starting 343 was prepared by reactions of cyclohexanone with n-butyl glyoxalate in the presence of piperidine in refluxing pyridine for 4 h to produce hydroxyketone 342, which underwent dehydration to 343 using I2 in refluxing dry benzene (Scheme 97).167 Three-component reaction of 1,2-diaminobenzenes, dialkyl acetylenedicarboxylates (DAAD), and ethyl bromopyruvate was developed by Piltan et al.168 to synthesize pyrrolo[1,2a]quinoxalines 347. Reactions were performed by refluxing a mixture of an equimolar amount of a 1,2-diaminobenzene, a DAAD, and ethyl bromopyruvate in CH3CN for 12 h. The proposed reaction mechanism involves the nucleophilic addition of enamine moiety of dihydroquinoxaline 345, in situ generated from reaction of 1,2-diaminobenzene with DAAD, via C atom to ethyl bromopyruvate to produce intermediate 346, which underwent cyclization and dehydration to afford corresponding pyrrolo[1,2-a]quinoxalines 347 in 88−93% yields. Reactions with 1,2-diaminobenzene possessing electron-withdrawing nitro substituent failed. Also, ethylenediamine was investigated in this reaction under similar conditions, which afforded the corresponding pyrrolo[1,2-a]pyrazine derivatives 348 in 83−85% yields (Scheme 98). A similar approach was developed to synthesize pyrrolo[2,1-c][1,4]benzoxazines 349 in 86−94% yields, from reaction of 2aminophenols, DAAD, and ethyl bromopyruvate in PEG using FeCl3 (20 mol %) at 100 °C, for 1 h (Scheme 98).169 Berlin et al.170 demonstrated that the 2,9-di(ethoxycarbonyl)dipyrrolo[1,2-a:2′,1′-c]pyrazines 351a and 2,11-di(ethoxycarbonyl)dipyrrolo[1,2-a:2′,1′-c]quinoxaline 351b could be synthesized from reaction of 2,3-dimethylpyrazine and 2,3-dimethylquinoxalin in two separate stages with two 182


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Scheme 95. Synthesis of Pyrrolo-isoquinoline 336 or Indolizino-indole 337a

336, R1 = Me, R2 = (+)-menthyl; cond. = DMF, 110 °C, 18 h; 73%; a/b = 5/1; R1 = Bn, R2 = Me; cond. = CH3CN, 80 °C, 16 h; 71%; a/b = 3.5/1; 337, R2 = (+)-menthyl; cond. = DMF, 120 °C, 15 h; 71%; a/b = 3/1; R2 = Me; cond. = CH3CN, 80 °C, 15 h; 68%; a/b = 3/1; 338, 68%; a/b = 2/1. a

Scheme 96. Synthesis of Indolizino-indole 341

Scheme 98. Synthesis of Pyrrolo[1,2-a]quinoxalines 347, [1,2-a]Pyrazines 348, and [2,1-c][1,4]Benzoxazines 349a

Scheme 97. Synthesis of Erythrinanone 344

a

347, R1 = H, Me, NO2; R2 = H, Me; R3 = Me, Et; 0−93%; 348, R3 = Me, Et; 83−85%; 349, R4 = H, Cl, Me; R3 = Me, Et, t-Bu; 86−94%.

acetone at 60 °C for 2 h, or dry ethyl methyl ketone under reflux condition for 3 h, then at room temperature during overnight, followed by exposure with NaOEt in EtOH at room

molecules of ethyl 3-bromopyruvate, respectively. Reaction of 2,3-dimethylpyrazine or 2,3-dimethylquinoxalin with the first molecule of ethyl 3-bromopyruvate was carried out in dry 183


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temperature, which resulted in the formation of 7-ethoxycarbonyl-1-methylpyrrolo[1,2-a]pyrazine 350a or 2-ethoxycarbonyl-4-methylpyrrolo[1,2-a]quinoxaline 350b, respectively. Conversion of 350a or 350b to the corresponding 351a or 351b was performed by reaction with a second molecule of ethyl 3bromopyruvate, in dry acetone or ethyl methyl ketone under reflux conditions, followed by treatment with NaOEt in EtOH at room temperature for 0.5 h, or KOH in water under reflux conditions for 1 h (Scheme 99).

Scheme 100. Synthesis of Tricyclic 2-Thioxoimidazolidinone 354a

Scheme 99. Synthesis of Dipyrrolo[1,2-a:2′,1′-c]pyrazine 351a and Dipyrrolo[1,2-a:2′,1′-c]quinoxaline 351ba

a R = Et, XC6H4 (X = 4-Cl, 3-MeO, 4-MeO); 52−73% (for last step); endo, 41−73%; exo, 0−12%. a

R = H, 350a, 80%; 351a, 37%; R−R = (CH)4, 350b, 93%; 351a, 56%.

membered copper intermediate 359, which underwent oxidative aromatization using air to afford imidazo[1,2a]pyridine 361 (Scheme 101).172

3.11. Imidazopyridines

Scheme 101. Synthesis of Imidazo[1,2-a]pyridines 361a

The imidazopyridines constitute a class of drugs, such as zolpidem, alpidem, saripidem, necopidem, and fasiplon, used as GABAA receptor agonists, and DS-1 as a proton pump inhibitor. Also, imidazopyridines have various applications as dyes, optical data carriers, pesticides, and fungicides. Oxidative condensation−cyclization of aldehydes with 2-aminomethylpyridines and cyclocondensation of 2-aminopyridines with αhaloketones or α-haloaldehydes are among the most important routes to synthesize imidazopyridine moieties. The synthesis of 2-thioxoimidazolidinone 354 was reported starting from ethyl glyoxalate. First, the aza-Diels−Alder (DA) reaction between α-imino ester, in situ derived from ethyl glyoxalate and enantiopure 1-phenylethylamine, and cyclopentadiene was carried out in the presence of TFA and BF3· OEt2 in DCM at −78 °C for 8 h. The DA adduct 352 then was hydrogenated over Pd(OH)2/C (5%) in absolute EtOH for 3 days, to give amino ester 353, which was transformed into tricyclic 2-thioxo-imidazolidinone 354, when treated with isothiocyanate in toluene at room temperature overnight, followed by refluxing in the presence of dry HCl in EtOH for 5 h. The yields for the last step are 52−73% (Scheme 100).171 Imidazo[1,2-a]pyridines 361 were synthesized via coppercatalyzed aerobic dehydrogenative cyclization of pyridines with O-acetyl oxime of methyl pyruvate. Reactions were carried out by heating a mixture of pyridine (3 equiv) with O-acetyl oxime in the presence of CuI (20 mol %) and Li2CO3 (20 mol %) in DMF at 95 °C for 1.5−2 h, and the corresponding imidazo[1,2α]pyridines 361 were obtained in 32−63% yields. The proposed reaction mechanism involves the oxidative addition of Cu(I) to oxime ester (355), followed by a new Cu−N bond formation via insertion of pyridine into the Cu−N bond of intermediate 356 through 1,2-positions of the pyridine ring to afford intermediate 357. By ketimine−enamine tautomerization of 357 to 358, and then Cu(I) salt removing, dihydroimidazo[1,2-a]pyridine 360 was generated through cyclic six-

R = H, Ph, R2 = H; R1−R2 = (CH)4; 32−63%.

a 1

Palacios et al.173 described the reaction of N-vinylic phosphazene 362 with ethyl glyoxalate in CHCl3 at room temperature for 0.5 h, to furnish ethyl 1-benzylimidazo[1,5a]pyridine-3-carboxylate 364 in 73% isolated yield. First, azaWittig reaction took place to form intermediate 363, which underwent cyclization leading to 364 (Scheme 102). 3-Bromoimidazo[1,2-a]pyridine-2-carboxylate derivatives 367 were synthesized from reaction of 2-aminopyridines with 184


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hydrazine hydrate in EtOH under reflux conditions, followed by treatment with Vilsmeier reagent (Scheme 104).175

Scheme 102. Synthesis of 1-Benzylimidazo[1,5-a]pyridine-3carboxylate 364

Scheme 104. Synthesis of Imidazothiadiazole-6-carboxylates 370

The synthesis of imidazo[1,5-a]quinoxalin-4-one 373 was achieved in three steps, starting with reaction of 4,5-dimethoxy2-nitroaniline with ethyl glyoxalate in MeOH at 65 °C for 17 h, followed by reaction with tosylmethyl isocyanide mediated with K2CO3 in absolute EtOH at 50 °C for 4 h under an atmosphere of argon to give ethyl 3-(4,5-dimethoxy-2-nitrophenyl)imidazole-4-carboxylate 372 in 68% yield,176a,b which was converted to 373 in 98% yield, when treated with Na2S2O4 in AcOH/water (1/1: v/v) at 105 °C for 6 h under N2 atmosphere. The last step proceeded by reduction of nitro group and then cyclization with ester group (Scheme 105).176b

ethyl bromopyruvate in 16−85% yields. Reactions were performed by MW irradiation of a solution of 2-aminopyridines and ethyl bromopyruvate (1.1 equiv) in DMSO at 80 °C for 10 min. A plausible reaction mechanism involves initial formation of imidazo[1,2-a]pyridine hydrobromide 366, via pyridinium ion 365, which underwent electrophilic bromination with bromodimethylsulfonium ion, formed by action of in situ generated HBr on DMSO. Additionally, 2-aminopyrimidine and 2-aminobenzothiazole were investigated under similar reaction conditions, leading to the corresponding fused imidazoles 368 and 369 in 30% and 48% yields, respectively (Scheme 103).174

Scheme 105. Synthesis of Imidazo[1,5-a]quinoxalin-4-one 373

Scheme 103. Synthesis of 3-Bromoimidazo[1,2-a]pyridine-2carboxylate 367a

3.12. Piperidines

The piperidine ring is a common motif found in many biologically active natural products and drugs, such as haliclonacyclamine F, incarvillatiene, manzamine A, reserpine, pseudodistomin C, corydendramine B, (S)-coniine, (S)anabasine, adalinine, and adaline. Also, they are present in pharmaceuticals, such as paroxetine, alvimopan, and morphine. Consequently, their synthesis has received much attention. NHeterocyclization of primary amines with diols and intramolecular hydroamination are among the most important routes for the synthesis of piperidines. InCl3-mediated aza-Prins reaction of N-tosyl homoallylicamines with 1.5 equiv of ethyl glyoxalate was investigated in DCM at room temperature for 1 h, and the corresponding piperidines 374 were obtaine in 20−21% yields, with excellent diastereoselectivity, due to a chairlike transition state (Scheme 106).177

a 367, R = H, 5-Cl, 5-Br, 3-Me, 5-CN, 3-BnO, 3-Me-5-Br, 4-Me-5-Br; 16−85%; 368, 30%; 369, 48%.

The reaction of 2-amino-1,3,4-thiadiazoles with ethyl bromopyruvate was developed to prepare imidazothiadiazole6-carboxylates 370. Reactions were conducted in dry EtOH under reflux conditions, for 6 h, and gave 370 in 35−48% yields, which were converted to [1,3,4]thiadiazole[2′,3′:2,3]imidazo[4,5-d]pyridazin-8(7H)-ones 371, when reacted with 185


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Scheme 106. Synthesis of 4-Chloropiperidines 374 via AzaPrins Reaction

Scheme 108. Synthesis of Ethyl 6-Oxopiperidin-2carboxylates 380a

a

Ar = XC6H4 (X = 4-Br, 4-Me, 4-MeO, 3-NO2, 4-CO2Et); 26−45%.

3.13. Tetrahydro- and Dihydropyridines

Tetrahydro- and dihydropyridines play important roles in medicinal chemistry, such as MPPP, a synthetic opioid drug with effects similar to those of morphine, and nifedipine and amlodipine as calcium channel blockers. They are also found in natural products, such as haouamine A and B, and compounds containing tetrahydro- and dihydropyridine structural motifs exhibit a broad range of biological activities. 2-Acetyl-1,4,5,6tetrahydropyridine was used as bread and rice flavor component. Hantzsch synthesis and aza-DA reaction are frequently used for the construction of dihydropyridines and tetrahydropyridines, respectively. Ethyl (2S,3S)-3-formyl-1-(4-methoxyphenyl)-1,2,3,4-tetrahydropyridine-2-carboxylate 383 was synthesized by reaction of α-imino glyoxalate with hemiacetal of glutaraldehyde (50% in water, 2 equiv) in the presence of organocatalyst VIII-1 (10 mol %) and NaHCO3 (10 mol %) in DMSO at room temperature for 4 h. The reaction proceeded by enamine (381) formation from glutaraldehyde and pyrrolidine moiety of VIII1 followed by nucleophilic addition to imine to produce intermediate 382, which was transformed into the corresponding THP-2-carboxylate 383 by cyclization and hydrolysis of iminium ion in 56% yield with >95:5 diastereoselectivity and 98% ee (Scheme 109).179 The synthesis of similar tetrahydropyridine-2-carboxylates 387 was reported by Lavilla et al.180 by treatment of 1-methyl1,4-dihydropyridine-3-carboxylates 384 with amines (2.2 equiv) and ethyl glyoxalate (1.2 equiv) in dry CH3CN using Sc(OTf)3

The synthesis of 4,6-bis(1H-indole-3-yl)-piperidine-2-carboxylates 378 was developed by Zhong et al.178 Treatment of chiral phosphoric acid V-3 (10 mol %) with a solution of 3vinylindole derivatives 375 and glyoxalate imine in DCM at room temperature for 1 h afforded 378 in 21−64% yields, with 75−99% ee. Transformation was initiated by nucleophilic addition of 3-vinylindole 375 via vinyl moiety to the glyoxalate imine to give intermediate 376, which underwent nucleophilic addition with a second molecule of 3-vinylindole 375 leading to intermediate 377. Intramolecular ring closure of 377 resulted in the formation of 378 (Scheme 107). Scheme 107. Synthesis of 4,6-Bis(1H-indole-3-yl)piperidine-2-carboxylates 378a

Scheme 109. Synthesis of Tetrahydropyridine-2-carboxylate 383

a R = H, 6-F, 5-Br, 7-Me, 5-MeO, 5-Br-7-Me; Ar = 4-XC6H4 (X = H, Br, MeO), 3,5-Me2C6H3; 21−64%, 75−99% ee.

Ethyl 6-oxopiperidin-2-carboxylates 380 were prepared by reaction of ethyl glyoxalate with substituted anilines (1 equiv) and 6-methyl-3,4-dihydro-2H-pyran-2-one 379 (1 equiv) in the presence of Sc(OTf)3 (20 mol %) and 4 Å MS in CH3CN at room temperature, followed by recyclization using SOCl2 in pyridine, and then epimerization using TFA, in 26−45% yields (Scheme 108).72 For the reaction mechanism, see Scheme 23. 186


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Scheme 110. Synthesis of 3-Formyltetrahydropyridine-2-carboxylates 387a

a

387, EWG = CO2Me, CN; R = n-Bu, i-Pr, Bn, 3-MeOBn, 4-MeOBn; 21−40%; 389, EWG = CO2Me, CN; R = n-Bu; 37−41%.

(20 mol %) as a catalyst and heating at 60 °C for 3 days. Reaction mechanism involves the nucleophilic addition of DHP 384 to the in situ generated glyoxalate imine to form iminium ion 385, which underwent hydrolysis to amino aldehyde 386 with water molecule, liberated from condensation of ethyl glyoxalate with amine. Amino aldehyde 386 was converted to 3formyltetrahydropyridine-2-carboxylates 387 by conjugate addition (route blue) followed by removal of a methyl amine molecule (route red). When reactions were carried out using 2.2 equiv of amine and 2.1 equiv of ethyl glyoxalate in dry CH3CN at room temperature in the presence of 4 Å MS, for removal of generated water molecule, octahydropyrido[2,3d]pyrimidine-2,4-dicarboxylate 389 was obtained in 37−41% yields, via addition of another amine molecule to iminium ion 385, followed by cyclocondensation of formed diamine 388 with another molecule of ethyl glyoxalate (Scheme 110). The synthesis of tetrahydro-2-pyridone scaffolds 392 was reported by Rutjes et al.181 via ring-closing metathesis (RCM) of ethyl 2-(pent-4-enoyl)aminoacrylates 391 using secondgeneration Grubbs’ catalyst IX-1. Ethyl 2-(pent-4-enoyl)aminoacrylates 391 were prepared by reaction of pent-4enamides 390 with ethyl pyruvate (2 equiv) in the presence of p-TsOH (10 mol %) and hydroquinone (10 mol %) in toluene with azeotropic removal of water using Dean−Stark apparatus. RCM reactions were carried out by heating a solution of ethyl 2-(pent-4-enoyl)aminoacrylates 391 in the presence of IX-1 (5 mol %) in toluene at 80 °C for 0.5−2 h to give the corresponding tetrahydro-2-pyridones 392 in 38−91% yields (Scheme 111). RCM reaction of (2R,3S)-diethyl 2-allylamino-3-vinylsuccinate 394 was developed for the synthesis of (2R,3S)-diethyl 1(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine-2,3-dicarboxylate 395 using Grubbs II generation catalyst (0.05−0.1 equiv) in dry DCM at room temperature overnight in 92% yield. 2Allylamino-3-vinylsuccinate 394 was prepared in two steps, by reaction of ethyl glyoxalate with equimolar amount of pmethoxyaniline in EtOH at room temperature for 0.5 h, followed by addition of E-ethyl 4-bromocrotonate (3 equiv) and In powder (2 equiv) and further stirring at 30 °C for 6 h to obtain N-aryl α-amino ester 393 in 80% yield, which was transformed to 394 by allylation using 6 equiv of allyl bromide in the presence of K2CO3 (3 equiv) and NaI (0.1 equiv) in CH3CN under reflux conditions for 24 h in 50% yield (Scheme 112).182 Chou and Hung183 reported the aza-DA reaction of glyoxalate imines with sulfur-substituted dienes leading to

Scheme 111. Synthesis of Tetrahydro-2-pyridones 392 by RCMa

R = H, Me, Et, OBn; R2 = H, Me, OBn; R1−R2 = (CH)4; 38−91% (for last step). a 1

Scheme 112. Synthesis of (2R,3S)-Diethyl 1-(4Methoxyphenyl)-1,2,3,6-tetrahydropyridine-2,3dicarboxylate 395

tetrahydropyridine-2-carboxylates 396. Reactions were performed by in situ generation of glyoxalate imine from reaction of ethyl glyoxalate with an amine hydrochloride in the presence of sulfur-substituted diene in DMF at room temperature for 24 h, to afford the corresponding tetrahydropyridine-2-carbopxylates 396 in 43−93% yields (Scheme 113). A similar three187


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with amino acrylate led to the formation of DHP 404 via THP 403 as reaction intermediate. The structures of obtained products are indicated in Scheme 115. Similarly, inverse electron demand aza-DA reaction of fluoroalkyl-substituted azadienes 405, in situ derived from ethyl glyoxalate by aza-Wittig reaction, with N-cyclohex-1-enyl and N- cyclopent-1-enyl pyrrolidines was reported. Reaction of trifluoromethyl-substituted azadiene 405 with N-cyclohex-1enyl pyrrolidines in CHCl3 at room temperature gave cycloadduct 406 (n = 2, R = F) in 80% yield in a regio- and stereoselective cycloaddition fashion, while reaction in toluene under reflux conditions afforded tetrahydroisoquinoline 407 in 43% yield through 406 by losing a pyrrolidine and then oxidation. When perfluoroethyl and perfluoroheptyl azadienes 405 were used in aza-DA reaction with N-cyclohex-1-enyl and N-cyclopent-1-enyl pyrrolidines in CHCl3, pyridines 409 were obtained in 42−70% yields. In the proposed reaction mechanism, first formed cycloadduct 406 underwent elimination of pyrrolidine with subsequent 1,5-H shift and then elimination of HF to produce intermediate 408, which transformed into corresponding pyridines 409 by enamine− imine tautomerization (Scheme 116).189 Hantzsch dihydropyridine (DHP) synthesis was developed for the preparation of symmetrical and unsymmetrical DHPs 410 bearing ethoxycarbonyl substituent on C-4 position. Reactions were carried out either by stirring a mixture of βdicarbonyl compound, amine (0.5 equiv), and ethyl glyoxalate (0.5 equiv) in the presence of montmorillonite-K10 at room temperature for 4−18 h, in the case of symmetrical DHPs, or by treating of a β-dicarbonyl compound with p-anisidine (1 equiv) in the presence of montmorrilonite-K10 for 6 h, then by addition of another β-dicarbonyl compound (1 equiv) and ethyl glyoxalate (1 equiv) and stirring for overnight, in the case of unsymmetrical DHPs. DHPs 410 were obtained in 51−90% yields (Scheme 117).190 In another report, Reddy et al.191 reported the Hantzsch DHPs synthesis using MCR of 2-methoxyaniline, ethyl glyoxalate (1.1 equiv), and ethyl 3,3-diethoxypropionate (2.5 equiv) and montmorillonite K10 as a catalyst in water at 90 °C for 10 h, to afford triethyl 1-(2-methoxyphenyl)-1,4-dihydropyridine-3,4,5-tricarboxylate 411 in 69% yield (Scheme 118). Balalaie et al.192 reported the synthesis of unsymmetrical polysubstituted 1,4-DHPs 412 by three-component reaction of primary amines (1.3 equiv), dialkyl acetylenedicarboxylates (DAAD) (1.3 equiv), and methyl (arylmethylidene)pyruvates in the presence of ZnCl2 (40 mol %) in DCE under reflux conditions. Reactions were completed in 8−12 h and gave the corresponding 1,4-DHPs 412 in 42−87% yields. The proposed reaction mechanism involves the Michael addition of in situ generated enamine from reaction of amine with DAAD, to the methylidene pyruvate, followed by cyclization of regenerated enamine with ketone through N atom and then removal of a molecule of water (Scheme 119). Synthesis of highly substituted 1,4-DHPs 416 and fused bicyclic THPs 417 was developed by Sc(OTf)3-catalyzed threecomponent reaction of arylamines, β,γ-unsaturated α-oxoesters, and β-dicarbonyl compounds. Reactions were conducted by refluxing a mixture of arylamines, β,γ-unsaturated α-oxoesters (1.2 equiv), and β-dicarbonyl compounds (2 equiv) in the presence of Sc(OTf)3 (10 mol %) and 1,10-phenanthroline (12 mol %) under Ar atmosphere in DCM for 14−72 h. Reactions proceeded via aza-DA reaction between in situ formed 1azadiene intermediate 414 and either enol or enamino ester of

Scheme 113. Synthesis of Tetrahydropyridine-2-carboxylates 396 by Aza-DA Reactiona

a 1

R = H, SPh; R2 = Me, Et, Bn, Ph; 43−93%.

component aza-DA reaction between benzylamine hydrochloride, ethyl glyoxalate (1.4 equiv), and various dienes (2 equiv) in DMF at room temperature under an atmosphere of argon was reported, in which corresponding THPs were obtained in 21−89% yields during 15−48 h.184 Also, aza-DA reaction of methyl glyoxalate with (S)-(−)-1-phenylethylamine and cyclopentadiene was developed in a multigram scale in the presence of TFA and BF3·OEt2 in DCM, yielding the single major exo-isomer in 56% yield.185 The solid-phase aza-DA reaction of in situ generated glyoxalate imines with dienes was also reported using Yb(OTf)3 as catalyst.186 Whiting et al.187 investigated the asymmetric aza-DA reaction between Danishefsky’s diene and N-p-methoxyphenyl imine, derived from methyl glyoxalate and p-methoxyaniline, using Lewis acids in the presence of chiral bis-oxazolidine VII-2 and diamine ligands X-1 under various conditions, which gave tetrahydropyridine-4-one 397 after hydrolysis. Reaction conditions are indicated in Scheme 114. Scheme 114. Synthesis of Tetrahydropyridine-4-one 397 via Aza-DA Reactiona

a Conditions (Lewis acid, ligand, additive, solvent) = MgI2, X-1, 2,6lutidine, CH3CN; 64%, 97% ee; Yb(OTf)3, X-1, 2,6-lutidine, toluene; 60%, 87% ee; Cu(OTf)2, X-1, none, CH3CN, 58%, 86% ee; FeCl3, VII-2, 4 Å MS, DCM, 67%, 92% ee.

Palacios et al.188 reported the preparation of 2-azadienes 399 by aza-Wittig reaction of N-vinylic phosphazenes 398 with ethyl glyoxalate and their inverse electron demand DA reaction with alkenes to afford THP or DHP derivatives. Reactions were carried out by in situ formation of 2-azadienes 399 from reaction of phosphazenes 398 with ethyl glyoxalate (1 equiv) in CHCl3 at room temperature for 0.5−6 h, followed by addition of an equimolar amount of an alkene and stirring at room temperature for 2−88 h. All reactions were conducted under N2 atmosphere. Reaction with E-cyclooctene led to corresponding THP-carboxylates 400 in 78−87% yields, with 1:1 diastereoselectivity. When cyclic enamines were used as dienophile component, THPs 401 were formed in 68% yield, which converted to pyridines 402 by removing an amine molecule and then aromatization, when heated at 80 °C for 48 h. Reaction 188


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Scheme 115. Synthesis of THPs 400 and DHP 404 by Inverse Electron Demand DA Reactiona

a 1

R , R3 = H, CO2Me; R2 = H, CO2Me, CO2Et; R4 = (CH2)5, O(CH2)2; n = 1, 2.

Scheme 116. Synthesis of Perfluoroalkyl-Substituted Pyridines 407 and 409 via Inverse Electron Demand Aza-DA Reactiona

Scheme 118. Synthesis of Triethyl 1-(2-Methoxyphenyl)-1,4dihydropyridine-3,4,5-tricarboxylate 411

Scheme 119. Synthesis of Unsymmetrical Polysubstituted 1,4-DHPs 412a

a 1

R = Me, Et; R2 = allyl, Bn, 4-XC6H4 (X = H, Br, MeO); Ar = 4XC6H4 (X = Cl, Me, MeO); 42−87%.

a

β-dicarbonyl compounds led to the corresponding 1,4-DHP-2carboxylates 416 in 63−95% yields. When 2-substituted βdicarbonyl compounds such as methyl 2-oxocyclohexanecarboxylate and methyl 2-oxocyclopentanecarboxylate were used, bicyclic ring fused THPs 417 were obtained in 51−66% yields, with 5.3/1−19/1 dr (Scheme 120).193 A similar approach to synthesize 1,4-DHPs 418 was developed by three-component reaction of arylamines, β,γunsaturated α-oxoesters, and cyclic ketones using YCl3 (10 mol %) and chiral silver phosphate V-4 (5 mol %) in toluene at room temperature. Reactions were performed via inverse electron demand DA reaction to afford the corresponding 1,4-DHPs 418 in 68−90% yields, with 86−96% ee (Scheme 121).194

n = 1, 2; R = F, CF3, C6F13.

Scheme 117. Synthesis of DHPs 410 by Hantzsch Reactiona

a

Symmetrical DHPs: R1 = R2 = Me, Ph, OMe, OEt, Oi-Pr, Ot-Bu, OBn; R3 = XC6H4 (X = H, 3-Cl, 4-Cl, 4-Me, 4-MeO, 3-CF3), 3,5Me2C6H3; 51−90%. Unsymmetrical DHPs: R1 = Me, Ph; R2 = Me, OMe, OEt, Oi-Pr, Ot-Bu; R3 = 4-MeOC6H4; 69−85%.

3.14. Pyridines

The synthesis of pyridines has attracted much attention, because they constitute skeletal moieties of many biologically active compounds and natural products, such as diploclidine,

β-dicarbonyl compounds 413, followed by elimination of a molecule of water or an amine from intermediate 415. Simple 189


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Scheme 120. Synthesis of Highly Substituted 1,4-DHPs 416 and Fused Bicyclic THPs 417a

R = Me, Et, Bn, 4-NO2Bn; R2 = Me, Ph; R3 = Me, OMe, OEt, Ot-Bu; Ar1 = 4-XC6H4 (X = H, Cl, Br, Me, MeO), 2,6-Cl2C6H3, β-Styryl; Ar2 = XC6H4 (X = H, 2-Cl, 3-Cl, 4-Cl, 4-Br, 2-I, 4-MeO), 3,4-(MeO)2C6H3; n = 1, 2; X = OH, Ar2NH; 416, 63−95%; 417, 51−66%, dr = 5.3/1−19/1. a 1

Scheme 122. Synthesis of Polyfunctional Pyridines 419a

Scheme 121. Synthesis of 1,4-DHPs 418 via Inverse Electron Demand DA Reactiona

a 1 R = Me, Ph, CF3; R2 = OMe, OEt, NHPh, N(CH2)2O; R3 = Me, XC6H4 (X = H, 2-NO2, 4-MeO); R4 = Me, Et; 47−92%.

Scheme 123. Synthesis of 2-Aminopyridine-4-carboxylates 420 via Guareschi Condensationa

a

R = Me, Et, Bn, 4-NO2Bn; Ar1 = 4-XC6H4 (X = H, Cl, Br, Me, MeO, NO2); Ar2 = 4-XC6H4 (H, 4-Cl, 4-Me, 4-MeO); X = CH2, S; 68−90%, 86−96% ee. a

420a, X = NH, R1 = NO2, R2 = Ph; 66%; 420b, X = O, R1 = CN, R2 = Me; 66%.

streptonigrin, lavendamycine, trigonelline, arecoline, niacin, nicotine, nornicotine, anabasine, actinidine, etc. Moreover, they have many applications in supramolecular chemistry. Oxidative aromatization of 1,4-DHPs, multicomponent reaction of aldehydes with malononitrile or acetophenone derivatives in the presence of nitrogen source, reaction of alkynones with βdicarbonyl compounds in the presence of NH4OAc, [3 + 3]type condensation of O-acetyl ketoximes and α,β-unsaturated aldehydes, and Bohlmann−Rahtz pyridine synthesis are among the most used routes to synthesize pyridine derivatives. Polyfunctional pyridines 419 were synthesized by oxidative multicomponent reaction of β,γ-unsaturated α-oxoesters and βketoesters or amides (1 equiv) and NH4OAc (2 equiv) in the presence of activated carbon (50% w) and 4 Å MS in AcOH/ toluene (1:4 v:v) under heating conditions and oxygen atmosphere. Pyridines 419 were obtained in 47−92% yields (Scheme 122).195a A similar procedure was also used by the same group for the synthesis of polyfunctional pyridines.195b,c Ethyl 2-amino-3-nitro-6-phenylpyridine-4-carboxylate 420a was synthesized via Guareschi condensation of nitroacetamidine (1.2 equiv) with ethyl benzoylpyruvate in EtOH under reflux conditions for 20 h, in 66% yield.196 Also, Guareschi− Thorpe reaction was developed to prepare 3-cyano-2-hydroxy6-methylisonicotinates 420b by reaction of cyanoacetamide with acetopyruvate (1 equiv) in the presence of Et2NH in EtOH at 60 °C (Scheme 123).197

The synthesis of ethyl 4-phenylpyridine-2-carboxylate 426 was reported by condensation of O-acetyl oxime of ethyl pyruvate with cinnamaldehyde (1.5 equiv) in the presence of CuI (20 mol %) and i-Pr2NH (2 equiv) in DMSO at 60 °C for 16 h in 52% yield. The proposed reaction mechanism involves the sequential single electron reduction of N−O bond of oxime using Cu(I) to produce iminyl-Cu(II) 421, which tautomerized to corresponding Cu(II)-enamide 422. The 422 attacked in situ generated iminium salt 423 from reaction of cinnamaldehyde with i-Pr2NH, and then protonated to regenerate iminium salt 424. DHP 425 was produced by deaminative cyclization of 424, which converted to pyridine 426 by oxidation using in situ formed Cu(II) salt (Scheme 124).198 Inverse electron demand aza-DA reaction of 1-azadiene 427 with electron-rich dienophiles to afford pyridines 429 was reported by Palacios et al.199 1-Azadiene 427 was synthesized by condensation of (E)-4-p-nitrophenyl-2-oxo-3-butenoate with (S)-p-toluensufinynimide (1 equiv) in the presence of Ti(OEt)4 (2 equiv) in THF under refluxed conditions for 2 h, and then subjected to aza-DA reaction with electro-rich dienophiles such as enolethers and enamines in DCM under reflux conditions overnight to afford the corresponding THPs 428, which converted to the corresponding pyridines 429 by elimination of sulfinyl and amine or alkoxy moieties on the resulting THPs 428 in 71−95% yields (Scheme 125). Also, a similar approach 190


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Scheme 124. Synthesis of 4-Phenylpyridine-2-carboxylate 426

Scheme 126. Synthesis of Pyridine 433 and DHP 435 via Aza-DA Reaction

was developed by Boger et al.200 leading to N-sulfinyl-THP-2carboxylates in 37−85% yields under various conditions. Scheme 125. Synthesis of Pyridine 429 via Inverse Electron Demand Aza-DA Reactiona

primary amines (1.1 equiv) in DCM at 20 °C for 3−96 h, pyridinium salt derivatives 438 were obtained in 85−96% yields. Reaction with ammonium acetate was performed in EtOH under reflux conditions for 4−36 h, which gave the corresponding pyridines 437 in 88−92% yields (Scheme 127). Scheme 127. Synthesis of Pyridinium Salts 438a

Ar = 4-NO2C6H4; X = (CH2)4N, R1 = R3 = H, R2 = H, CO2Et, R1− R2 = (CH2)4; 71−84%; X = OEt, R1 = R2 = R3 = H; 75%; X−R3 = O− (CH2)2, R1 = R2 = H; 95%. a

a 1 R = Ph, t-Bu; R2 = Me, Et, i-Pr, Bn, 4-XC6H4 (X = H, Cl, Me); 85− 96%.

Also, aza-DA reaction of 1-azadiene 431 with N-phenylmaleimide was performed in refluxing xylene under N2 atmosphere for 72 h, to produce pyridine 433 in 29% yield. Tetrahydropyridine 432 was proposed as a reaction intermediate, which was converted to pyridine 433 by removing a dimethylamine molecule and followed by aromatization. Reaction of 1-azadiene 431 with bromomaleic anhydride in THF under N2 atmosphere at room temperature for 36 h afforded the corresponding DHP 435 in 98% yield via [4 + 2] cycloaddition reaction to give 434 followed by losing a HBr molecule. 1-Azadiene 431 was prepared by Wittig reaction of phosphorane 430 with ethyl glyoxalate in DMF at room temperature for 1 h in 62% yield (Scheme 126).201 Katritzky et al.202 described the synthesis of 2-(ethoxycarbonyl)-4-phenylpyrylium salts 436 from reaction of α,βunsaturated ketones with ethyl pyruvate in the presence of BF3·OEt2 at 40−100 °C, and their conversion to corresponding pyridinium salts 438. By treatment of a pyrylium salt 436 with a

3.15. Fused Pyridines and Naphthyridines

Naphthyridine derivatives represent an important class of heterocycles as these ring systems occur in various natural products, especially in alkaloids, such as ascididemine, amphimedine, cystoditins, and meridine, and also in synthetic compounds with a wide range of biological activities. Moreover, fused pyridines are found in the many biologically active compounds and pharmaceuticals, such as cartazolate, etazolate, ICI-190,622, tracazolate, and L-745,870. Therefore, the synthesis of these heterocycles is of interest in medicinal and synthetic organic chemistry. Friedländer synthesis, [5 + 1] annulation of 3-ethynyl-2-aminopyridines with an aldehyde, and cyclocondensation of 2-aminoheterocycles with β-dicarbonyl compounds are mostly used for the synthesis of fused pyridine and naphthyridine derivatives. Lewis acid-catalyzed aza-DA reaction of 1,4-DHPs 439, 1,2DHP 440a, and dihydroquinolines 440b with in situ generated 191


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Scheme 128. Synthesis of Naphthyridines 441 and 442 via Aza-DA Reactiona

a

441, R1 = Me, Bn; R2 = CN, COMe, CO2Me, CONH2; R3 = H, CN; 63−86%, a:b = 1:2−2:1; 442b, R4 = H; 37%; 442, R4 = (CH)4; 63%, a:b = 4:1.

imines from reaction of ethyl glyoxalate with p-toluidine was reported. Reactions were carried out by addition of 4 Å MS and Lewis acid (InCl3 or Sc(OTf)3) (20 mol %) to a solution of an equimolar amount of ethyl glyoxalate and p-toluidine in dry CH3CN, followed by addition of DHPs 439 (1 equiv) and stirring under N2 atmosphere at room temperature overnight, and gave corresponding naphthyridines 441 in 63−86% yields, with 1:2−2:1 diastereoselectivity. Reaction with 1,2-DHP 440a led to the formation of naphthyridine 442b in 37% yield, as a single diastereoisomer, while reaction with 440b afforded the corresponding naphthyridine 442 in 63% yield, as a mixture of two diastereoisomers 442a and 442b in a ratio of 4:1 (Scheme 128).203 Also, a similar methodology was reported using different substituted anilines,204a and using Yb(OTf)3 as a Lewis acid catalyst.204b Moreover, unsaturated lactams 443 were reacted with ethyl glyoxalate and p-toluidine in the presence 4 Å MS and Sc(OTf)3 in CH3CN at room temperature for 48 h to provide the corresponding 1,6-naphthyridine-2-ones 445 in 43−61% yields, with 4:3−8:5 dr, via Povarov reaction. Also, sevenmembered unsaturated lactam worked well under similar reaction conditions. When pyrrolinone 444 possessing an exo double bond was treated with ethyl glyoxalate and p-toluidine under similar reaction conditions, the corresponding spiroPovarov adduct, tetrahydroquinoline derivative 446, was obtained in 60% yield with 1:1 dr (Scheme 129).205 Aza-DA reaction of ethyl glyoxalate derived imine of 3aminopyridine 447 with various olefins was developed by Palacios et al.,206 which afforded [4 + 2], [2 + 2], and/or [2 + 2 + 2] cycloadducts depending on olefins. Reactions were carried out by in situ generation of glyoxalate imine 447 by reaction of an equimolar amount of 3-aminopyridine and ethyl glyoxalate in CHCl3, followed by addition of an olefin (1 equiv) and BF3· Et2O (1 or 1.2 equiv) and stirring at room temperature for 3− 48 h. Reactions with styrene and indene afforded the corresponding 1,2,3,4-tetrahydro-1,5-naphthyridines 448 and 449 via regioselective [4 + 2] cycloaddition reaction in 60% and 68% isolated yields, respectively, while reactions with strained olefins, norbornene, and dicyclopentadiene led to the formation of the corresponding tetrahydronaphthyridines 450 and 452 and fused azetidines 451 and 453 in 55−65% and 14−15% isolated yields via [4 + 2] and [2 + 2] cycloaddition reactions, respectively. When imine 447 was reacted with norbornadiene, in addition to corresponding [4 + 2] (454) and [2 + 2] (455)

Scheme 129. Synthesis of 1,6-Naphthyridine-2-ones 445 via Povarov Reactiona

a n = 1; R1 = Bn, 4-MeC6H4; 43−61%, 4/3−8/5 dr; n = 2; R1 = H; 35%, 3/2 dr.

cycloadducts, ethyl 8-(pyridin-3-yl)-8-azatetracyclo[4.3.0.02,4.03,7]nonane-9-carboxylate 456 was formed via [2 + 2 + 2] cycloaddition reaction in 16% yield (Scheme 130). Tetrahydro-3-hydroxy-1,7- and 1,5-naphthyridin-2-ones 459 and 460 were prepared by reductive cyclization of ethyl 5-nitro4-pyridylpyruvate 457 and ethyl 3-nitro-2-pyridylpyruvate 458, respectively. Reductive cyclization was applied using H2 in EtOH on PtO2 catalyst for 2 h, and gave tetrahydronaphthyridines 459 or 460 in 69−75% yields, which could be converted to 1,5- or 1,7-naphthyridin-2(1H)-ones 461 or 462 by heating with p-TSCl in pyridine at 150 °C for 4 h, in 79% or 83% yields, respectively (Scheme 131).207 Thummel et al.208 described the synthesis of 4-carboxy-1,8naphthyridines 466−468 via Pfitzinger-type condensation of [2-(pivaloylamino)pyrid-3-yl]oxoacetic acid ethyl ester 463 with 2-acetylazaaromatic compounds using KOH in refluxing EtOH followed by acidification using AcOH. Hydrolysis of pivaloylamino group in 463 afforded 2-aminopyridine ethyl glyoxalate derivative 464, which underwent Claisen-type condensation with the enolate anion of 2-acetylazaaromatics to form 465. Cyclodehydration of 12 provided the corresponding 1,8-naphthyridines 466 in 53−94% yields. 4-Carboxybenzo[b]-1,8-naphthyridine 467 and bis-4-carboxy-1,8-naphthyridines 468 were also prepared using N-protected 2-aminoquinoline ethyl glyoxalate and diacetyl azaaromatic compounds 192


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Scheme 130. Synthesis of Tetrahydro-1,5-naphthyridines 448−450, 452, and 454 via Aza-DA Reactiona

a

Olefin = styrene, indene, norbornene, dicyclopentadiene, norbornadiene.

