DOI: 10.1002/chem.201403873
Full Paper
& Homogeneous Catalysis
Synthesis of Pyridazinones through the Copper(I)-Catalyzed Multicomponent Reaction of Aldehydes, Hydrazines, and Alkynylesters Anderson C. Mantovani,[a] Tales A. C. Goulart,[a] Davi F. Back,[b] and Gilson Zeni*[a]
Abstract: The copper-catalyzed multicomponent cyclization reaction, which combined aldehydes, hydrazines, and alkynylesters, was applied in the synthesis of pyridazinones. The reaction was regioselective and gave only six-membered pyridazinones in the complete absence of five-membered pyra-
zoles or a regioisomeric mixture. During this investigation, the use of 2-halobenzaldehyde as the starting material, under identical reaction conditions, gave 6-(2-ethoxyphenyl)pyridazinones after sequential Michael addition/1,2-addition/ Ullmann cross-coupling reactions.
Introduction
The innovative features of this multicomponent reaction are the preparation of six-membered pyridazinones instead of fivemembered azole derivatives.[6] We anticipated that this remarkable selectivity was attributed to the carbon nucleophile addition to the Michael acceptor, promoted by the copper salt, instead of nitrogen addition.
Five- and six-membered heterocycles, with two nitrogen atoms in the structure, are a structural motif of particular interest in synthetic and medicinal chemistry because they are present in a large number of natural products, many of which have biological activity.[1] Among the various methods developed thus far for the synthesis of five-membered heterocycles with two nitrogen atoms, the most useful approaches are based on the condensation of hydrazines with 1,3-dicarbonyl compounds and the intermolecular 1,3-dipolar cycloaddition of nitrilimines or diazo compounds to alkenes and alkynes (Scheme 1).[2] Despite the impressive progress achieved, the use of a 1,3-dipolar cycloaddition approach to six-membered heterocycles with two nitrogen atoms is relatively rare. The most common synthetic route involves the cyclization reaction of hydrazines with carbonyl compounds.[3] In addition to classical synthetic methods, multicomponent reactions, which combine three or more substrates in a single operation, facilitate the cyclization of acyclic substrates to afford various functionalized N-heterocycles.[4] However, this important tandem process has been efficiently used to prepare five-membered N-heterocycles.[5] Herein, we wish to extend the concept of multicomponent reactions and report the synthesis of pyridazinones 4 by using a copper-catalyzed multicomponent reaction, starting from aldehydes (1), hydrazines (2), and alkynylesters (3; Scheme 1).
Results and Discussion In the first attempt, we examined the reaction of phenylhydrazone 5 (the isolated product of the reaction of aldehyde 1 a with aryl hydrazine 2 a; 0.25 mmol), with ethyl 3-phenylpropiolate (3 a; 0.25 mmol), catalyzed by CuI (20 mol %) in CH2Cl2 (3 mL) at room temperature. These conditions gave a minor amount of pyridazinone 4 a (5 % yield) together with a large amount of inseparable regioisomer and aza-Michael addition product. The screening of solvents, such as EtOH, CH2Cl2, DMF, and MeCN, revealed that the use of MeCN gave pyridazinone 4 a in 32 % yield as a single isomer, which was separated from unreacted starting materials by column chromatography. After purification, the structural assignment of 4 a was based on NMR spectroscopy analysis and confirmed by X-ray diffraction, which showed the exact position of the two nitrogen atoms (Figure 1). Classical cyclocondensation of hydrazines with bketo esters gives a regioisomeric mixture of products.[7] Al-
[a] A. C. Mantovani, T. A. C. Goulart, Prof. Dr. G. Zeni Departamento de Qumica Orgnica Laboratrio de Sntese Reatividade, Avaliażo Farmacolgica e Toxicolgica de OrganocalcogÞnios, Universidade Federal de Santa Maria Santa Maria, Rio Grande do Sul, 97105-900 (Brazil) E-mail: [email protected] [b] Prof. Dr. D. F. Back Departamento de Qumica Inorgnica Laboratrio de Materiais Inorgnicos, Universidade Federal de Santa Maria Santa Maria, Rio Grande do Sul, 97105-900 (Brazil) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201403873. Chem. Eur. J. 2014, 20, 1 – 7
These are not the final page numbers! ÞÞ
Scheme 1. General reaction scheme for the synthesis of five- and six-membered heterocycles with two nitrogen atoms.
1
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
Full Paper Table 1. Effect of different reaction parameters on the preparation of pyridazinone 4 a.[a]
Figure 1. ORTEP view of compound 4 e. Ellipsoids are drawn at the 50 % probability level.
though under these conditions pyridazinone 4 a was obtained in low yield, neither a five-membered heterocyclic ring nor a regioisomeric mixture was formed. After these results, we concentrated our study in investigating different reaction parameters to improve the yield (Table 1). For instance, the use of a stoichiometric amount of CuI failed to give pyridazinone 4 a (Table 1, entry 1). A minor increase in yield was observed when CuI (1 equiv) was used in association with K2CO3 as a base and increasing the reaction temperature to 80 8C (Table 1, entry 2). In contrast, the yield significantly increased to 72 % when Cs2CO3 was used as base (Table 1, entry 3). Other bases proved to be less efficient than Cs2CO3 or no reaction occurred with Et3N (Table 1, entries 4–7). Increasing the amount of either CuI or Cs2CO3 led to a lower yield of 4 a (Table 1, entries 8–10). The use of other copper salts, such as CuCl and CuBr, did not further improve the yield of 4 a, and no reaction occurred when CuBr2 was used (Table 1, entries 11–13). To make the present cyclization more economical and environmentally attractive, we examined the catalytic activity of CuI. Variation in the catalyst amount from 50 to 10 mol % did not show any improvement in the yields of 4 a, even when using additives or changing the catalyst (Table 1, entries 14– 22). In copper-catalyzed reactions, the use of chelating ligands has a substantial effect and often leads to improved reactivity.[8] From this point of view, the reaction of 5 (0.25 mmol), 3 a (0.25 mmol), CuI (0.05 mmol), Cs2CO3 (0.25 mmol), and MeCN (3 mL) was examined with in presence of ligands L1–L7 (0.1 mmol), which are shown in Figure 2. Of these ligands, 1,10-phenanthroline (L4) was the most effective, and gave product 4 a in 94 % yield. Finally, we turned our attention to applying these conditions to a multicomponent reaction. Thus, when aldehyde 1 a (0.25 mmol), hydrazine 2 a (0.25 mmol), and alkynylester 3 a (0.25 mmol) were treated with CuI (0.05 mmol), L4 (0.1 mmol), and Cs2CO3 (0.25 mmol) in MeCN (3 mL) under &
&
Chem. Eur. J. 2014, 20, 1 – 7
www.chemeurj.org
Entry
Copper salt ([equiv])
Base ([equiv])
Yield[b] [%]
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17[c] 18[d] 19[e] 20[f] 21[g] 22
CuI (1) CuI (1) CuI (1) CuI (1) CuI (1) CuI (1) CuI (1) CuI (1.5) CuI (1) CuI (1) CuCl (1) CuBr (1) CuBr2 (1) CuI (0.5) CuI (0.2) CuI (0.1) CuI (0.2) CuI (0.2) CuI (0.2) CuI (0.2) CuI (0.2) [AuCl(PPh3)]
– K2CO3 (1) Cs2CO3 (1) KOH (1) NaHCO3 (1) Et3N (1) DBU (1) Cs2CO3 (1) Cs2CO3 (1.5) Cs2CO3 (2) Cs2CO3 (1) Cs2CO3 (1) Cs2CO3 (1) Cs2CO3 (1) Cs2CO3 (1) Cs2CO3 (1) Cs2CO3 (1) Cs2CO3 (1) Cs2CO3 (1) Cs2CO3 (1) Cs2CO3 (1) Cs2CO3 (1)
– 49 72 30 15 0 19 15 53 42 38 27 0 60 59 57 9 49 13 9 11 0
[a] The reaction was performed in the presence of 5 (0.25 mmol), 3 a (0.25 mmol), CuI, and MeCN (3 mL), under an argon atmosphere at 80 8C for 16 h. DBU = 1,5-diazabicyclo[5.4.0]undec-5-ene. [b] Yields were determined by GC analysis. [c] An oxygen atmosphere (balloon) was used. [d] nBu4NI (0.25 mmol) was used as an additive. [e] Silver triflate (AgOTf; 0.25 mmol) was used as an additive. [f] ZnCl2 (0.25 mmol) was used as an additive. [g] KI (0.25 mmol) was used as an additive.
