Copper-catalyzed oxidative cyclization of arylamides and β-diketones: new synthesis of 2,4,5-trisubstituted oxazoles

Abstract

A novel copper catalyzed approach to oxazoles via enamide intermediates was developed from benzamides and β-diketones. The successive condensation and cyclization reactions afforded various 2,4,5-trisubstituted oxazoles in good yields.

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Substituted oxazoles are an important class of heterocycles that are ubiquitous in biologically active molecules, including natural products, agrochemicals and pharmaceutical drugs.¹ A large number of oxazole-containing natural products have been isolated from marine invertebrates and microorganisms.² Moreover, many synthetic trisubstituted oxazoles have been evaluated to show activity against diabetes, breast cancer and pancreatic cancer (Fig. 1).³ Consequently, great effort has been paid on the development of efficient synthetic methods to access substituted oxazoles, and most of the existed methods are using ketone derivatives as the starting materials.⁴ Traditionally, a range of highly substituted and complex oxazoles are prepared via cyclodehydration of α-acylaminoketones, esters, or amides (the Robinson–Gabriel oxazole synthesis).⁵ Nevertheless, this method requires the use of highly functionalized diketone substrates (Scheme 1a). Additionally, catalytic decomposition of α-diazocarbonyl compounds in nitriles,⁶ photolysis and pyrolysis of N-acylisoozalones⁷ can provide alternative procedures for the preparation of functionalized oxazole derivatives. Transition metals such as copper,⁸ rhodium,⁹ ruthenium¹⁰ and gold¹¹ are successfully used as the cyclization catalysts to afford various substituted oxazoles.

Fig. 1 Selected oxazole-containing drugs.

Scheme 1 Various procedures for multi-substituted oxazole synthesis.

In recent years, enamides bearing β-vinylic C-heteroatom bonds are proved to be versatile cyclization precursors to construct the oxazole ring (Scheme 1b).¹² The groups of Buchwald and Stahl reported copper-mediated oxidative cyclization of enamides to 2,5-disubstituted oxazoles via vinylic C–H functionalization.¹³ This method provided a more direct approach to substituted oxazoles by avoiding the substrate functionalization. However, some highly functionalized enamide precursors require several steps to prepare. Therefore, the in situ formation of enamides from readily available starting materials such as β-diketones is highly desirable for one pot construction of oxazoles. There are only few reports on multi-substituted oxazole synthesis from β-diketones and arylamides or benzyl amines.¹⁴ Moreover, a leaving group need to be introduced into the α-position of β-diketones. Efficient method to prepare multi-substituted oxazoles in one pot from β-diketones without leaving substituents is highly desirable. Herein, we report an efficient copper-catalyzed oxidative cyclization strategy from readily available benzamides and β-diketones (via enamide intermediate), providing the 2,4,5-trisubstituted oxazoles in good yields (Scheme 1c).¹⁵ In the whole process, the acyl functional group is retained and located selectively at the ortho position of the oxygen atom.¹⁶

In the first experiment we examined the reaction between benzamide (1a) and pentane-2,4-dione (2a) in toluene using molecular oxygen as the oxidant. As shown in Table 1, four different copper salts were screened using p-toluenesulfonic acid (TsOH) as the acidic additive. Among the catalysts investigated, CuBr showed the best efficiency (entries 1–4). Various oxidants were investigated instead of oxygen using CuBr as the catalyst (entries 5–8). Among the various oxidants screened, K₂S₂O₈ showed the best activity and its use improved the reaction yield to 24% (entry 7). The choice of acidic additive is very important, and the product 3a could be obtained in 46% yield when acetic acid was used (entry 10). Slightly higher yield was obtained when the reaction was carried out in Cl₂CHCHCl₂ (entry 14). The reaction yield increased from 51% to 64% when the ratio of 1a : 2a changed to 2 : 1 (entry 15). The desired product could be obtained in 82% yield when the reaction temperature increased from 120 °C to 140 °C (entry 16). Compared with CuBr₂, CuBr showed better efficiency (entries 16 and 17).