Scheme 131. Synthesis of 1,5- or 1,7-Naphthyridin-2(1H)-ones 461 and 462

Scheme 132. Synthesis of 4-Carboxy-1,8-naphthyridines 466−468 via Pfitzinger-type Condensationa

a

466, N-Het1 = pyridin-2-yl, 4-carboxypyridin-2-yl, pyrazines-2-yl, 2-pyrrolyl, 1,10-phenanthroline-2-yl; 53−94%; 467, 65%; 468, N-Het2 = pyridine (2,6), 4-carboxypyridin (2,6), pyrimidine (4,6), 69−98%.

under similar conditions in 65% and 69−98% yields, respectively (Scheme 132). Volochnyuk et al.209 described the synthesis of a library of fused pyridine-4-carboxylic acids 469, such as pyrazolo[3,4b]pyridines, isoxazolo[5,4-b]pyridines, furo[2,3-b]pyridines, thieno[2,3-b]pyridines, and pyrido[2,3-d]pyrimidines, by Combes-type reaction of acyl pyruvates and electron-rich amino heterocycles, followed by hydrolysis of the ester moiety. Reactions were carried out either by refluxing a mixture of amino heterocycle and acyl pyruvate (1 equiv) in AcOH for 2− 4 h or by heating a mixture of amino heterocycle and acyl pyruvate in the presence of TMSCl (8 equiv) in DMF in a

sealed tube on the water bath for 4−8 h. Hydrolysis of esters was performed by refluxing a solution of pyridine-4-carboxylate in the presence of KOH in i-PrOH for 2−5 h (Scheme 133). Also, the reaction of electron-rich amino heterocycles with 3methoxalylchromone 470, prepared from reaction of 3(dimethylamino)-1-(2-hydroxyphenyl)propen-1-one with methyl 2-chloro-2-oxoacetate in the presence of pyridine, was developed to synthesize fused pyridine-2-carboxylates 473. Similarly, reactions were carried out either in refluxing AcOH or by heating in the presence of TMSCl in DMF at 80−100 °C and afforded the corresponding fused pyridines 473 in 44−89% yields. The proposed reaction mechanism involves conjugate 193


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Scheme 133. Synthesis of Fused Pyridine-4-carboxylic Acids 469a

Scheme 135. Synthesis of Heteroannulated Chromeno[3,4c]pyridin-5-ones 475a

a

Het−NH2 = 2-aminofuranes, 2-aminothiophenes, 5-aminopyrazoles, 5-aminoisoxazoles, and 6-aminotetrahydropyrimidine-2,4-diones; for full details, see ref 209.

addition of carbon atom of aminoheterocycle to the double bond of 470 to give intermediate 471, which underwent pyrone ring opening to intermediate 472. By intramolecular addition of the amino group to the carbonyl group followed by elimination of water molecule, pyridines 473 were produced (Scheme 134).210 Methyl 2-(4-chloro-2-oxo-2H-chromen-3-yl)-2-oxoacetate 474 was prepared in three steps starting from 4-hydroxycoumarin, and then subjected in reaction with electron-rich aminoheterocycles, N-substituted 2-amino-4-cyanopyrrole, and 4-amino-1,3-disubstituted-1H-imidazole-2(3H)-thione, to obtain the corresponding fused pyridines 475. Reactions were performed by heating a solution of 474 and aminoheterocycles (1.1 equiv) in dry DMF in the presence of TMSCl at 100−120 °C within 2−12 h under an atmosphere of argon, and heteroannulated chromeno[3,4-c]pyridin-5-ones 475 were produced in 38−82% yields, with excellent regioselectivity (Scheme 135).211 By treatment of 2-aminopyrroles with methyl 1H-indol-3-yl2-oxoacetates 476 (1 equiv) in the presence of AlCl3 (0.5 equiv) in dry MeOH at 70 °C, dihydro-6-oxo-benzo[f ]pyrrolo[2,3-b][1,7]naphthyridines 480 were obtained in 40−44% yields. In the proposed reaction mechanism, the carbon atom of the enamine moiety attached to the carbonyl group of ketoester 476 to form intermediate 477, which was converted to intermediate 478 by nucleophilic addition of amine to carbon-2 of indole and removal of a molecule of water. Aminal intermediate 478 underwent aromatization by indole cleavage and then subsequent lactam formation by attack of the amino group to the ester group 479 (Scheme 136).212

a 1

R = t-Bu, c-Pent, 2-Me-c-Hex, 4-MeOBn, 4-MeC6H4; R2 = Et, Ph; 38−82%.

Scheme 136. Synthesis of Dihydro-6-oxobenzo[f ]pyrrolo[2,3-b][1,7]naphthyridines 480a

a

R = t-Bu, c-Hex; 40−44%.

Scheme 134. Synthesis of Fused Pyridine-2-carboxylates 473a

a

Het−NH2 = 2-aminopyroles, 5-aminopyrazole, 5-aminopyrazolin-3-ones, 5-aminoimidazoline-2-ones, 4-aminothiazoles, 6-aminotetrahydropyrimidine-2,4-diones. 194


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3.16. Quinolines

Scheme 138. Synthesis of 3-Hydroxy-3,4-dihydroquinolin2(1H)-ones 484a

The quinoline skeleton is a common structural motif in a broad spectrum of biologically active compounds, including many natural products, such as quinine, quinidine, cinchonine, and cinchonidine. They are present in the structure of many pharmaceuticals, such as chloroquine, amodiaquine, mefloquine, camptothecin, and saquinavir. Moreover, they have application in organic synthesis as organocatalyst. Combes, Skraup, Friedländer, Knorr, Niementowski, and Conrad− Limpach synthesis, and Doebner, Doebner−Miller, Gould− Jacobs, Pfitzinger, and Povarov reactions are used commonly for the construction of quinoline structural motifs. 3-Hydroxy-3,4-dihydroquinolin-2(1H)-ones 482 were prepared by catalytic hydrogenation of 2-nitrophenylpyruvates 481 using H2 (1 MPa) mediated by cinchona alkaloid derivative I-3 and Pt/Al2O3 in a mixture of toluene/AcOH (9/1 or 49/1) at room temperature for 2−3 h. Both ketone and nitro groups underwent hydrogenation, which then was cyclized to afford dihydroquinoline-2-ones 482 in 35−97% yields, with 68−90% ee (Scheme 137).213

a 1

R = H, 7-Cl, 8-Me; R2 = Me, CF3, CO2Et; R3 = Me, Et; 47−88%.

Scheme 139. Synthesis of Quinolin-2-carboxylates 485,486 via Friedländer Synthesis

Scheme 137. Synthesis of 3,4-Dihydroquinolin-2(1H)-ones 482a

Augustine et al.217 reported propylphosphonic anhydride (T3P)-catalyzed Pictet−Spengler reaction between ethyl glyoxalate and 3′,5′-dimethoxybiphenyl-2-amines 487 to provide ethyl 5,6-dihydrophenanthridines-6-carboxylates 488 in 86−93% yields. Reactions were performed by stirring a mixture of equimolar amounts of biphenyl-2-amine 487, ethyl glyoxalate, and T3P in EtOAc at room temperature under an atmosphere of N2 for 8 h. When reaction of 3′,5′-dimethoxy-5methylbiphenyl-2-amine 487 with ethyl glyoxalate was conducted at 65 °C under O2 atmosphere, subsequent oxidative aromatization took place, and the corresponding quinoline was obtained in 87% yields. Similar reactions were carried out using 3-(3,5-dimethoxyphenyl)-2-aminopyridines 487 (X = N) leading to 5,6-dihydrobenzo[c][1,8]naphthyridines in 82− 84% yields 488 (X = N) (Scheme 140).

a 1

R = H, 5-F, 6-F, 7-F, 5-Me, 6-Me, 8-Me, 6-MeO, 8-MeO, 8-i-PrO, 6,7-Me2; R2 = Me, Et; 35−97%, 68−90% ee.

Additionally, the synthesis of 3-hydroxy-3,4-dihydroquinolin2(1H)-ones 484 was reported by Vanelle et al.214 in two steps. First, α-oxoesters was reacted with an equimolar amount of onitrobenzyl chlorides in the presence of tetrakis(dimethylamino)ethylene (TDAE) (1.1 equiv) in DMF at −20 °C for 1 h, then at room temperature for 2 h under N2 atmosphere, leading to α-hydroxy esters 483 in 60−73% yields. Reduction of nitro group and cyclization was performed by addition of Fe powder (20 equiv) to a solution of α-hydroxy esters 483 in AcOH and heating at 110 °C for 1 h, which afforded the corresponding quinoline-2-ones 484 in 47−88% yields (Scheme 138). Friedländer quinoline synthesis was extensively reported to synthesize quinoline derivatives. In this context, Miller et al.215 conducted the reaction by heating a mixture of o-nitrobenzaldehyde with an equimolar amount of methyl pyruvate in the presence of SnCl2 (5 equiv), ZnCl2 (5 equiv), and 4 Å MS in anhydrous EtOH at 70 °C under N2 atmosphere for 3 h, and methyl quinoline-2-carboxylate 485 was obtained in 70% yield (Scheme 139a). Treatment of 4-chloro-2-trifluoroacetylaniline with ethyl pyruvate (7 equiv) in the presence of 25 mol % of potassium prolinate and three drops of AcOH in DMSO at room temperature for 9 h afforded ethyl 6-chloro-4trifluoromethylquinoline-2-carboxylate 486 in 70% yield (Scheme 139b).216

Scheme 140. Synthesis of Dihydrophenanthridines and Dihydrobenzo[c][1,8]naphthyridines 488a

a

X = CH, R1 = H, 5-Me, 5-CF3, 5-OCF3, 4-NO2, 3,5-F2; R2 = H, Me; 86−93%; X = N, R1 = 5-Me, 5-CO2Me; R2 = H; 82−84%.

195


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pyruvates (3 equiv) in the presence of 1 mol % of In(OTf)3 or α-alkyl-substituted ketoesters (2.4 equiv) in the presence of 10 mol % of In(OTf)3 in CH3CN at 80 °C for 6−30 h.224 The proposed reaction mechanism involves the condensation of arylamine with α-oxoesters leading to iminium ion 491, which underwent nucleophilic addition by Brønsted or Lewis acidsinduced generated enol of another molecule of α-ketoester to produce intermediate 492. β-Amino ketone 492 transformed into the corresponding polysubstituted 1,2-dihydroquinolines 494 by cyclization of activated ketone group with electron-rich benzene ring, followed by removing a molecule of water (intermediate 493) (Scheme 142). Also, I2 was used as the catalyst in a similar reaction in CH3CN at 50 °C.225 PMP-imine derived from allylglyoxalate was treated with 2methylpropanal and 2-pyridylthiol in the presence of Yb(OTf)3 in DCM under N2 atmosphere at room temperature that resulted in the formation of 3,4-dihydroquinoline 498 in 97% yield. In the proposed reaction mechanism, enol of 2methylpropanal attached to Yb(OTf)3-activated imine to give 495, which underwent cyclization and dehydration to give intermediate 496. By nucleophilic addition of thiol to 496, THQ 497 was formed, which was not isolable and transformed into DHQ 498 by dehydrogenation (Scheme 143).226 The synthesis of quinoline-2-carboxylates 499 was reported by Yb(OTf)3-catalyzed three-component reaction of anilines, ethyl glyoxalate, and an enolizable aldehyde. Reactions were carried out by in situ generation of glyoxalate imine from reaction of aniline with ethyl glyoxalate (1.2 equiv) in DMSO at room temperature for 1 h, followed by addition of aldehyde (1.1 equiv) and Yb(OTf)3 (1 mol %) and heating at 90 °C for 16 h under O2, leading to the corresponding quinoline-2carboxylates 499 in 34−99% yields (Scheme 144).227 A similar methodology was reported by three-component reaction of anilines with ethyl glyoxalate and enolizable αoxoesters such as methyl pyruvate and ethyl benzylpyruvate to afford quinolone-2,4-dicarboxylates 500. Reactions were conducted by stirring a mixture of aniline, ethyl glyoxalate (1.1 equiv), and α-oxoesters (1.5 equiv) in the presence of FeCl3 (5 mol %) in CH3CN at room temperature or 60 °C under air atmosphere for 30−36 h, and quinolone-2,4dicarboxylates 500 were obtained in 31−88% yields (Scheme 145).228 Also, reaction of PMP-imine of ethyl glyoxalate with pentafluoropropen-2-ol was performed in refluxing toluene, followed by addition of TFA and refluxing additional 8 h to produce 3-fluoro-4-trifluoromethylquinoline-2-carboxylate 503 in 64% yield. The proposed reaction mechanism involves the nucleophilic addition of pentafluoropropen-2-ol to imine leading to 501, followed by intramolecular Friedel−Crafts reaction to form intermediate 502, which transformed into quinoline 503 by losing water and HF molecules (Scheme 146).229 Baba et al.230 have synthesized quinolin-4-carboxylate 504 by reaction of methyl pyruvate with benzylideneaniline (1.2 equiv) in the presence of HCl (5 mol %) in DMSO under an air atmosphere at 80 °C for 6 h in 43% yield. The reaction proceeded by enolization of methyl pyruvate and nucleophilic addition to protonated imine, followed by Friedel−Crafts intramolecular cyclization and dehydration and then oxidative aromatization using air (Scheme 147). A reversal Skraup−Doebner−Von Miller quinoline synthesis was reported by Chen et al.231 in which 4-arylquinoline-2carboxylates 505 were obtained in 42−83% yields. Reactions

Tetrahydroquinolines 489 were synthesized via fourcomponent reaction of various anilines with methyl pyruvate (1 equiv) in the presence of BINOL-based phosphoric acid V-5 as catalyst (5 mol %) in toluene at room temperature for 24 h. THQs 489 were obtained in 64−93% yields, with 87−99% ee and >20:1 diastereoselectivity. Also, reaction of methyl pyruvate (2 equiv) with two different anilines (1 equiv from each aniline) was carried out under similar conditions to give corresponding THQs 489 in 52−74% yields, with 90−99% ee and >20:1 diastereoselectivity, in which anilines with electrondonating groups took part in the benzenoid ring of quinoline and another one with electron-withdrawing groups formed the anilino group at C-4 position. When a similar reaction was carried out using p-methyoxyanilines (2 equiv) with different αoxoesters, methyl pyruvate (1 equiv), and t-butyl glyoxalate (1 equiv), interestingly the corresponding pyrolin-2-one 490 was obtained in 90% yield, with 72% ee (Scheme 141).218 Scheme 141. Four-Component Synthesis of THQs 489a

a 1

R = R2 = H, 3-Cl, 4-Cl, 4-Br, 3-I, 4-I, 3-Me, 4-Me, 4-CF3, 4-MeO, 4EtO, 4-MeS, 3,5-Me2, 3-I-5-MeO, 3-Br-4-Me; 64−93%, 87−99% ee, >20:1 dr; R1 = H, 4-Me, 3,5-Me2; R2 = 3-CF3, 4-CF3, 3,5-Cl2, 2-Cl-4Me; 52−74%, 90−99% ee, >20:1 dr.

Tandem reaction of α-oxoesters with primary or secondary aromatic amines for the synthesis of polysubstituted 1,2dihydroquinolines 494 has been developed by different research groups using various catalytic systems. Ji et al.219 conducted the reaction of arylamines with pyruvates (1.5 equiv) using Brønsted acid, HNO3, in CH3CN for 8−24 h, to afford 1,2-dihydroquinolines 494 in 31−96% yields. Waldmann et al.220 described a similar reaction using 2.2 equiv of pyruvates in the presence of AuCl3 (5 mol %), AgSbF6 (15 mol %) in CH3CN at room temperature for 8 h, which gave the corresponding 1,2-dihydroquinolines 494 in 51−85% yields. Moreover, similar reactions were developed using 2.2 equiv of methyl pyruvate in the presence of Bi(OTf)3 (5 mol %) in either CH3CN or CHCl3 at room temperature or MW irradiation,221 using 5 equiv of methyl pyruvate in the presence of MgBr2 (1 equiv) and Li2CO3 (50 mol %) and heating at 60− 90 °C for 1−3 h under solvent-free conditions,222 using methyl pyruvate (1.5 equiv) in the presence of an organocatalyst, fluorous hydrazine-1,2-bis(carbothioate) (5 mol %), and NCS (5 mol %) in CH3CN at 60 °C for 8−24 h,223 and using either 196


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Scheme 142. Synthesis of Polysubstituted 1,2-Dihydroquinolines 494a

R = H, 6-Cl, 6-OH, 6-n-Bu, 6-MeO, 6-NO2, 7-Br, 8-Me, 5-Cl-6-F, 6,7-NCH−CHCH; R1−R2 = 8-CH2CH2; R2 = R3 = H; R4 = Me, Et; cond. = HNO3 (10 mol %), CH3CN, 80 °C, 8−24 h, 31−96%;219 R1 = H, 6-MeO, 8-Ac, 8-Bz; R2 = R3 = H; R4 = Me, Et; cond. = AuCl3 (5 mol %), AgSbF6 (15 mol %), CH3CN, rt, 8 h, 51−85%;220 R1 = H, 6-Br, 6-I, 6-t-Bu, 6-Ph, 6-MeO, 6-PhO, 6-Ac, 6-NO2, 6-CN, 6,7-(MeO)2, 5,8-(MeO)2, 5,7Me2, 5,6,7-(MeO)3, 6-MeO-8-Me, 8-Ac, 5,6- or 7,8-(CH)4, R2 = R3 = H; R4 = Me; cond. = Bi(OTf)3 (5 mol %), CH3CN or CHCl3, rt or MW, 3− 168 h, 0−97%;221 R1 = 6-Me, 6-MeO, 6-CN, 8-MeO, 5,6-(CH)4, R2 = R3 = H; R4 = Me; cond. = MgBr2 (1 equiv), Li2CO3 (50 mol %), solvent-free, 60−90 °C, 1−3 h, 78−96%;222 R1 = H, 6-Cl, 6-Br, 6-OH, 6-Me, 6-n-Bu, 6-MeO, 6-NO2, 8-Me, 7,8-(CH)4; R2 = R3 = H; R4 = Me, Et; cond. = fluorous hydrazine-1,2-bis(carbothioate) organocatalyst (5 mol %), NCS (5 mol %), CH3CN, 60 °C, 8−24 h, 32−94%;223 R1 = H, 6-Cl, 6-OH, 6-nBu, 6-Me, 6-MeO, 6-NO2, 7-Br, 7-Me, 8-Me, 6,7-Me2, 5,6- or 7,6-(CH)4; R1−R2 = 8-CH2CH2; R2 = H, R3 = H, n-Pr, CH2CH2Ph; R4 = Me, Et; cond. = In(OTf)3 (1 or 10 mol %), CH3CN, 80 °C, 6−30 h, 43−95%.224 a 1

Scheme 143. Synthesis of 4-(2′Pyridylthio)tetrahydroquinoline 498

Scheme 145. Synthesis of Quinolone-2,4-dicarboxylates 500a

a 1

R = 6-F, 6-Cl, 6-Br, 6-OH, 6-CN, 6-Me, 6-n-Bu, 6-c-Hex, 6-Ac, 6MeO, 6-EtO, 6,7-(MeO)2; R2 = H, Bn; R3 = Me, Et; 31−88%.

Scheme 146. Synthesis of 3-Fluoro-4trifluoromethylquinoline-2-carboxylate 503

Scheme 144. Synthesis of Quinoline-2-carboxylates 499a

a 1

R = H, 6-F, 6-Br, 6-Me, 6-MeO, 6-CO2Me, 8-MeO; R2 = H, Me, Et, n-Pr, i-Pr, Bn; 34−99%.

were carried out by refluxing a mixture of aniline and γ-aryl-β,γunsaturated α-ketoester (2 equiv) in TFA for 8−18 h. The proposed reaction mechanism involves condensation of aniline with ketone moiety of γ-aryl-β,γ-unsaturated α-ketoester to give corresponding imines, which underwent intramolecular cyclization followed by oxidative aromatization leading to the corresponding quinoline-2-carboxylates 505 (Scheme 148).

A one-pot Doebner−Von Miller quinoline synthesis was developed to synthesize ethyl pyrroloquinoline 4-carboxylates 506 through reaction of 4- or 5-aminoindoles, aldehydes, and ethyl pyruvate in refluxing ethanolic HCl. Reactions were performed by heating a mixture of an equimolar amount of methyl pyruvate and an aldehyde in ethanolic HCl at 80 °C 197


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The reaction of β,γ-unsaturated α-oxoesters with N-aryl Ptrimethylphosphazenes 86a or N-aryl P-triphenylphosphazene 86b was investigated, in which isomeric 2-quinolincarboxylates or 4-quinolinecarboxylates 512 were obtained, respectively. By treatment of β,γ-unsaturated α-oxoesters with N-aryl Ptrimethylphosphazenes 86a, N-aryl 1-azadienes 508 were obtained via aza-Wittig reaction, oxazaphosphetane intermediates 507, which converted to 2-quinoline carboxylates 508 when heated in xylene under reflux condition for 24−48 h in 79−85% yields. Reaction of β,γ-unsaturated α-oxoesters with N-aryl P-triphenylphosphazenes 86b in CHCl3 under reflux condition for 24−48 h afforded the corresponding 4quinolinecarboxylates 512 in 79−83% yields, in which corresponding 1-azadienes 511, as reaction intermediate, were in situ generated via six-membered oxazaphosphetane 510 through 1,4-addition of the phosphazenes species 86b to the β,γ-unsaturated α-oxoesters and elimination of phosphine oxide. In the next step, reactions proceeded via 6πazaelectrocyclization of azadienes 508 or 511 followed by oxidative aromatization (Scheme 150).233 Three-component Povarov reaction between ethyl glyoxalate, p-toluidine, and heterocyclic systems 513 were developed to synthesize THQ derivatives 514. Reactions were conducted by in situ generation of imine from reaction of ethyl glyoxalate and p-toluidine in the presence of 4 Å MS and Sc(OTf)3 (20 mol %) in dry CH3CN at room temperature for 5 min, followed by addition of heterocyclic olefin 513 (1 equiv) and reacting either at room temperature for 12 h, or under heating at 50 °C for 12 h, or under MW irradiation for 10 min, which afforded the corresponding THQs 514 in 42−81% yields, with 1:1−5:1 dr. Further aromatization of obtained THQs 514 to corresponding quinolines 515 was carried out using DDQ (2 equiv) in CHCl3 at room temperature for 24 h, in 55% to quantitative yields (Scheme 151a).234 Similar reactions were reported using cyclic enamides 516 in the presence of either InCl3 (20 mol %)235 or squaric acid (5 mol %) or Sc(OTf)3236 in CH3CN at room temperature to obtain the corresponding THQs 517, which could be a synthetic intermediate of martinelline 518 with biological activity (Scheme 151b). Also, 2-carboxy-4-amidotetrahydroquinolines were synthesized by the reaction of aniline derivatives with glyoxalate esters using Na2SO4 in DCM to afford N-arylimino esters, followed by reaction with enamides in the presence of a catalytic amount of BF3·Et2O at room temperature within 1 h, in 40−60% yields.237 Lin et al.238 described the synthesis of quinolin-2carboxylates 520 by treatment of alkynes (1.5 equiv) with anilines (1 equiv) and ethyl glyoxalate (1 equiv) in the presence

Scheme 147. Synthesis of Methyl Quinolin-4-carboxylate 504

Scheme 148. Synthesis of 4-Arylquinoline-2-carboxylates 505 via Reversal Skraup−Doebner−Von Miller Reactiona

a 1

R = H, 6-F, 6-Cl, 8-Cl, 6-OH, 6-Me, 6-MeO, 8-MeO, 6-NO2, 8-NO2, 7,8-Me2, 5,6-(CH)4, 7,8-(CH)4; R2 = Me, Et; Ar = 4-XC6H4 (X = H, Cl, Me, MeO, NO2); 42−83%.

under N2 atmosphere for 1 h to afford β,γ-unsaturated αketoester, followed by addition of a solution of aminoindole in EtOH dropwise and heating at 100 °C for additional 2−10 h, and the corresponding pyrroloquinoline 4-carboxylates 506 were obtained in 15−50% yields (Scheme 149).232 Scheme 149. Synthesis of Ethyl Pyrroloquinoline 4Carboxylates 506 via Doebner−Von Miller Quinoline Synthesisa

a 1

R = H, Et; R2 = Me, Ph, PMP; 15−50%.

Scheme 150. Synthesis of Isomeric 2-Quinolincarboxylates 509 or 4-Quinolinecarboxylates 512a

a 1

R = 4-NO2C6H4, CO2Et; R2 = Me, OMe; 509, 79−85%; 512, 79−83%. 198


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Scheme 151. Synthesis of THQs 514 and 517 via Povarov Reactiona

a

X = NH, Y = NH, S; X = NHBn, Y = O, S; 514, 42−81%, 1:1−5:1 dr; 515, 55% to quant.; InCl3, R1 = Et; R2 = OMe; R3 = Me; 517b, 6%; R1 = Et; OBn; R2 = Me, OMe; R3 = Me; 517, 20−45%, a/b = 1:1−2:1; squaric acid or Sc(OTf)3, COR1 = Cbz; R2 = CO2Me; R3 = Et; squaric acid, 517, 92%, a/b = 2:1; Sc(OTf)3, 517, 72%, a/b = 1:2.

tetrafluoroborate (T+BF4−) (2 equiv) in DCM at 60 °C for 18 h. In the proposed reaction mechanism, in situ generated glyoxalate iminium ion underwent cycloaddition reaction with olefin to form tetrahydroquinoline, which transformed into quinolines 521 by dehydrogenation with T+BF4−, in 36−95% yields (Scheme 153).241

of I2 (10 mol %) in CH3NO2 under air atmosphere at room temperature or reflux conditions for 12 h, in 45−83% yields. The formation of quinolin-2-carboxylates 520 could be explained by in situ generation of glyoxalates imine, followed by imino-DA reaction with alkynes to afford intermediates 519, which underwent isomerization and then oxidative aromatization with O2 in air (Scheme 152). A similar approach was

Scheme 153. FeCl3-Catalyzed Synthesis of Quinoline-2carboxylates 521a

Scheme 152. Synthesis of Quinolin-2-carboxylates 520a

a 1 R = F, Cl, Ac, Me, MeO; R2 = n-Hex, 2-naphthyl, XC6H4 (X = H, 2Cl, 4-Cl, 4-t-Bu, 4-CF3); R3 = H, Me; 36−95%.

3.17. Isoquinolines

Isoquinoline alkaloids, such as cryptostyline I, pilocereine, peyophorine, tubocurarine, condrodendrine, magnoline, glaucine, and papaverine, are known for their various biological properties, including acetylcholinesterase inhibitory effects, antiproliferative, antiviral, antiplasmodial, and antihypertensive activities. The most common routes to isoquinolines are Pomeranz−Fritsch, Bischler−Napieralski, Pictet−Gams, and Pictet−Spengler reactions. Total synthesis of Ecteinascidin 743 (ET-743) 525 and related compounds, a family of tetrahydroisoquinoline alkaloids isolated from the Caribbean tunicate Ecteinascidia turbinate242 with potent cytotoxic activity against a variety of tumor cell lines, was reported by different research groups, in which Pictet−Spengler cyclization reaction of glyoxalates was widely used for construction of tetrahydroisoquinoline moiety 522−

a 1

R = Cl, MeO, NO2; R2 = CO2Et, XC6H4 (X = H, 3-Br, 4-Me); R3 = H, CO2Et; 45−83%.

developed for the synthesis of ethyl 4-ferrocenylquinoline-2carboxylate from reaction of aniline, ethyl glyoxalate, and ferrocenylacetylene in the presence of Ce(OTf)3 (10 mol %) in refluxing toluene for 3 h, in 22% yield.239 Using ethyl acetylene carboxylate in a similar reaction in the presence of Sc(OTf)3 (10 mol %) in refluxing EtOH afforded the corresponding quinoline-2,3-dicarboxylate in 34% yield.240 Additionally, one-pot synthesis of quinoline-2-carboxylates 521 from reaction of anilines (0.2 mmol), ethyl glyoxalate (1.2 equiv), and various olefins (2 equiv) was reported using FeCl3 (10 mol %) and 2,2,6,6-tetramethylpiperidine-1-oxoammonium 199


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Scheme 154. Pictet−Spengler Cyclization Reaction, a Key Step of the Total Synthesis of ET-743 (525)

524. Reaction conditions for the Pictet−Spengler cyclization steps are illustrated in Scheme 154.243 Similar methodology was applied for the synthesis of tetrahydro-1H-oxazolo[3,4-b]isoquinoline-5-carboxylates 527 by Pellet-Rostaing et al.244 and Honda et al.245 Treatment of (R)-4-(3,4-dimethoxybenzoyl)oxazolidin-2-one 526 with methyl dimethoxyacetate (20 equiv) mediated by 20 equiv of BF3· OEt 2 in refluxing DCM for 4 h furnished 1,3-transtetrahydroisoquinoline derivative 527 in 90% yield. A similar structural scaffold was prepared by two-step reaction of (S)-4(4-methoxybenzyl)oxazolidin-2-one 526 with ethyl glyoxalate (1.1 equiv) in the presence of 1H-benzotriazole (1.1 equiv) and p-TsOH (10 mol %) in toluene under reflux condition with azeotropic removal of water using Dean−Stark apparatus for overnight, followed by treatment of the obtained product with TiCl4 in CH3CN at 60 °C for 2 days to give the corresponding tetrahydroisoquinoline 527 in 76% yield (Scheme 155). Moreover, menthyloxy carbonyl-substituted tetrahydroisoqui-

nolines were prepared via Pictet−Spengler cyclization reaction of dopamine derivatives with menthyl pyruvate246 and menthyl glyoxalate.247 Hammad and Smith248 reported the three-component reaction of homophthalic anhydride 528, ethyl glyoxalate (1.2 equiv), and an amine (1 equiv) in the presence of KAl(SO4)2· 12H2O (50 mol %) as a Lewis acid, in CH3CN at room temperature. Reactions were completed in 7−8 h and afforded 1-oxo-1,2,3,4-tetrahydroisoquinoline derivatives 529 in 40− 85% yields (Scheme 156).

Scheme 155. Synthesis of Tetrahydro-1H-oxazolo[3,4b]isoquinoline-5-carboxylates 527a

a

Scheme 156. Synthesis of 1-Oxo-1,2,3,4tetrahydroisoquinoline 529a

R = 4-MeOC6H4, 2,4-(MeO)2Bn, 40−85%.

By benzoylation of imine, derived from condensation of methyl pyruvate with benzylamine, enamide 530 was obtained in 58% yield. Photocyclization of the enamide 530 under nonoxidative conditions in MeOH gave N-benzyl-1-oxo-1,2,3,4tetrahydroisoquinoline 531 in only 10% yield (Scheme 157).249 3.18. β-Carbolines

X = CO; R1 = OMe; R2 = Me; cond. = (MeO)2CHCO2Me, BF3· OEt2, DCM, reflux, 4 h, 90%;244 X = CH2; R1 = H; R2 = Et; cond. = (1) OHCCO2Et, benzotriazole, p-TsOH, toluene, Dean−Stark, overnight, 84%; (2) TiCl4, CH3CN, 60 °C, 2 days, 76%.245 a

β-Carbolines are present in numerous natural products, such as tryptamine, norharman, harman, harmine, β-CCE, harmaline, harmalol, and harmalan, which distributed widely in various 200


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hydantoins or thiohydantoins 535, when treated with isocyanates or isothiocyanates in CH3CN in the presence of i-Pr2NEt at room temperature or 75 °C, respectively (Scheme 159).

Scheme 157. Photoinduced Synthesis of 1-Oxo-1,2,3,4tetrahydroisoquinoline 531

Scheme 159. Synthesis of Tetracyclic Hydantoins or Thiohydantoins 535a

tissues and fluids of a variety of mammals, and possess various biological activities such as hypnotic, anxiolytic, antimicrobial, anti-HIV, antiviral, antitumor, anticonvulsant, and antioxidant activities. The Pictet−Spengler condensation is commonly used to synthesize β-carbolines. He et al.250 described the synthesis of β-carbolines via Pictet−Spengler reaction of α-siloxy α,β-unsaturated esters, silyl enol ethers of α-oxoesters, with tryptamine hydrochloride. Reactions were performed either by heating a mixture of tryptamine hydrochloride, α-siloxy α,β-unsaturated esters (1 equiv), and p-TsOH·H2O (1 equiv) in EtOH at 80 °C under an atmosphere of N2 overnight or by reaction of α-siloxy α,βunsaturated esters with p-TsOH·H2O (2 equiv) in EtOH at 80 °C under N2 atmosphere for 6 h, followed by addition of tryptamine hydrochloride (1 equiv) and heating at the same temperature overnight, to afford the corresponding β-carbolines 533 in 67−88% yields. Starting silyl enol ethers of α-oxoesters were prepared from reaction of phosphonate 532 with carbonyl compounds in the presence of LiHMDS in THF at room temperature overnight (Scheme 158). Also, Pictet−Spengler

a

534, R1 = H, F, Cl, Br, OH, Me, MeO, BnO; R2 = Me, i-Pr, PhCH2CH2, Ph, 2-furyl; 40−85%; 535, X = O, S; R1 = H; R2 = Me, PhCH2CH2, Ph; R3 = Ph, 3,4-Cl2C6H3; 68−86%.

Saxena et al.253 described an intramolecular Heck/aza-DA reaction of phosphoryloxy enecarbamate 537 with glyoxalate imines to give β-tetrahydrocarbolines 238. Reactions were performed in DMPU and MeTHF by in situ generation of BINOL-derived phosphoryloxy enecarbamates 537 from reaction of an imide 538 with (R)-BINOL-POCl (1.1 equiv) in the presence of KHMDS (1.2 equiv) at −78 °C, followed by addition of another equivalent of KHMDS, Pd(PPh3)4 (10 mol %), glyoxalate imine (1 equiv), TiCl4 (10 mol %), and BINOL (10 mol %), and stirring the resultant mixture at −40 °C for 4− 6 h. Reactions proceeded through indole-2,3-quinodimethane 539, as an intermediate, and the corresponding β-tetrahydrocarbolines 538 were obtained in 63−76% yields, with 88− 97% ee (Scheme 160). As outlined in Scheme 161, β-carboline 544 was synthesized in 60% yield, from reaction of ethyl 2-(acetoxyimino)-2-(1Hindol-2-yl)acetate with 4-octyne (1.5 equiv) using [Cp*RhCl2]2 (5 mol %) and Cu(OAc)2 (30 mol %) as catalyst in DMF at 60 °C under N2 atmosphere. The reaction proceeded by in situ generation of Cu(I) by reduction of Cu(II) with DMF, then Cu(I)-induced one electron reduction of N−O bond of oxime to generate the corresponding iminyl metal species 540, followed by transmetalation with Rh(III) to give iminyl rhodium(III) intermediates 541, which underwent ortho C− H rhodation. By alkyne insertion to rhodacycle 542, and then reductive elimination of Rh(I) species from 543, β-carboline 544 was produced.254

Scheme 158. Synthesis of β-Carbolines via Pictet−Spengler Reactiona

a 1

R COR2 = O(CH2CH2)2CH−CHO, c-PrCHO, 4-IC6H4CHO, 1Me-pyrrazole-4-CHO, 4-FC 6 H 4 (CO)Me, F 2 C(CH 2 CH 2 ) 2 CO, BnOCH(CH 2 CH 2 ) 2 CO, CbzN(CH 2 CH 2 ) 2 CO, CF 3 CH 2 N(CH2CH2)2CO, 2-indanone; R3 = H, CO2Et; 67−88%.

