DOI: 10.1002/chem.201400123
Communication
& Allylic Amidation
Palladium-Catalyzed Stereoselective Intramolecular Oxidative Amidation of Alkenes in the Synthesis of 1,3- and 1,4-Amino Alcohols and 1,3-Diamines Andrei V. Malkov,*[a] Darren S. Lee,[a] Maciej Barłg,[b] Mark R. J. Elsegood,[a] and Pavel Kocˇovsky´*[c, d] Dedicated to Professor Manfred Reetz on the occasion of his 70th birthday
Abstract: An efficient and practical Pd-catalyzed intramolecular oxidative allylic amidation provides facile access to derivatives of 1,3- and 1,4-amino alcohols and 1,3-diamines. The method operates under mild reaction conditions (RT) with molecular oxygen (1 atm) as the sole reoxidant of Pd. Excellent diastereoselectivities were attained with substrates bearing a secondary stereogenic center
Scheme 1. Palladium-catalyzed intramolecular amidation.
In recent years, palladium-catalyzed oxidative cyclization has evolved into an attractive, atom economical approach towards functionalized building blocks, with the CN and CO bonds in a 1,2- or 1,3-relationship.[1] Since this structural motive is featured in a plethora of pharmaceuticals and natural products, stereoselective synthesis of the corresponding heterocycles draws considerable attention, with a view that they can serve as surrogates of 1,2- and 1,3-amino alcohols. Intramolecular PdII-catalyzed allylic amidation, giving rise to protected amino alcohols 1, can proceed by two mechanistically different routes (Scheme 1). Thus, starting from the homoallylic alcohol derivatives 2, a CH activation protocol, involving the formation of p-allyl-PdII intermediates,[2] provides a convenient entry into a wide range of 1,2-amino alcohols.[3, 4] This [a] Prof. Dr. A. V. Malkov, Dr. D. S. Lee, Dr. M. R. J. Elsegood Department of Chemistry, Loughborough University Loughborough, LE11 3TU (UK) Fax: (+ 44) 1509-22-3925 E-mail: [email protected] [b] Dr. M. Barłg Department of Chemistry, Texas A&M University at Qatar P.O. Box 23874, Doha (Qatar) [c] Prof. Dr. P. Kocˇovsky´ Department of Organic Chemistry, Arrhenius Laboratory Stockholm University, SE 10691 Stockholm (Sweden) E-mail: [email protected] [d] Prof. Dr. P. Kocˇovsky´ on leave from: Department of Chemistry, WestChem University of Glasgow, Glasgow G12 8QQ (UK) address for future correspondence: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic Flemingovo 2, 16610 Prague 6 (Czech Republic) E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201400123. Chem. Eur. J. 2014, 20, 4901 – 4905
method is also applicable to the synthesis of the 1,3-analogues but it works well only with terminal alkenes, since internal alkenes proved to be rather poor substrates for the 1,3-functionalization. An alternative approach employs isomeric allylic alcohol derivatives 3 and is based on amidopalladation of the double bond, followed by b-hydride elimination, resulting in an allylic shift.[5] This method was also successfully employed in the synthesis of 1,2-diamines[5a,b] but turned out to be less efficient in the preparation of 1,3-analogues; furthermore, for the best results it requires (Z)-isomers of 3.[5c] Recently, we have reported on the diastereoselective PdIIcatalyzed carbonylative ring-closing amidation of 4 a (Scheme 2).[6] In this reaction, isoxazolidine 5 a was the main
Scheme 2. Palladium-catalyzed carbonylative cyclization.
product but minor quantities of 6 a, resulting from allylic amidation, were occasionally observed. We reasoned that developing a transformation of this type (4 a!6 a) into a general and practical method would open a convenient gateway to functionalized 1,3-amino alcohols and a variety of other related compounds with biologically useful properties.[7] Syntheses of isoxazolidines and related pyrazolidines by Pd-catalyzed cyclizations of the respective homoallylic hydroxylamine and hydrazine derivatives have been reported but these always employed terminal alkenes and were paired with other Pd-mediated processes, such as carbonylation[8] and arylation,[1j, 9] resulting in the loss of the double bond. 4901
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Communication Herein, we report on the development of a catalytic system that promotes b-hydride elimination after the initial amidopalladation step to restore the unsaturation, thus accomplishing an intramolecular allylic amidation. In our study on carbonylative cyclization of 4 a to produce 5 a, we have shown that the reaction occurs by syn amidopalladation and exhibits a high level of diastereoselectivity.[6a] Therefore, we envisaged that formation of isoxazolidine 6 a would follow the same stereochemical course.[10] To develop conditions for the palladium-catalyzed oxidative intramolecular allylic amidation, the Boc-protected primary hydroxylamine derivative 7 was selected as a model substrate (Table 1; Boc = tert-butyloxycarbonyl). The presence of an electron-withdrawing group at the nitrogen is known to be a prerequisite for the formation of the N–Pd species and for preventing nitrogen oxidation.