an argon atmosphere at 80 8C, pyridazinone 4 a was obtained in 64 % yield. In a similar way, this optimized procedure was then applied to different aldehydes 1, hydrazines 2, and alkynylesters 3; the results are listed in Table 2. The results show that pyridazinones 4 a–e were obtained in good yield, regardless of the substituents (electron-withdrawing or -donating groups) present on the aromatic ring of the aldehydes. When this cyclization was carried out with 4-nitro-benzaldehyde, product 4 g was not stable enough to be purified and characterized. The reactivity of aryl alkynylester 3 under the previously optimized reaction conditions was also investigated. Because aryl alkynylesters 3 substituted with both electron-withdrawing and -donating groups allowed the formation of pyridazinones 4 h–r in variable yields (from 40 to 85 %), the relationship between these two variables, substituents and yields, indicates a weak correlation. When we tried to extend the optimized conditions to an alkynylester, with an alkyl chain directly bonded to the triple bond, product 4 s was not detected at all. Next, the multicomponent reaction, with two different hydrazines, was examined for the preparation of pyridazinones 4 s–v. The opti2
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!
Full Paper Table 2. Synthesis of pyridazinone 4.[a,b]
Figure 2. Studies of the effect of ligands L1–L7 on the reaction.
mized conditions were efficient for hydrazines with a methyl group and chloro atom, which gave the corresponding pyridazinones in moderate to good yields. However, the use of unsubstituted or aliphatic hydrazines did not give the product, even when subjected to harsh reaction conditions. In this case, the absence of p bonds in the alkyl chain could result in a decreased reactivity for nucleophilic attack on the carbon–carbon triple bond. When we investigated the formation of pyridazinone 4 a, we observed that the ethoxyl group, from alkynylester 3, was not incorporated into the structure; this indicated that it could be released into the reaction medium. Thus, we speculate that this ethoxyl group should be a suitable internal nucleophile to promote the in situ Ullmann coupling. It has been well documented that copper(I) iodide, L4, and cesium carbonate are good reaction partners to promote the coupling of aryl halides and aliphatic alcohols.[9] Therefore, we applied exactly the same reaction conditions as those used in the preparation of pyridazinone 4 (Table 1) to the reaction of hydrazines, alkynylesters, and 2-halobenzaldehydes. The sequential Michael addition/1,2-cyclization addition/Ullmann cross-coupling reactions proceeded smoothly to give pyridazinones 6 a–c in good yields (Scheme 2). After these experimental results, we assumed that, when 2-halobenzaldehydes are used, the oxidative addition of copper iodide to the carbon–halogen bond occurs after pyridazinone ring formation supported by the interaction of copper with the nitrogen atom from the pyridazinone ring. This assumption can be further supported by the fact that the Ullmann coupling did not occur with 4-halobenzaldehyde derivatives. To investigate the role of the CuI catalyst, we carried out the reaction of aldehyde 1 a, hydrazine 2 a, and alkynylester 3 a under the optimized conditions in the absence of CuI. This reaction gave the aza-Michael addition adduct 7 as the sole product (Scheme 3).[10] In addition, when the reaction was performed with phenylhydrazone 5 (Table 1), pyridazinones 4 Chem. Eur. J. 2014, 20, 1 – 7
www.chemeurj.org
These are not the final page numbers! ÞÞ
[a] The reaction was performed in the presence of aldehyde 1 (0.25 mmol), hydrazine 2 (0.25 mmol), alkynylester 3 (0.25 mmol), CuI (0.05 mmol), L4 (0.1 mmol), Cs2CO3 (0.25 mmol), and MeCN (3 mL), under an argon atmosphere at 80 8C for 16 h. [b] Yield of product isolated after column chromatography. [c] The product of Ullmann coupling was obtained in 39 % yield. [d] The reaction was carried out by using 0.5 mmol of Cs2CO3.
were obtained in good yields. It seems clear that phenylhydrazone 5 is a possible intermediate in the multicomponent process. Based on these results, we propose that the cyclization 3
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
Full Paper Conclusion We have described a one-pot, three-component intermolecular cyclization involving aldehydes, hydrazines, and alkynylesters. This process provided efficient access to substituted pyridazinones in good to excellent yields. Application of the present methodology in the preparation of the Ullmann product was also investigated. The optimization reactions showed that the yields of the cyclization reaction were highly dependent on the presence and nature of the base and ligand; the best results were obtained when Cs2CO3 was used as the base and L4 was used as the ligand. The use of L4 in association with CuI avoided the use of equimolar amounts of copper salt and the use of a multicomponent reaction became the method with good atom economy. Carbon nucleophile addition to a Michael acceptor, promoted by the copper salt, instead of nitrogen addition was the main factor to prevent the formation of undesired azole derivatives, giving exclusively pyridazinones.
Scheme 2. Preparation of pyridazinones 6 a–c.
involves the initial formation of hydrazone 5 from the reaction of aldehydes 1 and hydrazines 2 (Scheme 3). Deprotonation of NH from hydrazones 5 gives, after resonance, intermediate a.[11] Intermediate a reacts with CuI to form cuprate b. The Michael addition of b into the carbon–carbon triple bond of the alkynylester[10] gives adduct c’, which after isomerization gives c.[12] Michael addition via a trans-copper adduct is in accordance with the known ability of organocopper reagents to undergo p complexation with a carbon–carbon triple bond and with a carbonyl group. The intramolecular 1,2-addition of nitrogen to the ester carbonyl functionality gives d, which delivers pyridazinone 4 (Scheme 3). Although intermediates c/c’ proposed in the mechanism could not be isolated, we tried to trap these intermediates with electrophiles. However, the addition of primary alkyl halides, a,b-unsaturated carbonyl compounds, and allyl bromide, or quenched with proton sources, did not allow any trapping products and gave only pyridazinone 4 as the product.
Experimental Section General procedure for copper-catalyzed tandem three-component reaction of aldehyde, arylhydrazine, and alkynylester Aldehyde (0.25 mmol), arylhydrazine (0.25 mmol), alkynylester (0.25 mmol), CuI (0.05 mmol), and L4 (0.1 mmol) in MeCN (3 mL) were added to a two-necked round-bottomed flask equipped with a reflux condenser, under an argon atmosphere. The reaction mixture was stirred for the indicated time at 80 8C. The mixture was filtered through silica gel with ethyl acetate and concentrated under vacuum. The residue was purified by flash chromatography (hexane/ethyl acetate = 20:1).