3.19. Pyridazines

cyclization of tryptamine with ethyl glyoxalate was reported in DCM at 45 °C for 4 h, followed by addition of TFA at −78 °C and then heating to room temperature.251 Moreover, Pictet−Spengler reaction of tryptamine hydrochloride with various α-oxoesters was developed by Fokas et al.252 using MeOH as reaction medium at 60 °C, to produce βtetrahydrocarbolines 534 in 40−85% yields. The obtained βtetrahydrocarbolines 534 could be converted to tetracyclic

Pyridazines are of considerable interest because of their occurrence in natural products, such as azamerone, pyridazomycin, antrimycin, and cirratiomycin A, and also their synthetic utility and applications in physical organic chemistry and liquid crystals. They exhibit a broad spectrum of biological activities, such as anti-HIV, antimalarial, antiviral, and anticancer properties. Cycloaddition reactions of 1,2,4,5-tetrazines with various dienophiles, and cyclocondensation of 1,4-dicarbonyl 201


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Scheme 160. Synthesis of β-Tetrahydrocarbolines 538 via Intramolecular Heck/Aza-DA Reactionsa

Scheme 162. Synthesis of Ethyl 5-Hydroxy-3(2H)pyridazinone-4-carboxylates 546a

a 1

R = H, 5-MeO, 5,7-(MeO)2, 5-Cl-7-MeO; R2 = H, Me, Bn, Boc, Tf; 63−76%, 88−97% ee.

compounds with hydrazine, are reported in the literature for the synthesis of pyridazine derivatives. Murphy et al.255 developed a two-step route to synthesize ethyl 6-substituted-5-hydroxy-3(2H)-pyridazinone-4-carboxylates 546a by reaction of α-oxoesters with ethyl hydrazinocarbonylacetate (1.1 equiv) in the presence of TFA in DMSO at 70 °C under N2 atmosphere for 16 h to give hydrazones of αoxoesters in 20−86% yields, followed by heating of obtained hydrazones 545 mediated by NaOAc (0.8 equiv) in DMF at 150 °C for 30 min to 2 h. 3(2H)-Pyridazinone-4-carboxylates 546a were obtained in 38−95% yields (Scheme 162a). Additionally, alkyl hydrazones of α-oxoesters, prepared by treatment of α-oxoesters with either alkyl hydrazines in EtOH at 80 °C or alkyl hydrazine-glyoxalic acid in the presence of NaOAc in EtOH at 80 °C, were acylated using ethyl malonyl chloride (1.2 equiv) in anhydrous dioxane at 100 °C under N2 atmosphere for 30 min. The obtained acyl hydrazones were converted into the corresponding 2,6-disubstituted-5-hydroxy3(2H)-pyridazinone-4-carboxylates 546b in 17−90% yields, when treated with NaOEt (1.2 equiv) in EtOH at room temperature for 20 min (Scheme 162b).256 Similar methodology was also applied for the synthesis of 4-(benzo[1,2,4]thiadiazin-3′-yl)-substituted pyridazine-2-ones.257 4-Hydroxypyrido[3,4-c]pyridazine 548b was synthesized by PPA-mediated Friedel−Crafts cyclization of ethyl pyruvate 3pyridylhydrazone 547 at 180 °C. 3-Pyridylhydrazone 547 was

a

546a, R = i-Bu, t-BuCH2, c-BuCH2, c-Pent, c-Hex, Ph, 2-thienyl, thiazole-5-yl; 38−95%; 546b, R1 = t-Bu, t-BuCH2, c-Pr, c-Bu, c-Hex, CF3CH2CH2, 2-thienyl, 5-Cl-2-thienyl, 5-Br-2-thienyl, 5-Me-2-thienyl, 3-thienyl, thiazole-3-yl, thiazole-5-yl; R2 = i-PrCH2CH2, c-PrCH2CH2, t-BuCH2, c-BuCH2, t-BuCH2CH2, Bn, 4-FBn, 3-Cl-4-FBn; 17−90%.

prepared via the Japp−Klingmann reaction of 3-pyridine diazonium chloride with ethyl 2-methylacetoacetate in ethanolic KOH at 0 °C for 10 min. First, pyrido[3,4c]pyridazin-4(1H)-one 548a was generated, which then tautomerized to 4-hydroxypyrido[3,4-c]pyridazine 548b (Scheme 163).258 3-Methyl-6-(1-methylhydrazinyl)pyrimidine-2,4(1H,3H)dione 549 was reacted with ethyl bromopyruvate in EtOH at room temperature for 3 h, followed by treatment with DEAD in toluene under heating conditions at 90 °C for 0.5 h to give 3ethoxycarbonyl-1,6-dimethylpyrimido[4,5-c]pyridazine-5,7(1H,6H)-dione 550 in 84% (Scheme 164).259 Abe et al.260 performed the reaction of 1,2-diaminoazaazulenium salts 551 with diethyl oxaloacetate or ethyl pyruvate (3 equiv) in CH3CN or EtOH in the presence of 5 equiv of K2CO3 at room temperature for 2−4 days, which resulted in the formation of the corresponding fused pyridazines, 2a,3diaza- and 1,2a,3-triazabenz[cd]azulenes 553, in 25−30% yields. Reaction of ethyl pyruvate with 1,8-diamino-azaazulenium salt 552 under similar conditions afforded the corresponding fused

Scheme 161. Synthesis of β-Carboline 544

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other methods rely on the condensation of carbonyl compounds with diamines. Recently, two examples of 4-(methoxycarbonyl)-2-(β-Dribofuranosyl)pyrimidines 556 were synthesized by Iaroshenko et al.261 via reaction of (β-D-ribofuranosyl)formamidine hydrochloride 555 with chloroketo esters 6, prepared from methyl aroylpyruvates and oxalyl chloride in DMF or DCM. Reactions were performed in the presence of K2CO3 and 4 Å MS in DMF at 0 °C for 2 h and gave the corresponding pyrimidines 556 in 33−42% yields (Scheme 166).

Scheme 163. Synthesis of 4-Hydroxy-7-pyrido[3,4c]pyridazine 548b

Scheme 166. Synthesis of β-D-Ribofuranosyl-Substituted Pyrimidines 556a Scheme 164. Synthesis of Pyrimido[4,5-c]pyridazine5,7(1H,6H)-dione 550

a

R = Ph, 2-thienyl; 33−42%.

Li et al.262 demonstrated that quinazoline derivatives 558 could be synthesized by reaction of aromatic amines with ethyl glyoxalate (1.2 equiv) when heated in toluene under reflux conditions in the presence of 10 mol % of CuBr2 for 5 days. Reactions were accomplished via Povarov reaction of in situ generated glyoxalate imine, followed by oxidation of intermediate 557 (Scheme 167). A similar reaction was reported using I2 (10 mol %) in MeNO2 under air atmosphere at room temperature for 12 h.238

triazine, 4-acetyl-1-phenyl-2a,3,5-triazabenz[cd]azulene 554, in 25% yield, via condensation in ester group (Scheme 165). Scheme 165. Synthesis of 2a,3-Diaza- and 1,2a,3Triazabenz[cd]azulenes 553 and 2a,3,5triazabenz[cd]azulene 554a

Scheme 167. Synthesis of Quinazoline Derivatives 558 via Cascade Povarov-Oxidation Reactiona

a

553, X = CH, N; Y = 2,4,6-Me3C6H2SO3; R1 = H, Et; R2 = H, CO2Et; 25−30%; 554, R2 = H, 25%.

3.20. Pyrimidines

a

Pyrimidines constitute an important class of natural products, such as nucleotides, caffeine, thiamine (vitamin B1), and alloxan. They are also found in many marketed drugs, including uramustine, tegafur, floxuridine, fluorouracil, cytarabine, trimethoprim, piromidic acid, tetroxoprim, metioprim, dipyridamole, trapidil, brodimoprim, tasuldine, and piribedil, which exhibit a broad range of activities, such as antineoplastic, antibacterial, antifungal, antiviral, and vasodilators properties. Pyrimidines can be prepared via the Biginelli reaction. Many

The synthesis of ethyl hexahydropyrrolo[1,2-a]quinazoline5-carboxylates 262 was reported via chiral bisphosphoric acid V-6-catalyzed enantioselective tandem hydride transfer (560 → 561)-ring closing reactions of iminium ion 561, in situ generated from reaction of ethyl 2-oxo-2-(2-(pyrrolidinyl)phenyl)acetates 559 with substituted anilines. Reactions were conducted by heating a solution of 559 and aniline (1.25 equiv) 203

R = 3-Cl, 4-Cl, 4-Br, 3-Me, 4-Me, 4-MeO; 51−76%.


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in the presence of 10 mol % of V-6 in toluene at 115 °C to furnish 562 in 32−81% yields, with 5:1−11:1 dr, and 72−84% ee (Scheme 168).263

yl)-2-oxoacetate 567b were subjected in a similar reaction with various substituted 2-aminopyrazoles and 5-amino-1,2,4triazoles. Reactions with 567a were carried out in refluxing AcOH for 36 h, and unexpected lactone ring annulated pyrazolo[1,5-a]pyrimidines and [1,2,4]triazolo[1,5-a]pyrimidines 570 were obtained in 60−85% yields. The formation of 570 was explained by conjugate addition of amine to 567a (route blue) followed by the formation of enaminone intermediate 568 by ring opening of cyclic ethers (route red). Intermediate 568 was transformed into final products by cyclocondensation to give compounds 569 and then lactonization between hydroxy and ester groups. By treatment of 567b with 5-amino-1,2,4-triazoles under similar conditions, a mixture of acetylated and decarboxylated pyrazolo[1,5-a]pyrimidines was produced. However, reaction in refluxing EtOH for 36 h furnished the corresponding ethyl 6(3-hydroxypropyl)pyrazolo- or ethyl 6-(3-hydroxypropyl)[1,2,4]triazolo[1,5-a]pyrimidine-7-carboxylates 569 in 74− 91% yields, in which the lactonization step did not tack place (Scheme 171).268

Scheme 168. Synthesis of Pyrrolo[1,2-a]quinazoline-5carboxylates 562a

3.21. Pyrazines

The piperazine and pyrazine cores are present in a number of natural products, especially alkaloids, such as barrenazine A and B, botryllazine A and B, flavacol, deoxyaspergillic acid, (−)-terezine A, (+)-septorine, 2,5-diisopropylpyrazine, actinopolymorphol C, dragmacidin A, B, C, and D, and piperazinomycin, and also in many biologically active compounds, possessing antifungal, antidepressant, antimycobacterial, antibacterial, antidiabetic, antimigraine, antithrombotic, and antiaggregating activities. Also, they have applications in metal coordination chemistry as N,N′-bidentate ligands. Therefore, the synthetic methods to preparae pyrazine moieties, such as condensation of α-diketones with 1,2diamines, Staedel−Rugheimer, and Gutknecht pyrazines synthesis, have been developed. Wojaczyńska et al.269 described the reaction of glyoxalate imine, derived from (1R,2R)-diaminocyclohexane, with a series of dienes. Reactions were performed by in situ generation of glyoxalate imine and then treatment with freshly distilled diene (1.2 equiv) mediated by TFA (1 equiv) and BF3·Et2O (1 equiv) in DCM for 20 h at room temperature. In the cases of cyclopentadiene, cyclohexadiene, and 1-methoxybutadiene, DA reaction took place, and the corresponding cycloadducts 571 were formed, which were cyclized to fused pyrazine-2-ones 572 and 573 by removal of a molecule of EtOH, while reaction with furan and pyrrole led to 3-oxo-4-(2-furyl)- and 3-oxo-4-(2pyrrolyl)-2,5-diazabicyclo[4.4.0]-decane 576, via Mannich-type reaction, respectively. Moreover, (1R,6R)-3-oxo-2,5diazabicyclo[4.4.0]decane 574 was synthesized and reacted with furan or pyrrole, which showed results similar to those of the one-pot procedure. Also, reaction of 574 with phenol derivatives proceeded via Mannich-type reaction to afford the corresponding Mannich adducts 575 (Scheme 172).269,270 Reaction of glycine amide hydrochloride with equimolar amount of substituted benzaldehydes in EtOH in the presence of Na2CO3 at 60−70 °C, followed by addition of 1 equiv of methyl benzoylpyruvate and heating under reflux conditions for 5 min, and then standing at room temperature for 24 h, afforded 3-arylidene-5-(benzoylmethylene)piperazine-2,6-diones 577 in 20−25% yields (Scheme 173).271 A series of 3-oxopiperazine-2-carboxamides 578, 3-oxotetrahydroquinoxaline-2-carboxamides 579, and 3,6-dioxopiper-

a

R = H, 3-Cl, 3-Me, 4-Me, 4-MeO; Ar = XC6H4 (X = H, 4-Cl, 4-Br, 4Me), 3,4-(MeO)2C6H3; 32−81%, 5:1−11:1 dr, 72−84% ee.

The synthesis of ethyl imidazo[1,2-c]quinazoline-5-carboxylate 564 was achieved by condensation of 2-(2-aminophenyl)4,5-dihydro-1H-imidazole 563 with ethyl glyoxalate (1.1 equiv) in the presence of MgSO4 (4−5 equiv) in anhydrous THF at room temperature, followed by dehydrogenation using either 5% Pd/C in refluxing xylene at 135−140 °C, under argon atmosphere for 36 h, or KMnO4 (2.05 equiv) and silica gel in CH3CN at room temperature for 12 h (Scheme 169).264 Scheme 169. Synthesis of Imidazo[1,2-c]quinazoline-5carboxylate 564

Reaction of β,γ-unsaturated γ-alkoxy-α-oxoesters 565a with 5-aminopyrazoles was investigated by Stepaniuk et al.265 Reactions were carried out by heating a solution of equimolar amounts of 565a and 5-aminopyrazoles in EtOH under reflux conditions for 10 h, and the corresponding ethyl pyrazolo[1,5a]pyrimidine-7-carboxylates 566a were obtained in 68−95% yields, regioselectively (Scheme 170a), while directly using ethyl 2,4-dioxopentanoate 565b (1.1 equiv) in refluxing EtOH led to the corresponding two regioisomers 566b,b′, with ethyl pyrazolo[1,5-a]pyrimidine-5-carboxylates 565b as major isomers (Scheme 170b).265,266 A similar reaction with ethyl 3ethoxymethylene-2,4-dioxopentanoate 565c in EtOH at 0 °C, followed by heating at 70 °C, in AcOH containing water for 5 h, resulted in ethyl 2-oxo-2-(pyrazolo[1,5-a]pyrimidin-6-yl)acetate 566c in nearly quantitative yield (Scheme 170c).267 Also, cyclic alkoxyeneoxoacetates, ethyl 2-(4,5-dihydrofuran3-yl)-2-oxoacetate 567a, and ethyl 2-(3,4-dihydro-2H-pyran-5204


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Scheme 170. Synthesis of Pyrazolo[1,5-a]pyrimidine Derivativesa

a

566a, R1 = H, Me; R2 = H, Me; R3 = Me, Et; R4 = H, Me; R5 = H, CO2Et, CONH2, CN; 68−95%; 566b,b′, R6 = H, Ph; 92% to quantitative, b/b′ = 73/27−90/10; 566c, quantitative.

Scheme 173. Synthesis of Piperazine-2,6-diones 577a

Scheme 171. Synthesis of Pyrazolo[1,5-a]pyrimidines and [1,2,4]Triazolo[1,5-a]pyrimidines 570a

a

Ar = 4-XC6H4 (X = Cl, Br), 3,4-(MeO)2C6H3; 20−25%.

endiamines in MeOH at room temperature for 24 h, followed by deprotection of Boc group using TFA (10%) in DCE at room temperature for 24 h, the corresponding 3-oxopiperazine2-carboxamides 578 or 3-oxotetrahydroquinoxaline-2-carboxamides 579 were obtained in 32−85% or 28−40% overall yields, respectively. However, reaction of ethyl glyoxalate (1.2 equiv), with isocyanides and primary amines with N-Boc-αamino acids under the same reaction conditions, afforded the corresponding 3,6-dioxopiperazine-2-carboxamides 580 in 63− 95% yields (Scheme 174).272 Direct cyclocondensation of α-oxoesters with α-aminoamides to produce 2,5-dihydroxypyrazines is limited to the reaction of

a R = H, Me; X = N, C−EWG (EWG = CN, CO2Et, CONH2); 570, n = 1, 60−85%; 569, n = 2, 74−91%.

azine-2-carboxamides 580 were prepared by Ugi-deprotectioncyclization reactions sequence. By treatment of 1.2 equiv of ethyl glyoxalate with equimolar amounts of carboxylic acids, isocyanides, and N-Boc-ethylenediamines or N-Boc-o-phenylScheme 172. Synthesis of Pyrazine-2-ones 572−576a

a

572, X = CH2, (CH2)2; 90−95%; 573, 32%; 575, R = Me, t-Bu; 29−40%, ∼1.7/1 dr; 576, X = O, NH; 15−80%. 205


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Scheme 174. Synthesis of Piperazine-2-carboxamides 578− 580a

Scheme 175. Synthesis of 2,5-Dihydroxypyrazines 582 and 2,5-Diacetoxypyrazines 583a

a 1 R = H, Me, Ph; R2 = Me, Et; R3 = Me, Et; R4 = H, Me, Ph; 582, 27− 70%; 583, 9−68%.

Scheme 176. Synthesis of 2-Hydroxyquinoxalines 284,285a

a

578, R1 = H, (CH2)4; R2 = H, Me, Bn; R3 = i-Pr, n-Bu, c-Hex, Bn, 2,6Me2C6H3, THF-2-ylmethyl; R4 = c-HexCH2, Bn, Ph(CH2)2, Ph2CH; 32−85%; 579, R3 = n-Bu, c-Hex, Bn; R4 = c-HexCH2, Ph2CH, MeSO2CH2; 28−40%; 580, R3 = c-Hex, N-Bn-piperidin-4-yl-CH2; R5 = H, Bn, N-Bn-imidazol-4-yl-CH2; R6 = Bn, Ph(CH2)3, 63−95%.

ethyl benzoylformate with phenylglycinamide in the presence of NaOEt in refluxing EtOH, which led to the corresponding 2,5-dihydroxypyrazines only in 19% yield. Therefore, the cyclocondensation of α-oxoesters with α-aminoamides was performed by preparation of N-(aminocarbonylmethyl)-αketoamides 581 from reaction of α-aminoamides either with ethyl benzoylformate in dry MeOH at room temperature or 40 °C or with α-ketalesters in dry MeOH (or EtOH) at room temperature or 40−50 °C, followed by hydrolysis of ketal moiety using TFA at room temperature for 2−3 days. Cyclization of 581 to 2,5-dihydroxypyrazines 582 was conducted using NaOMe, in MeOH under reflux conditions for 0.25−3 h. By refluxing a mixture of 581 and Ac2O in AcOH for 3−140 h, 2,5-diacetoxypyrazines 583 were formed in 9− 68% yields (Scheme 175).273 3.22. Quinoxalines a 584, R1 = Cl, Me, OMe; R2 = n-Pr, i-Pr, CF3, Cl(CH2)3, CO2Et; 585, R = H, Me; Ar = 4-XC6H4 (X = H, Cl, Me, MeO); 585a, 50−85%, 585b, 30−40%.

Because of their biological and pharmacological activities, and applications in dyes, multilayer OLEDs, and electron luminescent materials, and also as building blocks for the synthesis of anion receptors, cavitands, dehydroannulenes, and organic semiconductors, quinoxalines have received great attention, and a number of synthetic strategies have been developed for the preparation of substituted quinoxalines, including condensation of aryl-1,2-diamines with α-functionalized ketones, usually dicarbonyl compounds or their equivalents. In 2007, Teng et al.274 reported this same reaction using AcOH in DMF, in which corresponding quinoxaline-2-ones 584a were obtained, almost in the 2-hydroxyquinoxaline tautomeric form 584b (Scheme 176a). Sanna et al.275 described a similar reaction by either refluxing a solution of diamines and α-oxoesters in EtOH for 1−4 h or heating a mixture of diamines and α-oxoesters in 10% H2SO4 aqueous solution at 70−90 °C for 1−2 h. There are also other reports on the

similar reaction using various 1,2-diaminobenzene and αketoester derivatives under different conditions.276 By treatment of 5,6-diaminouracil hydrochloride with sodium salts of ethyl aroylpyruvates in pyridine under reflux conditions for 1 h, 7-hydroxy-2,4(1H,3H)-pteridinediones 585a were obtained in 50−85% yields. When reactions were conducted in refluxing 1 N HCl, isomeric 6-hydroxy-2,4(1H,3H)-pteridinediones 585b were produced in 30−40% yields (Scheme 176b).277 Chen et al.278 reported the synthesis of imidazo[1,5a]quinoxalin-4-ones 587 in four steps starting from condensation of o-phenylenediamines with ethyl glyoxalate. Reaction of o-phenylenediamines with ethyl glyoxalate was conducted in refluxing EtOH, leading to quinoxalin-2(1H)ones in 37−93% yields, which were protected using p206


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methoxybenzyl chloride in the presence NaH in DMF at room temperature for 12 h, in 54−70% yields. Reaction of PMBprotected quinoxalin-2(1H)-ones 586 with TosMIC in the presence of NaH in THF at room temperature for 4 h afforded 5-(p-methoxybenzyl)-imidazo[1,5-a]-quinoxalin-4-ones in 68− 97% yields that in treatment with a mixture of TfOH/anisole/ TFA in a 1/2/5 volume ratio at room temperature for a period of 6−8 h resulted in the formation of deprotected imidazo[1,5a]quinoxalin-4-ones 587 in 90−99% yields (Scheme 177).

Also, ethyl glyoxalate was reacted with 2-(N-Boc-amino)phenylisocyanide, mono-Boc-phenylenediamines, and carboxylic acids under Ugi reaction conditions, using TFE as solvent at room temperature, to give corresponding Ugi adducts 590, which were transformed into 3-(1H-benzo[d]imidazol-2-yl)3,4-dihydroquinoxalin-2(1H)-ones 592, when treated with 10% TFA in DCE for 10 min, under MW irradiation at 100 °C. The overall yields of 592 for two steps are 36−45%. Deprotection of both Boc groups in 590 led to unmasked two amines 591, which underwent cyclization with ester group to form 592 (route red). Alternatively, in some cases, cyclodehydration with amide groups (route blue) afforded the corresponding ethyl 2(1H-benzo[d]imidazol-2(3H)-ylidene)-2-(1H-benzo[d]imidazol-1-yl)acetates 593, in which no atom of ethyl glyoxalate was incorporated in the heterocyclic rings (Scheme 179).280

Scheme 177. Synthesis of Imidazo[1,5-a]quinoxalin-4-ones 587a

Scheme 179. Synthesis of 3-(1H-Benzo[d]imidazol-2-yl)-3,4dihydroquinoxalin-2(1H)-ones 592a

a

R = H, 7-OMe, 7-CO2Me, 8-MeO, 9-NO2.

3-(Tetrazol-5-yl)quinoxalin-2(1H)-one derivatives 589 were synthesized by Ugi-azide multicomponents reaction of monoN-Boc-protected-o-phenylenediamine derivatives, ethyl glyoxalate, isocyanides, and TMSN3, followed by acid-mediated deprotection and subsequent cyclization, and then oxidation. Ugi-azide MCRs were carried out by precondensation of monoN-Boc-protected-o-phenylenediamine with ethyl glyoxalate in DCE, followed by addition of isocyanides and TMSN3 and trifluoroethanol as a cosolvent at room temperature, which led to Ugi-tetrazole products 588 in 31−73% yields. By irradiation of 588 with 10% TFA in DCE under MW conditions, deprotection of Boc group and then cyclization occurred, which then underwent oxidation to 589, using oxygen of air in the presence of solid supported TEMPO (0.1 equiv) and CAN (0.2 equiv) in CH3CN under MW irradiation at 100 °C for 20 min (Scheme 178).279

a 1

R = H, Me; R2 = XC6H4 (X = H, 2-Br, 4-Ph, 3-MeO2S), 2-furyl, pyrazin-2-yl, 3-MeC6H4CONHCH2; 592, 36−45%, 593, 47−63%.

Scheme 178. Synthesis of 3-(Tetrazol-5-yl)quinoxalin2(1H)-one Derivatives 589a

Reaction of N-(2-aminophenyl)-N′-cyano-O-phenylisourea with 5-aryl-2,3-dihydrofuran-2,3-diones, a cyclic α-oxoesters, was investigated by Nekrasov et al.281 Reactions were performed in dioxane at 50−60 °C for 40 min, and the corresponding 3-(2-oxoarylethylidene)quinoxaline-2-ones 594 were obtained in 63−75% yields (Scheme 180). Similar structural motifs, 3-aroylmethylidene-1-phenyl1,2,3,4-tetrahydroquinoxalin-2-ones 595, were also prepared by cyclocondensation of aroylpyruvates with N-phenyl-ophenylenediamine in 44−86% yields. Reactions were carried out by heating a solution of equimolar amounts of aroylpyruvates and N-phenyl-o-phenylenediamine in i-PrOH under reflux conditions for 1 h. 1,2,3,4-Tetrahydroquinoxalin-2ones 595 were converted to 3-aroyl-5-phenyl-1,2,4,5-tetrahydropyrrolo-[1,2-a]quinoxaline-1,2,4-triones 596 when subjected with oxalyl chloride in anhydrous benzene under reflux conditions for 1 h, in 59−98% yields (Scheme 181).282

a 1 R = H, Me, Br; R2 = H, Me; R1−R2 = (CH)4; R3 = n-Bu, n-Pent, cPent, c-Hex, Bn, EtO2CCH2, 2-MeC6H4, 2,6-Me2C6H3; 588, 31−73%; 589, 27−66% (for two steps).

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Scheme 182. Synthesis of Triazines 597,598a

Scheme 180. Synthesis of 3-(2Oxoarylethylidene)quinoxaline-2-ones 594a

a

Ar = Ph, p-tolyl; 63−75%. a

597, Ar = 4-CNC6H4; R = H, Me; 27−59% (for two steps); 598, Ar = 2,3,5-Cl3C6H2; 54%.

Scheme 181. Synthesis of 1,2,3,4-Tetrahydroquinoxalin-2ones 595a

599, instead triazine derivatives 600, 5-thioxo-1H-1,2,4-triazole3-carboxylates 601, were obtained in 40−50% yields, along with desilylation (Scheme 183). Scheme 183. Synthesis of 5-Oxo-1,2,4-triazin-3-thion Derivatives 600a

a

Ar = 4-XC6H4 (X = H, F, Cl, Br, Me, MeO, EtO, NO2), 2-furyl, 5Me-2-furyl, 5-Cl-2-thienyl; 595, 44−86%; 596, 59−98%.

3.23. Triazines

1,2,4-Triazines are a well-known class of nitrogen heterocycles with a broad spectrum of biological activity, such as antagonists at the corticotropin releasing factor receptor, antiviral, antifungal, anticancer, and anti-HIV activities, and applications in pharmaceuticals, herbicides, pesticides, and dyes. Accordingly, a number of methodologies have been reported for the synthesis of 1,2,4-triazine derivatives, from which condensation of the amidrazones with 1,2-dicarbonyl compounds provides one of the most straightforward syntheses of 1,2,4-triazines. Dehydrative cyclocondensation reactions of amidrazone like moieties with α-oxoesters were reported to prepare 1,2,4triazinones or hydroxy-1,2,4-triazines tautomers. In this context, Leenders et al.283 described the synthesis of 3-arylamino-5hydroxy-1,2,4-triazines 597 in 27−59% yields, by one-pot preparation of hydrazinecarboximidamide intermediate, and then treatment with ethyl glyoxalate or ethyl pyruvate in MeOH at room temperature overnight, followed by heating at 80 °C in DMF for 48 h (Scheme 182a). Also, reaction of ethyl oxamidrazonate with ethyl 2-oxo-2-(2,3,5-trichlorophenyl)acetate in EtOH under reflux and photolysis conditions afforded ethyl 1,2,4-triazinone-5-oxo-3-carboxylate 598 in 54% yield (Scheme 182b).284 Additionally, many other research groups developed the application of this methodology for construction of different substituted 1,2,4-triazine derivatives.285 Bolm et al.286 demonstrated that the condensation of α-silylα-oxoesters with thiosemicarbazide (2 equiv) in EtOAc at 50 °C for 1 h gave the corresponding silylated thiosemicarbazones 599 in 65−84% yields, which were converted to 5-oxo-1,2,4triazin-3-thions 600, when treated with an excess amount of Na2CO3 or K2CO3 in MeOH/water (1/1: v/v) at 80 °C for 1 h. In the case of trimethylsilyl-substituted thiosemicarbazones

a 1

R = Et, Bn; R2 = Me, Et, Ph; R3 = Me, Et, t-Bu, Ph; 600, 72−88%; R1 = Me, Et, Bn; R2 = R3 = Me; 601, 40−50%.

One of the most extensively used approaches to synthesize 1,2,4-triazine-5-ones annulated to other heterocyclic rings is cyclodehydration of 2-hydrazino-aminoheterocycles with various α-oxoesters. Accordingly, Karpenko et al.287 reported the synthesis of 3-substituted 2H-1,2,4-triazino[2,3-c]quinazolin-2ones 604 from reaction of 4-hydrazinoquinazoline 602 with αoxoesters. Reactions were carried out by refluxing a solution of 602 and α-ketoester (1.1 equiv) in AcOH for 3−4 h. First, cyclocondensation afforded the corresponding 3-substituted 4H-[1,2,4]triazino[4,3-c]quinazolin-4-one 603 as the reaction intermediate, which underwent subsequent Dimroth-like rearrangement to give 3-substituted 2H-[1,2,4]triazino[2,3c]quinazolin-2-one derivatives 604 in 59−82.7% yields (Scheme 184a). Also, 2-methyl-3H-[1,2,4]triazino[3,2-b]quinazoline-3,10(4H)-dione 606 was prepared by condensation of 3-aminoquinazolin-4(3H)-one 605 with ethyl pyruvate in AcOH under heating conditions for 2 h, in 73% yield (Scheme 184b). 288 2-Methyl-3H-naphtho-[1′,2′:4,5]thiazole[3,2-b][1,2,4]triazine-3-one was obtained in 23% yield from similar condensation reaction of ethyl pyruvate with 3-amino-2iminonaphtho[1,2-d]thiazole in refluxing EtOH.289 By condensation of equimolar amounts of 3-hydrazinylquinoxalin-2(1H)-one 607 with aroylpyruvates in refluxing EtOH, the corresponding hydrazones were obtained in 60−65% yields, which were transformed into 1H-[1,2,4]triazino[4,3-a]208


Chemical Reviews

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Scheme 184. Synthesis of Triazino-quinazolin Derivatives 604 and 606a

Scheme 186. Synthesis of Prydazino-triazines 610 and 613,614a

a R = (CH2)nCO2Et (n = 0, 1, 2), CH(Me)CO2Et; 610, 39−78%; 613, 36% (for second step); 614, 25% (for second step). a

R = Me, Ph(CH2)2, Ph, 4-MeC6H4, 2-thienyl, 2,5-Cl2-3-thienyl; 604, 59−82.7%.

Scheme 187. Synthesis of Triazino-pyrazolo-1,3,5-triazine 616 and Triazino-perimidine 618

quinoxaline-1,5(6H)-dione derivatives 608 in 80−85% yields, by pyrolysis at 230 °C for 0.5 h (Scheme 185).290 Scheme 185. Synthesis of 1H-[1,2,4]Triazino[4,3a]quinoxaline-1,5(6H)-diones 608a

a

Ar = Ph, PMP; 80−85%.

conditions for 5 h, 1,2,4-triazino[4,3-a]perimidin-4(1H)-one 618 was prepared in 92% yield (Scheme 187b).294 There are other reports on the cyclocondensation of 2-pyridazinoaminoheterocycles with α-oxoesters to form fused triazine derivatives.295

Also, the synthesis of pyridazino-triazines was reported using a similar methodology, as in 2001, Wejroch et al.291 described the reaction of 6-hydrazinyl-4,5-dihydropyridazin-3(2H)-one 609 with α-oxoesters in EtOH at room temperature, to yield the corresponding hydrazones, which could be converted to 3substituted 8,9-dihydro-4H-pyridazino[6,1-c][1,2,4]triazine4,7(6H)-diones 610 when heated at 160−210 °C under solvent-free conditions. Additionally, one-step cyclocondensation reactions were performed by refluxing a mixture of 609 and α-oxoesters in EtOH (Scheme 186a). 4H-Pyridazino[6,1c][1,2,4]triazin-4-ones 613−614 were synthesized by reaction of 3-hydrazinopyridazine 611 or 6-hydrazinoimidazo[1,2-b]pyridazine 612 with ethyl pyruvate in refluxing EtOH in the presence of AcOH, followed by PPA-mediated cyclization of obtained hydrazones at elevated temperature (140−160 °C) for 1−1.5 h (Scheme 186b).292 The synthesis of 7H-1,2,4-triazino[4,3-e]pyrazolo[1,5-a]1,3,5-triazin-7-one 616 was reported by reaction of 4hydrazinopyrazolo[1,5-a]-1,3,5-triazine 615 with ethyl pyruvate (1.5 equiv) in refluxing EtOH in the presence of NaOMe during 5 h, in 30% yield (Scheme 187a).293 Furthermore, by treatment of 2-hydrazinyl-1H-perimidine 617 with an equimolar amount of ethyl pyruvate in glacial AcOH under reflux

3.24. Azepines and Diazepines

Nitrogen-containing heterocyclic seven-membered rings, azepine and diazepine derivatives, are found in many biologically active natural products and pharmaceuticals, such as (−)-tuberosutemonin, (−)-cephalotaxine, SB-462795, neostenine, neotuberostemonine, diazepam, flumazenil, temazepam, nimetazepam, nitrazepam, alprazolam, bretazenil, brotizolam, quazepam, and clobazam. A variety of methods exist in the literature for the preparation of these heterocycles, including ring-closing metathesis reaction, condensation reaction of 1,2-diamines with 1,3-dielectrophilic compounds, metal-catalyzed intramolecular hydroamination of unactivated carbon−carbon multiple bonds, aza-Wittig ring closure reaction, and intramolecular Michael additions. Tandem N-alkylation/π-allylation of α-imino-phenylglyoxalate, followed by RCM reaction, was developed by Curto and Kozlowski,296 to afford 2,3,6,7-tetrahydro-1H-azepine-2-carboxylate 621a and 1,2,3,6,7,8-hexahydroazocine-2-carboxylate 621b. N-Alkylation/π-allylation was performed using Grignard 209


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Scheme 188. Synthesis of 1H-Azepine-2-carboxylate 621a and Azocine-2-carboxylate 621ba

a

n = 1, 620a, 82%, 90% ee; 621a, 98%; n = 2, 620b, 85%, 86% ee; 621b, 95%.

reagent in THF under Ar atmosphere at −78 °C and then room temperature for 45 min, followed by cooling to −78 °C and addition of [η3-C3H5PdCl]2 (2.3 mol %) and (R)DIFLUORPHOS (4.5 mol %) and allyl acetate (1 equiv) and then warming to ambient temperature and stirring for additional 45 min, to give methyl 2-(but-3-enylamino)-2,5diphenylpent-4-enoate 620a and methyl 2-(pent-4-enylamino)2,5-diphenylpent-4-enoate 620b in 82% and 85% yields with 90% and 86% ee, respectively, via intermediate 619. By treatment of 620a and 620b with second-generation Hoveyda− Grubbs catalyst IX-2 (4.5 mol %), in toluene under MW irradiation (100 W) at 115 °C for 1 h, RCM reaction occurred to form 621a and 621b in 98% and 95% yields, respectively. 1,2,3,6,7,8-Hexahydroazocine-2-carboxylate 621b was converted to 1-iodo-3-phenyloctahydro-1H-pyrrolizine-3-carboxylate 622 by removing a PMP moiety, using 3 equiv of CAN in CH3CN/water mixture at room temperature for 45 min in 59% yield, followed by treatment with NIS (2 equiv) in DCM at ambient temperature for 1.5 h, in 67% yield (Scheme 188). Wang et al.297 reported the Pictet−Spengler condensation of 4-(2-anilinophenyl)-7-azaindole or deazapurine 623 with αoxoesters to give the corresponding fused benzoazepine derivatives 624 in more than 90% yields. Reactions were conducted in MeOH using HCl (4 N in dioxane) at 100 °C for 30 min (Scheme 189). The obtained benzoazepines exhibited potent Janus kinases (JAK) inhibitory activity. By treatment of substituted 2-nitrobenzoyl chlorides with glyoxalate imino-alcohol, in situ derived from reaction of methyl glyoxalate with ethanolamine in the presence of MS in DCM at room temperature, N-(2-nitrobenzoy1)oxazolidine-2carboxylates 625 were formed in 40−70% yields. Reactions were conducted using pyridine in DCM at 0 °C for 20 min.