[11] Therefore, the Boc group was chosen with a view of the simplicity of its introduction and removal. The screening commenced by using a minor modification of the reaction conditions previously employed for the carbonylative amidation of N-Boc homoallylic alkoxyamines.[6a] With Pd(OAc)2 (10 mol %) and Cu(OAc)2 (3 equiv) at 60 8C in MeCN, the desired vinyl isoxazolidine 8 was obtained in excellent yield after 16 h (Table 1, entry 1). Repeating the reaction at room temperature, however, led to a poor conversion (entry 2), showing that an elevated temperature is required for this system to operate efficiently. Reducing the loading of Cu(OAc)2 to 30 mol % also negatively affected the reaction rate (entry 3). To facilitate the reoxidation of Pd in the latter instance, oxygen (1 atm) was introduced to the system. However, rather
unexpectedly, ketone 9 (20 %) was found to be formed along with the desired alkene 8 (54 %; entry 4). Control experiments revealed that the Wacker–Tsuji oxidation[12] of olefin 8 to produce 9 under the same reaction conditions is rather sluggish, suggesting that the active species promoting the formation of 9 was generated in situ from the Pd-intermediate directly.[13] The yield of ketone 9 can be further improved by replacing Pd(OAc)2 (I) with [PdCl2(MeCN)2] (II) and adding quinolinyloxazoline L as a ligand (entries 5 and 6). Replacing copper salts with p-benzoquinone (BQ) as oxidant did not affect the latter outcome (entry 7). Furthermore, the additional oxidant proved redundant, as the best result (85 % conversion to 9 after 16 h) was obtained by using molecular oxygen as the sole oxidant (entry 8). To steer the reaction back towards alkene 8, we reverted to the ligand-free Pd(OAc)2 as a catalyst and molecular oxygen as the terminal oxidant; sodium acetate was introduced as a weak base. Solvents, such as toluene, THF, and DMSO showed modest conversions (entries 9–11). A real improvement was attained when the reaction was carried out in THF, using DMSO as an additive (10 mol %), which is consistent with the in situ formation of the highly catalytically active complex [Pd(DMSO)2(OAc)2] described by Stahl.[14] The reaction cleanly produced 8 in nearly quantitative yield at RT over 16 h (entry 12). Interestingly, the complex of Pd(OAc)2 with 1,2-bis(phenylsulfinyl)ethane (III) proved inferior (entry 13), as did the replacement of DMSO with DMF (entry 14) or using MeCN as a solvent (entry 15). This behavior suggests that, in the case of [Pd(DMSO)2(OAc)2], one of the DMSO ligands can dissociate, allowing coordination of the substrate. This option is apparently not available for the chelate III and/or for a high concentration of DMSO (i.e., when used as a solvent). Table 1. Optimization of the allylic amidation of homoallylic alkoxylamines.[a] With the optimal conditions in hand, we could embark on the investigation of the reaction scope (Scheme 3). Substrates 10 a–c and 11 a with an extended alkyl chain were examined first. Geometry of the starting alkene (E)-10 a and (Z)-11 a PdII [(mol %)] Oxidant [(equiv)][b] Solvent Additive [(equiv)] T [8C] Conv. [%] (8/9)[c] turned out to have no influence [d] 1 I (10) Cu(OAc)2 (3) MeCN None 60 95 (8) on the reactivity since both 2 I (10) Cu(OAc)2 (3) MeCN None RT 11 (8) readily afforded (E)-12 a as MeCN None 60 69 (8) 3 I (10) Cu(OAc)2 (0.3) 4 I (10) Cu(OAc)2 (0.3)/O2 MeCN None 60 74 (8,9)[e] a major product (81 and 76 %, 5 II (5) Cu(OAc)2 (0.3)/O2 MeCN L (0.4) 60 50 (9)[f] respectively), in contrast to the [f] 6 II (5) CuCl (0.3)/O2 MeCN L (0.4) 60 56 (9) allylic tosylcarbamates 3, where 7 II (5) BQ (0.3)/O2 MeCN L (0.4) 60 56 (9)[f] only the Z alkene is sufficiently 8 II (5) O2 MeCN L (0.4) 60 99 (9,8)[g] 9 I (10) O2 toluene NaOAc (0.2) 80 34 (8) reactive.[5c] Formation of minor THF NaOAc (0.2) 60 36 (8) 10 I (10) O2 quantities of the Z and terminal DMSO NaOAc (0.2) 60 37 (8) 11 I (10) O2 isomers were also observed in THF NaOAc/DMSO (0.2/0.1) RT 100 (8)[h] 12 I (5) O2 both instances. Cyclization of 13 III (10) O2 THF NaOAc (0.2) RT 39 (8) 14 I (5) O2 THF NaOAc/DMF (0.2/0.1) RT 52 (8) the more sterically encumbered MeCN NaOAc/DMSO (0.2/0.1) RT 35 (8) 15 I (5) O2 substrates 10 b and c resulted in [a] Conditions: 7 (0.25 mmol), solvent (3 mL), 16 h. [b] O2 was applied to the system using a balloon. [c] Deterslightly reduced yields of 12 b mined using 1H NMR spectroscopy. [d] Isolated yield 85 %. [e] 8 (54 %), 9 (20 %). [f] Ketone 9 was the major (61 %) and 12 c (51 %). product, only traces of 8 were observed. [g] 9 (85 %), 8 (14 %). [h] Isolated yield 98 %.
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Communication
Scheme 4. Synthesis of pyrazolidines (X = CO2iPr).
Scheme 3. Palladium-catalyzed intramolecular amidation.