2,5,6-Triphenylpyridazin-3(2H)-one (4 a) Pale-white solid; yield: 0.049 g, 61 %; m.p. 250–252 8C; 1H NMR (CDCl3, 400 MHz): d = 7.74 (d, J = 7.3 Hz, 2 H), 7.48 (t, J = 7.6 Hz, 2 H), 7.40–7.22 (m, 9 H), 7.17–7.14 (m, 2 H), 7.07 ppm (s, 1 H); 13C NMR (CDCl3, 100 MHz): d = 159.6, 146.5, 145.5, 141.4, 135.7, 135.2, 130.0, 129.2, 129.0, 128.7, 128.6, 128.4, 128.1, 128.0, 125.3 ppm; MS (EI, 70 eV): m/z (%): 324 (100), 296 (31), 191 (92), 189 (44), 165 (39), 105 (20), 77 (86); HRMS (ESI): m/z calcd for C22H16N2O + H: 325.1341 [M + H] + ; found: 325.1345.
2,5-Diphenyl-6-(p-tolyl)pyridazin-3(2H)-one (4 b) Yellow oil; yield: 0.056 g, 66 %; 1H NMR (CDCl3, 200 MHz): d = 7.74 (d, J = 7.0 Hz, 2 H), 7.52–7.24 (m, 6 H), 7.24–7.01 (m, 7 H), 2.30 ppm (s, 3 H); 13C NMR (CDCl3, 100 MHz): d = 159.6, 146.5, 145.5, 141.4, 138.6, 135.8, 132.2, 130.0, 129.1, 128.9, 128.7, 128.6, 128.4, 128.0, 125.3, 21.1 ppm; MS (EI, 70 eV): m/z (%): 338 (100), 323 (14), 205 (85), 164 (12), 77 (45); HRMS (ESI): m/z calcd for C22H16N2O + H: 339.1497 [M + H] + ; found: 339.1497.
6-(2-Chlorophenyl)-5-(2,5-dimethoxyphenyl)-2-phenylpyridazin-3(2H)-one (4 l) Orange oil; yield: 0.042 g, 40 %; 1H NMR (CDCl3, 400 MHz): d = 7.75– 7.72 (m, 2 H), 7.48 (t, J = 7.5 Hz, 2 H), 7.38 48 (t, J = 7.3 Hz, 1 H), 7.17 (s, 4 H), 7.03 (s, 1 H), 6.91 (dd, J = 3.1 Hz, J = 5.8 Hz, 1 H), 6.85 (d, J =
Scheme 3. Proposed mechanism for the preparation of 4 through the multicomponent reaction.
&
&
Chem. Eur. J. 2014, 20, 1 – 7
www.chemeurj.org
4
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!
Full Paper 2.1 Hz, 1 H), 6.65 (d, J = 9.0 Hz, 1 H), 3.78 (s, 3 H), 3.25 ppm (s, 3 H); 13 C NMR (CDCl3, 100 MHz): d = 159.5, 153.8, 149.7, 146.2, 143.1, 141.4, 134.8, 134.3, 130.8, 129.2, 128.6, 128.0, 127.8, 125.2, 115.8, 115.6, 112.3, 55.7, 55.2 ppm; MS (EI, 70 eV): m/z (%): 418 (100), 387 (50), 375 (15), 285 (35), 162 (14), 147 (10), 77 (57); HRMS (ESI): m/z calcd for C24H19ClN2O3 + H: 419.1162 [M + H] + ; found: 419.1168.
(m, 1 H), 4.09 (q, J = 7.2 Hz, 2 H), 1.14 ppm (t, J = 7.0 Hz, 3 H); C NMR (CDCl3, 100 MHz): d = 166.0, 148.0, 145.1, 140.2, 139.6, 137.7, 129.4, 129.1, 128.4, 127.9, 127.1, 126.9, 124.0, 123.1, 122.1, 121.8, 118.1, 110.6, 59.9, 13.9 ppm; MS (EI, 70 eV): m/z (%): 368 (88), 323 (33), 296 (100), 293 (11), 165 (11), 77 (12); MS (EI, 70 eV): m/z (%): 414 (100), 383 (65), 308 (56), 281 (46), 251 (46), 163 (10), 132 (22), 121 (21), 77 (38); HRMS (ESI): m/z calcd for C24H20N2O2 + H: 369.1603 [M + H] + ; found: 369.1609.
13
5-(2,5-Dimethoxyphenyl)-2-phenyl-6-p-tolylpyridazin-3(2H)one (4 o)
6-(2-Ethoxyphenyl)-5-(4-methoxyphenyl)-2-phenylpyridazin3(2H)-one (6 c)
Yellow solid; yield: 0.062 g, 62 %; m.p. 164–166 8C; 1H NMR (CDCl3, 400 MHz): d = 7.75 (d, J = 7.6 Hz, 2 H), 7.46 (t, J = 7.8, 2 H), 7.36 (t, J = 7.3, 1 H), 7.12 (d, J = 8.1 Hz, 2 H), 7.03 (s, 1 H), 6.99 (d, J = 7.8 Hz, 2 H), 6.87 (dd, J = 9.0 Hz, 1 H), 6.83 (d, J = 2.9 Hz, 1 H), 6.65 (d, J = 9.0 Hz, 1 H), 3.76 (s, 1 H), 3.23 (s, 1 H), 2.27 ppm (s, 1 H); 13C NMR (CDCl3, 100 MHz): d = 159.6, 153.7, 150.0, 147.4, 143.5, 141.6, 138.1, 133.4, 130.7, 128.6, 128.2, 127.8, 125.9, 125.3, 115.6, 115.5, 112.3, 55.7, 55.3, 21.0 ppm; MS (EI, 70 eV): m/z (%): 398 (100), 367 (50), 265 (33), 206 (22); HRMS (ESI): m/z calcd for C25H22N2O3 + H: 399.1709 [M + H] + ; found: 369.1719.
Dark-orange oil; yield: 0.054 g, 54 %; 1H NMR (CDCl3, 200 MHz): d = 7.71 (t, J = 7.2 Hz, 3 H), 7.52 (t, J = 7.8 Hz, 2 H), 7.39–7.23 (m, 4 H), 7.06–6.8 (m, 4 H), 4.12 (q, J = 7.0 Hz, 2 H), 3.85 (s, 3 H), 1.19 ppm (t, J = 7.2 Hz, 3 H); 13C NMR (CDCl3, 100 MHz): d = 166.0, 159.9, 147.6, 145.7, 140.2, 139.6, 130.8, 129.7, 129.3, 127.0, 126.9, 124.1, 123.0, 122.0, 121.9, 117.7, 113.3, 110.5, 59.9, 55.1, 14.0 ppm; MS (EI, 70 eV): m/z (%): 398 (65), 353 (28), 326 (100), 282 (21), 192 (13), 135 (26), 77 (33); HRMS (ESI): m/z calcd for C25H22N2O3 + H: 399.1709 [M + H] + ; found: 399.1700.
6-(4-Chlorophenyl)-2-(2,5-dimethylphenyl)-5-(4-methoxyphenyl)pyridazin-3(2H)-one (4 t)
X-ray crystallography
White solid; yield: 0.056 g, 54 %; m.p. 218–219 8C; 1H NMR (CDCl3, 400 MHz): d = 7.24–7.15 (m, 7 H), 7.08 (d, J = 8.8 Hz, 2 H), 7.03 (s, 1 H), 6.84 (d, J = 8.8 Hz, 2 H), 3.81 (s, 3 H), 2.35 (s, 3 H), 2.21 ppm (s, 3 H); 13C NMR (CDCl3, 100 MHz): d = 160.4, 159.6, 145.3, 145.2, 140.2, 136.6, 134.7, 133.9, 131.5, 130.8, 130.6, 130.1, 130.0, 129.0, 128.2, 127.6, 127.5, 114.1, 55.2, 20.7, 17.2 ppm; MS (EI, 70 eV): m/z (%): 416 (44), 399 (100), 305 (13), 255 (25), 212 (33), 176 (80), 151 (29), 105 (72), 77 (73); HRMS (ESI): m/z calcd for C25H21ClN2O2 + H: 417.1370 [M + H] + ; found: 417.1375.