The obtained N-(2-nitrobenzoy1)oxazolidine-2-carboxylates 625 were converted to 2,3-dihydrobenzo[e]oxazolo[3,2-a][1,4]diazepine-5,11(10H,11aH)-diones 626 by reduction of nitro group to amine using H2 on Pd/C in MeOH at room temperature, which underwent subsequent cyclization with the ester group. i-Bu2AlH-induced reduction of ester to aldehyde, followed by reduction of nitro group using either H2/Pd/C in MeOH at room temperature or SnCl2·2H2O in refluxing MeOH, led to 11-hydroxybenzo[e]oxazolo[3,2-a][1,4]diazepin-5(10H)-ones 627, which underwent dehydration to give 2,3-dihydrobenzo[e]oxazolo[3,2-a][1,4]diazepin-5(11aH)one 628 when refluxed for 0.5 h in CHCl3 (Scheme 190).298 Bicyclic-amino esters 353 were synthesized by aza-DA reaction of cyclopentadiene or cyclohexadiene with glyoxalate imine, prepared in quantitative yield by reaction of αmethylbenzylamine and ethyl glyoxalate in refluxing toluene with azeotropic removal of water. Reactions were conducted in DCM or DMF in the presence of TFA for cyclopentadiene and TFA-BF3·OEt2 for cyclohexadiene at −20 °C, leading to the corresponding cycloadducts in 55−60% yields, which underwent hydrogenative deprotection of benzyl moiety using H2 in the presence of Pd/C in EtOH, along with reduction of C−C double bond, to give 353 in 90−95% yields. Et3N-mediated benzoylation of 353 with 2-nitrobenzoyl chloride in DCM at 0 °C, followed by tandem reduction-cyclization reactions with Fe in refluxing AcOH, afforded the corresponding benzo[e]pyrido[1,2-a][1,4]diazepine-6,12(5H,6aH)-diones 629 in 65−75% yields, for the last step. The obtained 629 was reduced to benzo[e]pyrido[1,2-a][1,4]diazepines 630 using LiAlH4 in THF at 0 °C in 85−90% yields (Scheme 191).299 When THQ 489, synthesized by four-component reaction of anilines with methyl pyruvate as shown in Scheme 141, was heated in AcOH/TFE mixture at 60 °C in the presence of an excess amount of a primary amine, nucleophilic substitution took place at C-4 (632) via intermediate 631, which underwent subsequent lactamization to furnish benzo[e][1,4]diazepine-5carboxylates 633 in 55−91% yields, with 90−95% ee, and >20:1 dr (Scheme 192).218 Also, Ugi-deprotection-cyclization methodology was applied for the construction of benzodiazepine motifs. In this context, Hulme and Cherrier272 reported the Ugi four-component reaction of ethyl glyoxalate (1.2 equiv) and equimolar amounts of primary amines, isocyanides, and N-Boc-2-aminobenzoic acid to give Ugi-adducts in 39−84% yields, which underwent deprotection and subsequent cyclization to afford correspond-

Scheme 189. Synthesis of Fused Benzoazepine Derivatives 624a

a

X = CH, N; R = Me, Et; Ar = 4-HOC6H4, 4-NO2C6H4, 3-F-4-OHC6H3; >90%. 210


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Scheme 190. Synthesis of Benzo[e]oxazolo[3,2-a][1,4]diazepines 626−628a

a 1

R = H, MeO; R2 = H, OH, BnO.

Scheme 191. Synthesis of Benzo[e]pyrido[1,2a][1,4]diazepines 630a

Scheme 193. Synthesis of 2,5-Dioxo-benzo[e][1,4]diazepine3-carboxamides 634a

a 1

R = H, 7-Cl, 8-Cl; R2 = H, Me; R3 = n-Bu, c-Hex, 2,6-Me2C6H3; R4 = n-Pr, c-HexCH2, Ph(CH2)3; 30−78% (for second step).

a

n = 1, 2; R = H, Cl; 629, 65−75% (for last step); 630, 85−90%.

A similar methodology was developed by Ugi reaction between N-Boc-1,2-phenylenediamine, ethyl glyoxalate, N-Boc2-aminobenzoic acid, and 4-t-butylcyclohexen-1-yl isocyanide, followed by deprotection and subsequent cyclization leading to the corresponding benzo[e]quinoxalino[1,2-a][1,4]diazepine6,7,13(5H,8H)-triones 636. Reactions were carried by in situ generation of glyoxalate imine from reaction of N-Boc-1,2phenylenediamine with ethyl glyoxalate in DCM under MW irradiation at 130 °C for 15 min, followed by addition of NBoc-2-aminobenzoic acid and 4-t-butylcyclohexen-1-yl isocyanide, and also TFE and stirring for overnight to give Ugi adducts 635 in 45−71% yields, which underwent deprotection and cyclization in treatment with TFA (10%) in DCE under MW irradiation at 180 °C for 20 min. Cyclization products 636 were obtained in 70−78% yields. Using 2-(N-Boc-amino)benzylamine instead of N-Boc-1,2-phenylenediamine, under similar reaction conditions, the corresponding fused bisbenzodiazepines 637 were obtained in 50−56% yields (Scheme 194).300

Scheme 192. Synthesis of Benzo[e][1,4]diazepine-5carboxylates 633a

a 1

3.25. Miscellaneous N-Heterocycles

ing 2,5-dioxo-benzo[e][1,4]diazepine-3-carboxamides 634 in 30−78% yields. Ugi reactions were carried out in MeOH at room temperature for 24 h. Deprotection/cyclization processes were performed using TFA (10%) in DCE at room temperature for 24 h (Scheme 193).

meso-Tetra carboxylic ester-functionalized calix[4]pyrrole compound 638 was prepared by cyclocondensation reaction of pyrrole with ethyl pyruvate using HCl as catalyst in DCM at 0 °C for 2 h under an atmosphere of N2, followed by room temperature overnight, in 80% yield. Also, mixed condensation product 639 was obtained in 55% yield, when a solution of pyrrole, ethyl pyruvate (0.5 equiv) ,and acetone (0.5 equiv) in

R = H, OMe; Ar = Ph, PMP; R2 = n-Pr, Bn, indol-3-yl-(CH2)2; 55− 91%.

211


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Scheme 194. Synthesis of Benzo[e]quinoxalino[1,2-a][1,4]diazepines 636 and Fused Bis-benzodiazepines 637a

R = 4-t-Bu-cyclohex-1-en-yl; 636, R1 = H, Me; R2 = H, Cl, Me, MeO; R3 = H, Cl; R2−R3 = (CH)4; 70−78%; 637, R5 = Cl, Me, MeO; 50−56%.

a 4

dry solvent was treated with HCl at 0 °C under N2 atmosphere, and then room temperature overnight (Scheme 195).301

69−91% yields, with 54/46−99/1 diastereoselectivity (cis/ trans) (Scheme 196). A similar approach was reported using CH2N2 in Et2O at 0 °C, which led to the corresponding epoxyesters.303

Scheme 195. Synthesis of Ester-Functionalized Calix[4]pyrrole 638,639

Scheme 196. Synthesis of β-Trimethylsilyl-α,β-epoxyesters 640a

a 1 R = Me, i-Pr, Ph, Ph(CH2)2, Ph(CH2)3, PhCC; R2 = Et, t-Bu; 69−91%; cis/trans = 54/46−99/1.

Rahman et al.304 developed a method for the preparation of α,β-epoxyesters 642 from reaction of α-oxoesters with triphenylbismuthonium ylides 641. Reactions were conducted by in situ generation of 641 from reaction of bismuthonium salts with an equimolar amount of a base in THF at −78 °C for 10 min, followed by addition of an α-ketoester (1 equiv) and warming the mixture to room temperature. KOt-Bu, NaHMDS, and KHMDS were used as the bases, and the corresponding α,β-epoxyesters 642 were obtained in 62−82% yields, with high trans selectivity (Scheme 197). There are also some multistep syntheses of oxiranes, starting from α-oxoesters, in which first α-oxoesters were converted to 1,2-diols and then oxirane derivatives.305

4. SYNTHESIS OF O-HETEROCYCLES 4.1. Oxiranes

Oxirane moiety is present in the skeleton of a number of natural products, such as fumagillin, azinomycins A and B, cryptophycin A and B, triptolide, triptonid, epoxomicin, and trioxacarcin A, and also in drugs, for example, epothilones, beloranib, and carbamazepine epoxide, which exhibit a vast range of biological activity. Because epoxides underwent ringopening or rearrangement reactions, they are among the most versatile intermediates in organic synthesis, especially in the synthesis of polyether natural products, such as lasalocid A, isolasalocid A, and dioxepandehydrothyrsiferol. The preparation of β-trimethylsilyl-α,β-epoxyesters 640 was reported by Hari et al.302 through reaction of α-oxoesters with diazo(trimethylsilyl)methyl magnesium bromide (1.2 equiv), followed by treatment with pivalic acid (5 equiv). Reactions were carried out in THF at −78 °C. Reactions were completed in 1.5 h for each step, and α,β-epoxyesters 640 were obtained in

Scheme 197. Synthesis of α,β-Epoxyesters 642 Using Triphenylbismuthonium Ylides 641a

a

Base = KOt-Bu, NaHMDS, KHMDS; R1 = t-Bu, Ph; R2 = Me, Ph; 62−92%, cis/trans = 0/100−34/66. 212


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4.2. Oxetanes and β-Lactones

Scheme 199. Synthesis of Oxetane Derivatives 645,646a

Oxetanes are found in a number of natural products such as paclitaxel and related toxoids, oxetanocin A, thromboxane A2, merrilactone A, mitrephorone A, bradyoxetin, dictyoxetane, maoyecrystal I, and oxetin, and in pharmaceuticals with significant clinical effects. Additionally, β-lactone moiety is present in the structure of natural products, such as belactosins A, B, and C, and spongiolactone, and in some biologically active compounds, that is, oballuorin, valilactone, hymeglusin, lipstatin, and ebelacton A and B. Also, they are valuable intermediates for organic synthesis and in polymer chemistry. The most important routes to synthesize oxetanes and βlactones are Lewis acid-catalyzed [2 + 2] cycloadditions and nucleophile-catalyzed aldol-lactonizations. In 2001, Evans and Janey306 reported the bis(oxazoline) VII2−Cu(II) complex-catalyzed enantioselective [2 + 2] cycloaddition between trimethylsilylketene and α-oxoesters. Reactions were performed at −50 to −40 °C in DCM using 20 mol % of VII-2−Cu(II) complex as catalyst for 24−48 h, to give 3silyl-substituted β-lactones, which underwent desilylation using KF in CH3CN to β-lactones 643, in 86−99% yields, with 69− 99% ee. By treatment of trimethylsilylketene with ethyl benzylidenepyruvate, an β,γ-unsaturated α-ketoester, in the presence of VII-2−Cu(II) complex in DCM at −78 °C for 48 h, [4 + 2] cycloaddition occurred, and the corresponding δlactone 644 was obtained in 96% yield, with 97% ee, and 95/5 dr (Scheme 198).

a 645, 79%; 646a, R = Me; quant., endo/exo = 4/1; 646b, R = t-Bu; 65%.

Paternò−Büchi reaction of chiral phenylglyoxalate esters with furan derivatives was developed by D’Auria et al.308 to synthesize 6-phenyl-2,7-dioxabicyclo[3.2.0]hept-3-ene-6-carboxylate derivatives 647. Reactions were carried out using a large amount of furans under N2 atmosphere and photoirradiation for 7 h. In the case of 2-methyfuran, coupling reactions occurred at both double bonds, leading to a mixture of two adducts 647b and 647b, with a coupling adduct at the less hindered side of 2-methylfuran as a major product (647a). Reaction with 2-furylmethanol gave adducts, only obtained by coupling at the less hindered side (647a), while reaction with 2furylphenylmethanol occurred at the most hindered side of furan (647b). The yields of the obtained 2,7dioxabicyclo[3.2.0]hept-3-ene-6-carboxylates 647 were 9−65% (Scheme 200).

Scheme 198. Synthesis of β-Lactones 643 via [2 + 2] Cycloaddition Reactiona

Scheme 200. Synthesis of 6-Phenyl-2,7dioxabicyclo[3.2.0]hept-3-ene-6-carboxylates 647a

a 1

R = H, Me, Et, i-Pr, t-Bu, Ph, BrCH2; R2 = Me, Et; 643, 86−99%, 69−99% ee.

a 2 R = (S)-2-butyl, (S)-2-methylbutyl; R = H, 66%, 647a/647b = 1/1; R = Me, 647a, 36−60%, 647b, 9−12%; R = CH2OH, 647a, 35−46%; R = CH(OH)Ph, 647b, 63−65%.

Oxetane derivative 645 was synthesized by [2 + 2] cycloaddition reaction of ethyl pyruvate with 1,1-diethyoxyethylene under photochemical conditions. Photochemical reaction was applied using equimolar amounts of ethyl pyruvate and 1,1-diethyoxyethylene in benzene under N2 atmosphere, and ethyl 2-methyl-3,3-diethoxyoxet-2-yl-carboxylate 645 was obtained in 79% yield. Also, reaction of 2,2-diisopropyl-1,3dioxole with ethyl pyruvate or ethyl trimethylpyruvate was investigated under similar conditions, which gave the corresponding ethyl 2,4,6-trioxabicyclo[3.2.0]heptane-7-carboxylates 646a or 646b in quantitative or 65% yields, respectively. Exo and endo isomers of 646a were isolated, and the endo/exo ratio was determined as 4/1 (Scheme 199).307

The NHC-catalyzed reaction of 4-methylpent-2-enal with methyl benzoylformate was investigated by Burstein et al.309 leading to the corresponding β-lactone 650 in 22% yield, with 71/29 dr. Reactions were carried out in toluene using 10 mol % of NHC and DBU (0.1 equiv) under heating at 60 °C for 16 h. The proposed reaction mechanism involves the formation of enolate 648, by addition of NHC to unsaturated aldehyde, followed by protonation−deprotonation sequence. Nucleophilic addition of enolate 648 to methyl benzoylformate formed intermediate 649, which transformed into β-lactone 650 with cyclization and removal of NHC molecule (Scheme 201). 213


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dibenzoylacetylene, to the ketone group of α-ketoester to form intermediate 654, which cyclized to 655 (Scheme 203).311

Scheme 201. NHC-Catalyzed Synthesis of β-Lactone 650

Scheme 203. Synthesis of 3,7-Dioxa-2λ5phosphabicyclo[3.2.0]hept-4-ene-6-carboxylate 655

4-Silylmethyl-substituted oxetane-2-carboxylate derivatives 652 were synthesized by addition of allylsilane to α-oxoesters mediated by TiCl4. By treatment of α-oxoesters with 2 equiv of allylsilane and 1 equiv TiCl4 in toluene at 0 °C for 10−30 min, 652 was obtained in 62−96% yields. It is demonstrated that bulky substituents on silicon, such as i-Pr and t-Bu, were essential for the formation of oxetanes, as less hindered TMSsubstituted allylsilane led to the corresponding homoallyl alcohol as a sole product. Also, reactions of ethyl benzoylformate were investigated using SnCl4 in DCM, in which the corresponding oxetane 652 (via route a) or THF 653 (via route b) was obtained at −78 or 0 °C, respectively. A plausible reaction mechanism involves electrophilic addition of α-oxoesters to allylsilane, followed by cyclization of zwitterionic species 651 to the corresponding oxetanes 652 (Scheme 202).310

4.3. Tetrahydrofurans

Because of their existence in the structure of natural products and drugs, such as steganone, steganol, matairesinol, muricatacin, showdomycin, goniofufurone, kumausyne, amphidinolide C, japonicones M−P, neojaponicone A, and berkelic acid, which exhibit a broad spectrum of biological activities, tetrahydrofurans (THFs) have received great attention in organic synthetic and medicinal chemistry. Metal-catalyzed hydroalkoxylation of γ-hydroxy olefins, Mukaiyama oxidative cyclization, Prins-type cyclization, [3 + 2]-annulation of cyclopropanes and aldehydes, and cyclization of 1,4-diols are among the most useful methods for the construction of THF derivatives. Akiyama et al.312 demonstrated that silyl-substituted THFs 656 were prepared by treatment of (R)-allyldimethyl[(1naphthyl)phenylmethyl]silane (1.2 equiv) with α-oxoesters in toluene in the presence of SnCl4 (1.1 equiv) at −78 °C, for 1 h. Reactions occurred via diastereoselective [3 + 2] cycloaddition and gave the corresponding THFs 656 in 88−94% yields, with 55−85% de. Also, a similar methodology was reported using different allylsilanes in DCM, in which using less bulky substituted allylsilanes led to low yields of cycloadducts. Moreover, allylgermanes were used in the similar [3 + 2] cycloaddition reaction with α-oxoesters, which were conducted in dry toluene at −20 °C, to give germyl-substituted THFs 656 in 48−62% yields. Bearing bulky substituent on germanium is essential to result in a good yield of THFs (Scheme 204).313 For the mechanism, see Scheme 202, route b. Zhang et al.59 described the Cu(OTf)2-catalyzed reaction of glyoxalates with cyclobutanols 27 bearing dihydro-pyrrolyl or

Scheme 202. Synthesis of 4-Silylmethyl-Substituted Oxetane2-carboxylate Derivatives 652a

Scheme 204. Synthesis of THFs 656 via [3 + 2] Cycloaddition Reaction of Allylsilanes and Allylgermanesa

a 1

R = Me, i-Pr, Ph; R2 = i-Pr, t-Bu; R3 = Me, Ph; M = Ti, solvent = toluene, T = 0 °C; 652, 62−95%; R1 = Ph; R2 = t-Bu; R3 = Ph; M = Sn, solvent = DCM, T = 0 °C; 652, 0%; 653, 96%; T = −78 °C; 652, 59%; 653, 19%.

Reaction of dibenzoylacetylene and ethyl 3-bromopyruvate was investigated in the presence of Ph3P in dry ether, to afford ethyl 1-benzoyl-6-(bromomethyl)-2,2,2,4-tetraphenyl-3,7dioxa-2λ5-phosphabicyclo[3.2.0]hept-4-ene-6-carboxylate 655 in 98% yield, as two diastereomers in a ratio of 65/35. The proposed reaction mechanism involves the addition of zwitterion, generated by conjugate addition of Ph3P to

a 1

R = H; R2 = Ph; R3 = Me, Et, i-Pr, t-Bu, c-Hex; M = Si(Me2)[(R)PhCH(1-naphthyl)], solvent = toluene, T = −78 °C; 88−94%, 55− 85% de.312a R1 = H, Me; R2 = Me, Ph; R3 = Et; M = SiMe3, SiMe2Ph, Sit-BuMe2, Sit-BuPh2, solvent = DCM, T = rt or −78 °C; 48− 85%.312b,c R1 = H, Me; R2 = Me, Ph; R3 = Et; M = Gei-Pr3, solvent = toluene, T = −40 or −78 °C, 48−62%.313 214


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Scheme 206. Yb(OTf)3-Catalyzed Synthesis of Fused γLactones 662a

pyranyl moieties in the presence of 5 Å MS in acetone or THF at −10 °C or room temperature. THF 658 was obtained in 71− 96% yields with 5/1−100/1 dr. In a plausible reaction mechanism, cyclobutanol ring expanded by semipinacol rearrangement along with addition to ethyl glyoxalate to form intermediate 657, which underwent ring closure to the corresponding THFs 658 by hemiacetalization (Scheme 205). Scheme 205. Synthesis of THFs 658 via Semipinacol Rearrangementa

a n = 1, R1 = H, TBS; R2 = Et, t-Bu; X = O, NTs; 71−96%; 658a/658b = 5/1−13/1; n = 2, R1 = TMS, TBS; R2 = Et; X = O, 79−85%, 658a/ 658b = 5/1−100/1.

a

n = 0, 1, 2; R1 = H, Me; R2 = H, Me; 23−72%; 662a/662b = 10/1− 1/3.

Scheme 207. Synthesis of 3-Benzoyltetrahydrofuran-2carboxylates 664

The Yb(OTf)3-catalyzed electrophilic cyclization of glyoxalate imines, derived from unsaturated amines, was developed to prepare γ-lactone fused to five-, six-, and seven-membered aza-heterocycles. Reactions were carried out by in situ generation of imine 659 from reaction of an unsaturated amine with ethyl glyoxalate in the presence of anhydrous Na2SO4 in DCM at room temperature for 2.5 h, followed by addition of Yb(OTf)3 and stirring at the same temperature for an additional 12 h, leading to the corresponding fused γlactones 662 in 23−72% yields, with 1/3−10/1 dr. The proposed reaction mechanism involves the electrophilic addition of CC double bound to Yb3+-induced activated imines 659 to generate carbocation 660, which underwent cyclization with carbonyl group to carbocation 661 that was transformed into final product by addition of water and then removal of a molecule of EtOH (Scheme 206). With ethyl pyruvate and ethyl benzoylformate, reaction did not occur, while reaction with diethyl oxomalonate resulted in ethyl 2,5,5trimethyl-7-oxooctahydrofuro[3,4-b]pyridine-7a-carboxylate 663 in 69% yield.314 Reaction of 4-chlorobutyrophenone with methyl phenylglyoxalate was applied to synthesize THF 664, in which treating 4-chlorobutyrophenone with methyl phenylglyoxalate (1.4 equiv) mediated by KOt-Bu (2 equiv) in an aprotic solvent, THF, at −25 °C under Ar atmosphere, resulted in methyl 3benzoyltetrahydrofuran-2-carboxylate 664a in 41% yield, with about 3/1 dr. In addition to 664a, the corresponding t-butyl tetrahydrofuran-2-carboxylate 664b was obtained in 9% via trans-esterification. When reaction was carried out in dry EtOH at −18 °C for 12 h, and then 10 °C for 6 h, the corresponding ethyl THF-2-carboxylate 664c was obtained in 76% yield, with completely trans-esterification (Scheme 207).315

3-Aryl-3-hydroxy-5-methyldihydrofuran-2(3H)-ones 666 were synthesized in two steps, starting by aldol reaction of acetone with arylglyoxalate. Aldol reactions were conducted with 5 equiv of acetone in the presence of chiral diamine XI (10 mol %), and HCO2H (10 mol %) at room temperature for 36− 48 h, and aldol products 665 were obtained in 73−96% yields, with 88−95% ee. Reduction/cyclization of aldol products 665 was performed using NaBH(OAc)3 (3 equiv) in the presence of ACOH in THF at 0 °C for 5 h, followed by heating to room temperature and treating with 1 N HCl for 3 h. The THF derivatives 666 were obtained in 95−96% yields, with 10/1− 98/2 dr (Scheme 208).316 215


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presence of XIII (5 mol %) for 5 h at 45 °C, followed by treatment with NaBH4 in MeOH at 0 °C (Scheme 210).

Scheme 208. Synthesis of 3-Aryl-3-hydroxy-5methyldihydrofuran-2(3H)-ones 666a

Scheme 210. Synthesis of Ethyl 3-(2-Hydroxyphenylamino)2-oxotetrahydrofuran-3-carboxylate 670a

a

Ar = 4-XC6H4 (X = H, NO2), 95−96%.

Also, Mukaiyama aldol reaction of silyl enol ether with ethyl glyoxalate was developed under various conditions, where 2 equiv of Ti(Oi-Pr)4 loading with 20 mol % of dibromobinaphthol ligand XII and 4 Å MS in Et2O at 0 °C led to the best result, and the corresponding aldol adduct 667 was formed in 84% yield, with 98% ee. Obtained aldol product 667 transformed into the corresponding THF 668 in 75% yield, through reduction/lactonization sequence using NaBH4 in the presence of Et2BOMe in THF−MeOH (4/1) at −70 °C, followed by treatment with CSA in DCM at 0 °C to room temperature. The diastereoselectivity of the THF 668 was determined as 6.4/1 (Scheme 209).317 The obtained THF is a synthetic intermediate for psymberin, a marine cytotoxin.

a

R = Et, Bu, n-Hex, Bn, c-HexCH2; conditions, L-proline, PhCO2H, CH3CN, 0 °C, 5 h; 62−72%, >20:1 syn/anti, 99% ee; conditions, (S)XIII, DMAc, 45 °C, 5 h; 59−79%, 1, >20 syn/anti, 99% ee.

Scheme 209. Synthesis of THF 668a

a

Ethyl glyoxalate could be transformed into 5-oxo-3-phenyltetrahydrofuran-2,4-dicarboxylate derivatives 672 in two steps by Stetter/reductive cyclization sequence. By treatment of dimethyl arylidenemalonates with 2 equiv of ethyl glyoxalate, triazolium salt IV-2 (0.2 equiv), and Et3N (1 equiv) in toluene at room temperature for 16 h, under an atmosphere of N2, 3oxo-2-arylpropane-1,1,3-tricarboxylates 671 were obtained in 78−96% yields. Reduction of ketone group of 671 was performed using HCO2H:Et3N 5:2 azeotrope (5 equiv) in the presence of [RuCl2(p-cymene)]2 (2 mol %) and ligand X-2 (8 mol %) as catalyst, in DMF under heating at 75 °C for 16 h, which in situ underwent cyclization to 672 in 82−94% yields, with 89/11−96.5/3.5 ee, and >20/1 dr (Scheme 211). Also, reduction/cyclization sequences were applied using NaBH4 in MeOH at room temperature, followed by treatment with HCO2H:Et3N 5:2 azeotrope (1 equiv) in THF at 70 °C for 1 h.319 Stetter/reductive cyclization sequence was also reported in the construction of two different THFs, tetrahydrofuran-2carboxylate 675 and tetrahydrofuran-2-ol 676. Stetter reaction was applied between β,γ-unsaturated α-oxoesters and furfural (1.5 equiv) using 5 mol % of triazolium salt IV-3 and DIPEA (1 equiv) in DCM at 0 °C, to give ethyl 5-(furan-2-yl)-2,5dioxopentanoates 673 in 90−92% yields. By reduction of 673 with superhydride (2.01 equiv) in dry THF at −98 °C under inert atmosphere, and then slowly warming to −10 °C over 2 h, ethyl 4-aryl-5-(furan-2-yl)-2,5-dihydroxypentanoates 674 were obtained. The 674a was converted to tetrahydrofuran-2carboxylate 675 in 65% yield by refluxing with pyridinium ptoluenesulfonate (PPTS, 5 mol %) in benzene for 5 h. Further reduction of 674b using LiAlH4 (1 equiv) in dry THF at 0 °C

R = CHCHCO2Et, 75% (for two last steps).

The synthesis of ethyl 3-(2-hydroxyphenylamino)-2-oxotetrahydrofuran-3-carboxylate derivatives 670 was developed by Kano et al.318 via diastereo- and enantioselective Mannich reaction of ketimine 669, prepared by cyclocondensation of 2aminophenol with diethyl oxomalonate in toluene in the presence of 4 Å MS at 70 °C for 6 h, with aldehydes using axially chiral aminosulfonamide XIII, or L-proline as organocatalysts. Reactions were performed either using 0.1 mmol 669 and 5 equiv of aldehyde in CH3CN in the presence of L-proline (20 mol %) and benzoic acid (10 mol %) for 5 h at 0 °C, or using 0.1 mmol 669 and 3 equiv of aldehyde in DMAc in the 216


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boxylate in 83% yield (Scheme 213a). Also, [2 + 2 + 1] cyclocoupling manner was applied for the reaction of benzofuran-2,3-dione derivatives with CO and ethylene. Under similar conditions, reaction occurred at both ketone and ester carbonyl groups, depending on the steric effects of the substituent at the C-4 position, as the bulky t-Bu substituent retarded the reaction at the ketone moiety. With 4-H-, 4-Me-, and 4-MeO-substituted benzofuran-2,3-diones, reactions mostly took place at the ketone group, leading to 2H,3′H-spiro[benzofuran-3,2′-furan]-2,5′(4′H)-diones 678a as major products, while reaction of 4-t-Bu-substituted benzofuran-2,3-dione afforded the corresponding 3H,3′H-spiro[benzofuran-2,2′furan]-3,5′(4′H)-dione 678b as a sole product in 94% yield. In addition to ethylene, cyclopentene and cyclohexene worked well in the reaction and gave the corresponding 3H,3′Hspiro[benzofuran-2,2′-furan]-3,5′(4′H)-diones 679 as two diastereoisomers in a ratio of 9/1. Also, reaction using acetylenic compounds was investigated, in which products 680 were obtained by reacting at the ester moiety, regioselectively (Scheme 213b).322 Rh-induced reductive coupling of pent-4-en-2-yn-1-ol with methyl pyruvate resulted in the formation of 4-allylidene-3hydroxy-3-methyldihydrofuran-2-one 681. Reaction was carried out by heating a solution of methyl pyruvate with pent-4-en-2yn-1-ol (2.15 equiv) in DCE in the presence of Rh(COD)2OTf (1.9 mol %) and (R)-xylyl-WALPHOS III-2 (2.1 mol %) and triphenylacetic acid (1.9 mol %) at 60 °C, under an atmosphere of H2, and 681 was obtained in 80% yield with 91% ee (Scheme 214).323 Stannyl-substituted butyl 2,7-dioxabicyclo[3.2.0]hept-3-ene6-carboxylate 682, obtained from photoaddition of tributyl(furan-2-yl)stannane to butyl glyoxalate in benzene, was transformed into 3-hydroxytetrahydrofuro[2,3-b]furan-2(6aH)-one 684 in four steps. A Stille coupling of 682 with bromoveratrole in the presence of (Ph3P)4Pd in THF, followed by hydrolysis with 0.1 N HCl in THF and then reduction using NaBH4−CeCl3, led to the corresponding lactol 683 in 50% yield for two last steps. By treatment of lactol 683 with Otera’s distannoxane trans-esterification catalyst in toluene at 50 °C, furo-furan 684 was obtained in 68% yield as a mixture of two stereoisomers in a 1/1 ratio (Scheme 215).324 By esterification of some oxime and hydrazines of glyoxalic acid with β-bromo alcohols, using DCC and DMAP in dry DCM at room temperature for 12 h, the corresponding αoxime or α-hydrazines of 2-bromoethyl glyoxalate derivatives 685 were obtained, which underwent radical cyclization to furnish dihydro-2(3H)-furanones 686. Radical cyclization process was carried out under Ar atmosphere using Bu3SnH or Ph3SnH and AIBN in toluene, under heating at 110 °C for 1−4 h. Dihydro-2(3H)-furanone derivatives 686 were obtained in 49−85% yields. Also, 2-(phenylselanyl)cyclohexanol was used under similar conditions, which led to the corresponding THF-2-one in only 20% yield (Scheme 216).325 Additionally, there are some multistep processes for the construction of THF derivatives starting from α-oxoesters.326

Scheme 211. Synthesis of 5-Oxo-3-phenyltetrahydrofuran2,4-dicarboxylate Derivatives 672a

a

Ar = XC6H4 (X = H, 4-Cl, 2-Me, 4-Me, 4-MeO, 4-CN), 3,4(OCH2O)C6H3, 2-furyl, N-Ts-indol-3-yl, N-Boc-indol-3-yl; 82−94%, 89/11−96.5/3.5 ee, >20/1 dr.

for 10 min, followed by reacting with NaIO4 (2 equiv) in a mixture of acetone/water (2.2/1) at 0 °C for 10 min, led to tetrahydrofuran-2-ol 676 in 73% yield (Scheme 212).320 Scheme 212. Synthesis of Tetrahydrofuran-2-carboxylate 675 and Tetrahydrofuran-2-ol 676a

a

674a, Ar = 4-BrC6H4; 674b, Ar = Ph.

Ru3(CO)12-catalyzed [2 + 2 + 1] cyclocoupling of αoxoesters, ethylene, and CO to afford 5-oxo-tetrahydrofuran-2carboxylates 677 was developed by Tobisu et al.321 Reactions were carried out by heating a solution of α-oxoesters in toluene under the pressure of ethylene (3 atm) and CO (5 atm) in the presence of Ru3(CO)12 (2.5 mol %) and P(4-CF3C6H4)3 (7.5 mol %) at 160 °C for 20 h, leading to 677, in 28−99% yields. In the absence of P(4-CF3C6H4)3, yields were low, ranging from 0% to 36%. Under similar reaction conditions, diethyl oxomalonate led to diethyl 5-oxodihydrofuran-2,2(3H)-dicar-

4.4. Dihydrofurans

Dihydrofuran moieties are frequently found in natural products, such as (+)-furanomycin, salviasperanol, diplobifuranylone B, cryptoresinol, ascorbic acid (vitamin C), griseolic acid, αviniferin, dibalanocarpol, and kallolide, with a wide range of biological activity, such as anticonvulsant, antifungal, antiinflammatory activities, etc. Also, they have application as 217


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Scheme 213. Synthesis of Tetrahydrofuranons 677−680 via [2 + 2 + 1] Cyclocouplinga

a 677, R1 = Me, CF3, 4-XC6H4 (X = H, MeO, CF3), Ph(CH)2, CO2Me; R2 = Me, Et; 28−99%; R1 = Me, OMe; R2 = H; 678, 83−85% (a/b = 74/ 26−64/36); R1 = t-Bu; R2 = H; 678b, 94%; R1 = H; R2 = t-Bu; 678a, 73%; n = 1, 2; 679, 41−89% (∼9/1 dr); R3 = Me, Ph; R4 = Ph, TMS; 680, 83− 95%.

Scheme 214. Synthesis of 4-Allylidene-3-hydroxy-3methyldihydrofuran-2-one 681

Scheme 216. Synthesis of Dihydro-2(3H)-furanone Derivatives 686a

X = Br, SePh; R1 = H, n-Pr, Ph; R2 = H, n-Pr, Ph; R1−R2 = (CH2)n, n = 3, 4, 5; 685, 56−100%; 686, 20−85%. a

O-Protected isotetronic acid derivatives 688 were prepared by aldol/lactonization/O-protection sequence of α-oxoesters. Reactions proceeded by DBU/Et3N-mediated homoaldol reaction of α-oxoesters, followed by lactonization to give 687 and then protection using various electrophiles. Reactions were performed using 10 mol % of DBU and 42.5 mol % of Et3N in

building blocks for the synthesis of other biologically active compounds and natural products. There are many reported routes to dihydrofuran derivatives, such as intramolecular hydroalkoxylation of hydroxyallenic esters, intramolecular alkyne-carbonyl coupling, ring-closing metathesis reaction, and [4 + 1] cycloadditions of enones with diazo compounds.

Scheme 215. Synthesis of 3-Hydroxytetrahydrofuro[2,3-b]furan-2(6aH)-one 684

218


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intermediate 692. Using a combination of VIII-2 and a protic acid under different conditions, such as various acids and solvents, the corresponding homoaldol/lactonizations product 688 (R = H) was obtained in 31−93% yields, which exist in two tautomeric forms (Scheme 219).329

DCM at room temperature for 0.5 h, followed by addition of an electrophile and stirring at the same temperature overnight. Also, the unprotected isotetronic acid derivatives were synthesized using TMSCl as electrophile, which underwent deprotection during workup using a saturated aqueous solution of NH4Cl and NaCl (Scheme 217).327

Scheme 219. Asymmetric Homoaldol Reaction of Ethyl Pyruvate Using BB as Catalysta

Scheme 217. Synthesis of Isotetronic Acid Derivatives 688a

a 1 R = H, Me, n-Pr, EtO2CCH2, MeO2CCH2; R2 = Me, Et; R3 = Et, nBu, s-Bu, 2-Hex, Bn, Ph(CH2)3, Cl(CH2)2, allyl, 2-Me-2-propen-1-yl, propargyl, styryl-CH2, Ts, R4CO (R4 = Me, t-Bu, Bn, EtO2C(CH2)2, EtO2C(CH2)4, 4-ClC6H4, 4-MeOC6H4, propen-1-yl, styryl, Ts, MeSO2), i-Pr3Si; X = Cl, Br, OTs, OMs; 688, 22−89%; R3X = TMSCl; 688, 61−85%.

Et3N-catalyzed ABB′ three-component reaction of αoxoesters with methyl propiolate was reported by Tejedor et al.328 The reactions were performed using 2 equiv of αketoester and Et3N (20 mol %) in DCM at 0 °C for 1−4 h, leading to the corresponding 4-(3-methoxy-3-oxoprop-1enyloxy)-5-oxo-2,5-dihydrofuran-2-carboxylates 691 (isotetronic acid derivative) in 80−90% yields. Reactions proceeded by formation of allenolate 689 and then ammonium enolate 690, which underwent homoaldol reaction with another molecule of α-ketoester to generate aldol adduct. By a sequential lactonization−deprotonation reaction, leading to enol form 687, followed by a tandem Michael-addition− elimination on the β-ammonium acrylate counterion 690b, isotetronic acid derivatives 691 were produced (Scheme 218). Also, asymmetric homoaldol reaction of ethyl pyruvate was investigated using (S)-(+)-1-(2-pyrrodinylmethyl)pyrrolidine VIII-2 (30 mol %), at different conditions. Reaction in DMSO at room temperature resulted in ethyl 2-methyl-5oxo-2,5-dihydrofuran-2-carboxylate 693 in 74% yield, through

a

693, 74%; 688 (R = H), protic acid = TFA, TfOH, AcOH; solvent = DMSO, DMF, MeCN, i-PrOH; 31−93%.