The bis-homoallylic substrate 13 readily produced the tetrahydro-1,2-oxazine 14, which can be viewed as a protected form of 1,4-amino alcohol. The reaction was completed overnight at RT in 95 % yield, indicating that formation of the terminal alkene is highly favorable with this catalytic system. It is worth noting that there are only a handful of examples of cyclizations leading to 1,4-amino alcohol derivatives.[15] Diastereoselectivity of the cyclization was investigated with the aid of the enantioenriched hydroxylamine derivatives 15 a– f (Table 2), which in turn were synthesized from the respective homoallylic alcohols[6a, 16] of 92–97 % ee by the Mitsunobu method.[8b,d] Under the standard conditions (Table 1, entry 12), the cyclization furnished cis-isoxazolidines 16 a–f in nearly quantitative yields at RT and with high diastereoisomeric purity, irrespective of the nature and steric bulk of the substituent R. The excellent level of diastereocontrol attained in these reactions is in line with the syn-amidopalladation pathway[6a] that is likely to be operating here. Table 2. Oxidative amidation of chiral alkoxyamines.[a]
1 2 3 4 5 6
Substrate
R
Yield [%]
cis:transb]
15 a 15 b 15 c 15 d 15 e 15 f
Ph Bn PhCH2CH2 cC6H11 Et2CH nC6H13
98 96 96 96 95 93
> 30:1 18:1 > 30:1 > 30:1 > 30:1 > 30:1
[a] Conditions: 15 (0.25 mmol), solvent (3 mL), 16 h. [b] Determined by H NMR spectroscopy.
To expand the scope of this reaction, we examined the hydrazine analogues 17–19 (Scheme 4), which were synthesized from the respective alcohols[16] by Mitsunobu reaction, using diisopropyl azodicarboxylate as a nucleophile. In the Pd-catalyzed cyclization, the hydrazine derivatives 17–19 proved less reactive than their hydroxylamine-derived counterparts. A brief screening of the reaction conditions revealed that for the best results the catalyst has to be added in two portions within a 24 h interval (at RT). Using the optimized protocol, both (E)17 and (Z)-18 afforded pyrazolidine (E)-20 as a major product in good yields, mirroring the behavior of the ON analogues 10 a and 11 a. Cyclization of the secondary hydrazine derivative 19 proceeded uneventfully but furnished the trans-configured pyrazolidine 21 (Figure 1), in contrast to the hydroxylamine analogue 15 a, which produced the cis isomer 16 a under almost identical conditions.[17] The switch in the stereochemical outcome is likely to be due to the steric strain imposed by the additional bulky carbamate group, which is consistent with the report by Wolfe,[9d] who conducted a detailed investigation on the stereochemistry of Pd-catalyzed carboamidation. The synthetic utility of this cyclization strategy is illustrated by a short synthesis of b-d-2,3-dideoxy-3-amino-C-ribofuranoside (24; Scheme 5).[18, 19] Here, cleavage of the NO bond in 16 a by heating at reflux with Mo(CO)6 (5 equiv)[20] in a 9:1 MeCN/H2O mixture afforded the N-protected syn-1,3-amino alcohol 22 (61 %). The latter product was then oxidized with mCPBA in CH2Cl2 to furnish epoxide 23 (68 %) as a 7:1 mixture of diastereoisomers.[21–23] Subsequent cyclization was carried out in the presence of BF3·Et2O (10 mol %), and afforded the desired pure diastereoisomer 24 (68 %).
1
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Scheme 5. Synthesis of aza C-nucleoside analogue.
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Communication (4.1 mg, 0.05 mmol) and flushed with O2. A solution of DMSO (1.8 mL, 0.025 mmol) in THF (2 mL) was added, and a balloon of O2 was attached. A solution of the substrate (0.25 mmol) in THF (1 mL) was then added by syringe and the mixture was left stirring at room temperature overnight. The mixture was filtered through a pad of celite, which was then washed with ethyl acetate, and the solvent from the combined filtrate was evaporated in vacuo. The crude product was purified by flash chromatography on silica gel (2 15 cm) using a mixture of light-petroleum/AcOEt (10:1) as an eluent. Crystal data for 21: C19H26N2O4, M = 346.42, colorless block, 0.41 0.29 0.25 mm3, monoclinic, P21, a = 11.1404(18), b = 8.0196(13), c = 11.1622(18) , b = 107.072(2)8, V = 953.3(3) 3, Z = 2, m(MoKa) = 0.09 mm1, 1calcd = 1.207 g cm3, 17 201 reflections measured[25] with graphite monochromated MoKa radiation at T = 150 K (l = 0.71073 ), 4577 unique, Rint = 0.058, Twinned dataset with one dominant domain. The two domains are related by a 178.98 rotation about real axis [0 1 0]. The structure was refined against approximately detwinned data based on the major component. Solved by direct methods,[26] R1[F2>2s(F2)] = 0.038, wR2 (all data) = 0.096. Largest difference map features within 0.20 e 3. Absolute structure could not be reliably determined and was set from an unchanging chiral center in the starting material. H atom coordinates and Uiso parameters were freely refined except for Uiso for the H atoms on C(16), which were fixed at 1.5 times that of the carrier atom. CCDC 979771 contains the supplementary crystallographic data. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data request/cif.
Acknowledgements
Figure 1. Two views of the crystal structure of 21 highlighting the trans configuration.
In conclusion, we have developed an efficient, practical protocol for the Pd-catalyzed intramolecular oxidative allylic amidation that provides facile access to derivatives of 1,3- and 1,4amino alcohols and 1,3-diamines. The method operates under mild reaction conditions (RT) with molecular oxygen (1 atm) as the sole reoxidant of Pd. Excellent diastereoselectivities were attained with substrates bearing a secondary stereogenic center. Significantly, the reaction can be driven either to the vinylic derivative, such as 8 (Table 1, entry 12), or to the corresponding methylketone 9 (Table 1, entry 8) by a minor modification of the reaction conditions. This strategy combines highly enantioselective organocatalysis (for the preparation of chiral starting materials[16c,f]) with diastereocontrolled transition metal catalysis[24] and was successfully applied to a stereocontrolled synthesis of the enantiopure trisubstituted tetrahydrofuran derivative 24 that can be regarded as a C-nucleoside.