CCDC-974780 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/ data_request/cif.
Acknowledgements We are grateful to FAPERGS, CAPES, and CNPq (CNPq/INCT-catalise) for financial support. CNPq is also acknowledged for fellowships (G.Z., A.C.M., and T.A.C.G.). We thank the LMI-UFSM for support of X-ray crystallography results.
General procedure for copper-catalyzed tandem three-component reaction of aldehyde, arylhydrazine, and alkynylester and consecutive Ullmann coupling Aldehyde (0.25 mmol), arylhydrazine (0.25 mmol), alkynylester (0.25 mmol), CuI (0.05 mmol), and L4 (0.1 mmol) in MeCN (3 mL) were added to a two-necked round-bottomed flask equipped with a reflux condenser, under an argon atmosphere. The reaction mixture was stirred for the desired time at 80 8C. The mixture was filtered through silica gel with ethyl acetate and concentrated under vacuum. The residue was purified by flash chromatography (hexane/ethyl acetate = 20:1).
Keywords: copper · cyclization · heterocycles · homogeneous catalysis · multicomponent reactions [1] T. D. Heightman, A. T. Vasella, Angew. Chem. 1999, 111, 794; Angew. Chem. Int. Ed. 1999, 38, 750. [2] a) Y. L. Janin, Chem. Rev. 2012, 112, 3924; b) S. Fustero, M. Snchez-Rosell, P. Barrio, A. Simn-Fuentes, Chem. Rev. 2011, 111, 6984; c) O. A. Attanasi, P. Filippone, Synlett 1997, 1128. [3] a) S. G. Lee, J. J. Kim, D. H. Kweon, Y. J. Kang, S. D. Cho, S. K. Kim, Y. J. Yoon, Curr. Med. Chem. 2004, 11, 1461; b) P. J. Matyus, Het. Chem. 1998, 35, 1075. [4] a) P. Wipf, Z. Fang, L. Ferrie, M. Ueda, M. A. A. Walczak, Y. Yan, Pure Appl. Chem. 2013, 85, 1079; b) G. S. Singh, Z. Y. Desta, Chem. Rev. 2012, 112, 6104; c) R. Dalpozzo, G. Bartolib, G. Bencivennib, Chem. Soc. Rev. 2012, 41, 7247; d) S. Werner, S. D. Nielsen, P. Wipf, D. M. Turner, P. G. Chambers, S. J. Geib, D. P. Curran, W. J. Zhang, J. Comb. Chem. 2009, 11, 452; e) P. Wipf, C. R. J. Stephenson, Org. Lett. 2005, 7, 1137. [5] P. Liu, Y. Pan, Y. Xu, H. Wang, Org. Biomol. Chem. 2012, 10, 4696. [6] a) S. Safaei, I. Mohammadpoor-Baltork, A. R. Khosropour, M. Moghadam, S. Tangestaninejad, V. Mirkhani, New J. Chem. 2013, 37, 2037; b) X.-C. Tu, H. Feng, M.-S. Tu, B. Jiang, S.-L. Wang, S.-J. Tu, Tetrahedron Lett. 2012, 53, 3169; c) S. Safaei, I. Mohammadpoor-Baltork, A. R. Khosropour, M. Moghadam, S. Tangestaninejad, V. Mirkhani, Adv. Synth. Catal. 2012, 354, 3095; d) S. A. Raw, A. T. Turner, Tetrahedron Lett. 2009, 50, 696. [7] B. C. Hamper, M. L. Kurtzweil, J. P. Beck, J. Org. Chem. 1992, 57, 5680. [8] a) D. S. Surry, S. L. Buchwald, Chem. Sci. 2010, 1, 13; b) A. Klapars, J. C. Antilla, X. Huang, S. L. Buchwald, J. Am. Chem. Soc. 2001, 123, 7727.
5-(2,5-Dimethoxyphenyl)-6-(2-ethoxyphenyl)-2-phenylpyridazin-3(2H)-one (6 a) Dark-orange oil; yield: 0.042 g, 39 %; 1H NMR (CDCl3, 400 MHz): d = 7.72 (d, J = 8.0 Hz, 2 H), 7.68 (d, J = 8.5 Hz, 1 H), 7.51 (t, J = 7.5 Hz, 2 H), 7.39–7.29 (m, 2 H), 7.12 (s, 1 H), 7.03–6.84 (m, 5 H), 4.09 (q, J = 7.9 Hz, 2 H), 3.74 (s, 3 H), 3.65 (s, 3 H), 1.14 ppm (t, J = 7.2 Hz, 3 H); 13 C NMR (CDCl3, 100 MHz): d = 165.8, 153.5, 151.4, 144.6, 144.1, 140.3, 139.8, 129.4, 128.2, 127.0, 126.8, 123.9, 123.1, 122.1, 121.6, 119.2, 116.0, 114.6, 112.5, 110.6, 59.8, 56.6, 55.7, 14.0 ppm; HRMS (ESI): m/z calcd for C26H24N2O4 + H: 429.1814 [M + H] + ; found: 429.1819.
6-(2-Ethoxyphenyl)-2,5-diphenylpyridazin-3(2H)-one (6 b) Dark-orange oil; yield: 0.069 g, 75 %; 1H NMR (CDCl3, 200 MHz): d = 7.72 (t, J = 7.7 Hz, 3 H), 7.57–7.24 (m, 9 H), 7.04–6.97 (m, 2 H), 6.76 Chem. Eur. J. 2014, 20, 1 – 7
www.chemeurj.org
These are not the final page numbers! ÞÞ
5
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
Full Paper [9] a) G. E. Job, S. L. Buchwald, Org. Lett. 2002, 4, 3703; b) M. Wolter, G. Nordmann, G. E. Job, S. L. Buchwald, Org. Lett. 2002, 4, 973. [10] Z. Yuan, Y. Wei, M. Shi, Eur. J. Org. Chem. 2010, 4088. [11] X. Deng, N. S. Mani, Org. Lett. 2008, 10, 1307. [12] a) A. Alexakis, K. Croset, Org. Lett. 2002, 4, 4147; b) M. van Klaveren, E. S. M. Persson, A. Del Villar, D. M. Grove, J.-E. Bckvall, G. van Koten,
&
&
Chem. Eur. J. 2014, 20, 1 – 7
www.chemeurj.org
Tetrahedron Lett. 1995, 36, 3059; c) T. Saegusa, I. Murase, Y. Ito, Tetrahedron 1971, 27, 3795.
Received: June 8, 2014 Published online on && &&, 0000
6
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!