Gathergood et al.330 described the cross-aldol reaction of ethyl trifluoropyruvate with different substituted ethyl pyruvates catalyzed by (S)-t-Bu-BOX−Cu(OTf)2 (VII-2−Cu(II), 10 mol %) in the presence of N,N-dimethyl-p-toluidine (DMT, 5 mol %) in Et2O at room temperature, leading to the corresponding aldol adducts, which transformed into O-TBDMS protected isotetronic acid derivatives 694 in 28−66% yields, when treated with TBDMSCl in DCM in the presence of Et3N at room temperature for 24−48 h (Scheme 220). Borinic acid-catalyzed cross-aldol/lactonization reaction of phenylpyruvic acid with ethyl pyruvate was performed in water at 23 °C, which gave the corresponding isotetronic acid derivative in 51% yield.331 Also, reaction of dimethyl malonate with ethyl pyruvate in the presence of ZnCl2 was developed to

Scheme 218. Synthesis of Isotetronic Acid Derivatives 691a

a 1

R = H, Me, Et, n-Hept, t-Bu, Bn, MeO2CCH2; R2 = Me, Et; 80−90%. 219


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Scheme 220. Synthesis of O-TBDMS Protected Isotetronic Acid Derivatives 694 via Cross-Aldol Reactiona

a

Scheme 222. Synthesis of 1,6-Dioxaspiro[4.4]-non-3-en-2ones 701a

R = Me, i-Bu, n-Pent, c-Hex-CH2, allyl-CH2; 28−66%.

synthesize dimethyl 2-(2-(ethoxycarbonyl)-4-methyl-5-oxo-2,5dihydrofuran-2-yl)malonate.332 The reaction of alkanoic acid anhydrides with α-oxoesters was developed by Kishorebabu and Periasamy333 to give maleic anhydrides 697. By treatment of α-oxoesters with 2 equiv of alkanoic acid anhydrides, TiCl4 (2 equiv), and n-Bu3N (1.2 equiv) in DCE under N2 atmosphere, and refluxing for 12 h, maleic anhydrides 697 were obtained in 62−92% yields. TiCl4/ n-Bu3N-induced formed titanium-enolate 695 attacked the αoxoesters generating intermediate 696, which underwent dehydration and cyclization to maleic anhydrides 697. However, reaction of ethyl benzoylformate with phenyl acetyl chloride under the same reaction condition led to diphenylmaleic anhydride in 95% yield (Scheme 221).

a 1 R = H, n-Pr, Ph; R2 = Me, Ph; R3 = Me, EtO2C, 4-XC6H4 (X = H, F, Cl, Me, MeO); R4 = Me, Et; 701a, 41−85%; Ar = XC6H4 (X = 3-F, 4F, 2-Cl, 4-Cl, 2-Br, 4-Br, 2-Me, 3-CF3); 701b, 29−72%; 702, 15−40%.

Scheme 221. Synthesis of Maleic Anhydrides 697a

reaction conditions, in addition to 1,6-dioxaspiro[4.4]-non-3en-2-ones 701b, the corresponding 2-(7-oxo-9-aryl-1,6dioxaspiro[4.4]non-8-en-4-ylidene)acetates 702 were obtained in 15−40% yields, via second aldol reaction before the formation of cyclic hemiacetal (Scheme 222b).335 Ph3P-mediated reaction of methyl arylglyoxalates with dimethyl acetylenedicarboxylate (DMAD) (1.2 equiv) was reported in toluene at 70 °C, leading to 4-methoxy-5-oxo-2aryl-2,5-dihydrofuran-2,3-dicarboxylates 705 in 11−94% yields. Highly electron-attracting-substituted arylglyoxalate, methyl 4nitrophenylglyoxalate, led to high yield. Reactions occurred by conjugate addition of Ph3P to DMAD to form zwitterion 703, which nucleophilically attacked glyoxalate, and then cyclized to intermediate 704. Triphenylphosphonium group was replaced with methoxy via nucleophilic substitution by the addition (route blue)−elimination (route red) mechanism (Scheme 223).336

a

X = RCH2CO2; R = H, Me; Ar = 4-XC6H4 (X = H, Me, MeO); 62− 92%; X = Cl, R = Ar = Ph; 95%.

Reaction of cyclopropyl ketones with α-oxoesters was reported to afford 1,6-dioxaspiro[4.4]-non-3-en-2-ones 701a in 41−85% yields. Various Lewis acids were investigated, and 1 equiv of SnCl4 was selected due to the best results. Reactions were performed using 2 equiv of cyclopropyl ketones in DCE at 40 °C under Ar atmosphere. The proposed reaction mechanism involves hydrolysis of cyclopropyl ketone using ambient water in the presence of SnCl4 to give γ-hydroxy ketone 698, which underwent aldol-type reaction with α-ketoester (699), followed by nucleophilic addition of hydroxy group to ketone generating cyclic hemiacetal 700. By intramolecular trans-esterification with hemiacetal hydroxy, the corresponding 701a was obtained (Scheme 222a).334 Using 2 equiv of ethyl glyoxalate as αoxoester component and TMSOTf as Lewis acid under similar

Scheme 223. Synthesis of 5-Oxo-2,5-dihydrofuran-2,3dicarboxylates 705a

a

220

Ar = Ph, 4-NO2C6H4; 11−94%. dx.doi.org/10.1021/cr5004216 | Chem. Rev. 2015, 115, 151−264

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conjugate addition to β,γ-unsaturated α-oxoesters. Intermediate 712 underwent a proton transfer, leading to ylide 713, and subsequent addition of generated anion to ketone moiety of αoxoesters to give intermediate 714, which was transformed into final bicyclic dihydrofurans 716 by intramolecular SN2′ reaction (715). High diastereoselectivity arose from the chairlike transition stat 712, due to interaction between phosphine and the ester group of α-oxoesters (Scheme 225).338 Also, similar bicyclic dihydrofuran derivatives 722 were prepared by Ph3P-catalyzed [3 + 2] cycloaddition reaction of allenoate 717 with β,γ-unsaturated α-ketoester. Reactions were carried out by stirring a solution of β,γ-unsaturated α-ketoester with 1.5 equiv of 717 in the presence of 20 mol % of Ph3P in CHCl3 at 60 °C for 6−120 h, to afford the corresponding bicyclic dihydrofurans 722 in 39−98% yields. The transformation was initiated by nucleophilic addition of Ph3P into allenoate 717, generating zwitterion 718, which underwent Michael addition to β,γ-unsaturated α-ketoester, followed by Hshift to form intermediate 719. Nucleophilic addition, followed by cyclization via alkoxide addition (720), gave intermediate 721, which by proton transferring and then β-elimination led to the formation of bicyclic dihydrofurans 722 (Scheme 226).339 Esmaeili and Zendegani340 described the three-component reaction of isocyanides, dialkyl acetylenedicarboxylate (DAAD), and phenylglyoxalates to give γ-iminolactones, 5-(alkylimino)2-phenyl-2,5-dihydrofuran-2,3,4-tricarboxylates 724. Reactions were carried out by heating a solution of phenylglyoxalate, DAAD (1.1 equiv), and isocyanides (1.1 equiv) in refluxing dry benzene for 4 h, under Ar atmosphere. Reactions proceeded by addition of isocyanides to DAAD, leading to zwitterions 723, which were converted to iminolactones 724 via addition to glyoxalate and then cyclization (Scheme 227a). By applying a similar reaction using benzofuran-2,3-diones in DCM under reflux conditions, dialkyl 5′-(alkylimino)-3-oxospiro[benzofuran-2(3H),2′(5′H)-furan]-3′,4′-dicarboxylates 725 were obtained in 55−75% yield, via addition to the carbonyl of the ester moiety (Scheme 227b).341 The synthesis of 2,4-disubstituted 3-hydroxy-5-oxo-2,5dihydrofuran-2-carboxamides 727 was achieved by threecomponent Passerini reaction followed by Dieckmann condensation. Reactions were carried out by addition of isocyanide (1 equiv) to a solution of equimolar amounts of 2-substituted acetic acids and α-ketoester in THF at room temperature, and Passerini adducts 726 were obtained within 12−24 h, which underwent Dieckmann condensation using LDA (2 equiv) in dry THF under N2 atmosphere at −78 °C for

Xie et al.337 reported the synthesis of 2,3-dihydrofurans 710 using Morita−Baylis−Hillman carbonates 706. Subjecting β,γunsaturated α-oxoesters with 706 (2 equiv) in DMF or DMSO in the presence of Ar3P (10−20 mol %) at 80 °C for 0.6−3 h gave 2,3-dihydrofurans 710 in 66−96% yields. The proposed reaction mechanism involves the formation of the allylic phosphorus ylide 707, via an addition−elimination and deprotonation process, that nucleophilically attached to β,γunsaturated α-oxoesters leading to the intermediate 708, which converted to 709 through proton transfer. Intermediate 709 underwent cyclization through addition of oxygen anion to double bond, to afford 2,3-dihydrofurans 710, along with elimination of Ar3P (Scheme 224). Scheme 224. Synthesis of 2,3-Dihydrofurans 710 Using Morita−Baylis−Hillman Carbonates 706a

a 1

R = CO2Me, CO2Et, CO2Bu, CN; R2 = Me, i-Pr, Ment; Ar1 = XC6H4 (X = H, 3-Cl, 4-Cl, 3-Br, 4-Br, 3-Me, 4-Me, 4-MeO, 4-NO2), 2,4-Cl2C6H3, 3,4-(OCH2O)C6H3; Ar3P = Ph3P, (4-ClC6H4)3P; 66− 96%.

The Bu3P-catalyzed domino reactions of activated conjugated dienes 711 with β,γ-unsaturated α-oxoesters were investigated, by treatment of equimolar amounts of 711 and β,γ-unsaturated α-oxoesters with Bu3P (8 mol %) in CHCl3 at room temperature for 0.3−12 h under an atmosphere of N2, which resulted in diastereoselective formation of bicyclic dihydrofuran derivatives 716 in 56−80% yields. In the proposed reaction mechanism, intermediate 712 was formed by nucleophilic addition of Bu3P to the enoate double bond, followed by Scheme 225. Synthesis of Bicyclic Dihydrofuran Derivatives 716a

a

R = Et, Bn; Ar1 = 4-XC6H4 (X = H, Cl, Me), 2,4-Cl2C6H3, 2-furyl, 2-thienyl; Ar2 = XC6H4 (X = H, 4-Br, 3-Me, 4-Me, 4-MeO), 3,4-(OCH2O)C6H3, 2-naphthyl; 56−80%. 221


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Scheme 226. Synthesis of Bicyclic Dihydrofuran Derivatives 722a

a 1 R = Me, Ph; R2 = Me, Et, Bu, Bn; R3 = Me, Et, i-Pr; Ar = XC6H4 (X = H, 4-F, 4-Cl, 2-Br, 3-Br, 4-Br, 2-Me, 3-Me, 4-Me, 4-MeO, 4-NO2), 2,4Cl2C6H3, 1-naphthyl, 2-furyl, 2-thienyl, styryl; 39−98%.

Scheme 227. Synthesis of γ-Iminolactones 724,725a

a 724, R1 = Me, i-Pr, t-Bu; R2 = t-Bu, c-Hex; R3 = Me, Et; 66−92%; 725, R1 = Me, Et, i-Pr; R2 = t-Bu, c-Hex, t-BuCH2C(Me)2; R4 = H, Me; R5 = H, Me; 55−75%.

halopropenal, which attacked the ketone group of β,γunsaturated α-oxoesters to form intermediate 730. The intermediate 730 underwent acylation reaction (731) to give 732a, and NHC catalyst was regenerated. Reaction of βhalopropenal 728 with ethyl 2-oxo-4-phenylbut-3-ynoate under similar conditions led to the corresponding 2,5-dihydrofuran-2carboxylates 732a in 78% yield (Scheme 229a). The synthesis of similar 5-oxo-2-(2-arylprop-1-enyl)-2,5-dihydrofuran-2-carboxylate scaffolds 732b was achieved in 27−82% yields, by NHC XV-catalyzed reaction of 3-arylpropiolaldehyde with β,γunsaturated α-oxoesters (1.5 equiv) using 20 mol % of NHC, 40 mol % of LiOt-Bu, and LiCl (1 equiv) in THF at room temperature, under an atmosphere of Ar. Reactions proceeded via Breslow intermediate 733, which could be converted to allenolate 734 and attacked the ketone moiety of α-ketoester, con-coordinated to Li+, to give intermediate 735. By tautomerization/acylation of 735, 2,5-dihydrofuran-2-carboxylates 732b were produced along with regeneration of NHC XV (Scheme 229b). The reaction with methyl phenylglyoxalate did not occur as well, and led to the corresponding 2,5dihydrofuran-2-carboxylate only in 8% yields.344 By hydrolysis of the ester moiety of vinyl azides 12 (see Scheme 5) with NaOH in a mixture of dioxane/water at room temperature for 4−25 h, followed by acidification using HCl 10%, 5-aryl-4-azido-5-hydroxy-3-methyl-2-oxo-2,5-dihydrofurans 736 were formed in 50−59% yields (Scheme 230).52 The synthesis of 5-alkylidenetetronates 738 was reported by Schobert et al.345 via reaction of α-ketoester with ketenylidene-

0.5−1 h, and then room temperature for 1 h. The final products 727, possessing HIV-1 protease inhibitory activity, were obtained in 12−95% yields (Scheme 228).342 Scheme 228. Synthesis of 3-Hydroxy-5-oxo-2,5dihydrofuran-2-carboxamides 727a

a 1

R = Bn, PhCH(Me), Ph(CH2)2, 3,4,5-(MeO)3C6H2CH2, 4-tBuC6H4, 4-biphenyl, indol-3-yl, MeNH, N(Me)Boc; R2 = Me, i-Pr, Ph(CH2)2; R3 = Me, c-Pr, n-Bu, t-Bu, t-BuCH2, MeO(CH2)2, 4-tBuC6H4CH2, 4-ClC6H4(CH2)2, 12−95%.

In 2010, Wu et al.343 reported the synthesis of 5-oxo-2-(2arylprop-1-enyl)-2,5-dihydrofuran-2-carboxylates 732a from reaction of β,γ-unsaturated α-oxoesters with β-halopropenals 728 (1.5 equiv) in the presence of 10 mol % NHC XIV, and DBU (1.5 equiv) in THF at −20 °C for 2−12 h. The proposed reaction mechanism involves the generation of β-chloroconjugated Breslow intermediate 729, by action of NHC on β222


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Scheme 229. Synthesis of 5-Oxo-2-(2-arylprop-1-enyl)-2,5-dihydrofuran-2-carboxylates 732a

a 1

R = n-Pr, XC6H4 (X = H, 4-F, 4-Cl, 2-Me, 4-MeO), 2-furyl, styryl; R2 = Me, Et; Ar1 = 4-XC6H4 (X = H, Br, MeO, NO2), styryl; X = Cl, Br; 732a, 21−81%; R = XC6H4 (X = H, 4-Cl, 4-Me, 2-MeO, 3-MeO, 4-MeO, 4-Me2N), 3,4-Me2C6H3, 2-furyl, 3-thienyl, 2-naphthyl, n-Pent, c-Hex, (CH2)2OTHP, (CH2)2OTBS, (CH2)3OTBS, (CH2)3OBn, (CH2)2Ph, (CH2)3N(Ts)Et; Ar = XC6H4 (X = H, 4-Cl, 2-Me, 4-Me, 4-MeO), 3,4Me2C6H3; 732b, 27−82%.

3-Hydroxybutenolides 740 were synthesized by highly stereoselective oxy-Michael addition of (6S)-methyl δ-lactol to γ-substituted β,γ-unsaturated α-oxoesters followed by acidmediated deprotection. Deprotonation of (6S)-methyl δ-lactol with KHMDS in THF at −78 °C in the presence of 18-crown-6 (1.0 equiv), followed by addition of α-oxoesters (0.67 equiv) and stirring at the same temperature for 2 h, then quenching with AcOH (2 equiv), furnished oxy-Michael adducts 739 in 68−81% yields, with >95% dr. Subjecting oxy-Michael adducts 739 with MeOH in the presence of amberlyst-15 resin led to the removal of THP-protecting group, and subsequent ring closure and enolization to 3-hydroxybutenolides 740 in 87− 97% yields, with >95% dr (Scheme 232).346 Interrupted Feist−Bénary (IFB) reaction of ethyl bromopyruvates with β-dicarbonyl compounds, such as 1,3-cyclohexadione, acetyl acetone, and ethyl acetoacetate, was described using various thiourea derivatives XVI-1 and XVI-2 as organocatalysts. The reactions were conducted using 10 mol

Scheme 230. Synthesis of 5-Hydroxy-2-oxo-2,5dihydrofurans 736a

a

Ar = Ph, 4-biphenyl; 50−59%.

triphenylphosphorane (1.3 equiv) in toluene under reflux conditions for 12 h. O-Acylylidation of the enol tautomer of αketoester (737), followed by intramolecular Wittig reaction, led to 5-alkylidenetetronates 738 in 25−45% yields (Scheme 231). Scheme 231. Synthesis of 5-Alkylidenetetronates 738

Scheme 232. Synthesis of 3-Hydroxybutenolides 740a

a

a 1

a

R = H, Me; R2 = Me, Et, i-Pr; 25−45%. 223

R = t-Bu, n-Pent, c-Hex, Ph; 87−97%, >95% dr. dx.doi.org/10.1021/cr5004216 | Chem. Rev. 2015, 115, 151−264

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Scheme 233. Synthesis of 2,3-Dihydrofuranes 741−743a

741a, R1 = R2 = Me; R3 = H; 83−92%, 36−64% ee; 741a,b, R1 = Me; R2 = OEt; R3 = H; 78−91%, b/a = 87/13−94/6; 742, R1−R2 = (CH2)3; R3 = H; 89−94%, 64/36−97/3 dr, 4−65% ee. a

% of organocatalyst in THF at −78 °C. In the case of 1,3cyclohexadione, the corresponding ethyl 3-hydroxy-4-oxo2,3,4,5,6,7-hexahydrobenzofuran-3-carboxylates 742 were obtained in 89−94% yields, with 64/36−97/3 dr, and 4−65% ee. Reactions with acetyl acetone led to ethyl 4-acetyl-3-hydroxy-5methyl-2,3-dihydrofuran-3-carboxylate 741, while reaction with ethyl acetoacetate afforded two isomers, diethyl 3-hydroxy-5methyl-2,3-dihydrofuran-3,4-dicarboxylate 741a and ethyl 4acetyl-5-ethoxy-3-hydroxy-2,3-dihydrofuran-3-carboxylate 741b, via cyclization with ketone and ester moieties, respectively, with 741b as the major product (Scheme 233a).347 Also, phthalazine- and pyrimidine-cinchona alkaloid derivatives were used as the catalyst for the similar IFB reaction.348a,b Moreover, ionic liquids were developed for IFB reaction to produce the corresponding hydroxy dihydrofurans, which were converted to furan derivatives by heating via elimination of a water molecule.348c Similar methodology was reported for the construction of (2S,3R)-ethyl 3-hydroxy-4-oxo3,4,5,7-tetrahydro-2H-spiro(benzofuran-6,2′-[1,3]dithiane)-3carboxylate 743, an intermediate to synthesize variabilin (744a) and glycinol (744b), members of the phytoalexin family (Scheme 233b).348d By treatment of 2-bromo-3-(bromomethyl)-1,4-dimethoxyanthracene-9,10-dione 745 with 3 equiv of ethyl glyoxalate or ethyl pyruvate in the presence of TDAE (1 equiv) in anhydrous THF at −20 °C for 1 h and then room temperature for 2 h, nucleophilic addition to ketone moiety of α-oxoesters took place, and the corresponding α-hydroxy esters 746 were obtained in 46−67% yields, which underwent intramolecular Buchwald reaction, when subjected to Pd(OAc)2 (10 mol %), p-tolyl-BINAP (15 mol %), and 1.4 equiv of K2CO3 in toluene at 80 °C. Reactions were completed in 5−6 h, and ethyl anthra[2,3-b]furan-2-carboxylates 747 were formed in 70−84% yields (Scheme 234).349 Tsuchida et al.350 reported the synthesis of t-butyl 1,2dihydro-1-oxaazulene-3-carboxylates 749 by reaction of t-butyl aryloxypyruvates 748 with TMSC(Li)N2 (2 equiv) in Et2O at −78 °C for 1 h, and then under reflux conditions for 2 h. Reactions proceeded by in situ generation of alkylidenecarbenes by action of TMSC(Li)N2 on the ketone moiety of α-

Scheme 234. Synthesis of Ethyl Anthra[2,3-b]furan-2carboxylates 747a

a

R = H, Me; 70−84%.

ketoester, followed by cycloaddition to the benzene ring with subsequent ring expansion to oxaazulene 749 (Scheme 235). Scheme 235. Synthesis of t-Butyl 1,2-Dihydro-1-oxaazulene3-carboxylates 749a

a

R = 5-(H, Me), 6-(H, Br, Me, MeO, CF3); 7-(H, Me); 20−31%.

Quinolinylfuropyrazolone 751 was synthesized in 71% yield, by reaction of pyrazolylquinolinone 750 with ethyl pyruvate in the presence of NaOAc in glacial AcOH under reflux condition (Scheme 236).351 224


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was demonstrated that the hydrolysis of ketal moiety of nitroaldol adduct led to intermediate 756 by ring opening of 1,3-dioxolane, which converted, by heterocyclization (757) and then removing a molecule of ethylene glycol, to cyclic oxonium intermediate 758. Deprotonation, followed by elimination of nitrous acid, resulted in final furans 759 (Scheme 238).353

Scheme 236. Synthesis of Quinolinylfuropyrazolone 751

4.6. Dioxolanes

1,3-Dioxolanes have received great attention due to their presence in biologically active compounds such as dioxolane nucleosides with anticancer activity, and also they are a valuable synthetic intermediate as a protecting group of carbonyl compounds. Some synthetic routes leading to dioxolane derivatives are 1,3-dipolar cycloaddition reaction of carbonyl ylides with aromatic aldehydes, and Pd-catalyzed cyclization of 2-hydroxyethyl vinyl ethers. 7-(Chloromethyl)-5-methyl-3,6,8-trioxabicyclo[3.2.1]octane 761 was synthesized via condensation of threo-1,4-dichloro-2,3butanediol with ethyl pyruvate along with azeotropic removal of water to give 760, followed by LiAlH4-mediated reduction of ester moiety and then cyclization by SNi reaction (Scheme 239).354 The [3 + 2] cycloaddition reaction between carbonyl ylides 762 generated from 2,2-dicyano-3-aryloxirane and ethyl pyruvate or ethyl phenylglyoxylate was developed by Bentabed-Ababsa et al.355 in 2008. Reactions were carried out either by thermal heating in anhydrous toluene under reflux conditions and atmosphere of Ar or by MW heating under solvent-free conditions at 180 °C, and substituted dioxolanes 763 were obtained as a mixture of two isomers a and b in a ratio of 38/62−64/36 or 41/59−59/41, determined using 1H NMR spectra of the crude mixture, respectively. The major isomers were isolated in 18−56% yields (Scheme 240). Asymmetric cycloaddition reaction of carbonyl ylides 765, Rh2(OAc)4-induced in situ generated from diazoacetophenones 764, with α-oxoesters catalyzed by Sc(III)-Pybox-i-Pr-TFA complex was reported to afford 6,8-dioxabenzo[c]bicyclo[3.2.1]octan-2-ones 766. Reactions were carried out by addition of α-oxoesters, Rh2(OAc)4 (1 mol %), and TFA (5 mol %) to a mixture of (S,S)-Pybox-i-Pr VII-4 (5 mol %), Sc(OTf)3 (5 mol %), and 4 Å MS in DCM and cooling the mixture to −25 °C, followed by adding a solution of diazoacetophenone 764 (0.5 equiv) in DCM over a period of 1 h. 6,8-Dioxabenzo[c]bicyclo[3.2.1]octan-2-ones 766 were obtained in 77% to quantitative yields, with an exo/endo ratio of 68/32−97/3 (Scheme 241).356 Rh2(OAc)4-catalyzed tandem carbonyl ylide formation− cycloaddition reaction of diazoesters 767 with methyl glyoxalate was carried out in toluene at 110 °C, for 1 h, affording corresponding trimethyl 6,8-dioxabicyclo[3.2.1]octane-1,2,7-tricarboxylates 768 in 54−63.5% yields, a synthetic intermediate of zaragozic acid 769 (Scheme 242).357 Oxidative carbonylation of prop-2-ynyl α-oxoesters 770 was studied, in which by treatment of 770 with PdI2 (3.3 mol %) and KI (33 mol %) under a pressure of a 3/1 mixture of CO and air in MeOH at 65 °C for 24−30 h were obtained 2methoxy-5-(alkoxycarbonyl)methylene-[1,3]dioxolane derivatives 771 in 58−61% isolated yields. Reactions occurred by nucleophilic addition of MeOH to ester with subsequent 5-exodig cyclization and methoxycarbonylation (Scheme 243).358 As shown in Scheme 218, Et3N-catalyzed ABB′ threecomponent reaction of β-monosubstituted α-oxoesters with methyl propiolate gave 4-(3-methoxy-3-oxoprop-1-enyloxy)-5-

4.5. Furans

Furans constitute an important class of heterocycles, because they are found in many natural products and pharmaceuticals, such as bipinnatin B and J, ranitidine, perillene, furfuryl thiol, nitrofurazone, teulepicin, teubrevin G, furan fatty acids, gersolanes, pseudopteranes, rosefuran, agassizin, furodysin, and (−)-(Z)-deoxypukalide, which exhibit a broad range of biological activities. They are also useful as starting materials to produce pharmaceutically important compounds. Although a variety of furan syntheses are known, such as Paal−Knorr reaction, catalytic hydration of 1,3-diynes, intramolecular cyclization of 3-alkyne-1,2-diols, and cycloisomerization of acetylenic epoxides, allenones, and α-propargyl-β-keto esters, the development of new and convenient strategies is of considerable interest. Highly functionalized aminofuran derivatives 753 were synthesized in 70−90% yields from the reaction of alkyl isocyanides with dimethyl 2-oxo-3-arylidenesuccinates. Reactions were carried out by addition of an equimolar amount of isocyanide to a solution of dimethyl 2-oxo-3-arylidenesuccinates in DCM at −10 °C for 10 min, followed by warming to room temperature for 24 h. By conjugated addition of isocyanide into dimethyl 2-oxo-3-arylidenesuccinates, enolate ion 752 was obtained, which underwent cyclization and tautomerization to aminofuran 753 by addition of oxygen atom to carbon atom of isocyanide moiety (Scheme 237).352 Scheme 237. Synthesis of Aminofuran Derivatives 753a

a

R = t-Bu, Bz; Ar = XC6H4 (X = H, 4-Cl, 3-NO2, 4-NO2), 1-naphthyl, 2-furyl; 70−90%.

One-pot nitroaldol reaction of ketal-functionalized nitroalkanes 754 with glyoxalates, followed by acidic hydrolysis of ketal moiety, was reported to synthesize 5-substituted furan-2carboxylates 759. Reactions were performed by stirring a solution of equimolar amounts of the nitro compounds 754 and glyoxalates in EtOAc in the presence of amberlyst A21 at room temperature for 3−8 h, followed by removal of catalyst by filtration, and then treatment with amberlyst A15 and heating at 55 °C for 4−4.5 h, which gave furans 759 in 60−80% yields. It 225


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Scheme 238. Synthesis of 5-Substituted Furan-2-carboxylates 759a

a 1

R = Me, Et, n-Pent, Ph, 4-biphenyl, Ph(CH2)2; R2 = Et, n-Bu, Bn; 60−80%.

Scheme 239. Synthesis of Trioxabicyclo[3.2.1]octane 761

Scheme 241. Synthesis of 6,8Dioxabenzo[c]bicyclo[3.2.1]octan-2-ones 766a

Scheme 240. Synthesis of Dioxolanes 763a

a 1 R = Me, i-Pr; R2 = H, Me, Et, i-Pr, Ph, CO2Et; R3 = Me, Et, 4-XBn (X = H, F, Cl, Br); 77% to quant.; exo/endo = 68/32−97/3.

Scheme 242. Synthesis of 6,8-Dioxabicyclo[3.2.1]octane1,2,7-tricarboxylates 768

a

R = Me, Ph; Ar = 4-XC6H4 (X = H, Cl, MeO); 18−56%; 763a/763b = 38/62−64/36.

oxo-2,5-dihydrofuran-2-carboxylates (isotetronic acid derivatives) 691, while reaction of β,β-disubstituted α-oxoesters under the same condition led to fully substituted 1,3-dioxolane derivatives 774 in 56−88% yields. The proposed reaction mechanism involves the nucleophilic addition of acetylid anion I, generated by action of Et3N on methyl propiolate followed by deprotonation of another molecule of methyl propiolate, to β,βdisubstituted α-oxoesters to give intermediate 772, which underwent acetalization with a second molecule of α-oxoesters and subsequent ring closure via conjugate addition of oxy anoin (773) to propiolate moiety. 4,4-Dimethyldihydrofuran-2,3dione 775, a cyclic α-oxoester, produced spiro-dioxolane 776 in 84% yield (Scheme 244).328b 4.7. Hydropyrans and Pyrans

Pyran derivatives are vastly found in natural and synthetic products, such as cryptocaryalactone, kurzilactone, goniothala-

min, (+)-obolactone, (+)-cryptofoline, massarilactone B, aspergillide A, B, and D, mupirocin, and simvastatin, with a 226


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and elimination. When sterically hindered mesityliden pyruvate was treated with P(NMe2)3 in toluene under similar conditions, the corresponding dihydrofuran 783 was obtained in 61% yield, via dimerization by nucleophilic addition of oxyphosphonium dienolate 777a through α-position to β,γ-unsaturated αoxoesters, followed by ring closure by SN2 reaction along with elimination of (Me2N)3PO (782) (Scheme 245). The highly enantioselective synthesis of 4-aryl-2-hydroxy-3tosylamidomethyl-3,4-dihydro-2H-pyran-6-carboxylate derivatives 787 was achieved by asymmetric domino reaction of amino aldehyde with β,γ-unsaturated α-oxoesters using transperhydroindolic acid VIII-3 as a chiral organocatalyst. Reactions were performed using 2 equiv of aldehyde in the presence of 10 mol % VIII-3 and 20 mol % DABCO in nBuOH at room temperature for 12−36 h. Dihydropyran-6carboxylate derivatives 787 were obtained in 87−96% yields, with 82−93% ee. The stereochemical outcome was described by conjugate addition of in situ generated enamine 784 to β,γunsaturated α-oxoesters, in which the ketone group was directed toward the carboxylic acid group of VIII-3 due to the existence of a hydrogen bond, followed by cyclization of iminium-enolate 785 to afford cycloadduct 786, which was transformed into 787 through hydrolysis (Scheme 246).360 Wang and co-workers361 exhibited the use of diarylprolinol ether as catalyst for the reaction of aliphatic aldehydes with β,γunsaturated α-oxoesters, which led to the corresponding 4-aryl2-hydroxy-3,4-dihydro-2H-pyran-6-carboxylate derivatives in 70−80% yields that were converted to dihydropyrones through Dess−Martin oxidation. Reactions were carried out in water in the presence of PhCO2H at room temperature. Also, diarylprolinol ether was reported as the organocatalyst for Michael addition-cyclization of β,γ-unsaturated α-oxoesters with aldehydes, to afford 2-hydroxy-3,4-dihydro-2H-pyran-6carboxylates, which were subjected to Dess−Martin oxidation and stereocontrolled hydrogenation using H2/Pd/C to provide substituted tetrahydropyran-2-ones in 25−78% yields, with excellent enantioselectivities.362 Moreover, reaction of enamines, in situ generated from reaction between aliphatic aldehydes and chiral amines, with β,γ-unsaturated α-ketoester was developed to obtain similar DHPs structural motifs.363 Also, a similar reaction between β,γ-unsaturated α-oxoesters and 4-aryl-substituted 2-butenal was reported using 16 mol % of proline-squaramide organocatalyst VIII-4 in the presence of diethylacetamide (1 equiv) in THF at room temperature, to afford dihydropyran-2-carboxylates 789 in 57−82% yields, with 3/1 to >20/1 dr, and 75−91% ee within 24−120 h. Reactions were initiated by formation of dienamine 788 from reaction of organocatalyst VIII-4 and 2-butenal, followed by hetero-DA reaction with β,γ-unsaturated α-oxoesters to form dihydropyrane bearing enamine moiety, which underwent hydrolysis to the formylmethyl substituent. The obtained diastereoselectivity and enantioselectivity were attributed to the π-stacking between aromatic rings and H-bonding in the transition state 788 (Scheme 247).364 Isothiourea XVII-mediated intermolecular Michael addition−lactonization reaction of arylacetic acids and β,γunsaturated α-oxoesters was reported by Belmessieri et al.365 to synthesize 2-oxo-3,4-dihydro-2H-pyran-6-carboxylates 793. Reactions of equimolar amounts of arylacetic acids and β,γunsaturated α-oxoesters were conducted using DIPEA (1.5 equiv) and pivaloyl chloride (1.5 equiv) in DCM at 0 °C for 20 min, followed by addition of XVII (10 mol %) and additional DIPEA (2.5 equiv) and stirring at −30 °C for 16 h, which led to

Scheme 243. Synthesis of 2-Methoxy-5(alkoxycarbonyl)methylene-[1,3]dioxolanes 771a

a

R = Me, Ph; 70−75% (GC yields); 58−61% (isolated yields).

Scheme 244. Synthesis of Dioxolane Derivatives 771a

a 1

R = Me, i-Pr, Ph, 2-thienyl; R2 = H, Me, Ph, 2-thienyl; R3 = Me, Et; 56−88%.

wide range biological activities. They are also used as building blocks in the synthesis of natural products and pharmaceuticals. Prins-type reaction, HDA reactions of aldehydes with dienes, or α,β-unsaturated carbonyl compounds with electron-rich carbon−carbon double bonds are among the most useful routes for the synthesis of pyran moieties. Reductive trimerization of β,γ-unsaturated α-oxoesters was reported by Wang and Radosevich359 yielding dihydropyran 781. Reactions were applied using 1.05 equiv of P(NMe2)3 in toluene at −78 °C, then at room temperature. Transformations proceeded by the Kukhtin−Ramirez addition of P(NMe2)3 to β,γ-unsaturated α-oxoesters leading to oxyphosphonium dienolate 777b, followed by conjugate addition to another molecule of β,γ-unsaturated α-oxoesters and then cyclization to give intermediate 778. Dipolar intermediate 778 with oxyphosphonium enolate moiety, attached to an additional equivalent of β,γ-unsaturated α-oxoesters, and then underwent cyclopropanation to generate intermediate 779, which was converted to dihydropyran 781 by Kukhtin−Ramirez addition, followed by ring opening of cyclopropane (780), isomerization, 227


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Scheme 245. Synthesis of Dihydropyran Derivatives 781a

a

R = Me, Et, i-Pr; Ar = 4-XC6H4 (X = H, F, Cl, Br, Me, MeO), 2-furyl; 38−85%.

Scheme 246. Synthesis of Dihydropyran-6-carboxylate Derivatives 787a

Scheme 247. Synthesis of Dihydropyran-2-carboxylates 789a

a

a

Ar1 = XC6H4 (X = H, 2-F, 2-Br, 3-Br, 4-Br, 4-Me, 4-CF3, 4-MeO2C, 4-NO2), 2,6-Cl2C6H3, 3-pyridyl; Ar2 = XC6H4 (X = H, 2-Me, 4-F), 3,5(MeO)2C6H3, 3,4-(CH2OCH2)C6H3, 2-thienyl, 2-naphthyl; 57−82%, 3/1 to >20/1 dr, 75−91% ee.

R = Me, Et, i-Pr, Bn; Ar = XC6H4 (X = H, 4-F, 2-Cl, 4-Cl, 2-Br, 3-Br, 4-Br, 4-Me, 3-MeO, 4-MeO), 2,6-Cl2C6H3, 2-furyl, 2-naphthyl; 87− 96%, 82−93% ee.

the corresponding 2-oxo-3,4-dihydro-2H-pyran-6-carboxylates 793 in 62−87% yields, with 80/20−96/4 dr and 83−99% ee. 228


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Scheme 248. Synthesis of 2-Oxo-3,4-dihydro-2H-pyran-6-carboxylates 793a

a 1 R = Me, n-Pent, XC6H4 (X = H, 3-Br, 4-Br, 4-MeO, 4-NO2), 2-furyl, 3-pyridyl, 2-naphthyl; R2 = Me, Et, i-Pr; Ar = XC6H4 (X = H, 4-Br, 2-Me, 3Me, 4-Me, 4-MeO), 2-thienyl, 1-naphthyl, 2-naphthyl, N-Me-indol-3-yl; 62−87%, 80/20−96/4 dr, 83−99% ee.