We thank Prof. Jan-E. Bckvall for valuable discussions, the EPSRC for grant No. EP/E011179/1, Loughborough University for a studentship to D. S. L. and additional support, and the Axel Wenner–Gren Foundation for a sabbatical scholarship to P. K. COST Office support through ORCA action is also appreciated. Keywords: allylic compounds · amination · cyclization · homogeneous catalysis · palladium
Experimental Section General procedure for Pd-catalyzed intramolecular allylic amidation of alkoxyamine derivatives: A 10 mL flask was charged with palladium acetate (2.8 mg, 0.013 mmol) and sodium acetate Chem. Eur. J. 2014, 20, 4901 – 4905
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Sigman, Inorg. Chem. 2007, 46, 1903 – 1909; d) J. A. Keith, P. M. Henry, Angew. Chem. 2009, 121, 9200 – 9212; Angew. Chem. Int. Ed. 2009, 48, 9038 – 9049. For the closely related metal-catalyzed Mimoun oxidation, see, e.g.: a) H. Mimoun, I. Serre de Roch. L. Sajus, Bull. Soc. Chim. Fr. 1969, 1481; b) E. Vedejs, J. Am. Chem. Soc. 1974, 96, 5944 – 5946. a) Z. Lu, S. S. Stahl, Org. Lett. 2012, 14, 1234 – 1237; b) T. Diao, P. White, I. Guzei, S. S. Stahl, Inorg. Chem. 2012, 51, 11898 – 11909. a) B. Janza, A. Studer, J. Org. Chem. 2005, 70, 6991 – 6994; b) A. Barco, N. Baricordi, S. Benetti, C. De Risi, G. P. Pollinib, V. Zanirato, Tetrahedron 2007, 63, 4278 – 4283; c) R. W. Bates, R. H. Snell, S. Winbush, Synlett 2008, 1042 – 1044; d) R. L. LaLonde, Z. J. Wang, M. Mba, A. D. Lackner, F. D. Toste, Angew. Chem. 2010, 122, 608 – 611; Angew. Chem. Int. Ed. 2010, 49, 598 – 601. a) J. Nokami, K. Nomiyama, S. Matsuda, N. Imai, K. Kataoka, Angew. Chem. 2003, 115, 1311 – 1314; Angew. Chem. Int. Ed. 2003, 42, 1273 – 1276; b) T.-P. Loh, C.-L. K. Lee, K.-T. Tan, Org. Lett. 2002, 4, 2985 – 2987; c) A. V. Malkov, M. Bell, P. Ramrez-Lpez, L. Biedermannov, L. Rulsˇek, L. Dufkov, M. Kotora, F. Zhu, P. Kocˇovsky´, J. Am. Chem. Soc. 2008, 130, 5341 – 5348; d) A. V. Malkov, M. A. Kabeshov, M. Barłg, P. Kocˇovsky´, Chem. Eur. J. 2009, 15, 1570 – 1573; e) A. V. Malkov, M. Barłg, Y. Jewkes, J. Mikusˇek, P. Kocˇovsky´, J. Org. Chem. 2011, 76, 4800 – 4804; f) C. A. Incerti-Pradillos, M. A. Kabeshov, A. V. Malkov, Angew. Chem. 2013, 125, 5446 – 5449; Angew. Chem. Int. Ed. 2013, 52, 5338 – 5341; g) A. V. Malkov, S. Stoncˇius, M. Bell, F. Castelluzzo, P. Ramrez-Lpez, L. Biedermannov, L. Rulsˇek, V. Langer, P. Kocˇovsky´, Chem. Eur. J. 2013, 19, 9167 – 9185. The relative configuration of 21 was confirmed by NMR spectroscopy and X-ray crystallography (see the Supporting Information). For overviews on C-nucleosides, see: a) V. E. Marquez, M. Lim, Med. Res. Rev. 1986, 6, 1 – 40; b) J. Sˇtambasky´, M. Hocek, P. Kocˇovsky´, Chem. Rev. 2009, 109, 6729 – 6764. The l-enantiomer of 24 has been prepared in the same way from the enantiomer of 16 a. For the method, see ref. [6a] and: S. Cicchi, A. Goti, A. Brandi, A. Guarna, F. De Sarlo, Tetrahedron Lett. 1990, 31, 3351 – 3354. For the epoxidation stereocontrolled by carbamate and amide groups, see: a) P. Kocˇovsky´, Tetrahedron Lett. 1986, 27, 5521; b) P. Kocˇovsky´, I. Stary´, J. Org. Chem. 1990, 55, 3236 – 3243; for the first example of carbamate stereocontrol in cyclic olefins, see: c) K. Ponsold, G. Schubert, M. Wunderwald, D. Tresselt, J. Prakt. Chem. 1981, 323, 819 – 828; for the first example of a stereocontrolled epoxidation of cycloalkene tosylamides, see: d) J.-E. Bckvall, K. Oshima, R. E. Palermo, K. B. Sharpless, J. Org. Chem. 1979, 44, 1953 – 1957. The diastereoselectivity of this epoxidation is actually quite remarkable. Note that the analogous vinylcarbinol EtCH(OH)CH=CH2 affords the corresponding epoxides as 2:3 and 4:1 mixtures on epoxidation with mCPBA and tBuOOH/(acac)2VO, respectively: a) E. D. Mihelich, Tetrahedron Lett. 1979, 20, 4729; b) B. E. Rossiter, T. R. Verhoeven, K. B. Sharpless, Tetrahedron Lett. 1979, 20, 4733; for overviews, see: c) P. Kocˇovsky´, F. Turecˇek, J. Hjcˇek, Synthesis of Natural Products: Problems of Stereoselectivity Vol. 2, CRC Press, Boca Raton, Florida 1986, pp. 138 – 143; d) A. H. Hoveyda, D. A. Evans, G. C. Fu, Chem. Rev. 1993, 93, 1307 – 1370. The relative configuration of epoxide 23 was inferred from the structure of the product of its opening (24). Allylic alcohols and acetates, formally derived from 15, undergo cyclization in the presence FeCl3.6H2O as catalyst but with lower diastereoselectivity: a) J. Cornil, A. Gu riont, S. Reymond, J. Cossy, J. Org. Chem. 2013, 78, 10273 – 10287; for a related activation with Pd and/or Mo, see: b) I. Stary´, I. Star, P. Kocˇovsky´, Tetrahedron Lett. 1993, 34, 179 – 182; c) A. V. Malkov, I. R. Baxendale, D. Dvorˇk, D. J. Mansfield, P. Kocˇovsky´, J. Org. Chem. 1999, 64, 2737 – 2750; d) A. V. Malkov, S. L. Davis, I. R. Baxendale, W. L. Mitchell, P. Kocˇovsky´, J. Org. Chem. 1999, 64, 2751 – 2764; e) A. V. Malkov, P. Spoor, V. Vinader, P. Kocˇovsky´, J. Org. Chem. 1999, 64, 5308 – 5311. APEX 2 and SAINT (2009) software for CCD diffractometers. Bruker AXS Inc., Madison, USA. G. M. Sheldrick, Acta Crystallogr. 2008, A64, 112 – 122.
Received: January 11, 2014 Published online on March 24, 2014
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& Allylic Amidation
Palladium-Catalyzed Stereoselective Intramolecular Oxidative Amidation of Alkenes in the Synthesis of 1,3- and 1,4-Amino Alcohols and 1,3-Diamines Andrei V. Malkov,*[a] Darren S. Lee,[a] Maciej Barłg,[b] Mark R. J. Elsegood,[a] and Pavel Kocˇovsky´*[c, d] Dedicated to Professor Manfred Reetz on the occasion of his 70th birthday
Abstract: An efficient and practical Pd-catalyzed intramolecular oxidative allylic amidation provides facile access to derivatives of 1,3- and 1,4-amino alcohols and 1,3-diamines. The method operates under mild reaction conditions (RT) with molecular oxygen (1 atm) as the sole reoxidant of Pd. Excellent diastereoselectivities were attained with substrates bearing a secondary stereogenic center
Scheme 1. Palladium-catalyzed intramolecular amidation.
In recent years, palladium-catalyzed oxidative cyclization has evolved into an attractive, atom economical approach towards functionalized building blocks, with the CN and CO bonds in a 1,2- or 1,3-relationship.[1] Since this structural motive is featured in a plethora of pharmaceuticals and natural products, stereoselective synthesis of the corresponding heterocycles draws considerable attention, with a view that they can serve as surrogates of 1,2- and 1,3-amino alcohols. Intramolecular PdII-catalyzed allylic amidation, giving rise to protected amino alcohols 1, can proceed by two mechanistically different routes (Scheme 1). Thus, starting from the homoallylic alcohol derivatives 2, a CH activation protocol, involving the formation of p-allyl-PdII intermediates,[2] provides a convenient entry into a wide range of 1,2-amino alcohols.[3, 4] This [a] Prof. Dr. A. V. Malkov, Dr. D. S. Lee, Dr. M. R. J. Elsegood Department of Chemistry, Loughborough University Loughborough, LE11 3TU (UK) Fax: (+ 44) 1509-22-3925 E-mail: [email protected] [b] Dr. M. Barłg Department of Chemistry, Texas A&M University at Qatar P.O. Box 23874, Doha (Qatar) [c] Prof. Dr. P. Kocˇovsky´ Department of Organic Chemistry, Arrhenius Laboratory Stockholm University, SE 10691 Stockholm (Sweden) E-mail: [email protected] [d] Prof. Dr. P. Kocˇovsky´ on leave from: Department of Chemistry, WestChem University of Glasgow, Glasgow G12 8QQ (UK) address for future correspondence: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic Flemingovo 2, 16610 Prague 6 (Czech Republic) E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201400123. Chem. Eur. J. 2014, 20, 4901 – 4905
method is also applicable to the synthesis of the 1,3-analogues but it works well only with terminal alkenes, since internal alkenes proved to be rather poor substrates for the 1,3-functionalization. An alternative approach employs isomeric allylic alcohol derivatives 3 and is based on amidopalladation of the double bond, followed by b-hydride elimination, resulting in an allylic shift.[5] This method was also successfully employed in the synthesis of 1,2-diamines[5a,b] but turned out to be less efficient in the preparation of 1,3-analogues; furthermore, for the best results it requires (Z)-isomers of 3.[5c] Recently, we have reported on the diastereoselective PdIIcatalyzed carbonylative ring-closing amidation of 4 a (Scheme 2).[6] In this reaction, isoxazolidine 5 a was the main
Scheme 2. Palladium-catalyzed carbonylative cyclization.