Full Paper
FULL PAPER & Homogeneous Catalysis A. C. Mantovani, T. A. C. Goulart, D. F. Back, G. Zeni* && – &&
All in! A copper-catalyzed multicomponent cyclization reaction, which combined aldehydes, hydrazines, and alkynylesters, was applied to the synthesis of pyridazinones (see scheme). The reac-
Chem. Eur. J. 2014, 20, 1 – 7
tion was regioselective to give only sixmembered pyridazinones in the complete absence of five-membered pyrazoles or a regioisomeric mixture.
www.chemeurj.org
These are not the final page numbers! ÞÞ
7
Synthesis of Pyridazinones through the Copper(I)-Catalyzed Multicomponent Reaction of Aldehydes, Hydrazines, and Alkynylesters
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
Full Paper
& Homogeneous Catalysis
Synthesis of Pyridazinones through the Copper(I)-Catalyzed Multicomponent Reaction of Aldehydes, Hydrazines, and Alkynylesters Anderson C. Mantovani,[a] Tales A. C. Goulart,[a] Davi F. Back,[b] and Gilson Zeni*[a]
Abstract: The copper-catalyzed multicomponent cyclization reaction, which combined aldehydes, hydrazines, and alkynylesters, was applied in the synthesis of pyridazinones. The reaction was regioselective and gave only six-membered pyridazinones in the complete absence of five-membered pyra-
zoles or a regioisomeric mixture. During this investigation, the use of 2-halobenzaldehyde as the starting material, under identical reaction conditions, gave 6-(2-ethoxyphenyl)pyridazinones after sequential Michael addition/1,2-addition/ Ullmann cross-coupling reactions.
Introduction
The innovative features of this multicomponent reaction are the preparation of six-membered pyridazinones instead of fivemembered azole derivatives.[6] We anticipated that this remarkable selectivity was attributed to the carbon nucleophile addition to the Michael acceptor, promoted by the copper salt, instead of nitrogen addition.
Five- and six-membered heterocycles, with two nitrogen atoms in the structure, are a structural motif of particular interest in synthetic and medicinal chemistry because they are present in a large number of natural products, many of which have biological activity.[1] Among the various methods developed thus far for the synthesis of five-membered heterocycles with two nitrogen atoms, the most useful approaches are based on the condensation of hydrazines with 1,3-dicarbonyl compounds and the intermolecular 1,3-dipolar cycloaddition of nitrilimines or diazo compounds to alkenes and alkynes (Scheme 1).[2] Despite the impressive progress achieved, the use of a 1,3-dipolar cycloaddition approach to six-membered heterocycles with two nitrogen atoms is relatively rare. The most common synthetic route involves the cyclization reaction of hydrazines with carbonyl compounds.[3] In addition to classical synthetic methods, multicomponent reactions, which combine three or more substrates in a single operation, facilitate the cyclization of acyclic substrates to afford various functionalized N-heterocycles.[4] However, this important tandem process has been efficiently used to prepare five-membered N-heterocycles.[5] Herein, we wish to extend the concept of multicomponent reactions and report the synthesis of pyridazinones 4 by using a copper-catalyzed multicomponent reaction, starting from aldehydes (1), hydrazines (2), and alkynylesters (3; Scheme 1).
Results and Discussion In the first attempt, we examined the reaction of phenylhydrazone 5 (the isolated product of the reaction of aldehyde 1 a with aryl hydrazine 2 a; 0.25 mmol), with ethyl 3-phenylpropiolate (3 a; 0.25 mmol), catalyzed by CuI (20 mol %) in CH2Cl2 (3 mL) at room temperature. These conditions gave a minor amount of pyridazinone 4 a (5 % yield) together with a large amount of inseparable regioisomer and aza-Michael addition product. The screening of solvents, such as EtOH, CH2Cl2, DMF, and MeCN, revealed that the use of MeCN gave pyridazinone 4 a in 32 % yield as a single isomer, which was separated from unreacted starting materials by column chromatography. After purification, the structural assignment of 4 a was based on NMR spectroscopy analysis and confirmed by X-ray diffraction, which showed the exact position of the two nitrogen atoms (Figure 1). Classical cyclocondensation of hydrazines with bketo esters gives a regioisomeric mixture of products.[7] Al-
[a] A. C. Mantovani, T. A. C. Goulart, Prof. Dr. G. Zeni Departamento de Qumica Orgnica Laboratrio de Sntese Reatividade, Avaliażo Farmacolgica e Toxicolgica de OrganocalcogÞnios, Universidade Federal de Santa Maria Santa Maria, Rio Grande do Sul, 97105-900 (Brazil) E-mail: [email protected] [b] Prof. Dr. D. F. Back Departamento de Qumica Inorgnica Laboratrio de Materiais Inorgnicos, Universidade Federal de Santa Maria Santa Maria, Rio Grande do Sul, 97105-900 (Brazil) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201403873. Chem. Eur. J. 2014, 20, 1 – 7
These are not the final page numbers! ÞÞ
Scheme 1. General reaction scheme for the synthesis of five- and six-membered heterocycles with two nitrogen atoms.
1
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
Full Paper Table 1. Effect of different reaction parameters on the preparation of pyridazinone 4 a.[a]
Figure 1. ORTEP view of compound 4 e. Ellipsoids are drawn at the 50 % probability level.
though under these conditions pyridazinone 4 a was obtained in low yield, neither a five-membered heterocyclic ring nor a regioisomeric mixture was formed. After these results, we concentrated our study in investigating different reaction parameters to improve the yield (Table 1). For instance, the use of a stoichiometric amount of CuI failed to give pyridazinone 4 a (Table 1, entry 1). A minor increase in yield was observed when CuI (1 equiv) was used in association with K2CO3 as a base and increasing the reaction temperature to 80 8C (Table 1, entry 2). In contrast, the yield significantly increased to 72 % when Cs2CO3 was used as base (Table 1, entry 3). Other bases proved to be less efficient than Cs2CO3 or no reaction occurred with Et3N (Table 1, entries 4–7). Increasing the amount of either CuI or Cs2CO3 led to a lower yield of 4 a (Table 1, entries 8–10). The use of other copper salts, such as CuCl and CuBr, did not further improve the yield of 4 a, and no reaction occurred when CuBr2 was used (Table 1, entries 11–13). To make the present cyclization more economical and environmentally attractive, we examined the catalytic activity of CuI. Variation in the catalyst amount from 50 to 10 mol % did not show any improvement in the yields of 4 a, even when using additives or changing the catalyst (Table 1, entries 14– 22). In copper-catalyzed reactions, the use of chelating ligands has a substantial effect and often leads to improved reactivity.[8] From this point of view, the reaction of 5 (0.25 mmol), 3 a (0.25 mmol), CuI (0.05 mmol), Cs2CO3 (0.25 mmol), and MeCN (3 mL) was examined with in presence of ligands L1–L7 (0.1 mmol), which are shown in Figure 2. Of these ligands, 1,10-phenanthroline (L4) was the most effective, and gave product 4 a in 94 % yield. Finally, we turned our attention to applying these conditions to a multicomponent reaction. Thus, when aldehyde 1 a (0.25 mmol), hydrazine 2 a (0.25 mmol), and alkynylester 3 a (0.25 mmol) were treated with CuI (0.05 mmol), L4 (0.1 mmol), and Cs2CO3 (0.25 mmol) in MeCN (3 mL) under &
&
Chem. Eur. J. 2014, 20, 1 – 7
www.chemeurj.org
Entry
Copper salt ([equiv])
Base ([equiv])
Yield[b] [%]
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17[c] 18[d] 19[e] 20[f] 21[g] 22
CuI (1) CuI (1) CuI (1) CuI (1) CuI (1) CuI (1) CuI (1) CuI (1.5) CuI (1) CuI (1) CuCl (1) CuBr (1) CuBr2 (1) CuI (0.5) CuI (0.2) CuI (0.1) CuI (0.2) CuI (0.2) CuI (0.2) CuI (0.2) CuI (0.2) [AuCl(PPh3)]
– K2CO3 (1) Cs2CO3 (1) KOH (1) NaHCO3 (1) Et3N (1) DBU (1) Cs2CO3 (1) Cs2CO3 (1.5) Cs2CO3 (2) Cs2CO3 (1) Cs2CO3 (1) Cs2CO3 (1) Cs2CO3 (1) Cs2CO3 (1) Cs2CO3 (1) Cs2CO3 (1) Cs2CO3 (1) Cs2CO3 (1) Cs2CO3 (1) Cs2CO3 (1) Cs2CO3 (1)
– 49 72 30 15 0 19 15 53 42 38 27 0 60 59 57 9 49 13 9 11 0
[a] The reaction was performed in the presence of 5 (0.25 mmol), 3 a (0.25 mmol), CuI, and MeCN (3 mL), under an argon atmosphere at 80 8C for 16 h. DBU = 1,5-diazabicyclo[5.4.0]undec-5-ene. [b] Yields were determined by GC analysis. [c] An oxygen atmosphere (balloon) was used. [d] nBu4NI (0.25 mmol) was used as an additive. [e] Silver triflate (AgOTf; 0.25 mmol) was used as an additive. [f] ZnCl2 (0.25 mmol) was used as an additive. [g] KI (0.25 mmol) was used as an additive.