Scheme 249. Synthesis of 3-Benzamido-2-oxo-3,4-dihydro-2H-pyran-6-carboxylates 797a

a 1

R = Me, Et, i-Pr, 4-BrBn; R2 = Me, i-Bu, Bn; Ar1 = XC6H4 (X = H, 2-F, 3-F, 3-Br, 4-Br, 4-Me, 4-EtO, 4-NO2), 2-furyl; Ar2 = 3-XC6H4 (X = H, Cl, Br); cis, 44−96%, 20−97% ee;366 R1 = Et; R2 = Me, i-Pr, i-Bu, Bn; Ar1 = 4-XC6H4 (X = H, Cl, MeO); Ar2 = 4-XC6H4 (X = H, CF3, Me, MeO), 3,5Me2C6H3, 3,5-(CF3)2C6H3, 3,5-(MeO)2C6H3, 3,4,5-(MeO)3C6H2; 70−99%, cis/trans = 77/23−99/1, 1−89% ee.367

The transformation was initiated by acylation of XVII with in situ generated mixed anhydride 790, followed by formation of anion enolate 791, which attached to β,γ-unsaturated αoxoesters via Michael addition to give zwitterion intermediate 792 that was converted to final products by lactonization along with regeneration of XVII (Scheme 248). Reported diastereoand enantioselectivities were attributed to the favored transition state 794, indicated in Scheme 248. Reactions of β,γ-unsaturated α-oxoesters with oxazolones were reported using cinchona alkaloid I-4,366 and axially chiral guanidine base (R)-XVIII,367 which afforded the corresponding 3-benzamido-2-oxo-3,4-dihydro-2H-pyran-6-carboxylates 797. Ying et al.366 carried out the reaction by addition of 20 mol % catalyst I-4 to a mixture of β,γ-unsaturated α-oxoesters and

oxazolones (1.1 equiv) in Et2O and stirring at room temperature for 3 h, leading to 797 in 44−96% yields, with 20−97% ee. Reactions using axially chiral guanidine base (R)XVIII were performed using 2 mol % (R)-XVIII in either THF at room temperature for 1.5−6 h, or in Et2O at −60 °C to room temperature for 3−5 h, which gave the corresponding 797 in 70−99% yields, with a cis/trans ratio of 77/23−99/1. The proposed reaction mechanism involves the Michael addition of enolate form of oxazolones 795 into β,γ-unsaturated α-oxoesters, followed by intramolecular O-acylation along with ring opening of the azlactone moiety (796). However, the inverse electron demand HDA reaction between the enol form of oxazolones and β,γ-unsaturated α-oxoesters was also 229


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Scheme 250. Synthesis of Spiro-dihydropyrans 799,800a

a

X = CH2, (CH2)2, C(OCH2CH2O), O, NCO2Et; Y = CH2, O; R1 = H, n-Pr, i-Pr, c-Pr, c-Hex, n-Hept, XC6H4 (X = H, 4-F, 2-Me, 4-MeO), 2-furyl; R2 = H, Me; R3 = Me, Et; 799, 65−89%, 84/16- 99/1 dr, 62−98% ee.368 X = CH2, (CH2)2, C(OCH2CH2O), O; R1 = XC6H4 (X = H, 4-F, 4-Cl, 2Me, 4-Me, 4-MeO, 3-NO2), 2-thienyl, N-Ts-indol-3-yl; R3 = Me, Et; 62−99%, 66−97% ee.369

Scheme 251. Synthesis of Spiro-3,4-dihydro-2H-pyrans 805a

a

X = Cl, Br; n = 0, Y = CH2; n = 1, Y = CH2, O, NTs; R = Me, Et; Ar = XC6H4 (X = H, 4-F, 4-Cl, 4-Me, 4-MeO, 3-NO2), 2-furyl, 2-thienyl, N-Tsindol-3-yl; 805, 42−91%; 806, 65−96%.

hemiacetal to lactone with PCC in DCM under reflux conditions (Scheme 250b).369 The synthesis of spiro-3,4-dihydro-2H-pyrans 805 was achieved by a tandem Rauhut−Currier/acetalization reaction of cyclic β-halo-α,β-unsaturated aldehydes 801 and β,γunsaturated α-oxoesters. By addition of DBU (1.5 equiv) in a solution of β,γ-unsaturated α-ketoester and 801 (1.5 equiv) in anhydrous toluene at 0 °C under N2 atmosphere and stirring at the same temperature for 1−6 h, the corresponding spiro-3,4dihydro-2H-pyrans 805 were obtained in 42−91% yields. Further conversion of spiro-3,4-dihydro-2H-pyrans 805 to spiro-3,4-dihydro-2H-pyran-2-ones 806 was applied by oxidation with PCC. The proposed reaction mechanism involves the generation of anion enolate 802 by conjugate addition of DBU to 801, followed by intermolecular Michael addition to β,γunsaturated α-ketoester to form intermediate 803, which underwent cyclization to give intermediate 804. By γ-proton transferring and removal of DBU, cyclic hemiacetal products 805 were formed (Scheme 251).370 Cascade Michael−hemiketalization reaction was reported using quinine-derived thiourea-tertiary amine catalyst XVI-1 to

reported as a reaction mechanism to construct 797 (Scheme 249). Wang et al.368 developed bifuctional amino-squaramide I-5 for the Micheal addition/hemiacetalization domino sequence between α-formyl-substituted cyclic ketones 798a and β,γunsaturated α-oxoesters leading to spiro-3,4-dihydropyrans 799. Reactions were performed using 1.5 equiv of 798a, 10 mol % of I-5, and Et3N (1 equiv) in dry DCM at −20 °C under a N2 atmosphere for 7−48 h, followed by addition of acetyl chloride (1.5 equiv) and an additional amount of Et3N (1.5 equiv) and stirring at 0 °C for 2 h, which gave the corresponding spiro-3,4-dihydropyrans 799 in 65−89% yields, 84/16 to >99/1 dr, and more than 60% ee (Scheme 250a). Also, an acyclic α-formyl ester was investigated under similar conditions, and the corresponding dihydropyran was formed in 68% yield, with 57/43 dr. The same group reported the synthesis of spiro-dihydropyranones 800 via a similar Micheal addition/hemiacetalization reaction using (DHQD)2PYR I-6 (10 mol %) as organocatalyst in a mixture of toluene/t-BuOH at −20 °C for 12−108 h, followed by oxidation of cyclic 230


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Scheme 252. Synthesis of Dihydropyrans 807,808 via Cascade Michael−Hemiketalization Reactiona

a 1

R = OMe, OEt, Me, Ph; R2 = Me, Et, i-Pr, allyl; Ar = XC6H4 (X = H, 4-F, 3-Cl, 4-Cl, 4-Br, 4-Me, 4-MeO), 2-thienyl; 807, 57−96%, 23/1 to >30/1 dr, 81−97% ee;371 R1 = XC6H4 (X = H, 4-F, 4-Cl, 2-Br, 4-Br, 4-NO2), 2,4-Cl2C6H3, 2,5-(MeO)2C6H3, 2-furyl, Ph(CH2)2; R2 = Me, Et, i-Pr, t-Bu, allyl, Bn, 4-BrBn; Ar = 4-XC6H4 (X = H, F, Br, MeO); 808, 70−95%, 87−96% ee.372

Scheme 253. Synthesis of 4H-Pyran Derivatives 809a

synthesize trifluoromethyl-substituted dihydropyrans 807. Reactions were applied between β,γ-unsaturated α-ketoester (1.2 equiv) and 4,4,4-trifluoroacetoacetate in the presence of 10 mol % of XVI-1 in DCM at room temperature for 14−20 h, and the corresponding trifluoromethyl-substituted dihydropyrans 807 were formed in 57−96% yields, with 23/1 to >30/1 dr, and up to 81% ee (Scheme 252a).371 The reaction of αsubstituted cyano ketones with β,γ-unsaturated α-oxoesters using bifunctional thiourea-tertiary amine catalyst XVI-3 was reported to give chiral dihydropyrans 808. Reactions were conducted using 1.1 equiv of α-substituted cyano ketones in Et2O at room temperature in the presence of catalyst XVI-3 (2 mol %) for 12 h. Dihydropyrans 808 were synthesized in 70− 95% yields, with 87−96% ee (Scheme 252b).372 Also, Feng et al.373 reported the reaction of α-substituted cyano ketones with β,γ-unsaturated α-oxoesters using a bifunctional organocatalyst N,N′-dioxide XIX-1 leading to corresponding dihydropyrans 808 in 76−99% yields, with 82−99% ee. By treating 1.1 equiv of malononitrile with β,γ-unsaturated αoxoesters in toluene in the presence of chiral bifunctional thiourea-tertiary amine catalysts XVI-4 (5 mol %) at −30 °C for 12 h, 4H-pyran derivatives 809 were synthesized, via asymmetric Michael addition-cyclization reaction, in 50−68% yields, with 75−88% ee (Scheme 253).374 Pei et al.375 developed an efficient DABCO-catalyzed reaction of β,γ-unsaturated α-oxoesters with allenic esters to give the highly functionalized dihydropyran derivatives 812, regioselectively. Reactions were conducted using 1.2 equiv of allenic esters in the presence of DABCO (20 mol %) in THF at −10 °C for 24 h, leading to a mixture of ethyl 2-(2-ethoxy-2oxoethylidene)-3,4-dihydro-2H-pyran-6-carboxylates 812 and diethyl 6-methyl-4H-pyran-2,5-dicarboxylates 814 in 57−95% yields in a 3/1 to >20/1 ratio. The proposed reaction mechanism involves the conjugate addition of both isomeric forms of zwitterion 810a and 810b, in situ generated from reaction of DABCO with allenic esters, to the β,γ-unsaturated α-oxoesters to form enol intermediates 811a and 811b, which underwent cyclization to 812 and 813 with removal of a molecule of Et3N, respectively. Intermediate 813 could be converted to 814 by isomerization (Scheme 254).

a

R = Me, i-Pr, allyl, Bn, 4-BrBn; Ar = XC6H4 (X = H, 4-F, 4-Cl, 4-Br, 2-Br, 4-EtO, 4-NO2), 2,4-Cl2C6H3, 2,5-(MeO)2C6H3; 50−68%, 75− 88% ee.

Conjugate addition-cyclization reaction between dimethyl oxoglutaconate and α,β-unsaturated hydrazones (1.1 equiv) was carried out in CH3CN at room temperature to prepare highly substituted dihydropyrans 816. Reactions were completed in 24 h, and the corresponding dihydropyrans 816 were obtained in 20−54% yields, via intermediate 815 (Scheme 255).376 Sequential aldol reaction of ketene diethylacetal with αoxoesters was developed for the synthesis of 4,4,6,6tetraethoxytetrahydro-2H-pyran-2-carboxylates 820. Reactions were catalyzed with in situ generated chiral bisoxazolinecopper(II) complex VII-2-Cu (20 mol %), and performed using 3 equiv of ketene diethylacetal in anhydrous Et2O at −15 to −78 °C under an atmosphere of N2, overnight, to afford 820 in 55−80% yields, with 53−93% ee. Stereoselectivity of the reaction was illustrated with coordination of α-oxoesters to VII2-Cu in a bidentate fashion 817, to which ketene diethylacetal attached via the Si-face of ketone moiety, to give intermediate 818, which underwent reaction with another molecule of ketene diethylacetal, leading to 819, from which tetrahydro-2Hpyran-2-carboxylates 820 were obtained. By hydrolysis of ketal moieties using HCO2H in a mixture of DCM/pentane at 0 °C for 3 h, 4-ethoxy-6-oxo-3,6-dihydro-2H-pyran-2-carboxylates 821 were formed in 50−72% yields (Scheme 256).377 231


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ones 826. Reactions were carried out by addition of Grignard reagent (1.1 equiv) to a suspension of β,γ-alkenyl α-iminoesters in THF at −78 °C under Ar atmosphere, and then warming to 40 °C and stirring for 25 min, followed by heating and addition of aldehydes (5 equiv) under reflux conditions for 1.5 h, to give the corresponding 3-amino-5,6-dihydro-2H-pyran-2-ones 826 in 25−81% yields. The transformation could be explained by Nalkylation of β,γ-alkenyl α-iminoesters with Grignard reagent, giving magnesium dienolate 824, which converted to 5,6dihydro-2H-pyran-2-ones 826 by the γ-addition to the aldehyde to form magnesium aldolate 825, followed by intramolecular cyclization along with a concomitant elimination of EtOMgBr (Scheme 258). The hetero-DA reaction was extensively used for the construction of dihydropyran (DHP) derivatives. Originally, α-oxoesters serve as dienophile components in the HAD reaction via ketone moiety. In this context, Oi et al.380 reported HAD reaction between various dienes (1.5 equiv) and glyoxalates in the presence of [Pd(S-BINAP)(PhCN)2](BF4)2 III-3-Pd (2 mol %) and 3 Å MS in CHCl3 at room temperature under an atmosphere of N2 during 20 h, and the corresponding DHPs 827 were obtained in 33−77% yields, with 7−98% ee (Scheme 259a). In addition to HAD reaction, heteroene reaction also occurred. In 2009, Mori et al.381 developed the synthesis of methoxy-substituted dihydropyrans 828 via thiourea XVI-6-catalyzed HAD reaction of 1-methoxy-substituted dienes with α-oxoesters (0.25 equiv) in toluene or DCM at room temperature and 1 GPa pressure. Reactions were conducted using 30 mol % of thiourea XVI-6 for 10 h, which gave the corresponding dihydropyrans 828 in 63−89% and 26−81% yields, in toluene and DCM, respectively (Scheme 259b). Menthoxyaluminum and lanthanide chiral catalysts,382 ethylene-bridged bissulfoximines chiral ligands in the presence of Cu(II),383 and some Lewis acids384a,b were also used for the HAD reaction of different dienes with α-oxoesters in a enantioselective and diastereoselective manner. Also, uncatalyzed HAD reaction of ethyl glyoxalate was reported for the synthesis of ulosonic acid384c and sugars.384d The HAD reaction of a variety of α-oxoesters with Danishefsky’s diene was reported by different research groups, leading to dihydropyran-4-ones. Johannsen et al.385 applied this methodology using bisoxazoline ligand VII-2 in combination with Cu(II) salts. Reactions were carried out by in situ generation of complex VII-2-Cu in dry DCM, and then addition of α-oxoesters and Danishefsky’s diene (1.2 equiv) and stirring at −40 °C for 30 h, followed by treatment with TFA at 0 °C for 1 h, which gave the corresponding dihydropyran-4ones 829a in 77−95% yields, and 77−99% ee. A similar approach was developed by Wolf et al.386 (Scheme 260a). In(III)-pybox VII-5, complex-catalyzed asymmetric HAD reaction was reported by treatment of α-oxoesters with 1.5 equiv of Danishefsky-type dienes in dry DCM at room temperature for 18−24 h, using 10 mol % of InI3 and 12 mol % of ligand VII-5 in the presence of 4 Å MS. Subsequent hydrolysis using TFA resulted in the formation of dihydropyran-4-one derivatives 829b in 10−84% yields, with 30−95% ee (Scheme 260b).387 However, there are other examples on the construction of dihydropyran-4-one derivatives by HDA reaction between α-oxoesters and Danishefsky-type dienes using various catalytic systems.388 The synthesis of 2,3-dihydropyrans 828b was developed via a microwave-assisted multicomponent enyne cross metathesis/ HDA reaction. By irradiation of a mixture of an alkyne, ethyl

Scheme 254. Synthesis of 2H-Pyran-6-carboxylates 812 and 4H-Pyran-2,5-dicarboxylates 814a

a

R = c-Pr, XC6H4 (X = H, 4-Cl, 2-Br, 3-Br, 4-Br, 4-Me), 2,4-Cl2C6H3, 2-naphthyl, 2-furyl, 2-thienyl; 57−95%, 812/813 = 3/1 → 20/1.

Scheme 255. Synthesis of Highly Substituted Dihydropyrans 816a

a 1

R = H, Me, i-Pr; R2 = H, Me, Et, n-Pr, Ph; R3 = H, Me; 20−54%.

Yang and Shi378 developed the synthesis of 5,6-dihydropyran-2-ones 823 via TMSOTf-mediated reaction of cyclopropyl aryl ketones with α-oxoesters in DCE at 60 °C for 12 h. Reactions were performed using 1 equiv of TMSOTf to afford 5,6-dihydropyran-2-ones 823 in 35−97% yields. The transformation was initiated by TMSOTf induced ring opening of cyclopropyl moiety with ambient water to form the corresponding γ-hydroxy ketones, trans-esterification reaction on α-oxoesters (822) of which, followed by intramolecular aldol reaction, led to the formation of 5,6-dihydropyran-2-ones 823 (Scheme 257). A similar approach was applied using equimolar amounts of SnCl4 as Lewis acid in DCE at 60 °C leading to 5,6-dihydropyran-2-ones 823 in 12−58% yields. Very recently, Tanaka et al.379 reported highly regioselective tandem N-alkylation-vinylogous aldol reaction of β,γ-alkenyl αiminoesters to synthesize 3-amino-5,6-dihydro-2H-pyran-2232


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Scheme 256. Synthesis of Tetraethoxytetrahydro-2H-pyran-2-carboxylates 820a

a 1

R = Me, Et, i-Pr, BrCH2, Ph, styryl; R2 = Me, Et; 820, 55−80%, 53−93% ee; 821, 50−72%.

Scheme 257. Synthesis of 5,6-Dihydropyran-2-ones 823a

Scheme 259. Synthesis of Dihydropyrans 827,828 via HDA Reactiona

a 1

R = H, Me, n-Hex, c-Hex, 4-XC6H4 (X = H, Cl, Me, MeO); R2 = Me, Et; Ar = 4-XC6H4 (X = H, F, Me), 2,6-Me2C6H3, 2-thienyl; 35− 97%.

Scheme 258. Synthesis of 3-Amino-5,6-dihydro-2H-pyran-2ones 826a

a 1

R = H, Me; R2 = H, Me; R3 = Me, Et, i-Pr, n-Bu; 827, 33−77%, 7− 98% ee; R3 = Me, Et; R4 = Me, CF3, Ph, 2-furyl; R3−R4 = o-phenylen; 828, 26−89%.

preparation of furanose−pyranose 1,3-C−C-linked disaccharides and D,L-gulose ethyl glycoside were also prepared by a similar methodology.389 Cationic RhI/H8-binap complex-catalyzed [2 + 2 + 2] cycloaddition reaction of 1,6-enynes 830 with α-oxoesters was developed to synthesize fused dihydropyrans 831. The reactions proceeded at 80 °C in DCM using 2 equiv of an αketoester in the presence of 10 mol % of cationic RhI/H8-binap complex prepared in situ from reaction of (R)-H8-binap and [Rh(cod)2]BF4 in DCM by introducing H2 into the solution. Reactions were completed within 16 h, and led to the formation of the corresponding fused dihydropyrans 831 in 17−99% yields, with 94−99% ee (Scheme 262).390 Moreover, the HDA reaction of β,γ-unsaturated α-oxoesters with a variety of alkenes was reported, in which β,γ-unsaturated

a 1

R = H, 4-XC6H4 (X = H, MeO), 2-thienyl; R2 = Et, i-Bu, n-Oct, Cl(CH2)4, vinyl-(CH2)2, 1,3-dioxolan-2-yl-(CH2)2, 1,3-dioxan-2-yl(CH2)2; Ar1 = Ph, 2,6-Me2C6H3, 2-thienyl; Ar2 = 4-XC6H4 (X = H, Cl, MeO), 2-thienyl, 2-pyridyl, styryl, PhCC; 25−81%.

vinyl ether (9 equiv), and ethyl glyoxalate (2 equiv) in degassed toluene in the presence of the second generation Grubbs’ catalyst, at 80 °C, 2,3-dihydropyrans 828b were obtained in 40−75% yields, with a trans/cis ratio of 2/1. First, a diene was in situ generated by cross metathesis of an alkyne with ethyl vinyl ether, which then underwent HDA reaction with ethyl glyoxalate (Scheme 261). The synthetic intermediates for the 233


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and 4 Å MS at −70 °C. Reactions were completed in 0.5−12 h and gave a quantitative yield of a mixture of desired THP-2carboxylates 832a and DA adducts 833a in a ratio of 78/22− 87/13. The THP-2-carboxylates 832a were obtained with up to 98% ee. In the case of 3-substituted cyclopentadienes, reactions led to the corresponding THP-2-carboxylates 832a, mostly as a minor product in 15−95% yields, with 96−99% ee, in which cyclopentadienes act as dienophile through a substituted double bond. When reactions were conducted using 1,3-disubstituted cyclopentadienes, THP-2-carboxylates 832a were produced as major products in 85−99% yields, with 94−99% ee (Scheme 263a). A similar reaction was reported by Zhu et al.392 using chiral N,N′-dioxide(XIX-2)−Cu(OTf)2 complex as catalyst. By treatment of β,γ-unsaturated α-oxoesters with cyclopentadiene in DCM in the presence of 0.5 mol % of XIX-2/Cu(OTf)2 under an atmosphere of N2 at 25 °C for 15 min, the corresponding DA adducts 833b were obtained as major products in a ratio of 94/6−99/1 endo/exo isomers, while reaction using 1.5 mol % of complex at −25 °C for 12 h gave the corresponding HDA adducts, THP-2-carboxylates 832b, as major products with up to 99% ee (Scheme 263b). The construction of THP-2-carboxylate derivatives 832 by HDA reaction of β,γ-unsaturated α-oxoesters with cyclopentadiene was also reported using Pybox/lanthanide(III) triflates catalytic systems.393 The HDA reaction of β,γ-unsaturated α-oxoesters with 2,3dihydrofuran was reported using N,N′-dioxide (XIX-2)− Er(OTf)3 complex (0.5 mol %) as catalyst. Reactions were carried out in DCM at 0 °C using 4 equiv of 2,3-dihydrofuran to afford cycloadducts 834, in 81−99% yields with 92−99% ee (Scheme 264).394 A similar reaction was developed by Thorhauge et al.395 using t-Bu-substituted copper(II) bis(dihydrooxazole) VII-2-Cu as catalyst, leading to the corresponding THP-2-carboxylates 834 in 51−96% yields, with more than 97.5% ee. Also, HDA reaction of β,γ-unsaturated α-oxoesters with various alkenes was developed to synthesize THP-2-carboxylates. Vinyl ethers are among the most used dienophile in this reaction. Cu(II)−Hydroxy oxazoline ligand XX-catalyzed HDA reaction of ethyl vinyl ether with β,γ-unsaturated α-oxoesters was described leading to 6-ethoxy-THP-2-carboxylates 835 in 83−98% yields, with 63/37−80/20 ratio of exo/endo isomers. Reactions were carried out in EtOAc using 3 equiv of ethyl vinyl ether in the presence of 10 mol % Cu(OTf)2/XX complex at 0 °C for 3 h. The ee of major exo cycloadducts was determined as 45−88% (Scheme 265).396 Also, the 6-ethoxyTHP-2-carboxylates 835 were prepared by C2-symmetric Cu(II)/bis(oxazoline) complex VII-2-Cu-catalyzed HDA reaction of ethyl vinyl ether with β,γ-unsaturated α-oxoesters. Reactions were performed using 2 mol % of catalyst VII-2-Cu, 3 Å MS and 3 equiv of ethyl vinyl ether in THF at 0 °C to give cycloadducts 835 in 87−98% yields, with an exo/endo ratio of 20/1−59/1 and up to 96% ee for exo isomer (Scheme 265).397 Moreover, there are other reports on the [4 + 2] heterocycloaddition between β,γ-unsaturated α-oxoesters and vinyl ethers leading to THP-2-carboxylates in the literature.395,398 In addition to vinyl ethers, enamines were also investigated in the HDA reaction with β,γ-unsaturated α-oxoesters to synthesize THF-2-carboxylates bearing an amine substituent at C−6.399 In this context, Eiden and Winkler400 performed the HDA reaction between a variety of β,γ-unsaturated α-oxoesters and enamines, in absolute MeOH, leading to the corresponding

Scheme 260. Synthesis of Dihydropyran-4-one 829 via HDA Reactiona

a 1

R = Me, Ph; R2 = Me, Et; 829a, 77−95%, 77−99% ee;385 R1 = Me, iPr, Ph; R2 = Et; R1−R2 = C(Me)2CH2; 829a, 10−95%, 10−91% ee;386 R1 = H, Me, i-Pr, CH2Br, CCTMS; R2 = Me, Et, i-Pr, t-Bu, c-Pent; R3 = H, Me; 829b, 10−84%, 30−95% ee.387

Scheme 261. Synthesis of 2,3-Dihydropyrans 828b via Enyne Cross Metathesis/HDA Reactiona

a R = Ph, TMS, BrCH2, TMSOCH2, PMBOCH2, BocNHCH2, (EtO)2CH, Cl(Me)2C; 40−75%; trans/cis = 2/1.

Scheme 262. Synthesis of Fused DHP 831 via [2 + 2 + 2] Cycloaddition Reactiona

a Z = O, NTs, C(CO2Me)2; R1 = Me, Ph, 4-BrC6H4, CO2Me; R2 = H, Me; R3 = Me, Ph, CO2Et; 17−99%, 94−99% ee.

α-oxoesters contributed in the reaction as diene to give THP-2carboxylate derivatives. Accordingly, Lv et al.391 developed a binary-acid catalyst PentaF-V-7/InBr3 for the synthesis of THP2-carboxylates 832a via HDA reaction of β,γ-unsaturated αoxoesters with substituted cyclopentadiene derivatives, by performing the reactions in DCM using 5 equiv of cyclopentadiene in the presence of InBr3 (1 mol %), V-7 (2 mol %), 234


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Scheme 263. Synthesis of THP-2-carboxylates 832 via HDA Reactiona

a 1

R = Me, Et, i-Pr; R2 = R3 = H; Ar = XC6H4 (X = H, 2-F, 4-Cl, 4-Me, 4-Ph), 3,4-Cl2C6H3; 832a+833a, 88−99%, 832a/832a = 78/22−87/13, 832a, >98% ee; R1 = Me; R2 = Me, c-Hex, Bn; R3 = H; Ar = XC6H4 (X = H, 4-Cl, 4-Br); 832a, 15−95%, 95−99% ee; R1 = Me; R2 = R3 = Me, allyl, Bn, 4BrBn, 4-MeBn, CH2Bn, (CH2)2CO2Me; Ar = XC6H4 (X = H, 4-Cl, 4-Br), 3-thienyl; 832a, 85−99%, 94−99% ee;391 R1 = Me, Et; Ar = XC6H4 (X = H, 4-F, 4-Cl, 3-Br, 4-Br, 4-CN, 4-Me, 4-MeO, 3-NO2, 4-NO2, 4-Ph), 2,4-Cl2C6H3, 3,4-(OCH2O)C6H3, 2-naphthyl, 2-thienyl, styryl; 832b/833b = 22/78−65/35, 832b, >99% ee.392

Scheme 264. Synthesis of THP-2-carboxylates 834 via HDA Reactiona

Scheme 266. Synthesis of 2-(Dialkylamino)-3,4-dihydro-2Hpyran-6-carboxylates 836a

a

Ar = XC6H4 (X = H, 3-F, 3-Cl, 4-Cl, 3-MeO, 4-MeO, 4-NO2); NR2 = Me2N, Et2N, pyrrolidin, piperidine, morpholine, N-Me-piperazine; 43−88%.

a

R = Me, Et; Ar = XC6H4 (X = H, 4-F, 2-Cl, 4-Cl, 4-Br, 4-Me, 3-MeO, 4-MeO, 3-NO2), 2,4-Cl2C6H3, 3,4-(OCH2O)C6H3, 2-naphthyl, 2thienyl, styryl; 81−99%, 92−99% ee.

N-vinyl-1,3-oxazolidin-2-ones to afford the corresponding cycloadducts, THF-2-carboxylates 837. Reactions were carried out either using 5 mol % Eu(fod)3 in cyclohexane under reflux conditions or using 50 mol % SnCl4 in DCM at −78 °C for 3 h. Reactions led to the formation of 6-oxazolidine-substituted THP-2-carboxylates 837 in 44−83% yields, with 40/60−98/2 endo/exo ratio. The endo-cycloadducts were obtained in >96/ 4% and 96% ee.397

2-(dialkylamino)-3-isopropyl-4-aryl-3,4-dihydro-2H-pyran-6carboxylates 836 in 43−88% yields (Scheme 266). Gohier et al.401 developed the Lewis acid-mediated HDA reaction between β,γ-unsaturated α-oxoesters and β-substituted 235


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Scheme 267. Synthesis of 6-Oxazolidine-Substituted THP-2-Carboxylates 837,838 via HDA Reactiona

a

387, R1 = Ph, 3,4,5-(MeO)3C6H2; R2 = Me; R3 = H, Me, Ph, 3,4-(OCH2O)C6H3CH2; cond. = Eu(fod)3, cyclohexane, reflux; 57−77%, endo/exo = >98/2; cond. = SnCl4, DCM, −78 °C, 3 h; 44−83%, endo/exo = 40/60−95/5; 388, n = 0, 1; R1 = Me, Et, OEt, 4-XC6H4 (X = H, Cl, Br, Me, MeO), 3,4,5-(MeO)3C6H2; R2 = Me, Et, n-Pr, n-Bu; cond. = Eu(fod)3, cyclohexane, reflux, 60 h; 70−91%, endo/exo = 73/27−98/2.

oxoesters with α-chloroaldehydes as the dienophile precursors. Reactions were carried out using 1.6 equiv of α-chloroaldehydes in the presence of 2 mol % NHC IV-4 and 1.5 equiv of Et3N in EtOAc at room temperature for 6−8 h, and afforded the corresponding 2-oxo-3,4-dihydro-2H-pyran-6-carboxylates 841 in 70−85% yields, with 95−99% ee (Scheme 268). The

position. The transformation required the formation of Breslow-type intermediate 839 from the reaction of the NHC and the α-chloroaldehyde followed by generation of enol 840 by elimination of halide, and then subsequent HDA reaction with β,γ-unsaturated α-oxoesters. Moreover, NHC IV-4catalyzed HDA reaction of α,β-unsaturated aldehydes with β,γ-unsaturated α-oxoesters led to similar DHPs in 51−91% yields, with 96−99% ee, in which reactions were carried out by 2 equiv of α,β-unsaturated aldehydes and 1 equiv of β,γunsaturated α-oxoesters using 10 mol % NHC IV-4, and 15 mol % N-methylmorpholine in DCM at 40 °C for 24 h.409 Also, the NHC IV-6-catalyzed [4 + 2] cycloaddition reaction between β,γ-unsaturated α-oxoesters and disubstituted ketenes was reported to afford 3,3,4-trisubstituted-2-oxo-3,4-dihydro2H-pyran-6-carboxylates 842. Reactions were performed using 2.4 equiv of ketene in the presence of 10 mol % of NHC IV-6 and 10 mol % Cs2CO3 in toluene at room temperature under an atmosphere of Ar. Reactions were completed in 16 h, and led to 842 in 66−96% yields, as two stereoisomers (anti and syn). In the case of γ-alkyl-substituted β,γ-unsaturated αoxoesters, 842 were obtained in 78−96% yields, with 60/40− 82/18 dr, in which the anti-isomer was the major isomer, while syn-842 was the major isomer in the case of γ-aryl-substituted β,γ-unsaturated α-oxoesters, which resulted in the formation of 842 in 66−95% yields. In addition to 842, an isomerization product 843 was obtained in low yield. Reactions proceeded via an azolium enolate intermediate like 840 (Scheme 269).410 The synthesis of ethoxycarbonyl-substituted pyrylium salts 844−846 was developed by Katritzky et al.411 Treatment of ethyl pyruvate with 2 equiv of benzylideneacetophenone in Ac2O by dropwise addition of an aqueous solution of HClO4 (70%) at 40 °C, followed by stirring at room temperature for 12 h, afforded 2-ethoxycarbonyl-4,6-diphenylpyrylium perchlorate 844 in 41% yields. By treatment of 2 equiv of ethyl pyruvate with benzaldehyde under similar conditions, 2,6diethoxycarbonyl-4-phenylpyrylium perchlorate 845 was formed in 11% yield, while using SbF5 at room temperature for 3 h led to the formation of isomeric pyrylium salt, 2,4diethoxycarbonyl-6-phenylpyrylium hexachloroantimonate 846, in 28% yield. The formation of 846 was assumed by condensation between two molecules of ethyl pyruvate, followed by reaction with benzaldehyde (Scheme 270). Moreover, the BF4− and TFO− salts of 844 and BF4− salt of 846 were reported by the same research group.412 The obtained pyrylium salts were converted to other heterocyclic

Scheme 268. Synthesis of 2-Oxo-3,4-dihydro-2H-pyran-6carboxylates 841 via NHC-Catalyzed HDA Reactiona

a 1

R = n-C10H21, Bn, CH2OTBS; R2 = n-Pr, c-Hex, 4-tolyl; X = Cl; cond. = NHC IV-4, Et3N, EtOAc, rt, 6−8 h; 70−85%, 95−99% ee;406 R1 = H, Bn; R2 = n-Pr, 4-tolyl; X = Cl; cond. = NHC IV-4, aq K2CO3, toluene, rt, 4−6 h; 73−80%, >99% ee;407 R1 = Bn; R2 = Ph; X = 4NO2C6H4CO2; cond. = NHC IV-5, Et3N, THF, rt; 54%, dr = 69/ 31.408

same research group described the similar NHC IV-4-catalyzed HDA reaction of β,γ-unsaturated α-oxoesters with αchloroaldehyde bisulfite adducts using 5 mol % NHC IV-4 and 1.6 equiv of aqueous K2CO3 in EtOAc at room temperature for 4−6 h, which led to the formation of 2-oxo3,4-dihydro-2H-pyran-6-carboxylates 841 in 73−80% yields, with >99% ee.407 Ling and Smith408 reported a similar approach using aldehyde, possessing PNB leaving group at α236


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Reactions of β,γ-unsaturated α-ketoester with cyclic ketones were reported using 15 mol % of Yb(OTf)3 in the presence of ligand XXI (30 mol %) in THF at 4 °C, leading to 8a-hydroxy4-arylhexahydro-4H-chromene-2-carboxylates 849 in 60−81% yields, with 3/1−9/1 dr, and 80−99% ee. The proposed reaction mechanism involves in situ generation of enamine 847 from reaction of cyclic ketone with YbIII chelated XXI, followed by chelation with β,γ-unsaturated α-ketoester and subsequent HDA reaction to give cyclic aminal 848, which was transformed into 849 by hydrolysis and regenerating the catalyst (Scheme 271).414

Scheme 269. Synthesis of 2-Oxo-3,4-dihydro-2H-pyran-6carboxylates 842a

Scheme 271. Synthesis of 8a-Hydroxy-4-arylhexahydro-4Hchromene-2-carboxylates 849a

a 1

R = Et; R2 = Me, n-Pent; R3 = Me; Ar = 4-XC6H4 (X = H, Br, MeO); 78−96%, anti/syn = 60/40−82/18; R1 = Me, Et; R2 = XC6H4 (X = H, 3-Br, 4-Br, 4-MeO); R3 = Me, Et, i-Pr; Ar = 4-XC6H4 (X = H, F, Br, Me); 66−99%, anti/syn = 42/58−32/68.

Scheme 270. Synthesis of Ethoxycarbonyl-Substituted Pyrylium Salts 844−846

a

X = CH2, CHMe, O, S; R = Me, Et, Bn, 4-NO2Bn; Ar = XC6H4 (X = H, 4-Cl, 4-Br, 4-Me, 4-MeO, 3-NO2, 4-NO2), 2-naphthyl; 60−81%, 3/ 1−9/1 dr, 80−99% ee.

The Cu(OTf)2-tetrahydroisoquinoline N,N′-dioxide ligand XIX-4 catalytic system was used for the synthesis of methyl 2hydroxy-5-oxo-4-arylhexahydro-2H-chromene-2-carboxylates 850 from reaction of cyclohexa-1,3-dione with β,γ-unsaturated α-ketoester. Reactions were conducted by stirring a solution of an equimolar amount of cyclohexa-1,3-dione and β,γ-unsaturated α-ketoester in the presence of 2 mol % of Cu(OTf)2 and ligand XIX-4 in DCM at room temperature for 12 h. Products 850 were obtained in 68−91% yields, with 70−89% ee (Scheme 272a).415 There are other reports on a similar methodology using different catalytic systems in the literature.416 Also, reaction of β,γ-unsaturated α-oxoesters with cyclohexa-1,2-dione was reported using chiral bifunctional thiourea-tertiary amine catalyst XVI-7, to produce the corresponding 2-hydroxy-8-oxo-hexahydro-2H-chromene-2carboxylates 851 in 72−97% yields, and 92−97% ee (Scheme 272b).417 2-Hydroxy-5-oxo-2,3,4,5-tetrahydropyrano[3,2-c]chromene2-carboxylates 852 were synthesized via Michael addition of 4hydroxycoumarin to β,γ-unsaturated α-oxoesters followed by hemiacetalization. Reactions were performed with 4-hydroxycoumarin (0.1 mmol) and β,γ-unsaturated α-oxoesters (1.1 equiv) in the presence of N,N′-dioxide XIX-3 (5 mol %), Ni(acac)2 (5 mol %), and 4 Å MS in DCE at 0 °C for 4−10 h,

compounds such as pyridinium salts202,412a and pyridotriazines.413 4.8. Chromanes and Chromenes

Chromane and chromene cores are broadly found in natural products and pharmaceuticals, such as vitamin E, diversonol, afzelechin, cordotolide A, lotthanongine, and flavonoids. They exhibit a wide range of biological activity, that is, antibacterial, antitumor, antioxidant, antileishmanial, and potent cytotoxic activities. Therefore, the development of new synthetic routes leading to these heterocycles is of interest. Catalytic multicomponent reaction of β-dicarbonyl or phenolic compounds with aldehyde and ring-closing metathesis reaction are among the most used approaches for the construction of chromane and chromene derivatives. 237


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Scheme 272. Synthesis of 2-Hydroxy-2H-chromene-2-carboxylates 850,851a

a

850, Ar = 4-XC6H4 (X = H, F, Cl, Me, MeO, NO2), 3,4-(OCH2O)C6H3, 2-naphthyl; 68−91%, 70−89% ee; 851, R1 = Et, XC6H4 (X = H, 2-Cl, 3Cl, 4-Cl, 4-F, 2-Br, 4-i-Pr, 4-MeO, 4-MeS, 4-allylO, 3-PhO, 4-BnO, 4-NO2), 1-naphthyl, 2-thienyl; R2 = Me, Et; 72−97%, 92−97% ee.

