Synthesis of substituted pyrroles using a silver-catalysed reaction between isocyanoacetates/benzyl isocyanides and chromones

Abstract

A novel synthetic strategy to construct substituted-pyrroles has been developed using silver-catalysed reactions between isocyanides/benzyl isocyanides and chromones. These reactions proceed under mild conditions and yield polysubstituted pyrroles with efficient yields. The silver catalyst plays a key role in sequestering and activating the isocyano group and in sequential Michael addition and cyclization reactions.

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Substituted pyrroles represent an important class of nitrogen-containing heterocycles that are often observed in natural products,¹ pharmaceutical substances,² and bioactive materials.³ A large numbers of pyrrole derivatives have been found to act as biological agents, including, a tubulin polymerization inhibitor,⁴ a Cdc7 kinase inhibitor,⁵ a potassium-competitive acid blocker (P-CAB),⁶ and a pesticide, pyoluteorin⁷ (Fig. 1). As a result of these findings, considerable attention has been paid to developing efficient methods for the synthesis of pyrrole derivatives. The most frequently used methods to synthesize pyrroles employ the classical Hantzsch and Paal–Knorr procedures, but these synthetic approaches require multistep operations, harsh conditions, and do not confer regioselectivity.⁸ More efficient and environmentally friendly reactions, such as the Paal–Knorr reaction, have been reported.⁹ Although a variety of methods for the synthesis of functionalized pyrrole derivatives have recently been developed,¹⁰ direct access to polyfunctionalized pyrroles from common, commercially available starting materials, is still a challenge.

Fig. 1 Representative examples of pyrrole derivatives. Isocyanoacetates have been widely used in organic synthesis and are useful building blocks for the generation of N-heterocycles¹¹ because of their multi-reaction centres, such as an isocyanide group, which includes an acidic CH fragment and a carboxylic acid with a protecting group. The cycloaddition reaction of isocyanoacetates provides an ideal route to substituted pyrroles due to the efficiency of the reaction. Historically, the Barton–Zard synthesis, which represents the reaction between an activated alkene and an activated methylene isocyanide under basic conditions, has been the most efficient method for the synthesis of substituted pyrroles (Scheme 1 eqn (1)).¹² However, poor yields and unwanted by-products limit this synthesis approach. Recently, the cycloaddition of isocyanide has been extended to incorporate alkynes with the help of a transition metal-catalyst (Scheme 1 eqn (2)).¹³ The copper or silver salts employed increase the selective chemical transformations involving terminal alkynes. Based on these results, isocyanoacetates represent a very attractive starting material for investigations of synthetic applications.

Chromones are an additional class of starting materials that are used for constructing various biological heterocycles.¹⁴ The use of 3-formylchromone in the synthesis of pyrroles has previously been reported (Scheme 1 eqn (3)).¹⁵ Based on these previous studies, we believe that chromones may be coupled with the reaction of isocyanoacetates for the synthesis of pyrrole derivatives (Scheme 1 eqn (4)).

Scheme 1 Methods for the synthesis of pyrroles from isocyanoacetates, including the method described in this manuscript.

Our initial efforts focused on the reaction between 4H-chromen-4-one 1a and ethyl 2-isocyanoacetate 2a in the presence of silver salts and bases. Following the reaction, the corresponding pyrrole derivative 3a was produced with moderate yields (Table 1, entry 1). Notably, no by-product from the dimerization of isocyanides was observed in this reaction.

Table 1 Optimization of the reaction conditions^a

Entry	Catalyst	Temp (°C)	Solvent	Base	Yield^b (%)
a Reaction condition: 1a (0.5 mmol, 1.0 equiv.), 2a (0.75 mmol, 1.5 equiv.), base (2.0 equiv.), and silver salts (20 mol%) in solvent (3.0 mL) under air.b Isolated yields.c The reaction was carried out without silver salt.d NR = no reaction.e Silver salts (10 mol%) was used.f The reaction was carried out without base.
1	Ag2O	rt	NMP	K2CO3	64
2	Ag2O	50	NMP	K2CO3	66
3	Ag2O	100	NMP	K2CO3	76
4	Ag2O	130	NMP	K2CO3	75
5	Ag2O	100	DMSO	K2CO3	70
6	Ag2O	100	DMF	K2CO3	80
7	Ag2O	100	Dioxane	K2CO3	63
8	Ag2O	100	DMF	KOAc	73
9	Ag2O	100	DMF	Cs2CO3	70
10	Ag2O	100	DMF	DBU	50
11	Ag2CO3	100	DMF	K2CO3	98
12	AgNO3	100	DMF	K2CO3	93
13	AgOTf	100	DMF	K2CO3	79
14	AgNTf2	100	DMF	K2CO3	80
15^c	—	100	DMF	K2CO3	NR^d
16^e	Ag2CO3	100	DMF	K2CO3	77
17^f	Ag2CO3	100	DMF	—	20

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Based on these results, we attempted optimize the reaction conditions (Table 1). The investigation of different reaction temperatures indicated that the optimal temperature was 100 °C (Table 1, entries 1–4). Once the optimum temperature was defined, several solvents were screened (Table 1, entry 3, entries 5–7). DMF, instead of NMP, produced 3a in an 80% yield, which was the best result (Table 1, entry 6). Moreover the effect of bases was also studied. The results found that K₂CO₃ was the optimal base (Table 1, entry 6, entries 8–10); the presence of base was critical for improving the yield of the reaction (Table 1, entry 17). The effects of silver salts on the reaction were studied, and Ag₂CO₃ was found to be the optimal silver salt (Table 1, entry 6, entries 11–14); it is worth noting that a decrease in the concentration of Ag₂CO₃ resulted in a reduced yield (Table 1, entry 16). It is also worth noting that the reaction would not occur in the absence of silver salts (Table 1, entry 15). As a result of these studies, the optimal reaction conditions were found to include Ag₂CO₃ (20 mol%) and K₂CO₃ (2.0 equiv.) in DMF (3.0 mL) at 100 °C for 1 h.