an argon atmosphere at 80 8C, pyridazinone 4 a was obtained in 64 % yield. In a similar way, this optimized procedure was then applied to different aldehydes 1, hydrazines 2, and alkynylesters 3; the results are listed in Table 2. The results show that pyridazinones 4 a–e were obtained in good yield, regardless of the substituents (electron-withdrawing or -donating groups) present on the aromatic ring of the aldehydes. When this cyclization was carried out with 4-nitro-benzaldehyde, product 4 g was not stable enough to be purified and characterized. The reactivity of aryl alkynylester 3 under the previously optimized reaction conditions was also investigated. Because aryl alkynylesters 3 substituted with both electron-withdrawing and -donating groups allowed the formation of pyridazinones 4 h–r in variable yields (from 40 to 85 %), the relationship between these two variables, substituents and yields, indicates a weak correlation. When we tried to extend the optimized conditions to an alkynylester, with an alkyl chain directly bonded to the triple bond, product 4 s was not detected at all. Next, the multicomponent reaction, with two different hydrazines, was examined for the preparation of pyridazinones 4 s–v. The opti2
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!
Full Paper Table 2. Synthesis of pyridazinone 4.[a,b]
Figure 2. Studies of the effect of ligands L1–L7 on the reaction.
mized conditions were efficient for hydrazines with a methyl group and chloro atom, which gave the corresponding pyridazinones in moderate to good yields. However, the use of unsubstituted or aliphatic hydrazines did not give the product, even when subjected to harsh reaction conditions. In this case, the absence of p bonds in the alkyl chain could result in a decreased reactivity for nucleophilic attack on the carbon–carbon triple bond. When we investigated the formation of pyridazinone 4 a, we observed that the ethoxyl group, from alkynylester 3, was not incorporated into the structure; this indicated that it could be released into the reaction medium. Thus, we speculate that this ethoxyl group should be a suitable internal nucleophile to promote the in situ Ullmann coupling. It has been well documented that copper(I) iodide, L4, and cesium carbonate are good reaction partners to promote the coupling of aryl halides and aliphatic alcohols.[9] Therefore, we applied exactly the same reaction conditions as those used in the preparation of pyridazinone 4 (Table 1) to the reaction of hydrazines, alkynylesters, and 2-halobenzaldehydes. The sequential Michael addition/1,2-cyclization addition/Ullmann cross-coupling reactions proceeded smoothly to give pyridazinones 6 a–c in good yields (Scheme 2). After these experimental results, we assumed that, when 2-halobenzaldehydes are used, the oxidative addition of copper iodide to the carbon–halogen bond occurs after pyridazinone ring formation supported by the interaction of copper with the nitrogen atom from the pyridazinone ring. This assumption can be further supported by the fact that the Ullmann coupling did not occur with 4-halobenzaldehyde derivatives. To investigate the role of the CuI catalyst, we carried out the reaction of aldehyde 1 a, hydrazine 2 a, and alkynylester 3 a under the optimized conditions in the absence of CuI. This reaction gave the aza-Michael addition adduct 7 as the sole product (Scheme 3).[10] In addition, when the reaction was performed with phenylhydrazone 5 (Table 1), pyridazinones 4 Chem. Eur. J. 2014, 20, 1 – 7
www.chemeurj.org
These are not the final page numbers! ÞÞ
[a] The reaction was performed in the presence of aldehyde 1 (0.25 mmol), hydrazine 2 (0.25 mmol), alkynylester 3 (0.25 mmol), CuI (0.05 mmol), L4 (0.1 mmol), Cs2CO3 (0.25 mmol), and MeCN (3 mL), under an argon atmosphere at 80 8C for 16 h. [b] Yield of product isolated after column chromatography. [c] The product of Ullmann coupling was obtained in 39 % yield. [d] The reaction was carried out by using 0.5 mmol of Cs2CO3.
were obtained in good yields. It seems clear that phenylhydrazone 5 is a possible intermediate in the multicomponent process. Based on these results, we propose that the cyclization 3
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
Full Paper Conclusion We have described a one-pot, three-component intermolecular cyclization involving aldehydes, hydrazines, and alkynylesters. This process provided efficient access to substituted pyridazinones in good to excellent yields. Application of the present methodology in the preparation of the Ullmann product was also investigated. The optimization reactions showed that the yields of the cyclization reaction were highly dependent on the presence and nature of the base and ligand; the best results were obtained when Cs2CO3 was used as the base and L4 was used as the ligand. The use of L4 in association with CuI avoided the use of equimolar amounts of copper salt and the use of a multicomponent reaction became the method with good atom economy. Carbon nucleophile addition to a Michael acceptor, promoted by the copper salt, instead of nitrogen addition was the main factor to prevent the formation of undesired azole derivatives, giving exclusively pyridazinones.
Scheme 2. Preparation of pyridazinones 6 a–c.
involves the initial formation of hydrazone 5 from the reaction of aldehydes 1 and hydrazines 2 (Scheme 3). Deprotonation of NH from hydrazones 5 gives, after resonance, intermediate a.[11] Intermediate a reacts with CuI to form cuprate b. The Michael addition of b into the carbon–carbon triple bond of the alkynylester[10] gives adduct c’, which after isomerization gives c.[12] Michael addition via a trans-copper adduct is in accordance with the known ability of organocopper reagents to undergo p complexation with a carbon–carbon triple bond and with a carbonyl group. The intramolecular 1,2-addition of nitrogen to the ester carbonyl functionality gives d, which delivers pyridazinone 4 (Scheme 3). Although intermediates c/c’ proposed in the mechanism could not be isolated, we tried to trap these intermediates with electrophiles. However, the addition of primary alkyl halides, a,b-unsaturated carbonyl compounds, and allyl bromide, or quenched with proton sources, did not allow any trapping products and gave only pyridazinone 4 as the product.
Experimental Section General procedure for copper-catalyzed tandem three-component reaction of aldehyde, arylhydrazine, and alkynylester Aldehyde (0.25 mmol), arylhydrazine (0.25 mmol), alkynylester (0.25 mmol), CuI (0.05 mmol), and L4 (0.1 mmol) in MeCN (3 mL) were added to a two-necked round-bottomed flask equipped with a reflux condenser, under an argon atmosphere. The reaction mixture was stirred for the indicated time at 80 8C. The mixture was filtered through silica gel with ethyl acetate and concentrated under vacuum. The residue was purified by flash chromatography (hexane/ethyl acetate = 20:1).