Scheme 273. Synthesis of Chromene-2-carboxylates 825−853a

a

Cond. a, 852, R1 = H, 6-Me; R2 = Me, Et; Ar = XC6H4 (X = H, 4-F, 3-Cl, 4-Cl, 3-Br, 4-Br, 3-Me, 4-Me, 4-Ph, 3-MeO, 4-MeO), 3,4-(OCH2O)C6H3, 2-naphthyl, 2-thienyl, styryl; 78−99%, 85−90% ee; Cond. b, 852, R1 = H; R2 = Me, Et, i-Pr, Bn; Ar = XC6H4 (X = H, 4-F, 4-Cl, 2-Br, 4-Br, 4-Me, 3EtO, 4-NO2), 2-furyl, Ph(CH2)2; 78−99%, 84−93% ee; 853, X = O; R3 = Me; R4 = H; Ar = 4-XC6H4 (X = H, Cl); 99%, 93−94% ee; 850, R5 = H, Me; 98−99%, 90−91% ee; Cond. c, 852, R1 = H, 6-Me; R2 = Me, Et, i-Pr, allyl; Ar = XC6H4 (X = H, 4-F, 3-Cl, 4-Cl, 4-Br, 4-Me, 4-MeO), 2-thienyl; 95−99%, 74−79% ee; 853, X = O; R3 = Me; R4 = H or X = NMe; R3−R4 = (CH)4; Ar = Ph; 92−99%, 74% ee; 850, R5 = H, Me; 97−99%, 79−85% ee.

and afforded the corresponding 852 in 78−99% yields, with 85−90% ee.418 A similar approach was developed using thiourea-tertiary-amine catalyst XVI-9 (5 mol %) in Et2O at room temperature for 2 h,419 XVI-5 (10 mol %) in THF at room temperature for 1−3 h,420 or XVI-10 (10 mol %) in PhCF3 at −25 °C,421 in which products 852 were obtained in 78−99% yields, with 84−93% ee, 90−98% yields, with 90−98% ee, or 95−99% yields, with 74−79% ee, respectively. In addition to 4-hydroxycoumarin, several other cyclic 1,3-dicarbonyl compounds were studied, leading to the formation of the

corresponding THP derivatives. Under reaction conditions similar to those mentioned above, using XVI-9, THPs 850 and 853 were obtained in 98−99% yields, with 91−94% ee; however, XVI-5 afforded THPs 850 and 853 in 92−99% yields, with 74−85% ee (Scheme 273).419,420 There is another report on the similar methodology on the construction of tetrahydropyrano[3,2-c]chromene-2-carboxylates using (S)-tBu-BOX-Cu(OTf)2 catalyst VII-2-Cu.422 Also, 2-hydroxy-5,10-dioxo-3,4,5,10-tetrahydro-2H-benzo[g]chromene-2-carboxylates 854 were prepared from Michael 238


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addition of 2-hydroxy-1,4-naphthoquinone to β,γ-unsaturated α-oxoesters using thiourea-tertiary-amine catalyst XVI-8. Reactions were conducted by stirring a mixture of 2-hydroxy1,4-naphthoquinone with 1.1 equiv of β,γ-unsaturated αoxoesters in the presence of XVI-8 (10 mol %) in DCE at −20 °C for 24−36 h, to give 854 in 94−99% yields, with 90− 98% ee (Scheme 274).423

in the presence of catalyst XVI-11 (10 mol %) in Et2O at room temperature for 36 h, and chromanes 855−856 were obtained in 79−90% yields, with 82−96% ee (Scheme 275a).424 By treatment of an equimolar amount of naphthols and β,γunsaturated α-oxoesters in the presence of 20 mol % of bifunctional thiourea-tertiary-amine-catalyst XVI-4, in DCM at room temperature for 6−48 h, followed by dehydration using a drop of concentrated H2SO4 and stirring at room temperature for an additional 30 min, naphthopyran derivatives 857 were obtained in 51−91% yields, with 57−90% ee (Scheme 275b).425 Also, AuCl3/AgOTf-catalyzed reaction between 2naphthol and a β,γ-unsaturated α-ketoester in refluxing DCE during 6 h was developed for the construction of a naphthopyran derivative 857.426 Wu et al.427 reported the synthesis of 4-aryl-2H-chromenes 860 from reaction of β,γ-unsaturated α-oxoesters with phenolic compounds. Reactions were carried out by heating a solution of a phenolic compound with 1.1 equiv of β,γ-unsaturated αoxoesters in the presence of trityl chloride (1.1 equiv) and 4 Å MS in TFA under reflux conditions for 12 h, which afforded the corresponding 4-aryl-2H-chromenes 860 in 78−90% yields. Reaction with phenols possessing electron-withdrawing substituents, such as 4-nitrophenol, did not occurr. In the proposed reaction mechanism, Friedel−Crafts alkylation/cyclodehydration of phenols with β,γ-unsaturated α-oxoesters resulted in the formation of 4H-chromenes 858, which were converted to 2Hchromenes 860 by intermolecular hydrogen transfer to trityl chloride, leading to benzopyrylium ion 859, followed by hydration with water (Scheme 276). Also, chromanes 861 were synthesized via catalytic oxaMichael addition/Friedel−Crafts alkylation reactions of metaEDG-substituted phenols with β,γ-unsaturated α-oxoesters. Reactions were conducted using 2 equiv of phenols in the presence of Mg(OTf)2 (10 mol %) and bisoxazoline ligand VII-

Scheme 274. Synthesis of 2H-Benzo[g]chromene-2carboxylates 854a

a 1

R = Et, XC6H4 (X = H, 4-F, 2-Cl, 3-Cl, 4-Cl, 2-Br, 4-i-Pr, 4-MeO, 4BnO, 4-PhO, 4-allylO, 4-MeS), 1-naphthyl, 2-thienyl; R2 = Me, Et; 94−99%, 90−98% ee.

Chromanes 855,856 were prepared via tertiary aminethioureas XVI-11-catalyzed Friedel−Crafts alkylation/cyclization reactions of naphthols with a variety of β,γ-unsaturated αoxoesters. Reactions were performed using 2 equiv of naphthols

Scheme 275. Synthesis of Chromanes 855−857 via Friedel−Crafts Alkylation/Cyclization Reactionsa

a 855, R = Me, Et, Bn; Ar = XC6H4 (X = H, 2-F, 4-F, 2-Cl, 4-Cl, 4-Br, 3-Me, 4-CF3), 2-F-5-BrC6H3, 2-Br-5-FC6H3, 2-furyl, 2-thienyl, 2-naphthyl; 79− 86%, 82−96% ee; 856, R = Me; Ar = Ph, 3-MeC6H4, 2-thienyl; 86−90%, 86−91% ee; 857, R1 = H, 6-Br, 7-MeO; R2 = Me, Et, i-Pr, Bn, allyl; Ar = XC6H4 (X = H, 4-F, 3-Cl, 4-Cl, 2-Br, 4-Br, 4-EtO, 4-NO2), 2,5-(MeO)2C6H3; 52−91%, 57−90% ee.

239


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Scheme 276. Synthesis of 4-Aryl-2H-chromenes 860a

Scheme 278. Synthesis of 4H-Chromenes 865 via Cascade Michael−Aldol Reactiona

a 1

R = 4-F, 4-Cl, 4-Br, 4-Me, 4-t-Bu, 4-Ph, 4-MeO, 2,3-(CH)4, 3,4(CH)4; R2 = Me, Et; Ar = 4-XC6H4 (X = H, Cl, Me, MeO); 78−90%.

3 (11 mol %) and p-methyl-N,N-dimethylaniline (10 mol %) as an additive in anhydrous toluene at 0 °C, overnight. Chromanes 861 were obtained in 43−95% yields, with 13− 80% ee (Scheme 277).428 Lyle et al.429 reported a similar methodology using C2-symmetric 2,2′-bipyridyl copper(II) triflate complex.

a 1

R = H, 4-Cl, 4-Me, 4-MeO, 5-MeO; R2 = t-Bu, n-Pent, Ph(CH2)2, XC6H4 (X = H, 3-F, 4-F, 4-Cl, 4-Br, 4-Me, 4-MeO, 3-NO2, 4-NO2), 2furyl, 2-thienyl; 69−99%, 93−99% ee.

Scheme 277. Synthesis of Chromanes 861 via Oxa-Michael Addition/Friedel−Crafts Alkylationa

ester to give zwitterion 866, which nucleophilically attached into 2-(2-hydroxyaryl)-2-oxoacetates to generate intermediate 867. Proton transferring, followed by cyclization led to intermediate 868, which converted to the final products 869 by removal of (p-FC6H4)3P. Similarly, [4 + 2] annulation reaction of 2-(2-hydroxyaryl)-2-oxoacetates with allenylsulfone (3 equiv) was performed in THF using 50 mol % of sodium ptoluenesulfinate (SPTS) at room temperature for 24 h, leading to the corresponding chromans 870 in 30−48% yields (Scheme 279). Clerici and Porta432 demonstrated the synthesis of 4hydroxy-3-phenylcoumarins 872 via Ti(III)-mediated reaction of methyl benzoylformate with substituted salicylaldehydes followed by lactonizations under acidic conditions. By stirring an equimolar amount of benzoylformate and salicylaldehydes in glacial AcOH in the presence of TiCl3 (2.3 equiv) at 0 °C for 1 h, reductive C−C bond formation took place to give intermediates 871, which underwent lactonizations by treatment with p-TSA·H2O in refluxing benzene for 5 h (Scheme 280). Ethyl 4-oxo-4H-chromene-2-carboxylates 874 were prepared by treatment of 2-hydroxy acetophenone derivatives with diethyl oxalate in a solution of Na in dry EtOH under reflux conditions, leading to ethyl 4-(2-hydroxyphenyl)-2,4-dioxobutanoate 873a, which existed as ring tautomer, ethyl 2-hydroxy4-oxochroman-2-carboxylate 873b, in 39−67% yields, that underwent dehydration to the desired products 874 when heated in EtOH in the presence of an acid under reflux conditions in 47−96% yields (Scheme 281a).433 Ethyl 3methy1-4-oxo-L-phenyl-1H-pyrano[2,3-c]pyrazole-6-carboxylate 876 was prepared in 86% yield, by reaction of 4-acetyl-3methyl-1-phenylpyrazol-5-one with diethyl oxalate in the presence of NaOEt in EtOH to give the corresponding pyruvate 875, followed by cyclization using HCl (Scheme 281b).434

a R = OMe, NMe2; Ar = 4-XC6H4 (X = H, F, Cl, Br); 43−95%, 13− 80% ee.

An enantioselective cascade Michael-aldol reaction between ethyl 2-(2-hydroxy-4-methoxyphenyl)-2-oxoacetate and variety of propynals was developed for the synthesis of 4H-chromenes 865 in 69−99% yields, with 93−99% ee. Reactions were applied by equimolar amounts of ethyl 2-(2-hydroxy-4methoxyphenyl)-2-oxoacetate and propynals in the presence of diarylprolinol silyl ether VIII-5 (15 or 25 mol %) in toluene at −15 to −10 °C, for 6−60 h. Reactions were initiated by oxaMichael addition of ethyl 2-(2-hydroxy-4-methoxyphenyl)-2oxoacetate to iminium ion 862, in situ generated by reaction of propynals with VIII-5, to give allenamine 863, which underwent intramolecular aldol reaction with ketone moiety of α-ketoester 864, followed by hydrolysis (Scheme 278).430 The synthesis of chromans 868 was reported by Hu et al.431 via (p-FC6H4)3P-catalyzed reaction between ethyl 2-(2hydroxyaryl)-2-oxoacetates and alkyl 2,3-butadienoate. Reactions were conducted by stirring a solution of 2-(2hydroxyaryl)-2-oxoacetates and alkyl 2,3-butadienoate (2 equiv) in toluene in the presence (p-FC6H4)3P (20 mol %) at 60 °C for 48 h, to give the corresponding chromans 869 in 33−97% yields, as a mixture of E and Z isomers. The transformation involves the addition of (p-FC6H4)3P to allenic 240


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Scheme 279. Synthesis of Chromans 869,870a

with ethyl 2-oxo-2-phenylacetate in 46% yield, with 76% ee. Reaction was applied in DCM at room temperature for 36 h, using 2 equiv of 2-oxo-2-phenylacetate and 5 mol % of [Rh((R,R)-III-4)]BF4 as catalyst. As shown in Scheme 282, a possible reaction mechanism involves oxidative addition of Rh(I) to aldehyde C−H bond, followed by syn addition of Rh− H to alkyne leading to acylrhodium intermediate 878. By regioand stereoselective insertion of 2-oxo-2-phenylacetate to 878, oxarhodacycle 879 was generated, which was transformed into 880 by reductive elimination of Rh(I).435 Ueno et al. 436 described the Pd-catalyzed [4 + 2] cycloaddition reaction of o-(silylmethyl)benzyl carbonates 881 with methyl 2-oxo-2-arylacetates leading to isochromanes 885 in 35−93% yields. Reactions were conducted by treatment of 1.5 equiv of 881 with 2-oxo-2-arylacetates in the presence of Pd(η 3 -C 3 H 5 )Cp (3 mol %) and DPEphos (bis[2(diphenylphosphino)phenyl] ether, 6.6 mol %) in dry DMF at 120 °C for 3−24 h. By action of Pd(0) on 881, 2palladaindan 882 was formed, which underwent η 1 −η 3 isomerization to give (η3-benzyl)palladium 883. By nucleophilic addition of zwitterion 883 into ketone moiety of α-ketoester, followed by cyclization through addition of alkoxide on the η3benzyl in 884, isochromanes 885 were produced (Scheme 283). (1S,3S)-Ethyl 3-[3-(dimethylamino)-3-oxopropyl]isochroman-1-carboxylate 887, a synthetic intermediate of tricyclic benzomorphan analogues 888, was synthesized in 93% yield, via oxa-Pictet−Spengler reaction of (S)-4-hydroxyN,N-dimethyl-5-phenylpentanamide 886 with ethyl glyoxalate using BF3·OEt2 as catalyst in DCM at room temperature for 6 h, followed by heating at 40 °C for 4 days (Scheme 284a).437 Also, oxa-Pictet−Spengler reaction was developed for the synthesis of methyl 6-methoxy-1-methylisochroman-1-carboxylate 889 by treatment of 2-(3-methoxyphenyllethanol) with methyl pyruvate in the presence of a catalytic amount of pTsOH in EtOH. Isochroman-1-carboxylate 889 was obtained in 80% yield (Scheme 284b).438 Treatment of 1-allyl-3,4-dimethoxybenzene with methyl trifluoropyruvate (1.3 equiv) in the presence of several drops of TfOH in anhydrous DCM at 20 °C, for 1 h, furnished isochromane derivative 891 via cyclization of intermediate 890 (Scheme 285).439 The Ph3P-catalyzed [4 + 2] annulation of chromonyl-αoxoesters 470 with acetylene carboxylates was described to synthesize tricyclic benzopyrones 894. Reactions were carried out using 20 mol % of Ph3P in toluene at 60 °C for 10−30 min, which led to tricyclic benzopyrones 894 in 70−87% yields. The transformation was initiated by conjugate addition of zwitterion 892, in situ generated by addition of Ph3P to acetylene carboxylate, to chromonyl-α-oxoesters 470, followed by intramolecular cyclization via addition−elimination mechanism 893, with removal of Ph3P (Scheme 286).440 From treatment of a solution of 5-(3-methoxyphenyl)-8methyl-2-oxa-8-azabicyclo[3.3.1]nonane 895 in H2SO4/Et3N (pH = 3) with methyl glyoxalate in the presence of Et3N in water at 80 °C for 18 h, under N2 atmosphere, hexahydro-1Hpyrano[3,4-c]pyridine-1-carboxylate 896 was obtained in 52% yield, which transformed into 7-(cyclopropylmethyl)-1-methyloctahydro-1H-pyrano[3,4-c]pyridin-4a-yl)phenol 897, possessing antinociceptive activity (Scheme 287).441

a

869, R1 = Et, t-Bu, Bn; R2 = H, 4-Cl, 3-Me, 4-Me, 5-Me, 5-t-Bu, 5MeO; PAr3 = P(p-FC6H4)3; E, 11−48%, Z, 31−50%; 870, R2 = H, 4Cl, 4-Me, 5-Me, 5-Et, 5-t-Bu, 4,5-Me2; Ar = 4-ClC6H4; 30−38%.

Scheme 280. Synthesis of 4-Hydroxy-3-phenylcoumarins 872a

a 1 R = H, 5-Cl, 5-Br, 5-OH, 3-MeO, 5-MeO; 871, 62−80%; 872, 82− 93%.

4.9. Isochromanes and Isochromenes

Isochromane and isochromene derivatives have received great attention due to their occurrence in natural and non-natural products, such as pseudodeflectusin, 8-hydroxy-3,5-dimethylisochroman-1-one, chermesinone B, S-(+)-XJP, pergillin, dihydropergillin, ochratoxin A and R-(−)-mellein, and aspergiones A−F, monocerolide, BCH2051, cis-deoxydihydrokalafungin, possessing antihypertensive, antifungal, antitumor, antibacterial, antirheumatic, and anticoagulant activities. There are a number of routes leading to isochromane and isochromene derivatives, including oxa-Pictet−Spengler reaction, oxidative coupling of benzyl alcohols with alkynes, sequential intramolecular cyclization and hydrogenation of oalkynylacetophenones, and iodocyclization of 2-(1-alkynyl)benzylic alcohols. The synthesis of ethyl 1-oxo-4-pentylidene-3-phenylisochroman-3-carboxylate 880 was reported via Rh-catalyzed enantioselective [4 + 2] annulation of 2-(hex-1-ynyl)benzaldehyde 877 241


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Scheme 281. Synthesis of 4H-Chromene-2-carboxylates 874 and 1H-Pyrano[2,3-c]pyrazole-6-carboxylate 876a

a

R = H, 5,6-(CH)4, 6,7-(CH)4, 7,8-(CH)4; 873, 39−67%; 874, 47−96%; 876, 86%.

Scheme 282. Synthesis of 1-Oxo-3-phenylisochroman-3carboxylate 880

Scheme 284. Synthesis of Isochroman-1-carboxylate 887 and 889 via Oxa-Pictet−Spengler Reaction

Scheme 283. Synthesis of Isochromanes 885a

Scheme 285. Synthesis of Isochromane Derivative 891

cosmetics industry. Also, 1,3-dioxane is one of the most important protecting groups of carbonyl compounds. There are a number of methodologies, such as reaction of carbonyl compounds with 1,3-diols, for preparing dioxane derivatives. 1,3-Dioxinone derivatives were extensively synthesized via [4 + 2] cycloaddition reaction of carbonyl group of aldehydes or ketones with in situ generated ketenes from thermolysis of 2,3dihydrofuran-2,3-diones.442 In this context, Vostrov et al.443 conducted the reaction of 2,3-dihydrofuran-2,3-diones with an equimolar amount of a carbonyl compound in refluxing dry

a 1

R = H; R2 = Me, Et; Ar = 4-XC6H4 (X = H, MeO, CF3), 2,4Me2C6H3, 1-naphthyl, 2-naphthyl, 2-furyl; 35−93%; R2 = Me; Ar = Ph, R1 = 3-Me; 75%, 5-Me/8-Me = 90/10; R1 = 6-Me; 74%, 5-Me/8-Me = 87/13; R1 = 3-Ph; 63%, 5-Ph/8-Ph = 52/48.

4.10. Dioxanes

The dioxane nucleus is present in several natural and bioactive molecules, such as theopederin D, cytotoxic, and antimuscarinic agents. They have applications in the pharmaceutical and 242


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Scheme 286. Synthesis of Tricyclic Benzopyrones 894a

Scheme 289. Synthesis of Tricyclic Acetal 901

exhibit biological activities, such as antidepressant, anxiolytic, antipsychotic, angiotensin-II-receptor-antagonist, and anti-inflammatory properties. There are no general routes for the synthesis of oxepin moieties; however, some multistep methods have been developed to construct oxepin structural motifs in the literature. Reaction of alkylidene pyruvate esters with P(NMe2)3 (0.53 equiv) in toluene at −78 °C, then at room temperature, gave the corresponding 2,5-dihydrooxepins 902 in 11−44% yields, differing from the reaction of arylidene pyruvate esters, as illustrated in Scheme 245 (Scheme 290).359

a 1

R = H, CO2Me, CO2Et; R2 = Me, Et; 70−87%.

Scheme 287. Synthesis of Hexahydro-1H-pyrano[3,4c]pyridine-1-carboxylate 896

Scheme 290. Synthesis of 2,5-Dihydrooxepins 902a

a 1

R = Me, t-Bu; R2 = Me, Et; 11−44%.

Photoreaction of cyclopropylmethyl 2-oxo-2-phenylacetate was investigated in the presence of O2 in benzene, in which a mixture of products was obtained along with 4,5-dihydrooxepin-2(3H)-one 905 in low yield. The reaction proceeded by γH abstraction (903), followed by ring opening of cyclopropylmethyl moiety to form intermediate 904, which underwent cyclization to afford 4,5-dihydrooxepin-2(3H)-one 905 (Scheme 291).445

xylene for 30−40 min, leading to the corresponding 4H-1,3dioxin-4-ones 898 in 75−94% yields (Scheme 288). Scheme 288. Synthesis of 4H-1,3-Dioxin-4-ones 898a

Scheme 291. Synthesis of 4,5-Dihydrooxepin-2(3H)-one 905

a 1 R = H, Ph; R2 = Bn, 4-XC6H4 (X = Br, MeO); R1−R2 = (CH)4, (CH)6; Ar = 4-XC6H4 (X = H, Me), 2,5-Me2C6H3; 75−94%.

Oxidation of bromoalkyne 899 using KMnO4 in MeOH in the presence of NaHCO3 and MgSO4 led to the corresponding α-ketoester 900 in 84% yield, which was converted to tricyclic acetal 901 via reaction between the ketone moiety and the 3and 6-OH groups, when treated with HF−pyridine at −78 °C to room temperature, in which not only the silyl ether but also the 3- and 4-benzyl ethers had been cleaved (Scheme 289).444

5. SYNTHESIS OF N,O-HETEROCYCLES

4.11. Oxepins

5.1. Isoxazoles

Oxepin rings are frequently encountered in many natural and bioactive molecules, such as pacharin, bauhiniastatin, bauhinoxepin B, radulanin A, pterulone, ptaeroxylin, heliannuol B, tournefolic acid B, oxepinamides A−C, and janoxepin, which

Isoxazole moieties are broadly found in natural products and pharmaceuticals, such as muscimol, ibotenic acid, cloxacillin, oxacillin, dicloxacillin, floxacillin, danazol, and valdecoxib, with a wide range of biological activity and clinical properties, 243


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Scheme 292. Synthesis of Isoxazolidine-3-carboxylates 906,907a

a 906a, R1 = Me, Et, Bn, MeO2C(CH2)2, [S(CH2)2S]CHCH2; R2 = Me, Et; R4 = n-Pent, CH2OH, CH2OAc, (CH2)2OH, CO2Me, CO2Et, OR (R = Et, t-Bu, Ac); R5 = H, CO2Et; 63−97%, trans/cis = 61/39−98/2; 906b, R2 = Et, t-Bu; R4 = H, R5 = H, Me; R6 = Me, Et; R4−R6 = (CH2)2; 43−83%, exo/endo = 31/69−77/23; 907, R3 = Me, Bn; R4 = H, OBn; R5 = H, OBn, OAc; R6 = Bn, Ac; R7 = H, OBn, OAc; R8 = H, OBn; 50.5−82.4%, α/β = 1/3.1−14.8/1.

Spiro ketosyl isoxazolidines 907 were obtained in 50.5−82.4% yields, in a 1/3.1−14.8/1 ratio of α/β (Scheme 292c).449 The synthesis of spiro-isoxazolines 902 was developed by Smietana et al.450 in a one-pot procedure by treatment of Oprotected hydroxy-2,4-dioxoesters 908 with hydroxyl amine hydrochloride (3 equiv) in EtOH at room temperature for 3 h. Spiro-isoxazolines 909 were obtained in 6−80% yields. Starting O-protected hydroxy-2,4-dioxoesters 908 were prepared by protection of hydroxy ketones, followed by reaction with diethyl oxalate in the presence of NaOEt in EtOH in 62−74% yields (Scheme 293). Similarly, thiopyran-fused isoxazole-3-

including antibacterial, COX-2 inhibitory, antinociceptive, antiinflammatory, and anticancer activities, and brain-lesioning agent. Also, they have served as versatile building blocks in organic synthesis. 1,3-Dipolar cycloaddition of nitrile oxides and nitrones, condensation of hydroxylamine with 1,3dicarbonyl compounds and α,β-unsaturated carbonyl compounds, and cycloisomerization of α,β-acetylenic oximes are among the most useful approaches for the synthesis of isoxazoles derivatives. Isoxazolidines were conveniently prepared by 1,3-dipolar cycloaddition reaction of nitrones with variety of alkenes.446 In this context, Nguyen et al.447 developed the 1,3-dipolar cycloaddition reaction between dipolarophiles with nitrones, prepared from reaction of α-oxoesters with 1.1 equiv of Nbenzylhydroxylamine in the presence of NaOAc (1.2 equiv) in MeOH at room temperature for 16 h. 1,3-Diopolar cycloaddition reactions were carried out using 2−10 equiv of dipolarophile under heating and solvent-free conditions for 4− 76 h, leading to isoxazolidine-3-carboxylates 906a in 63−97% yields, with 61/39−98/2 ratio of trans/cis (Scheme 292a). Also, asymmetric 1,3-dipolar cycloaddition reaction of glyoxalate derived nitrones with alkyl vinyl ethers (2 equiv) was performed using Cu(OTf)2 (25 mol %) and ligand VII-2 (30 mol %) in dry DCM at room temperature under an atmosphere of N2 for 20−38 h, to give the corresponding isoxazolidine-3carboxylates 906b in 43−83% yields, with a 31/69−77/23 ratio of exo/endo. Determined ee’s for the exo and endo isomers were 0−90% and 0−94%, respectively (Scheme 292b).448 Spiro ketosyl isoxazolidines 907 were synthesized by 1,3-dipolar cycloaddition reaction of 1-methylenesugars with ethyl glyoxalate derived nitrones, either using BF3·OEt2 (1.3 equiv) in the presence of 4 Å MS in DCM under Ar atmosphere at −78 °C for 4 h, and then increasing the temperature to 0 °C, or by refluxing in benzene under an atmosphere of Ar for 24 h.

Scheme 293. Synthesis of Spiro-isoxazolines 909a

a 1

R = (CH2)n (n = 1, 2, 4); CHMe, (CH)2CH2; R2 = TBDMS, THP; 6−80%.

carboxylates were synthesized from the condensation reaction of oxothiopyranyl glyoxalates with hydroxylamine hydrochloride in refluxing AcOH for 7−8 min.118a−c,451 5.2. Oxazoles

Oxazoles constitute an important class of heterocyclic compounds, vastly found in natural products and drugs, such as muscoride A, diazonamde A, telomestatin, hennoxazole A, ulapualide A, leucamide A, bengazole A, disorazole C1, 244


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with TosMIC in the presence of DBU in DCM at 0 °C, in 80% yield.455 By treatment of 5-aryl-2,3-dihydrofuran-2,3-diones with an equimolar amount of cyanamide in anhydrous benzene, ether, or dioxane at room temperature for 2−4 h, 2-imino-5phenacycliden-4-oxazolidones 913 were obtained in 82−96% yields (Scheme 296).456

phorboxazole A, siphonazole, madumycin I, and oxaprozin. Additionally, oxazolines have applications as metal ligands in asymmetric catalysts and as synthetic intermediates or protecting groups in organic synthesis. General synthetic methods for oxazoline derivatives include the 1,3-dipolar cycloaddition of vinyl epoxides with imines, condensation of carboxylic acids with 2-aminoethanol, followed by dehydrative cyclization, aminohydroxylations of alkenes, cyclization of βhydroxyamides, cyclodehydration of α-acylaminoketone, Robinson−Gabriel, Van Leusen, and Fischer synthesis. The synthesis of 4-(2-oxooxazolidine-3-carbonyl)-2-thioxooxazolidine-5-carboxylate derivatives 911 via aldol additioncyclization sequences was reported by Vecchione et al.452 αIsothiocyanato imide 910 was treated with 1.1 equiv of αketoester in the presence of bifunctional thiourea catalyst XVI12 (5 mol %) in methyl t-butyl ether at room temperature for 1.5−48 h to afford the corresponding 2-thioxooxazolidine-5carboxylates 911 in 70−99% yields, with 70/30−85/15 dr (Scheme 294). A similar approach was developed by Jiang et

Scheme 296. Synthesis of 2-Imino-5-phenacycliden-4oxazolidones 913a

a

R = H, Me, Br; Ar = 4-XC6H4 (X = H, Cl, Me, MeO); 82−96%.

Treatment of ethyl 2-(2-amidothiazol-4-yl)-2-p-tosyloxyiminoacetate 914 with ketones in the presence of Et3N and EtSH at room temperature for 5 days gave 2,2-disubstituted-4-(2amidothiazol-4-yl)-5-oxo-2,5-dihydro-1,3-oxazoles 917 in 28− 54% yields. The proposed reaction mechanism involves the formation of sulfenylimine 915 by the action of EtSH on 914, followed by cleavage of the N−S bond with another molecule of EtSH, generating α-iminocarboxylate derivative 916 and EtSSEt. α-Iminocarboxylate 916 underwent cyclocondensation with ketones along with removal of EtOH, to give 917 (Scheme 297).457

Scheme 294. Synthesis of 2-Thioxooxazolidine-5carboxylates 911a

Scheme 297. Synthesis of 5-Oxo-2,5-dihydro-1,3-oxazoles 917a a

R = Me, XC6H4 (X = H, 2-Cl, 4-Cl, 4-Br, 4-CF3, 4-Me, 4-t-Bu, 3MeO, 4-MeO), 2,4-Cl2C6H3, 3,4-Cl2C6H3, 3,5-F2C6H3, 2-naphthyl, 2thienyl; 70−99%, 70/30−85/15 dr.

al.453 using rosin-derived tertiary amine-thiourea catalyst in toluene at room temperature to afford the corresponding 2thioxooxazolidine-5-carboxylates in up to 92% yields, with 70/ 30−97/3 dr, and 81−99% ee. Shibata et al.454 reported a one-pot procedure for the construction of 5-phenyloxazolidine-2,4-diones 912 by allylation of methyl benzoylacetate using allyltri-n-butyltin and Bu2SnI2, followed by reaction with isocyanates. Allylation reaction was performed in THF at room temperature; the obtained mixture was treated with isocyanates (3 equiv) at room temperature for 1 h, with subsequent heating at 60 °C for 3 h, to give the corresponding 5-phenyloxazolidine-2,4-diones 912 in 82−92% yields (Scheme 295). There is another report on the synthesis of one example of oxazole moiety in the total synthesis of natural products, by reaction of ethyl glyoxalate

R = CHO, Ac; R2 = Me; R3 = Me, Et; R2−R3 = (CH2)5; 28−54%.

a 1

Okonya et al.458 reported a method for the synthesis of 2oxazolone-4-carboxylates 918 through the reaction of 3nosyloxy- and 3-bromo-α-oxoesters with methyl carbamate. Reactions were conducted by refluxing a solution of 3-nosyloxyα-oxoesters (4 mmol) and methyl carbamate (5 equiv) in toluene in the presence of 10 mol % p-TsOH, overnight, to afford the corresponding 2-oxazolone-4-carboxylates 918 in 41−84% yields. However, reactions with 3-bromo-α-oxoesters were performed using AgOTf (1 equiv) in the presence or absence of p-TsOH (10 mol %) in refluxing toluene, overnight, leading to 2-oxazolone-4-carboxylates 918 in 49−79% or 30− 68% yields, respectively (Scheme 298). A similar methodology was investigated by reaction of β-(2,4dinitrobenzenesulfonyloxy)-α-oxoesters with acetamide or

Scheme 295. Synthesis of 5-Phenyloxazolidine-2,4-diones 912a

a 1

R = H, Me; R2 = Ph, 4-MeOC6H4, Ts; 82−92%. 245


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Scheme 298. Synthesis of 2-Oxazolone-4-carboxylates 918a

occurrence in natural products, such as myrioxazine A, trichodermamides A−C, aspergillazine A, and gliovirin, and also in drugs, such as phendimetrazine, prepitant, BW 306U, phenmetrazine, 3-benzhydrylmorpholine, fenbutrazate, edivoxetine, morazone, reboxetine, which act as appetite suppressant, selective norepinephrine reuptake inhibitor, anti-inflammatory, anti-HIV, antihypertensive, antibiotic, antithromobotic, and anticonvulsantand agents. Moreover, they are valuable intermediates in the synthesis of other natural and biologically important molecules. The most useful methods for the preparation of oxazine moieties include the reaction of a diol or olefin with a nitrile under acidic conditions, reaction of aminoethanol or o-aminophenol with 1,2-electrophiles, cyclodehydration of hydroxyl amides, and elimination of water from β-acylamino-carbonyl compounds. 4H-5,6-Dihydro-1,2-oxazines 923 were prepared via tandem oxime formation−epoxide ring-opening sequences, by treatment of 4,5-epoxy-α-ketoester 922a with hydroxylamine hydrochloride in the presence of a base. The reaction was performed using 1.1 equiv of K2CO3 in DMF or EtOH at room temperature for 16 h, which gave 4H-5,6-dihydro-1,2-oxazine 923a in 14−64% yield, respectively. The reaction of epoxy-αketoester 922b with hydroxylamine hydrochloride was carried out in a mixture of CH3CN/water in the presence of NaOAc at room temperature for 12 h, followed by treatment with SiO2 in EtOAc at room temperature for 8 h, to afford the corresponding 4H-5,6-dihydro-1,2-oxazine 923b in 72% overall yield for two steps, a synthetic intermediate of trichodermamide A and trichodermamide B 924, isolated from the marine fungus Trichoderma virens (Scheme 301).461

a 1 R = H, Me, i-Pr, i-Bu, n-Pent, Ph, Bn, AcCH2; R2 = Me, Et; X = ONs (Cond.: p-TsOH, toluene, reflux, overnight), 41−84%; X = Br (Cond.: AgOTf, p-TsOH, toluene, reflux, overnight), 49−79%; X = Br (Cond.: AgOTf, toluene, reflux, overnight), 30−68%.

benzamide to give 2-substituted oxazole-4-carboxylates 919. By treat ment of ethyl p yruvat e with [hydroxy(2,4dinitrobenzenesulfonyloxy)iodo]benzene (HDNIB) (1.2 equiv) in MeCN under reflux conditions, β-(2,4-dinitrobenzenesulfonyloxy)-α-oxoester was in situ generated, which was subjected with amides (3 equiv) and refluxed for an additional 10 h, leading to oxazoles 919 in 62−71% yields (Scheme 299).459 Scheme 299. Synthesis of 2-Substituted Oxazole-4carboxylates 919a

a

Scheme 301. Synthesis of 4H-5,6-Dihydro-1,2-oxazines 923

R = Me, Ph; 62−71%.

Reaction of Mitsunobu reagent with α-oxoesters was described by Otte et al.460 to give 1,3,4-oxadiazole-2,3(2H)dicarboxylates 921. Reactions were conducted in THF using 1.2 equiv of azodicarboxylate and 1.5 equiv of PPh3 at room temperature, and afforded 1,3,4-oxadiazole-2,3(2H)-dicarboxylates 921 in 71−93% yields. The proposed reaction mechanism involves the nucleophilic addition of Ph3P-induced generated azodicarboxylate anion to the ketone moiety of αoxoesters to form intermediate 920, which underwent intramolecular SN2 reaction, resulting in the formation of 921, along with the removal of Ph3PO molecule (Scheme 300). 5.3. Oxazines

The chemistry of oxazines has received great attention in medicinal and synthetic organic chemistry, due to their Scheme 300. Synthesis of 1,3,4-Oxadiazole-2,3(2H)dicarboxylates 921a Condensation reaction of salicylamide with α-oxoesters, such as ethyl pyruvate and ethyl glyoxalate, was reported by Fitton and Ward462 in 1971, to furnish 3,4-dihydro-4-oxo-2H-1,3benzoxazine carboxylates 925. Reaction with ethyl pyruvate was performed in refluxing benzene with azeotropic removal of water using Dean−Stark apparatus for 15 h, and led to ethyl 3,4-dihydro-2-methyl-4-oxo-2H-1,3-benzoxazine-2-carboxylate 925 in 70% yield. Reactions with ethyl glyoxalate were conducted by heating a mixture of salicylamide and ethyl glyoxalate at 100 °C for 3−6 h, to afford the corresponding

a 1

R = i-Pr, Bn; R2 = Me, Ph, MeO2C(CH2)2; 71−93%. 246


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2,3,4,11b-tetrahydro-[1,3]oxazino[2,3-a]isoquinoline-2-carboxylate 930 in 30% yield, with 6/1 dr. The reaction of ethyl trifluoropyruvate was carried out using 0.25 equiv from each allenoates and isoquinoline, under similar conditions, which resulted in the formation of 2-(trifluoromethyl)-2,11b-dihydro[1,3]oxazino[2,3-a]isoquinoline-2,3-dicarboxylates 933 in 45− 46% yields, with 2/1−3/1 dr. Reactions were initiated by in situ generation of zwitterion 929a or 929b, via addition of isoquinoline to allenoate. Ethyl glyoxalate underwent reaction with dipole 929a to give 930; however, ethyl trifluoropyruvate reacted with dipole 929b to form enamine 931, which nucleophilically attached to another molecule of ethyl trifluoropyruvate. By deprotonation and subsequent enamination of intermediate 932, [1,3]oxazino[2,3-a]isoquinolines 933 were obtained (Scheme 304). Esmaeili and Nazer465a developed the reaction of benzofuran-2,3-diones with dialkyl acetylenedicarboxylates and isoquinoline to afford spiro[1,3]oxazino[2,3-a]isoquinoline derivatives 936. Reactions were performed at −10 °C in dry DCM for 5 min, and then at room temperature for 30 min. The proposed reaction mechanism involves the in situ generation of zwitterion 934 by nucleophilic addition of isoquinoline to DAAD, which transformed into final spiro[1,3]oxazino[2,3a]isoquinolines 936 by nucleophilic addition to ketone (935b) or ester (935a) moiety of benzofuran-2,3-diones, followed by intramolecular cyclization. Interestingly, the reaction took place at the ester moiety to form spiro[1,3]oxazino[2,3-a]isoquinolines 936a in 50−71% yields; however, reaction at ketone moiety led to the corresponding spiro[1,3]oxazino[2,3a]isoquinolines 936b in 13−25% yields, as minor products (Scheme 305). Reaction between ethyl pyruvate, electrondeficient acetylenic compounds, and isoquinoline was reported leading to [1,3]oxazino[2,3-a]isoquinoline-2,3,4-tricarboxylates in good yields, in which reactions occurred at the ketone moiety.465b Palacios et al.466 described the aza-HDA reaction of azadienes with ethyl glyoxalate or diethyl oxomalonate to synthesize 2H-1,3-oxazines. In the case of ethyl oxalate, reactions were carried out either in CHCl3 at 80 °C under reflux conditions under an atmosphere of N2 for 144 h or in Et2O in the presence of 1 mol % of LiClO4 at room temperature under N2 atmosphere for 14−20 h, affording the corresponding 2H-1,3-oxazine derivatives 937 in 63−76% or 65−78% yields, respectively. Reactions with diethyl oxomalonate were conducted in Et2O in the presence of 1 mol %

ethyl 3,4-dihydro-4-oxo-2H-1,3-benzoxazine-2-carboxylates in 50−58% yields (Scheme 302). Scheme 302. Synthesis of Ethyl 3,4-Dihydro-4-oxo-2H-1,3benzoxazine-2-carboxylates 925a

a 1

R = H, 6-Br; R2 = H, Me; 50−70%.