product but minor quantities of 6 a, resulting from allylic amidation, were occasionally observed. We reasoned that developing a transformation of this type (4 a!6 a) into a general and practical method would open a convenient gateway to functionalized 1,3-amino alcohols and a variety of other related compounds with biologically useful properties.[7] Syntheses of isoxazolidines and related pyrazolidines by Pd-catalyzed cyclizations of the respective homoallylic hydroxylamine and hydrazine derivatives have been reported but these always employed terminal alkenes and were paired with other Pd-mediated processes, such as carbonylation[8] and arylation,[1j, 9] resulting in the loss of the double bond. 4901
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Communication Herein, we report on the development of a catalytic system that promotes b-hydride elimination after the initial amidopalladation step to restore the unsaturation, thus accomplishing an intramolecular allylic amidation. In our study on carbonylative cyclization of 4 a to produce 5 a, we have shown that the reaction occurs by syn amidopalladation and exhibits a high level of diastereoselectivity.[6a] Therefore, we envisaged that formation of isoxazolidine 6 a would follow the same stereochemical course.[10] To develop conditions for the palladium-catalyzed oxidative intramolecular allylic amidation, the Boc-protected primary hydroxylamine derivative 7 was selected as a model substrate (Table 1; Boc = tert-butyloxycarbonyl). The presence of an electron-withdrawing group at the nitrogen is known to be a prerequisite for the formation of the N–Pd species and for preventing nitrogen oxidation.[11] Therefore, the Boc group was chosen with a view of the simplicity of its introduction and removal. The screening commenced by using a minor modification of the reaction conditions previously employed for the carbonylative amidation of N-Boc homoallylic alkoxyamines.[6a] With Pd(OAc)2 (10 mol %) and Cu(OAc)2 (3 equiv) at 60 8C in MeCN, the desired vinyl isoxazolidine 8 was obtained in excellent yield after 16 h (Table 1, entry 1). Repeating the reaction at room temperature, however, led to a poor conversion (entry 2), showing that an elevated temperature is required for this system to operate efficiently. Reducing the loading of Cu(OAc)2 to 30 mol % also negatively affected the reaction rate (entry 3). To facilitate the reoxidation of Pd in the latter instance, oxygen (1 atm) was introduced to the system. However, rather
unexpectedly, ketone 9 (20 %) was found to be formed along with the desired alkene 8 (54 %; entry 4). Control experiments revealed that the Wacker–Tsuji oxidation[12] of olefin 8 to produce 9 under the same reaction conditions is rather sluggish, suggesting that the active species promoting the formation of 9 was generated in situ from the Pd-intermediate directly.[13] The yield of ketone 9 can be further improved by replacing Pd(OAc)2 (I) with [PdCl2(MeCN)2] (II) and adding quinolinyloxazoline L as a ligand (entries 5 and 6). Replacing copper salts with p-benzoquinone (BQ) as oxidant did not affect the latter outcome (entry 7). Furthermore, the additional oxidant proved redundant, as the best result (85 % conversion to 9 after 16 h) was obtained by using molecular oxygen as the sole oxidant (entry 8). To steer the reaction back towards alkene 8, we reverted to the ligand-free Pd(OAc)2 as a catalyst and molecular oxygen as the terminal oxidant; sodium acetate was introduced as a weak base. Solvents, such as toluene, THF, and DMSO showed modest conversions (entries 9–11). A real improvement was attained when the reaction was carried out in THF, using DMSO as an additive (10 mol %), which is consistent with the in situ formation of the highly catalytically active complex [Pd(DMSO)2(OAc)2] described by Stahl.[14] The reaction cleanly produced 8 in nearly quantitative yield at RT over 16 h (entry 12). Interestingly, the complex of Pd(OAc)2 with 1,2-bis(phenylsulfinyl)ethane (III) proved inferior (entry 13), as did the replacement of DMSO with DMF (entry 14) or using MeCN as a solvent (entry 15). This behavior suggests that, in the case of [Pd(DMSO)2(OAc)2], one of the DMSO ligands can dissociate, allowing coordination of the substrate. This option is apparently not available for the chelate III and/or for a high concentration of DMSO (i.e., when used as a solvent). Table 1. Optimization of the allylic amidation of homoallylic alkoxylamines.[a] With the optimal conditions in hand, we could embark on the investigation of the reaction scope (Scheme 3). Substrates 10 a–c and 11 a with an extended alkyl chain were examined first. Geometry of the starting alkene (E)-10 a and (Z)-11 a PdII [(mol %)] Oxidant [(equiv)][b] Solvent Additive [(equiv)] T [8C] Conv. [%] (8/9)[c] turned out to have no influence [d] 1 I (10) Cu(OAc)2 (3) MeCN None 60 95 (8) on the reactivity since both 2 I (10) Cu(OAc)2 (3) MeCN None RT 11 (8) readily afforded (E)-12 a as MeCN None 60 69 (8) 3 I (10) Cu(OAc)2 (0.3) 4 I (10) Cu(OAc)2 (0.3)/O2 MeCN None 60 74 (8,9)[e] a major product (81 and 76 %, 5 II (5) Cu(OAc)2 (0.3)/O2 MeCN L (0.4) 60 50 (9)[f] respectively), in contrast to the [f] 6 II (5) CuCl (0.3)/O2 MeCN L (0.4) 60 56 (9) allylic tosylcarbamates 3, where 7 II (5) BQ (0.3)/O2 MeCN L (0.4) 60 56 (9)[f] only the Z alkene is sufficiently 8 II (5) O2 MeCN L (0.4) 60 99 (9,8)[g] 9 I (10) O2 toluene NaOAc (0.2) 80 34 (8) reactive.[5c] Formation of minor THF NaOAc (0.2) 60 36 (8) 10 I (10) O2 quantities of the Z and terminal DMSO NaOAc (0.2) 60 37 (8) 11 I (10) O2 isomers were also observed in THF NaOAc/DMSO (0.2/0.1) RT 100 (8)[h] 12 I (5) O2 both instances. Cyclization of 13 III (10) O2 THF NaOAc (0.2) RT 39 (8) 14 I (5) O2 THF NaOAc/DMF (0.2/0.1) RT 52 (8) the more sterically encumbered MeCN NaOAc/DMSO (0.2/0.1) RT 35 (8) 15 I (5) O2 substrates 10 b and c resulted in [a] Conditions: 7 (0.25 mmol), solvent (3 mL), 16 h. [b] O2 was applied to the system using a balloon. [c] Deterslightly reduced yields of 12 b mined using 1H NMR spectroscopy. [d] Isolated yield 85 %. [e] 8 (54 %), 9 (20 %). [f] Ketone 9 was the major (61 %) and 12 c (51 %). product, only traces of 8 were observed. [g] 9 (85 %), 8 (14 %). [h] Isolated yield 98 %.