2,5,6-Triphenylpyridazin-3(2H)-one (4 a) Pale-white solid; yield: 0.049 g, 61 %; m.p. 250–252 8C; 1H NMR (CDCl3, 400 MHz): d = 7.74 (d, J = 7.3 Hz, 2 H), 7.48 (t, J = 7.6 Hz, 2 H), 7.40–7.22 (m, 9 H), 7.17–7.14 (m, 2 H), 7.07 ppm (s, 1 H); 13C NMR (CDCl3, 100 MHz): d = 159.6, 146.5, 145.5, 141.4, 135.7, 135.2, 130.0, 129.2, 129.0, 128.7, 128.6, 128.4, 128.1, 128.0, 125.3 ppm; MS (EI, 70 eV): m/z (%): 324 (100), 296 (31), 191 (92), 189 (44), 165 (39), 105 (20), 77 (86); HRMS (ESI): m/z calcd for C22H16N2O + H: 325.1341 [M + H] + ; found: 325.1345.
2,5-Diphenyl-6-(p-tolyl)pyridazin-3(2H)-one (4 b) Yellow oil; yield: 0.056 g, 66 %; 1H NMR (CDCl3, 200 MHz): d = 7.74 (d, J = 7.0 Hz, 2 H), 7.52–7.24 (m, 6 H), 7.24–7.01 (m, 7 H), 2.30 ppm (s, 3 H); 13C NMR (CDCl3, 100 MHz): d = 159.6, 146.5, 145.5, 141.4, 138.6, 135.8, 132.2, 130.0, 129.1, 128.9, 128.7, 128.6, 128.4, 128.0, 125.3, 21.1 ppm; MS (EI, 70 eV): m/z (%): 338 (100), 323 (14), 205 (85), 164 (12), 77 (45); HRMS (ESI): m/z calcd for C22H16N2O + H: 339.1497 [M + H] + ; found: 339.1497.
6-(2-Chlorophenyl)-5-(2,5-dimethoxyphenyl)-2-phenylpyridazin-3(2H)-one (4 l) Orange oil; yield: 0.042 g, 40 %; 1H NMR (CDCl3, 400 MHz): d = 7.75– 7.72 (m, 2 H), 7.48 (t, J = 7.5 Hz, 2 H), 7.38 48 (t, J = 7.3 Hz, 1 H), 7.17 (s, 4 H), 7.03 (s, 1 H), 6.91 (dd, J = 3.1 Hz, J = 5.8 Hz, 1 H), 6.85 (d, J =
Scheme 3. Proposed mechanism for the preparation of 4 through the multicomponent reaction.
&
&
Chem. Eur. J. 2014, 20, 1 – 7
www.chemeurj.org
4
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!
Full Paper 2.1 Hz, 1 H), 6.65 (d, J = 9.0 Hz, 1 H), 3.78 (s, 3 H), 3.25 ppm (s, 3 H); 13 C NMR (CDCl3, 100 MHz): d = 159.5, 153.8, 149.7, 146.2, 143.1, 141.4, 134.8, 134.3, 130.8, 129.2, 128.6, 128.0, 127.8, 125.2, 115.8, 115.6, 112.3, 55.7, 55.2 ppm; MS (EI, 70 eV): m/z (%): 418 (100), 387 (50), 375 (15), 285 (35), 162 (14), 147 (10), 77 (57); HRMS (ESI): m/z calcd for C24H19ClN2O3 + H: 419.1162 [M + H] + ; found: 419.1168.
(m, 1 H), 4.09 (q, J = 7.2 Hz, 2 H), 1.14 ppm (t, J = 7.0 Hz, 3 H); C NMR (CDCl3, 100 MHz): d = 166.0, 148.0, 145.1, 140.2, 139.6, 137.7, 129.4, 129.1, 128.4, 127.9, 127.1, 126.9, 124.0, 123.1, 122.1, 121.8, 118.1, 110.6, 59.9, 13.9 ppm; MS (EI, 70 eV): m/z (%): 368 (88), 323 (33), 296 (100), 293 (11), 165 (11), 77 (12); MS (EI, 70 eV): m/z (%): 414 (100), 383 (65), 308 (56), 281 (46), 251 (46), 163 (10), 132 (22), 121 (21), 77 (38); HRMS (ESI): m/z calcd for C24H20N2O2 + H: 369.1603 [M + H] + ; found: 369.1609.
13
5-(2,5-Dimethoxyphenyl)-2-phenyl-6-p-tolylpyridazin-3(2H)one (4 o)
6-(2-Ethoxyphenyl)-5-(4-methoxyphenyl)-2-phenylpyridazin3(2H)-one (6 c)
Yellow solid; yield: 0.062 g, 62 %; m.p. 164–166 8C; 1H NMR (CDCl3, 400 MHz): d = 7.75 (d, J = 7.6 Hz, 2 H), 7.46 (t, J = 7.8, 2 H), 7.36 (t, J = 7.3, 1 H), 7.12 (d, J = 8.1 Hz, 2 H), 7.03 (s, 1 H), 6.99 (d, J = 7.8 Hz, 2 H), 6.87 (dd, J = 9.0 Hz, 1 H), 6.83 (d, J = 2.9 Hz, 1 H), 6.65 (d, J = 9.0 Hz, 1 H), 3.76 (s, 1 H), 3.23 (s, 1 H), 2.27 ppm (s, 1 H); 13C NMR (CDCl3, 100 MHz): d = 159.6, 153.7, 150.0, 147.4, 143.5, 141.6, 138.1, 133.4, 130.7, 128.6, 128.2, 127.8, 125.9, 125.3, 115.6, 115.5, 112.3, 55.7, 55.3, 21.0 ppm; MS (EI, 70 eV): m/z (%): 398 (100), 367 (50), 265 (33), 206 (22); HRMS (ESI): m/z calcd for C25H22N2O3 + H: 399.1709 [M + H] + ; found: 369.1719.
Dark-orange oil; yield: 0.054 g, 54 %; 1H NMR (CDCl3, 200 MHz): d = 7.71 (t, J = 7.2 Hz, 3 H), 7.52 (t, J = 7.8 Hz, 2 H), 7.39–7.23 (m, 4 H), 7.06–6.8 (m, 4 H), 4.12 (q, J = 7.0 Hz, 2 H), 3.85 (s, 3 H), 1.19 ppm (t, J = 7.2 Hz, 3 H); 13C NMR (CDCl3, 100 MHz): d = 166.0, 159.9, 147.6, 145.7, 140.2, 139.6, 130.8, 129.7, 129.3, 127.0, 126.9, 124.1, 123.0, 122.0, 121.9, 117.7, 113.3, 110.5, 59.9, 55.1, 14.0 ppm; MS (EI, 70 eV): m/z (%): 398 (65), 353 (28), 326 (100), 282 (21), 192 (13), 135 (26), 77 (33); HRMS (ESI): m/z calcd for C25H22N2O3 + H: 399.1709 [M + H] + ; found: 399.1700.
6-(4-Chlorophenyl)-2-(2,5-dimethylphenyl)-5-(4-methoxyphenyl)pyridazin-3(2H)-one (4 t)
X-ray crystallography
White solid; yield: 0.056 g, 54 %; m.p. 218–219 8C; 1H NMR (CDCl3, 400 MHz): d = 7.24–7.15 (m, 7 H), 7.08 (d, J = 8.8 Hz, 2 H), 7.03 (s, 1 H), 6.84 (d, J = 8.8 Hz, 2 H), 3.81 (s, 3 H), 2.35 (s, 3 H), 2.21 ppm (s, 3 H); 13C NMR (CDCl3, 100 MHz): d = 160.4, 159.6, 145.3, 145.2, 140.2, 136.6, 134.7, 133.9, 131.5, 130.8, 130.6, 130.1, 130.0, 129.0, 128.2, 127.6, 127.5, 114.1, 55.2, 20.7, 17.2 ppm; MS (EI, 70 eV): m/z (%): 416 (44), 399 (100), 305 (13), 255 (25), 212 (33), 176 (80), 151 (29), 105 (72), 77 (73); HRMS (ESI): m/z calcd for C25H21ClN2O2 + H: 417.1370 [M + H] + ; found: 417.1375.