Table 1 Optimization of the reaction conditions^a

Entry	Catalyst	Oxidant	Additive	Solvent	Yield^b [%]
a Conditions: 1a (0.2 mmol), 2a (0.3 mmol), catalyst (20 mol%), oxidant (2.0 equiv.), additive (2.0 equiv.), solvent (0.4 mL), 120 °C, 36 h under argon (under oxygen for entries 1–4).b GC yield based on 1a.c 1a (0.4 mmol), 2a (0.2 mmol), yield based on 2a.d At 140 °C.
1	Cu(OAc)2	O2	TsOH	Toluene	8
2	CuSO4	O2	TsOH	Toluene	7
3	CuBr2	O2	TsOH	Toluene	11
4	CuBr	O2	TsOH	Toluene	12
5	CuBr	DDQ	TsOH	Toluene	Trace
6	CuBr	TBHP	TsOH	Toluene	5
7	CuBr	K2S2O8	TsOH	Toluene	24
8	CuBr	Dess–Martin	TsOH	Toluene	7
9	CuBr	K2S2O8	CF3COOH	Toluene	11
10	CuBr	K2S2O8	CH3COOH	Toluene	46
11	CuBr	K2S2O8	PivOH	Toluene	32
12	CuBr	K2S2O8	CH3COOH	DMF	10
13	CuBr	K2S2O8	CH3COOH	1,4-Dioxane	44
14	CuBr	K2S2O8	CH3COOH	Cl2CHCHCl2	51
15^c	CuBr	K2S2O8	CH3COOH	Cl2CHCHCl2	64
16^c^,^d	CuBr	K2S2O8	CH3COOH	Cl2CHCHCl2	82
17^c^,^d	CuBr2	K2S2O8	CH3COOH	Cl2CHCHCl2	70

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The scope of this reaction was studied under the optimized conditions (Table 2). Arylamides with electron-donating group at the para position smoothly coupled with pentane-2,4-dione (2a) to give the heterocyclic products in high yields (entries 1–4). When halogen substituents presented at the para position of amides, the corresponding products were obtained in fairly good yields (entries 5–7). For example, 68% yield of 3g which could be converted to other useful compounds easily was obtained when an active bromo substituent existed. Strong electron-withdrawing substituent significantly decreased the reaction yield. For example, when 4-nitrobenzamide (1h) was used in the reaction, the desired product 3h was observed in only 38% yield (entry 8). Similar yield was observed when the methyl substituent shifted from para to meta position (entries 2 and 9).

Table 2 Reaction of pentane-2,4-dione (2a) with various aromatic amides^a

Entry	Arylamides		Product	Yield^b [%]
a Conditions: 1 (0.4 mmol), 2a (0.2 mmol), CuBr (20 mol%), K2S2O8 (0.4 mmol), AcOH (0.4 mmol), Cl2CHCHCl2 (0.4 mL), 140 °C, 36 h under argon.b Isolated yield based on 2a.
1	R^1 = H	1a	3a	83
2	R^1 = CH3	1b	3b	81
3	R^1 = OCH3	1c	3c	82
4	R^1 = tert-butyl	1d	3d	84
5	R^1 = F	1e	3e	75
6	R^1 = Cl	1f	3f	70
7	R^1 = Br	1g	3g	68
8	R^1 = NO2	1h	3h	38
9		1i	3i	80

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The scope of the reaction with β-diketones is outlined in Table 3. 1,3-Diphenylpropane-1,3-dione (2b) reacted with benzamide to give (2,4-diphenyloxazol-5-yl)(phenyl)methanone (3j) in 81% yield (entry 1). Besides symmetrical β-diketones, various unsymmetrical β-diketones were also employed in the oxidative cyclization reaction, providing the corresponding products in moderate to good yields (entries 2–9). For regioselectivity of the unsymmetrical β-diketones, the steric hindrance is a key factor. In all cases, 5-acyl substituted oxazoles were the major products. When 1-(naphthalen-1-yl)butane-1,3-dione (2h) was used, the 5-acyl substituted oxazole 3p was obtained almost as the sole product (entry 7). Furthermore, extension of this reaction to heteroaryl β-diketones proved to be successful (entry 8). It is important to point out that changing the substituting position on the aromatic ring of 1-phenylbutane-1,3-dione (2c) greatly influenced the reaction yields of the corresponding products (entries 6 and 9). Unfortunately, no desired product was observed when β-diketone was replaced by ethyl acetoacetate.