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Scheme 4. Synthesis of pyrazolidines (X = CO2iPr).
Scheme 3. Palladium-catalyzed intramolecular amidation.
The bis-homoallylic substrate 13 readily produced the tetrahydro-1,2-oxazine 14, which can be viewed as a protected form of 1,4-amino alcohol. The reaction was completed overnight at RT in 95 % yield, indicating that formation of the terminal alkene is highly favorable with this catalytic system. It is worth noting that there are only a handful of examples of cyclizations leading to 1,4-amino alcohol derivatives.[15] Diastereoselectivity of the cyclization was investigated with the aid of the enantioenriched hydroxylamine derivatives 15 a– f (Table 2), which in turn were synthesized from the respective homoallylic alcohols[6a, 16] of 92–97 % ee by the Mitsunobu method.[8b,d] Under the standard conditions (Table 1, entry 12), the cyclization furnished cis-isoxazolidines 16 a–f in nearly quantitative yields at RT and with high diastereoisomeric purity, irrespective of the nature and steric bulk of the substituent R. The excellent level of diastereocontrol attained in these reactions is in line with the syn-amidopalladation pathway[6a] that is likely to be operating here. Table 2. Oxidative amidation of chiral alkoxyamines.[a]
1 2 3 4 5 6
Substrate
R
Yield [%]
cis:transb]
15 a 15 b 15 c 15 d 15 e 15 f
Ph Bn PhCH2CH2 cC6H11 Et2CH nC6H13
98 96 96 96 95 93
> 30:1 18:1 > 30:1 > 30:1 > 30:1 > 30:1
[a] Conditions: 15 (0.25 mmol), solvent (3 mL), 16 h. [b] Determined by H NMR spectroscopy.
To expand the scope of this reaction, we examined the hydrazine analogues 17–19 (Scheme 4), which were synthesized from the respective alcohols[16] by Mitsunobu reaction, using diisopropyl azodicarboxylate as a nucleophile. In the Pd-catalyzed cyclization, the hydrazine derivatives 17–19 proved less reactive than their hydroxylamine-derived counterparts. A brief screening of the reaction conditions revealed that for the best results the catalyst has to be added in two portions within a 24 h interval (at RT). Using the optimized protocol, both (E)17 and (Z)-18 afforded pyrazolidine (E)-20 as a major product in good yields, mirroring the behavior of the ON analogues 10 a and 11 a. Cyclization of the secondary hydrazine derivative 19 proceeded uneventfully but furnished the trans-configured pyrazolidine 21 (Figure 1), in contrast to the hydroxylamine analogue 15 a, which produced the cis isomer 16 a under almost identical conditions.[17] The switch in the stereochemical outcome is likely to be due to the steric strain imposed by the additional bulky carbamate group, which is consistent with the report by Wolfe,[9d] who conducted a detailed investigation on the stereochemistry of Pd-catalyzed carboamidation. The synthetic utility of this cyclization strategy is illustrated by a short synthesis of b-d-2,3-dideoxy-3-amino-C-ribofuranoside (24; Scheme 5).[18, 19] Here, cleavage of the NO bond in 16 a by heating at reflux with Mo(CO)6 (5 equiv)[20] in a 9:1 MeCN/H2O mixture afforded the N-protected syn-1,3-amino alcohol 22 (61 %). The latter product was then oxidized with mCPBA in CH2Cl2 to furnish epoxide 23 (68 %) as a 7:1 mixture of diastereoisomers.[21–23] Subsequent cyclization was carried out in the presence of BF3·Et2O (10 mol %), and afforded the desired pure diastereoisomer 24 (68 %).
1
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Scheme 5. Synthesis of aza C-nucleoside analogue.