CCDC-974780 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/ data_request/cif.
Acknowledgements We are grateful to FAPERGS, CAPES, and CNPq (CNPq/INCT-catalise) for financial support. CNPq is also acknowledged for fellowships (G.Z., A.C.M., and T.A.C.G.). We thank the LMI-UFSM for support of X-ray crystallography results.
General procedure for copper-catalyzed tandem three-component reaction of aldehyde, arylhydrazine, and alkynylester and consecutive Ullmann coupling Aldehyde (0.25 mmol), arylhydrazine (0.25 mmol), alkynylester (0.25 mmol), CuI (0.05 mmol), and L4 (0.1 mmol) in MeCN (3 mL) were added to a two-necked round-bottomed flask equipped with a reflux condenser, under an argon atmosphere. The reaction mixture was stirred for the desired time at 80 8C. The mixture was filtered through silica gel with ethyl acetate and concentrated under vacuum. The residue was purified by flash chromatography (hexane/ethyl acetate = 20:1).
Keywords: copper · cyclization · heterocycles · homogeneous catalysis · multicomponent reactions [1] T. D. Heightman, A. T. Vasella, Angew. Chem. 1999, 111, 794; Angew. Chem. Int. Ed. 1999, 38, 750. [2] a) Y. L. Janin, Chem. Rev. 2012, 112, 3924; b) S. Fustero, M. Snchez-Rosell, P. Barrio, A. Simn-Fuentes, Chem. Rev. 2011, 111, 6984; c) O. A. Attanasi, P. Filippone, Synlett 1997, 1128. [3] a) S. G. Lee, J. J. Kim, D. H. Kweon, Y. J. Kang, S. D. Cho, S. K. Kim, Y. J. Yoon, Curr. Med. Chem. 2004, 11, 1461; b) P. J. Matyus, Het. Chem. 1998, 35, 1075. [4] a) P. Wipf, Z. Fang, L. Ferrie, M. Ueda, M. A. A. Walczak, Y. Yan, Pure Appl. Chem. 2013, 85, 1079; b) G. S. Singh, Z. Y. Desta, Chem. Rev. 2012, 112, 6104; c) R. Dalpozzo, G. Bartolib, G. Bencivennib, Chem. Soc. Rev. 2012, 41, 7247; d) S. Werner, S. D. Nielsen, P. Wipf, D. M. Turner, P. G. Chambers, S. J. Geib, D. P. Curran, W. J. Zhang, J. Comb. Chem. 2009, 11, 452; e) P. Wipf, C. R. J. Stephenson, Org. Lett. 2005, 7, 1137. [5] P. Liu, Y. Pan, Y. Xu, H. Wang, Org. Biomol. Chem. 2012, 10, 4696. [6] a) S. Safaei, I. Mohammadpoor-Baltork, A. R. Khosropour, M. Moghadam, S. Tangestaninejad, V. Mirkhani, New J. Chem. 2013, 37, 2037; b) X.-C. Tu, H. Feng, M.-S. Tu, B. Jiang, S.-L. Wang, S.-J. Tu, Tetrahedron Lett. 2012, 53, 3169; c) S. Safaei, I. Mohammadpoor-Baltork, A. R. Khosropour, M. Moghadam, S. Tangestaninejad, V. Mirkhani, Adv. Synth. Catal. 2012, 354, 3095; d) S. A. Raw, A. T. Turner, Tetrahedron Lett. 2009, 50, 696. [7] B. C. Hamper, M. L. Kurtzweil, J. P. Beck, J. Org. Chem. 1992, 57, 5680. [8] a) D. S. Surry, S. L. Buchwald, Chem. Sci. 2010, 1, 13; b) A. Klapars, J. C. Antilla, X. Huang, S. L. Buchwald, J. Am. Chem. Soc. 2001, 123, 7727.
5-(2,5-Dimethoxyphenyl)-6-(2-ethoxyphenyl)-2-phenylpyridazin-3(2H)-one (6 a) Dark-orange oil; yield: 0.042 g, 39 %; 1H NMR (CDCl3, 400 MHz): d = 7.72 (d, J = 8.0 Hz, 2 H), 7.68 (d, J = 8.5 Hz, 1 H), 7.51 (t, J = 7.5 Hz, 2 H), 7.39–7.29 (m, 2 H), 7.12 (s, 1 H), 7.03–6.84 (m, 5 H), 4.09 (q, J = 7.9 Hz, 2 H), 3.74 (s, 3 H), 3.65 (s, 3 H), 1.14 ppm (t, J = 7.2 Hz, 3 H); 13 C NMR (CDCl3, 100 MHz): d = 165.8, 153.5, 151.4, 144.6, 144.1, 140.3, 139.8, 129.4, 128.2, 127.0, 126.8, 123.9, 123.1, 122.1, 121.6, 119.2, 116.0, 114.6, 112.5, 110.6, 59.8, 56.6, 55.7, 14.0 ppm; HRMS (ESI): m/z calcd for C26H24N2O4 + H: 429.1814 [M + H] + ; found: 429.1819.
6-(2-Ethoxyphenyl)-2,5-diphenylpyridazin-3(2H)-one (6 b) Dark-orange oil; yield: 0.069 g, 75 %; 1H NMR (CDCl3, 200 MHz): d = 7.72 (t, J = 7.7 Hz, 3 H), 7.57–7.24 (m, 9 H), 7.04–6.97 (m, 2 H), 6.76 Chem. Eur. J. 2014, 20, 1 – 7
www.chemeurj.org
These are not the final page numbers! ÞÞ
5
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
Full Paper [9] a) G. E. Job, S. L. Buchwald, Org. Lett. 2002, 4, 3703; b) M. Wolter, G. Nordmann, G. E. Job, S. L. Buchwald, Org. Lett. 2002, 4, 973. [10] Z. Yuan, Y. Wei, M. Shi, Eur. J. Org. Chem. 2010, 4088. [11] X. Deng, N. S. Mani, Org. Lett. 2008, 10, 1307. [12] a) A. Alexakis, K. Croset, Org. Lett. 2002, 4, 4147; b) M. van Klaveren, E. S. M. Persson, A. Del Villar, D. M. Grove, J.-E. Bckvall, G. van Koten,
&
&
Chem. Eur. J. 2014, 20, 1 – 7
www.chemeurj.org
Tetrahedron Lett. 1995, 36, 3059; c) T. Saegusa, I. Murase, Y. Ito, Tetrahedron 1971, 27, 3795.
Received: June 8, 2014 Published online on && &&, 0000
6
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!
Full Paper
FULL PAPER & Homogeneous Catalysis A. C. Mantovani, T. A. C. Goulart, D. F. Back, G. Zeni* && – &&
All in! A copper-catalyzed multicomponent cyclization reaction, which combined aldehydes, hydrazines, and alkynylesters, was applied to the synthesis of pyridazinones (see scheme). The reac-
Chem. Eur. J. 2014, 20, 1 – 7
tion was regioselective to give only sixmembered pyridazinones in the complete absence of five-membered pyrazoles or a regioisomeric mixture.
www.chemeurj.org
These are not the final page numbers! ÞÞ
7
Synthesis of Pyridazinones through the Copper(I)-Catalyzed Multicomponent Reaction of Aldehydes, Hydrazines, and Alkynylesters
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