Table 3 Reactions of 1a with various β-diketones^a

Entry	Ketone	Product	Yield^b [%]
a Conditions: 1a (0.4 mmol), 2 (0.2 mmol), CuBr (20 mol%), K2S2O8 (2.0 equiv.), AcOH (2.0 equiv.), Cl2CHCHCl2 (0.4 mL), 140 °C, 36 h under argon.b Isolated yield based on 2.c 48 h.
1^c	2b: R^2 = R^3 = Ph	3j	81
2	2c: R^2 = Ph, R^3 = CH3	3k : 3k′ (3 : 1)	82
3	2d: R^2 = 4-Me–C6H5, R^3 = CH3	3l : 3l′ (4 : 1)	81
4	2e: R^2 = 4-MeO–C6H5, R^3 = CH3	3m : 3m′ (4 : 1)	76
5	2f: R^2 = 4-F–C6H5, R^3 = CH3	3n : 3n′ (3 : 1)	66
6	2g: R^2 = 4-Cl–C6H5, R^3 = CH3	3o : 3o′ (4 : 1)	73
7	2h: R^2 = 1-naphthyl, R^3 = CH3	3p : 3p′ (80 : 1)	75
8	2i: R^2 = 2-thienyl, R^3 = CH3	3q : 3q′ (8 : 1)	77
9	2j: R^2 = 2-Cl–C6H5, R^3 = CH3	3r : 3r′ (4 : 1)	50

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A series of control experiments were designed to investigate the reaction mechanism (Scheme 2). When the reaction of 1a with 2a was stopped after 2 h, 4a and 3a were obtained in 8% and 9% yields, respectively (Scheme 2a). The starting materials could be smoothly converted into the desired product 3a with extension of time whereas no significant change was observed for intermediate 4a (Scheme 2b). The isolated 4a could be further transformed into 3a in 80% yield under the standard reaction conditions (Scheme 2c). These results suggested that enamide might be the key intermediate during the formation of oxazoles. Only trace amounts of 3a and 4a were observed when two equiv. of TEMPO was added to the reaction mixture (Scheme 2d). This means that a radical process was possibly involved in this transformation. Based on these competition experiments and related literatures,¹³ a possible mechanism to illustrate this reaction is presented in Scheme 3. Condensation of 1a with 2a yields an enamide intermediate 4a which can be further converted into a radical cation A in the presence of Cu(II), and Cu(I) is released and oxidized into Cu(II). The cyclization of A generates intermediate B. Subsequent oxidation of the intermediate B by Cu(II) provides the product 3a and releases Cu(I) which can be re-oxidized to participate the next catalytic cycle.

Scheme 2 Control experiments.

Scheme 3 Proposed mechanism.

Conclusions

In conclusion, we have developed a novel approach for the synthesis of oxazoles using CuBr as the catalyst. Readily available β-diketones and primary arylamides were used as the starting materials. 5-Acyl substituted oxazoles were obtained as the sole products in all cases. Halogen substituted benzamides also could be employed for this kind of transformation. This strategy affords an efficient approach for the synthesis of biologically active oxazoles with acyl substituents from readily available starting materials with cheap and low toxic copper catalyst. The generality and synthetic applications of this methodology are under investigation.

Acknowledgements

This work was supported by the National Natural Science Foundation of China (21172185, 21372187), the Hunan Provincial Innovative Foundation for Postgraduate (CX2014B258), the New Century Excellent Talents in University from Ministry of Education of China (NCET-11-0974) and the Research Fund for the Doctoral Program of Higher Education of China, Ministry of Education of China (20124301110005).