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Communication (4.1 mg, 0.05 mmol) and flushed with O2. A solution of DMSO (1.8 mL, 0.025 mmol) in THF (2 mL) was added, and a balloon of O2 was attached. A solution of the substrate (0.25 mmol) in THF (1 mL) was then added by syringe and the mixture was left stirring at room temperature overnight. The mixture was filtered through a pad of celite, which was then washed with ethyl acetate, and the solvent from the combined filtrate was evaporated in vacuo. The crude product was purified by flash chromatography on silica gel (2 15 cm) using a mixture of light-petroleum/AcOEt (10:1) as an eluent. Crystal data for 21: C19H26N2O4, M = 346.42, colorless block, 0.41 0.29 0.25 mm3, monoclinic, P21, a = 11.1404(18), b = 8.0196(13), c = 11.1622(18) , b = 107.072(2)8, V = 953.3(3) 3, Z = 2, m(MoKa) = 0.09 mm1, 1calcd = 1.207 g cm3, 17 201 reflections measured[25] with graphite monochromated MoKa radiation at T = 150 K (l = 0.71073 ), 4577 unique, Rint = 0.058, Twinned dataset with one dominant domain. The two domains are related by a 178.98 rotation about real axis [0 1 0]. The structure was refined against approximately detwinned data based on the major component. Solved by direct methods,[26] R1[F2>2s(F2)] = 0.038, wR2 (all data) = 0.096. Largest difference map features within 0.20 e 3. Absolute structure could not be reliably determined and was set from an unchanging chiral center in the starting material. H atom coordinates and Uiso parameters were freely refined except for Uiso for the H atoms on C(16), which were fixed at 1.5 times that of the carrier atom. CCDC 979771 contains the supplementary crystallographic data. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data request/cif.
Acknowledgements
Figure 1. Two views of the crystal structure of 21 highlighting the trans configuration.
In conclusion, we have developed an efficient, practical protocol for the Pd-catalyzed intramolecular oxidative allylic amidation that provides facile access to derivatives of 1,3- and 1,4amino alcohols and 1,3-diamines. The method operates under mild reaction conditions (RT) with molecular oxygen (1 atm) as the sole reoxidant of Pd. Excellent diastereoselectivities were attained with substrates bearing a secondary stereogenic center. Significantly, the reaction can be driven either to the vinylic derivative, such as 8 (Table 1, entry 12), or to the corresponding methylketone 9 (Table 1, entry 8) by a minor modification of the reaction conditions. This strategy combines highly enantioselective organocatalysis (for the preparation of chiral starting materials[16c,f]) with diastereocontrolled transition metal catalysis[24] and was successfully applied to a stereocontrolled synthesis of the enantiopure trisubstituted tetrahydrofuran derivative 24 that can be regarded as a C-nucleoside.
We thank Prof. Jan-E. Bckvall for valuable discussions, the EPSRC for grant No. EP/E011179/1, Loughborough University for a studentship to D. S. L. and additional support, and the Axel Wenner–Gren Foundation for a sabbatical scholarship to P. K. COST Office support through ORCA action is also appreciated. Keywords: allylic compounds · amination · cyclization · homogeneous catalysis · palladium
Experimental Section General procedure for Pd-catalyzed intramolecular allylic amidation of alkoxyamine derivatives: A 10 mL flask was charged with palladium acetate (2.8 mg, 0.013 mmol) and sodium acetate Chem. Eur. J. 2014, 20, 4901 – 4905
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[1] For reviews, see: a) L. S. Hegedus, in Comprehensive Organic Synthesis Vol. 4 (Eds: M. F. Semmelhack), Pergamon Press, Elmsford, 1991, pp. 551 – 569; b) T. Hosokawa, S.-I. Murahashi, in Handbook of Organopalladium Chemistry for Organic Synthesis Vol. 2 (Eds: E. Negishi, A. de Meijere), John Wiley and Sons, NewYork, 2002, pp. 2169 – 2192; c) T. Hosokawa, in Handbook of Organopalladium Chemistry for Organic Synthesis Vol. 2 (Eds: E. Negishi, A. de Meijere), John Wiley and Sons, New York, 2002, pp. 2211 – 2225; d) G. Zeni, R. C. Larock, Chem. Rev. 2004, 104, 2285 – 2309; e) S. S. Stahl, Angew. Chem. 2004, 116, 3480 – 3501; Angew. Chem. Int. Ed. 2004, 43, 3400 – 3420; f) E. M. Beccalli, G. Broggini, M. Martinelli, S. Sottocornola, Chem. Rev. 2007, 107, 5318 – 5365; g) A. Minatti, K. MuÇiz, Chem. Soc. Rev. 2007, 36, 1142 – 1152; h) V. Kotov, C. C. Scarborough, S. S. Stahl, Inorg. Chem. 2007, 46, 1910 – 1923; i) R. I. McDonald, G. Liu, S. S. Stahl, Chem. Rev. 2011, 111, 2981 – 3019; j) D. Schultz, J. Wolfe, Synthesis 2012, 44, 351 – 361; k) J. L. Roizen, M. E. Harvey, J. Du Bois, Acc. Chem. Res. 2012, 45, 911 – 922. [2] For an early work on allylic activation catalyzed by PdII, see: a) J. E. McMurry, P. Kocˇovsky´, Tetrahedron Lett. 1984, 25, 4187 – 4190; b) J. E. McMurry, P. Kocˇovsky´, Tetrahedron Lett. 1985, 26, 2171 – 2172; c) S. Hansson, A. Heumann, T. Rein, B. kermark, J. Org. Chem. 1990, 55, 975 – 984; d) S. E. Bystrçm, E. M. Larsson, B. kermark, J. Org. Chem. 1990, 55, 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Received: January 11, 2014 Published online on March 24, 2014
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