6H-Pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole derivatives 928 were prepared in two steps. Cyclocondensation of indoline 926 with α-oxoesters, such as ethyl glyoxalate, ethyl pyruvate, and diethyl oxomalonate in the presence of MsOH (0.1 equiv) in THF at 50 °C for 2 h, or using p-TsOH (0.1 equiv) in toluene at 80 °C for 1.5 h, gave the corresponding fused 1,3oxazines 927 in 24−84% yields, which underwent oxidative aromatization to 928 in 91−98% yields, when subjected to DDQ (1.1 equiv) in toluene at 80 °C for 4 h (Scheme 303).463 Scheme 303. Synthesis of 6HPyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole Derivatives 928a

a

R = H, Me, CO2Et; 927, 24−84%; 928, 91−98%.

Reactions of isoquinoline and allenoates with ethyl glyoxalate and ethyl trifluoropyruvate were developed by Yang et al.464 to synthesize 1,3-oxazino[2,3-a]isoquinoline derivatives 930 and 933. The reaction of ethyl glyoxalate was conducted in DCM at room temperature using 2 equiv of each allenoate and isoquinoline to afford ethyl 4-(2-ethoxy-2-oxoethylidene)-

Scheme 304. Synthesis of 1,3-Oxazino[2,3-a]isoquinoline Derivatives 930 and 933a

a

930, 30%, 6/1 dr; R = Et, Bn; 933, 45−46%, 2/1−3/1 dr. 247


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Scheme 305. Synthesis of Spiro[1,3]oxazino[2,3-a]isoquinolines 936a

a 1

R = Me, Et, i-Pr; R2 = H, Me; R3 = H, Me; 936a, 50−71%; 936b, 13−25%.

Scheme 306. Synthesis of 2H-1,3-Oxazines 937−940a

a 937, R1 = 3-pyridyl; R2 = Ph, 2-furyl, 2-thienyl; 63−78%; 938, R1 = Ph, 3-pyridyl, 2-thienyl, 5-Me-2-furyl, 2-pyrrolyl, 3-indolyl; R2 = Ph, 2-furyl, 2thienyl, 3-pyridyl; 48−88%, a/b = 70/30−100/0; 939, R2 = Ph, 2-furyl, 2-thienyl; 60−80%; 940a, R1 = 4-NO2C6H4; R2 = H, Ph; R4 = Et, menthyl; 43−92%; 940b, R1 = 4-NO2C6H4; R4 = Et, menthyl; 52−86%.

LiClO4 at room temperature under N2 atmosphere for 1−96 h, which gave 2H-1,3-oxazines 938 in 43−88% yields, with a 70/ 30−100/0 ratio of 938a/938b. Also, aza-Wittig-HDA reactions of phosphazenes with ethyl glyoxalate (2 equiv) were conducted in CHCl 3 at room temperature under N 2 atmosphere for 12−68 h, which gave 2H-1,3-oxazine-2,6dicarboxylates 939 in 72−80% yields. A similar reaction was performed using alkoxycarbonyl-substituted azadienes in THF at 60 °C or CHCl3 under reflux conditions for 16−20 h, leading to 2H-1,3-oxazines 940 in 43−92% yields (Scheme 306).467 When N-vinylic amidines, 2-azadienes, were subjected to diethyl oxomalonate in CHCl3 at room temperature under an atmosphere of N2 for 24 h, the HDA reaction (941) did not occurr, and, interestingly, diethyl 4-dialkylamino-2-ethoxycarbonylmethyl-2,5-dihydro-[1,3]oxazine-6,6-dicarboxylates 944 were obtained in 37−42% yields. Reactions proceeded by nucleophilic addition of tautomeric form 942 to the keton moiety of oxomalonate to give intermediate 943, which underwent intramolecular cyclization to final 1,3-oxazines 944 (Scheme 307).468

Scheme 307. Synthesis of 2,5-Dihydro-[1,3]oxazine-6,6dicarboxylates 944a

a

248

R2N = Et2N, (CH2)5N; 37−42%.


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2H-Benzo[b][1,4]oxazin-2-one derivatives were prepared by condensation of o-aminophenole derivatives with α-oxoesters. Reaction of o-aminophenole, in situ prepared by reduction of corresponding nitro compound using H2 in the presence of Pd/ C in EtOH, with methyl pyruvate in absolute EtOH at room temperature for 5 h led to the corresponding 2H-benzo[b][1,4]oxazin-2-one 950 in 87% yields (Scheme 310a).471

The reaction of 5-aryl-2,3-dihydro-2,3-furandiones with some N-cyano compounds was developed to synthesize 4H-1,3oxazin-4-ones 945,946. By heating a solution of 5-aryl-2,3dihydro-2,3-furandiones and N-cyano compounds in toluene or dioxane under reflux conditions for 0.5 or 1 h, the corresponding 4H-1,3-oxazin-4-ones 945,946 were obtained in 62−98% yields. The synthesis of 4H-1,3-oxazin-4-ones 945,946 was illustrated by decarbonylation of 5-aryl-2,3dihydro-2,3-furandiones to form aroylketen, followed by [4 + 2] cycloaddition reaction with CN moiety (Scheme 308).469

Scheme 310. Synthesis of 2H-Benzo[b][1,4]oxazin-2-one Derivatives 950−953

Scheme 308. Synthesis of 4H-1,3-Oxazin-4-ones 945,946a

a Ar = 4-XC6H4 (X = H, Cl, Me, MeO); 945, 80−98%; R1 = H, SMe; R2 = NMe2, NHPh; Ar = Ph, 4-MeC6H4; 946, 62−70%.

By heating a solution of 4-ethoxycarbonyl-5-phenyl-2,3dihydrofuran-2,3-dione in xylene in the presence of a heterocumulene or Schiff base under reflux conditions for 1.5 h, 5-ethoxycarbonyl-4H-1,3-oxazine-4-ones 947−949 were obtained in 35−70% yields, via [4 + 2] trapping of in situ generated α-oxoketene as a reaction intermediate (Scheme 309).96 Stadler et al.470 described a similar [4 + 2] cycloaddition reaction between carbomethoxypivaloylketene, generated by FVP of 5-t-butyl-4-methoxycarbonyl-2,3-dihydrofuran-2,3-dione, and heterocumulenes and Schiff base for the construction of corresponding 4H-1,3-oxazine derivatives in 32−53% yields. Cycloaddition reaction with ethyl vinyl ether and ethoxyacetylene was also investigated to give the corresponding γ-pyrone derivatives in 32−80% yields.

Ribofuranosyl-substituted benzo[b][1,4]oxazin-2-one 952 was synthesized in 41% yields, by condensation of o-aminophenole with ribofuranosyl-2-oxoacetate 951 in refluxing dry benzene during 2 h (Scheme 310b).472 3-Benzylidene-2-oxo-3,4dihydro-2H-benzo[b][1,4]oxazine-5-carboxylate 953, a synthetic intermediate of (Z)-3-benzylidene-3,4-dihydro-2-oxo2H-benzo[b][1,4]oxazine-5-carboxylic acid, a bioactive benzoxazinone, isolated from a fermentation broth of Streptomyces sp. TA-3037, was synthesized by condensation of corresponding oaminophenole with methyl 3-phenylpyruvate in the presence of p-TsOH (2.5 mol %) in toluene at 110 °C for 24 h, under an

Scheme 309. Synthesis of 5-Ethoxycarbonyl-4H-1,3-oxazine-4-ones 947−949a

a

947, Ar1 = 4-XC6H4 (X = H, Cl, Me); 65−70%; 948, 35%; 949, Ar2 = 4-XC6H4 (X = H, Cl, Me); 55−63%. 249


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6. SYNTHESIS OF N,S- AND N,SE-HETEROCYCLES

atmosphere of N2, in 53% yield (Scheme 310c).473 There are other reports on the construction of 1,4-benzoxazine derivatives by a similar methodology in the literature.474 Moreover, some multistep syntheses of morpholine derivatives were described in the literature using various α-oxoesters.475

6.1. Thiazoles

A large number of natural products contain thiazole and thiazolines heterocycles, such as largazole, telomestatin, bacillamide A−C, neobacillamide A, urukthapelstatin A, venturamide A and B, aerucyclamides A−D, hexamollamide, hoiamide A, bisebromoamide, etc., which exhibit anticonvulsant, sedative, antidepressant, anti-inflammatory, antihypertensive, antihistaminic, and antiarthritic activities. Micrococcin P1, isolated from Staphylococcus equorum, with six thiazole rings in its structure exhibits antibacterial activity. Also, they have wide range of applications in synthetic organic chemistry, especially in diastereoselective reactions as chiral auxiliaries, and in organic functional materials such as fluorescent dyes and liquid crystals. Intramolecular cyclization of aminoethyl thiolesters and N-(β-hydroxyethyl)-thioamides, condensation of thioethanol amine with nitriles, esters, and imines, Hantzsch thiazole synthesis, dehydrative cyclization of α-amidoketones using Lawesson’s reagent, and reaction of thioamides or thioureas with α-haloketones are vastly used to synthesize thiazoline and thiazole derivatives. Treatment of cysteamine hydrochloride with ethyl glyoxalate in toluene/water in the presence of NaHCO3 at 5 °C, and then room temperature for 16 h, provided ethyl thiazolidine-2carboxylate 959, which was used for the synthesis of thiazolidine derivatives with adamantyl group 960, exhibiting in vitro human 11β-HSD1 inhibitory activity (Scheme 313).477

5.4. Oxazepines

Oxazepines are important in the field of biochemistry due to their wide range of biological activities and medicinal applications, such as BACE1, BACE2, and PI3 kinase inhibitory activity, and in the treatment of neurological, Alzheimer’s, and psychiatric diseases. Loxapine, used primarily in the treatment of schizophrenia, is an oxazepine-based drug. While there is no common route for the synthesis of oxazepine, a number of multistep approaches have been developed until date. Treatment of 4-ethoxycarbonyl-5-phenyl-2,3-dihydrofuran2,3-dione with an equimolar amount of N,N′-diisopropylcarbodiimide under solvent-free conditions at room temperature for 12 h afforded 5-ethoxycarbonyl-3-isopropyl-2-isopropylimino4-phenyl-1,3-oxazepine-6,7-dione 954 in 68% yield (Scheme 311).96 Scheme 311. Synthesis of Isopropylimino-4-phenyl-1,3oxazepine-6,7-dione 954

Scheme 313. Synthesis of Ethyl Thiazolidine-2-carboxylate 959 Pictet−Spengler−Grieco cyclization of 3-allyl piperazin-2ones 955 with ethyl glyoxalate was described, leading to tetrahydro-2H-6,9-methanopyrazino[1,2-d][1,4]oxazepine1,7(9H)-diones 958. The reactions were performed in MeOH at 65 °C during 3 days, and 958 was obtained in 25−50% yield. Reactions proceeded by addition of alkene onto the iminium ion 956, in situ generated from reaction of 955 with ethyl glyoxalate, to give intermediate 957, which was captured by carboxylate group (Scheme 312).476

t-Butyl 5,5-dimethyl-3-thiazoline-2-carboxylate 961 was obtained by Asinger method from reaction of α-mercaptoisobutyraldehyde, NH3, and t-butyl glyoxalate in 63% yield. Reaction was carried out by in situ generation of αmercaptoisobutyraldehyde from reaction of α-bromoisobutyraldehyde with H2S (gas) in the presence of Et3N in DCM at −10 °C during 90 min, followed by addition of t-butyl glyoxalate at 20 °C and then saturation with dry NH3 gas during 4 h (Scheme 314).478

Scheme 312. Synthesis of Tetrahydro-2H-6,9methanopyrazino[1,2-d][1,4]oxazepine-1,7(9H)-diones 958a

Scheme 314. Synthesis of t-Butyl 5,5-Dimethyl-3-thiazoline2-carboxylate 961

a

R = Me, CH2OBn; 25−50%. 250


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Zambroń et al.481 reported the SnCl4-mediated cyclization reaction of ethyl 2-(3-methoxyphenylthio)-2-(2-oxo-4(vinyloxy)azetidin-1-yl)acetate 965 in anhydrous DCM at 0 °C under the Ar atmosphere to afford ethyl 2-oxo-1,2,4,9btetrahydroazeto[1,2-c]benzo[e][1,3]thiazine-4-carboxylate 966 in 67% yield, as a mixture of two isomers (966a/966b) in a ratio of 45/22. The starting 965 was prepared in three steps by reaction of 4-(vinyloxy)azetidin-2-one with ethyl glyoxalate in toluene at 110 °C, followed by replacement of hydroxy group with m-methoxythiophenol moiety using SOCl2 in the presence of 2,6-lutidine in dry THF at −20 °C under Ar, and then treatment of the obtained chloride with m-methoxythiophenol in the presence of K2CO3 and TBAB in dry CH3CN at room temperature in 79% yield, for the two last steps (Scheme 317).

Reaction of ethyl pyruvate methylthio(thiocarbonyl)hydrazone with 4-chlorobenzoyl chloride (2 equiv) was developed for the synthesis of ethyl 3-(4-chlorobenzoyl)-2methyl-5-(methylthio)-2,3-dihydro-1,3,4-thiadiazole-2-carboxylate 962 in 83% yield. Reaction was performed in CHCl3 under reflux conditions for 4 h. Starting hydrazone was prepared by condensation of ethyl pyruvate with methylthio(thiocarbonyl)hydrazide in the presence of HBr (Scheme 315).479 Scheme 315. Synthesis of 2,3-Dihydro-1,3,4-thiadiazole-2carboxylate 962

Scheme 317. Synthesis of Tetrahydroazeto[1,2c]benzo[e][1,3]thiazine-4-carboxylate 966a

6.2. Thiazines

Thiazine nucleus is present in compounds possessing a variety of pharmacological activities, such as calcium channel blockers, phosphodiesterase 7 inhibitors, 5-HT3 antagonists, and antipsychotics agents, and also in natural products, such as thiaplakortones A−D, antimalarial thiazine alkaloids. Threecomponent reaction of alkynes, thioureas, and aldehydes, HDA reaction of hydrazono thioketones with dienophiles, and reaction of amines with sulfur powder in the presence of I2 are reported routes to thiazine derivatives. The [3 + 3] cyclocondensation reaction of thioamide with an excess amount of 3-(diethoxymethyl)-2-oxobut-3-enoates in the presence of Et3N in DCM at room temperature for 3 h provided 5-(diethoxymethyl)-4-hydroxy-1,3-thiazinane-4-carboxylates 963 in 50−68% yields, which were converted to the corresponding dehydrated products 964, by treatment of 963 with catalytic amount of HBr in acetone/water under reflux conditions for 3 h. The acetal deprotection also occurred, and led to the corresponding 5-formyl-3,6-dihydro-2H-1,3-thiazine4-carboxylates 964 in 74−95% yields (Scheme 316).480

a

ArSH = 3-MeOC6H4SH; 67%, 966a/966b = 45/22.

Reaction of 5-aryl-2,3-dihydrofuran-2,3-dione with 4-amino3-mercapto-l,2,4,-(4H)-triazole was developed for the synthesis of 2-aroylmethylene-lH-2,3-dihydro-l,2,4-triazoio[3,4-b]-1,3,4thiadiazin-3-ones 968. Reactions were carried out in dioxane at room temperature for 6 h to give 968 in 45−71% yields, which exhibited antiflammatory activity. N-(3-Mercapto-4H1,2,4-triazol-4-yl)-2,4-dioxo-4-phenylbutanamide 967 was reported as the reaction intermediate (Scheme 318).482

Scheme 316. Synthesis of 5-Formyl-3,6-dihydro-2H-1,3thiazine-4-carboxylates 964a

Scheme 318. Synthesis of l,2,4-Triazoio[3,4-b]-1,3,4thiadiazin-3-ones 968a

a 1

a

R = Me, Et, t-Bu; R2 = Me, t-Bu; 963, 50−68%; 964, 74−95%. 251

Ar = 4-XC6H4 (X = H, Cl, Br, Me, MeO); 45−71%. dx.doi.org/10.1021/cr5004216 | Chem. Rev. 2015, 115, 151−264

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6.3. Thiazepines

6.4. Selenazoles

Thiazepine moieties are found in a number of natural products, such as rubiothiazepine alkaloid, exhibiting cytotoxic and antiHIV activity, and in pharmaceuticals and biologically active compounds, such as temocapril, diltiazem, omapatrilat, discorhabdin-Q, CGP 37157, and tianeptine, with a wide range of medicinal properties. However, there are no common methods for the construction of thiazepine rings; various multistep syntheses have been reported. The synthesis of 3-hydroxy-2-(4-methoxyphenyl)-2,3dihydrobenzo[b][1,4]thiazepin-4(5H)-ones 971 was reported by Komiyama et al.483 in four steps starting from 3-chloro-3-(4methoxyphenyl)-2-oxopropanoates. Treatment of 3-chloro-3(4-methoxyphenyl)-2-oxopropanoates with sodium o-nitrophenylthiolate in toluene at room temperature gave βarylthio-α-ketoester 969, which was reduced to the corresponding 2-hydroxy-3-(4-methoxylphenyl)-3-(2-nitrophenylsulfanyl)propionates 970 using bakers’ yeast in 36−48% yields as a mixture of two diastereoisomers. α-Hydroxyesters 970 were transformed into 971 by reduction of nitro group using FeSO4· 7H2O in the presence of NH4OH in EtOH/water in 70−84% yields, followed by lactamization in the presence or in the absence of p-TsOH in refluxing xylene, in 70−94% yields (Scheme 319). The obtained 2,3-dihydrobenzo[b][1,4]-

However, the selenazole derivatives are rare in nature, and the synthesis of selenazole derivatives has gradually increased because of their interesting pharmaceutical applications. For example, selenazofurin showed significant antiviral, antitumor, and antibacterial activities. Thus, many synthetic methods to selenazole derivatives have been extensively investigated, in which cyclocondensation of selenocarboxamides with αhaloketones is one of most useful. The synthesis of 2-dialkylamino-1,3-selenazoles 975 was reported by cyclocondensation reaction of N,N-dialkylselenoureas with methyl and ethyl pyruvates. Reactions were carried out by stirring a solution of pyruvate (5 equiv) and N,Ndialkylselenourea in the presence of 6 equiv of FeCl3 in dry EtOH at room temperature under Ar atmosphere for 3 h, to give the corresponding 2-dialkylamino-1,3-selenazoles 975 in 80−90% yields.485 Reactions were initiated by condensation of selenourea with ketone moiety of pyruvate to generate intermediate 972, followed by FeCl3 induced oxidative cyclization to give intermediate 973. By H-abstraction along with nucleophilic addition of EtOH, 973 was converted to 974, which underwent aromatization to 1,3-selenazoles 975 by removal of a molecule of EtOH (Scheme 320).486 Scheme 320. Synthesis of 2-Dialkylamino-1,3-selenazoles 975a

Scheme 319. Synthesis of 2,3Dihydrobenzo[b][1,4]thiazepin-4(5H)-ones 971a

a 1

R 2N = Me2N, Et2N, morpholine, piperidine; R2 = Me, Et; 80−90%.

β-D-Ribofuranosyl-substituted 1,3-selenazole-4-carboxylate 977 was prepared in 98% yield, by in situ generation of selenocarboxamide 976 from reaction of cyanosugar with H2Se (gas) in the presence of DMAP in absolute EtOH under an atmosphere of Ar at 23 °C, followed by addition of ethyl αbromopyruvate and stirring for 0.5 h (Scheme 321).487

7. SYNTHESIS OF S-, S,O-, AND SI,O-HETEROCYCLES a

Ar = 4-MeOC6H4; R = Me; 970, 48%, anti/syn = 80/20; R = t-Bu; 970, 36%, anti/syn = 15/85.

7.1. Thiophenes

Thiophenes constitute an important class of heterocycles, due to their occurrence in natural products, such as biotin, banminth, and echinothiophene, and their vital biological activities. Moreover, they have many applications in supramolecular chemistry and advanced materials, such as conjugated polymers, organic conductors, semiconductors, and light emitting devices. Thiophene derivatives have been prepared by various methods, such as Gewald and Paal−Knorr reactions, intramolecular cyclization of 1-mercapto-3-yn-2-ols, and reaction of enolizable thioamides with α-haloketones.

thiazepin-4(5H)-ones 971 could be converted to diltiazem, a drug possessing calcium antagonist activity.484 Starting 3chloro-3-(4-methoxyphenyl)-2-oxopropanoates were readily prepared by Darzens condensation reaction of anisaldehyde with dichloroacetates in the presence of t-BuOK in THF at −40 °C. 252


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Scheme 321. Synthesis of β-D-Ribofuranosyl-Substituted 1,3Selenazole-4-carboxylate 977

(ethoxycarbonyl)thiophene-3-carboxylic acid 982 was obtained in 34% yield, and 87% purity (Scheme 323).489 Scheme 323. Synthesis of 2-Acetamido-4(ethoxycarbonyl)thiophene-3-carboxylic acid 982

3-Hydroxythiophenes 979 were prepared from reaction of αoxoesters with thiodiacetonitrile in 67−68% yields. Reactions were conducted in dry MeOH using NaOMe at 0 °C for 24 h. Reactions occurred by Knoevenagel condensation with ketone moiety to give intermediate 978, followed by Dieckmann condensation and then aromatization (Scheme 322a).488 Also, 7.2. Thiopyrans

Scheme 322. Synthesis of 3-Hydroxythiophenes 979,980a

Thiopyran derivatives exhibit a broad spectrum of biological activities, such as antiproliferative, antiameobic, microfilaricidal, antifungal, and ikk2 inhibitory activity, and are widely used as versatile building blocks in organic synthesis. The HDA reaction of thiocarbonyl compounds with various dienes is a common route to the preparation of thiopyrans. The HDA reactions of ethyl thioxoacetate 983 with various dienes were investigated by Bladon et al.490 producing thiopyran derivatives. Reactions were carried out by in situ generation of ethyl thioxoacetate 983 by treatment of ethyl mercaptoacetate with NCS in dry benzene at room temperature for 2 h, followed by addition of a solution of a diene in benzene and methanol containing Et3N at room temperature. 2,3Dimethylbuta-l,3-diene and cyclohexa-1,3-diene were converted to the corresponding thiopyrans 984a,b in 65% and 37% yields, respectively. Reaction with thebaine 986 led to the corresponding cycloadduct 987 in 67% yield, which was converted to isomeric adduct 988 when heated in toluene under reflux conditions for 8 h. Also, anthracene was subjected in a similar reaction, resulting in the formation of cycloadduct 985 in 37% yield (Scheme 324). Also, HDA reaction of 2,3-dimethylbutal,3-diene with a variety of 4-substituted 3-oxo-2-thioxobutanoates was reported, leading to the corresponding thiopyrans in 46−93% yields.491,492 7.3. Oxathiolanes a

Because of their pharmacological properties, oxathiolanes have received great attention in recent years. The biological activity of oxathiolane steroids, such as apricitabine, cevimeline, emtricitabine, racivir, 2′-epi-lamivudine, and lamivudine acid, was extensively studied, as emtricitabine is marketed as nucleoside reverse transcriptase inhibitor for the treatment of HIV infection in adults and children. Reactions of epoxides with CS2 or isothiocyanates are mostly used for the synthesis of oxathiolanes. 5-Hydroxyoxathiolane 989 was obtained by heating a solution of menthyl glyoxylate hydrate and dithiane diol in toluene followed by recrystallization in n-hexane in the presence of Et3N, which were converted to Lamivudine 990, an anti-HIV agent that has also been developed for the treatment of hepatitis B (Scheme 325).493

979, R = Me, Ph; 67−68%; 980, 40%, a/b = 24/16.

3-ribofuranosyl-substituted 4-hydroxythiophene 980 was synthesized by a similar reaction between dimethyl thiodiacetate and ribofuranosyl-2-oxoacetate 951 in the presence of NaOMe in MeOH at 20 °C during 60 h, in 40% yield, as a mixture of triand disilylated products 980a/980b in a ratio of 24/16 (Scheme 322b).472 The Gewald reaction on solid support was developed between an activated nitrile compound and ethyl 2-oxo-4phenylbutanoate in the presence of S8 and morpholine, to afford aminothiophene 981. Reaction was performed in EtOH under reflux conditions for 8 h. By acetylation of the amine group, followed by cleavage of Wang resin solid support using TFA in DCM/water, 2-acetamido-5-benzyl-4253


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Scheme 324. Synthesis of Thiopyran Derivatives 984−988 via HDA Reaction

Scheme 325. Synthesis of 5-Hydroxyoxathiolane 989

Scheme 326. Synthesis of Methyl 2-Hydroxy-9-oxa-3thiabicyclo[3.3.1]nonane-2-carboxylate 993

996 were obtained in 22−93% yields, with 0−77% de (Scheme 327). Dihydropyran derivatives, silyl enol ethers, and phenyl

7.4. 1,4-Oxathianes

There are a few natural products possessing oxathiane moieties, such as raphanuside, which was isolated from the seeds of Raphanus sativus L., and some oxathiane derivatives were developed for their biological activities, such as antiinflammatory and antiplatelet aggregating activities. Some multistep procedures were reported for the construction of oxathianes. Methyl 6,7,8-tris(benzyloxy)-2-hydroxy-9-oxa-3thiabicyclo[3.3.1]nonane-2-carboxylate 993 was synthesized in 88% yield from methyl 2-[-6-(acetylthiomethyl)-3,4,5-tris(benzyloxy)tetrahydro-2H-pyran-2-yl]-2-oxoacetate 992, by intramolecular hemithioacetalization through removal of the S-acetyl protecting group using hydrazine hydrate in methanol. The starting α-ketoester 992 was prepared by oxidation of corresponding bromoalkyne 991 with KMnO4 in the presence of NaHCO3 and MgSO4 in aqueous MeOH, in 71% yield (Scheme 326).444 Inverse electron demand HDA reaction of 4-substituted 3oxo-2-thioxobutanoates 995 with electron-rich dienophiles, such as p-methoxystyrenes and ethyl vinyl ether, was reported by Boccardo et al.492 to give 1,4-oxatiine derivatives 996. Reactions were carried out by in situ generation of 995 by treatment of thiophthalimide precursors 994 with an equimolar amount of pyridine in CHCl3 at room temperature, followed by addition of dienophile (1 equiv) and stirring at the same temperature for 10−70 h, and the corresponding 1,4-oxatiines

Scheme 327. Synthesis of 1,4-Oxatiines 996 via HDA Reactiona

a 1 R = Me, CH2OMenthyl, γ-butyrolacton-5-yl; R2 = Me, menthyl, 2phenylcyclohexyl, CH(Me)CO2Me; R3 = EtO, PMP; R4 = H, Me; 22− 93%, 0−77% de.

vinyl thioethers were also used as dienophile in a similar HDA reaction with 4-substituted 3-oxo-2-thioxobutanoates 995, leading to the corresponding cycloadducts in 40−89% yields.494 7.5. Dioxasilocine

The synthesis of (S,E)-isopropyl 2,2-di-t-butyl-5,8-dihydro-4H1,3,2-dioxasilocine-4-carboxylates 1000 was developed by insertion of silylene into the allylic carbon−oxygen bond of vinyl epoxides, followed by in situ allylation of i-propyl 254


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glyoxalate. Reactions were carried out by warming a −20 °C cooled solution of vinyl epoxides with silacyclopropane (1.5 equiv) and AgOTs (2 mol %) in toluene/THF to room temperature, with subsequent addition of 2.2 equiv i-propyl glyoxalate and stirring for another 1 h, at room temperature. In the proposed reaction mechanism, insertion of silylene into the allylic carbon−oxygen bond of vinyl epoxide led to silaoxetane 997, which underwent complexation with aldehyde group to hypervalent silicon compound 998. 5,8-Dihydro-4H-1,3,2dioxasilocine-4-carboxylate 1000 was formed through chairlike transition state 999, selectively, due to the preferential pseudoequatorial position of the −CH2− group of the silaoxetane ring in the transition state (Scheme 328).495

ASSOCIATED CONTENT S Supporting Information *

Structures of ligands, complexes, and catalysts I−XXI. This material is available free of charge via the Internet at http:// pubs.acs.org.

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]; [email protected]. Notes

The authors declare no competing financial interest. Biographies

Scheme 328. Synthesis of 5,8-Dihydro-4H-1,3,2dioxasilocine-4-carboxylate 1000a

a 1

R = H, (CH2)2Ph, (+)-BnOCH2CH(Me); R2 = H, Me; 71−81%. Bagher Eftekhari-Sis was born in 1980 in Sis, Shabestar, Iran. He obtained his B.Sc. in Applied Chemistry from the University of Tabriz in 2004 and M.Sc. in Organic Chemistry from Sharif University of Technology with Prof. Mohammed M. Hashemi in 2006. Also, he received his Ph.D. under the supervision of Prof. Mohammed M. Hashemi in 2009 and then joined the Chemistry Department of the University of Maragheh. His research field involves the synthetic utility of dicarbonyl compounds, especially in the synthesis of heterocycles, organic synthesis, solid supported catalyst, sensors, nanobiosensors, and bioimaging.

8. CONCLUSION This Review covers an overview of the use of α-oxoesters and their derivatives in the synthesis of heterocyclic compounds. First, the methods for synthesis of α-oxoesters were described, and then their uses in heterocycles synthesis were presented in order of heteroatom type considering the ring size and the number of heteroatoms. Thanks to the different reactivity of ketone (or aldehyde) and ester functional groups, reactions of α-oxoesters were performed in different ways: (a) reactions occurred in a more reactive ketone (or aldehyde) group and αoxoesters have provided one carbon atom in the ring of heterocycles to produce alkoxycarbonyl substituent, (b) reaction took place at the ester group leading to the heterocycle with acyl substituent, (c) both ketone (or aldehyde) and ester groups contributed in the reaction to provide two carbon atoms of heterocycles ring, and (d) in the case of β,γ-unsaturated αoxoesters, both the ketone and the carbon−carbon double bond took part in the reaction, affording three carbon atoms of the heterocycles rings. However, the syntheses of varying types of heyterocycles through different one or multistep reactions on α-oxoesters are presented. The future evolution of other methodologies promises new routes to synthesize new heterocylic compounds that were previously thought to be inaccessible. As a broad spectrum of synthesized heterocycles with different substituents, especially ester moiety, by using αoxoesters and their derivatives, the reported methods could be useful in pharmaceutical, medicinal, and natural products synthesis.

Maryam Zirak was born in Til, Shabestar, Iran. She received her B.Sc. in Pure Chemistry and M.Sc. in Organic Chemistry from the University of Tabriz. She obtained her Ph.D. in 2010 from the University of Tabriz on the topic of pyrone-based heterocycles and its applications in Medicinal Chemistry under the advisement of Prof. Aziz Shahrisa. She then joined the Chemistry Department of the Payame Noor University of Mahabad-West Azerbaijan, Iran, and her research field involves the development of new methodologies for the synthesis of heterocycles. 255


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ACKNOWLEDGMENTS B.E.-S. thanks Dr. M. Amini (University of Maragheh), M. Razzaghi (The University of Iowa), and M. Samet (University of Minnesota) for kind help. We thank Elahe Sorkh for preparing the cover art. We would also like to thank the anonymous reviewers for their constructive comments. REFERENCES (1) Liu, Y.; Ding, G.; Li, Y.; Qu, J.; Ma, S.; Lv, H.; Liu, Y.; Wang, W.; Dai, J.; Tang, Y.; Yu, S. Org. Lett. 2013, 15, 5206. (2) Tanaka, Y.; Satake, M.; Yotsu-Yamashita, M.; Oshima, Y. Heterocycles 2013, 87, 2037. (3) Sun, Y.-L.; Bao, J.; Liu, K.-S.; Zhang, X.-Y.; He, F.; Wang, Y.-F.; Nong, X.-H.; Qi, S.-H. Planta Med. 2013, 79, 1474. (4) Zhuang, P.-Y.; Zhang, G.-J.; Wang, X.-J.; Zhang, Y.; Yu, S.-S.; Ma, S.-G.; Liu, Y.-B.; Qu, J.; Li, Y.; Chen, N.-H. Planta Med. 2013, 79, 1453. (5) Eamvijarn, A.; Gomes, N. M.; Dethoup, T.; Buaruang, J.; Manoch, L.; Silva, A.; Pedro, M.; Marini, I.; Roussis, V.; Kijjoa, A. Tetrahedron 2013, 69, 8583. (6) Long, C.; Aussagues, Y.; Molinier, N.; Marcourt, L.; Vendier, L.; Samson, A.; Poughon, V.; Mutiso, P. B. C.; Ausseil, F.; Sautel, F.; Arimondo, P. B.; Massiot, G. Phytochemistry 2013, 94, 184. (7) Wang, H.-Y.; Wang, J.-S.; Zhang, Y.; Luo, J.; Yang, M.-H.; Wang, X.-B.; Kong, L.-Y. Chem. Pharm. Bull. 2013, 61, 1075. (8) Fukaya, H.; Hitotsuyanagi, Y.; Aoyagi, Y.; Shu, Z.; Komatsu, K.; Takeya, K. Chem. Pharm. Bull. 2013, 61, 1085. (9) Ibrahim, S. R. M.; Mohamed, G. A.; Shaala, L. A.; Youssef, D. T. A.; Sayed, K. A. E. Planta Med. 2013, 79, 1480. (10) Zhang, T.-T.; Liu, Z.-W.; Wang, W.-J.; Tong, Y.-B.; Xu, F.-F.; Yuan, J.-Q.; Liu, B.; Zhang, X.-Q.; Ye, W.-C. Heterocycles 2013, 87, 2047. (11) Eftekhari-Sis, B.; Zirak, M.; Akbari, A. Chem. Rev. 2013, 113, 2958. (12) Shiri, M.; Heravi, M. M.; Soleymanifard, B. Tetrahedron 2012, 68, 6593. (13) (a) Desimoni, G.; Faita, G.; Quadrelli, P. Chem. Rev. 2013, 113, 5924. (b) Nolsöe, J. M. J.; Weigelt, D. J. Heterocycl. Chem. 2009, 46, 1. (14) Haggerty, J. G.; Kelly, T. R.; Schmidt, T. E. Synthesis 1972, 544. (15) For example, see: Jung, M. E.; Shishido, K.; Davis, L. H. J. Org. Chem. 1982, 47, 891. (16) Sugawara, M.; Baizer, M. M. Tetrahedron Lett. 1983, 24, 2223. (17) (a) Xiang, J. M.; Li, B. L. Chin. Chem. Lett. 2009, 20, 55. See also: (b) Wadhwa, K.; Yang, C.; West, P. R.; Deming, K. C.; Chemburkar, S. R.; Reddy, R. E. Synth. Commun. 2008, 38, 4434. (c) Micetich, R. G. Org. Prep. Proc. 1970, 2, 249. (18) Shimizu, H.; Murakami, M. Chem. Commun. 2007, 2855. (19) (a) Ozawa, F.; Kawasaki, N.; Yamamoto, T.; Yamamoto, A. Chem. Lett. 1985, 567. See also: (b) Yanashita, H.; Sakakura, T.; Kobayashi, T.-A.; Tanaka, M. J. Mol. Catal. 1988, 48, 69. (c) Mizushima, E.; Hayashi, T.; Tanaka, M. Green Chem. 2001, 3, 76. (d) Ozawa, F.; Kawasaki, N.; Okamoto, H.; Yamamoto, T.; Yamamoto, A. Organometallics 1987, 6, 1640. (e) Sakakura, T.; Yamashita, H.; Kobayashi, T.; Hayashi, T.; Tanaka, M. J. Org. Chem. 1987, 52, 5733. (20) Thasana, N.; Prachyawarakorn, V.; Tontoolarug, S.; Ruchirawat, S. Tetrahedron Lett. 2003, 44, 1019. (21) Nagaki, A.; Ichinari, D.; Yoshida, J.-i. Chem. Commun. 2013, 49, 3242. (22) Raghunadh, A.; Meruva, S. B.; Kumar, N. A.; Kumar, G. S.; Rao, L. V.; Kumar, U. K. S. Synthesis 2012, 44, 283. (23) Tada, N.; Ban, K.; Nobuta, T.; Hirashima, S.-i.; Miura, T.; Itoh, A. Synlett 2011, 1381. (24) Mahmood, S. J.; McLaughlin, M.; Hossain, M. M. Synth. Commun. 1999, 29, 2967. (25) Photis, J. M. Tetrahedron Lett. 1980, 21, 3539. (26) Guo, S.; Huang, H.; Fu, Q.; Hu, W. Synlett 2006, 2486. 256


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