Notes and references

1. (a) D. C. Palmer and E. C. Taylor, The Chemistry of Heterocyclic Compounds. Oxazoles: Synthesis, Reactions, and Spectroscopy, Parts A & B, Wiley, New Jersey, 2004, vol. 60; (b) I. J. Turchi, Ind. Eng. Chem. Prod. Res. Dev., 1981, 20, 32; (c) I. J. Turchi and M. J. S. Dewar, Chem. Rev., 1975, 75, 389; (d) J. Zhang and M. A. Ciufolini, Org. Lett., 2011, 13, 390; (e) B. Wang, T. M. Hansen, L. Weyer, D. Wu, T. Wang, M. Christmann, Y. Lu, L. Ying, M. M. Engler, R. D. Cink, C. S. Lee, F. Ahmed and C. J. Forsyth, J. Am. Chem. Soc., 2011, 133, 1506.
2. (a) N. Lindquist, W. Fenical, G. D. Van Duyne and J. Clardy, J. Am. Chem. Soc., 1991, 113, 2303; (b) Z. Cruz-Monserrate, H. C. Vervoort, R. L. Bai, D. Newman, S. B. Howell, G. Los, J. T. Mullaney, M. D. Williams, G. R. Pettit, W. Fenical and E. Hamel, Mol. Pharmacol., 2003, 63, 1273; (c) J. Kobayashi, M. Tsuda, H. Fuse, T. Sasaki and Y. Mikami, J. Nat. Prod., 1997, 60, 150; (d) For selected examples on natural products synthesis containing 2,4-disubsituted oxazole moiety, see: J. Li, S. Jeong, L. Esser and P. G. Harran, Angew. Chem., Int. Ed., 2001, 40, 4765; (e) K. C. Nicolaou, D. Y. K. Chen, X. Huan, T. Ling, M. Bella and S. A. Snyder, J. Am. Chem. Soc., 2004, 126, 12888; (f) J. R. Davis, P. D. Kane and C. J. Moody, J. Org. Chem., 2005, 70, 7305.
3. (a) Y. Momose, T. Maekawa, T. Yamano, M. Kawada, H. Odaka, H. Ikeda and T. Sohda, J. Med. Chem., 2002, 45, 1518; (b) W. S. Yang, K. Shimada, D. Delva, M. Patel, E. Ode, R. Skouta and B. R. Stockwell, ACS Med. Chem. Lett., 2012, 3, 35; (c) A. Y. Shaw, M. C. Henderson, G. Flynn, B. Samulitis, H. Han, S. P. Stratton, H. H. S. Chow, L. H. Hurley and R. T. Dorr, J. Pharmacol. Exp. Ther., 2009, 331, 636.
4. For the classical synthetic methods to oxazoles, see: (a) I. J. Turchi and M. J. S. Dewar, Chem. Rev., 1975, 75, 389; (b) For the recent examples of synthetic methods to oxazoles, see: B. Shi, A. J. Blake, W. Lewis, I. B. Campbell, B. D. Judkins and C. J. Moody, J. Org. Chem., 2010, 75, 152; (c) W. He, C. Li and L. Zhang, J. Am. Chem. Soc., 2011, 133, 8482; (d) I. Cano, E. Álvarez, M. C. Nicasio and P. J. Pérez, J. Am. Chem. Soc., 2011, 133, 191; (e) J. Xie, H. Jiang, Y. Cheng and C. Zhu, Chem. Commun., 2012, 48, 979; (f) W. J. Xue, Q. Li, Y. P. Zhu, J. G. Wang and A. X. Wu, Chem. Commun., 2012, 48, 3485; (g) J. P. Weyrauch, A. S. K. Hashmi, A. Schuster, T. Hengst, S. Schetter, A. Littmann, M. Rudolph, M. Hamzic, J. Visus, F. Rominger, W. Frey and J. W. Bats, Chem.–Eur. J., 2010, 16, 956; (h) Z. Li, L. Ma, J. Xu, L. Kong, X. Wu and H. Yao, Chem. Commun., 2012, 48, 3763; (i) X. Liu, R. Cheng, F. F. Zhao, D. Zhang-Negrerie, Y. F. Du and K. Zhao, Org. Lett., 2012, 14, 5480; (j) A. Herrera, R. Martínez-Alvarez, P. Ramiro, D. Molero and J. Almy, J. Org. Chem., 2006, 71, 3026.
5. (a) R. Robinson, J. Chem. Soc., 1909, 2167; (b) S. Gabriel, Chem. Ber., 1910, 43, 1283; (c) For selected recent examples, see: E. Biron, J. Chatterjee and H. Kessler, Org. Lett., 2006, 8, 2417; (d) J. F. Sanz-Cervera, R. Blasco, J. Piera, M. Cynamon, I. Ibáñez, M. Murguía and S. Fustero, J. Org. Chem., 2009, 74, 8988; (e) M. J. Thompson, H. Adams and B. Chen, J. Org. Chem., 2009, 74, 3856.
6. M. P. Doyle, W. E. Buhro, J. G. Davidson, R. C. Elliot, J. W. Hoekstra and M. Oppenhuizen, J. Org. Chem., 1980, 45, 3657.
7. R. H. Prager, J. A. Smith, B. Weber and C. M. Williams, J. Chem. Soc., Perkin Trans. 1, 1997, 2665.
8. R. Martín, A. Cuenca and S. L. Buchwald, Org. Lett., 2007, 9, 5521.
9. A. S. K. Hashmi, J. P. Weyrauch, W. Frey and J. W. Bats, Org. Lett., 2004, 6, 4391.
10. M. D. Milton, Y. Inada, Y. Nishibayashi and S. Uemura, Chem. Commun., 2004, 2712.
11. (a) B. Clapham, C. Spanka and K. D. Janda, Org. Lett., 2001, 3, 2173; (b) Y. R. Lee, S. H. Yeon, Y. Seo and B. S. Kim, Synthesis, 2004, 2787.
12. For the cyclization of enamides bearing β-vinylic carbonheteroatom bonds, see the following: (i) C–Br bond: (a) C. Shin, Y. Sato, H. Sugiyama, K. Nanjo and J. Yoshimura, Bull. Chem. Soc. Jpn., 1977, 50, 1788; (b) J. Das, J. A. Reid, D. R. Kronenthal, J. Singh, P. D. Pansegrau and R. H. Mueller, Tetrahedron Lett., 1992, 33, 7835; (c) S. K. Chattopadhyay, J. Kempson, A. McNeil, G. Pattenden, M. Reader, D. E. Rippon and D. Waite, J. Chem. Soc., Perkin Trans. 1, 2000, 2415; (d) K. Schuh and F. Glorius, Synthesis, 2007, 15, 2297 (ii) C–I bond: ; (e) P. M. T. Ferreira, L. S. Monteiro and G. Pereira, Eur. J. Org. Chem., 2008, 4676; (f) P. M. T. Ferreira, E. M. S. Castanheira, L. S. Monteiro, G. Pereira and H. Vilaça, Tetrahedron, 2010, 66, 8672 (iii) C–S bond: ; (g) N. C. Misra and H. Ila, J. Org. Chem., 2010, 75, 5195.
13. (a) C. W. Cheung and S. L. Buchwald, J. Org. Chem., 2012, 77, 7526; (b) A. E. Wendlandt and S. S. Stahl, Org. Biomol. Chem., 2012, 10, 3866; (c) R. Martin, A. Cuenca and S. L. Buchwald, Org. Lett., 2007, 9, 5521; (d) C. Zhang, C. H. Tang and N. Jiao, Chem. Soc. Rev., 2012, 41, 3464.
14. (a) C. F. Wan, J. T. Zhang, S. J. Wang, J. M. Fan and Z. Y. Wang, Org. Lett., 2010, 12, 2338; (b) J. C. Lee, H. J. Choi and Y. C. Lee, Tetrahedron Lett., 2003, 44, 123.
15. The reactions in ref. 14a mainly provided ester substituted oxazoles and there is only one example for acetyl substituted oxazole synthesis. The position of the acetyl group in ref. 14a is ortho to the nitrogen atom which is different with ours.
16. During the preparation of this manuscript, Jiang and co-workers reported a similar method for oxazole preparation from amides and ketones using PdCl₂/CuBr₂ as catalysts and NaHCO₃ as the base: M. F. Zheng, L. B. Huang, H. W. Huang, X. W. Li, W. Q. Wu and H. F. Jiang, Org. Lett., 2014, 16, 5906.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra14394a

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