The structure of 3a was established by X-ray crystal structure analysis (Fig. 2).

Fig. 2 X-ray crystal structure of ethyl 4-(2-hydroxybenzoyl)-1H-pyrrole-2-carboxylate 3a (probability 30%).

To study the capacity of this reaction method, a variety of chromones 1 were reacted with isocyanides 2 under the optimal reaction conditions to produce substituted-pyrroles 3. The results are shown in Table 2. When both electron-donating and -withdrawing groups were located on the benzene rings, the chromones yielded substituted-pyrroles with efficient yields (Table 2, 3a–3t). Electronic effects had little influence on the sequential reactions with isocyanoacetates. Different alkyl, halo, and methoxy groups located in the aryl ring of chromones 1 produced pyrrole derivatives 3a–3o with excellent yields. Moreover, multigroup chromones 1 were also compatible with the reaction process and produced substituted-pyrroles with excellent yields (Table 2, 3p–3r). In addition, both an aryl-substituted compound (1s) and methyl 2-isocyanoacetate (2t) were found to be suitable substrates (Table 2, 3s and 3t). Other activated methylene isocyanides, such as tosylmethyl isocyanide and benzyl isocyanide, may be used to incorporate structural diversity into the pyrrole ring. However, when a benzyl isocyanide (2u) was used, the pyrrole derivative was produced with a moderate yield and the reaction required more time (Table 2, 3u). When a tosylmethyl isocyanide was used under the optimal conditions, it failed to yield the expected pyrrole. However, on the whole, the silver-catalysed reaction of activated methylene isocyanides with a broad range of chromones provides a powerful method for the synthesis of 2,4-disubstituted pyrroles.

Table 2 Scope of the reaction of chromones with isocyanoacetates/benzyl isocyanide^a,b

a Reaction condition: 1a (0.5 mmol, 1.0 equiv.), 2a (0.75 mmol, 1.5 equiv.), K₂CO₃ (1.0 mmol 2.0 equiv.), and Ag₂CO₃ (20 mol%) DMF (2.0 mL) at 100 °C for 1 h under air.b Isolated yields.c The reaction time is 12 h.

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The proposed reaction mechanism (Scheme 2) based on previously published works. The initial step involves the formation of a silver-isocyanide complex A generated from 2a in the presence of silver catalyst. As described in previous studies, the silver salts coordinate the isocyano group and activate the isocyanides (1) for the cycloaddition reaction.^13c An intermolecular Michael addition of compound 1a and complex A produces intermediate C. An intramolecular cyclization reaction occurs under alkaline conditions to produce complex D. Complex D undergoes a 1,3-hydrogen shift followed by protonation mediated by KHCO₃ to yield 3a, thus completing the catalytic cycle for Ag₂CO₃.

Scheme 2 Proposed reaction mechanism.

Conclusions

This manuscript described the silver-catalysed synthesis of 2,4-disubstituted pyrroles from isocyanoacetates/benzyl isocyanides and a variety of chromones. This synthetic approach represents an extremely simple, efficient, and economical method of producing biologically active pyrrole derivatives with excellent yields. Further studies of the reaction mechanism and the application of these products are under investigation in our laboratory.

Acknowledgements

This study was supported by the National Natural Science Foundation of China (grant number 81321092) and SKLDR/SIMM (SIMM1403ZZ-01).

Notes and references

1. (a) H. Fan, J. Peng, M. T. Hamann and J.-F. Hu, Chem. Rev., 2008, 108, 264; (b) R. Jansen, S. Sood, V. Huch, B. Kunze, M. Stadler and R. Müller, J. Nat. Prod., 2014, 77, 320.
2. (a) A. Schäfer, A. Wellner, M. Strauss, A. Schäfer, G. Wolber and R. Gust, J. Med. Chem., 2012, 55, 9607; (b) G. La Regina, R. Silvestri, M. Artico, A. Lavecchia, E. Novellino, O. Befani, P. Turini and E. Agostinelli, J. Med. Chem., 2007, 50, 922.
3. (a) M. Lazerges, K. Chane-Ching, S. Aeiyach, S. Chelli, B. Peppin-Donnat, M. Billon, C. Lombard, F. Maurel and M. Jouini, J. Solid State Electrochem., 2009, 13, 231; (b) S. Hamilton, M. J. Hepher and J. Sommerville, Sens. Actuators, B, 2005, 107, 424.
4. G. La Regina, R. Bai, A. Coluccia, V. Famiglini, S. Pelliccia, S. Passacantilli, C. Mazzoccoli, V. Ruggieri, L. Sisinni, A. Bolognesi, W. M. Rensen, A. Miele, M. Nalli, R. Alfonsi, L. Di Marcotullio, A. Gulino, A. Brancale, E. Novellino, G. Dondio, S. Vultaggio, M. Varasi, C. Mercurio, E. Hamel, P. Lavia and R. Silvestri, J. Med. Chem., 2014, 57, 6531.
5. M. Menichincheri, C. Albanese, C. Alli, D. Ballinari, A. Bargiotti, M. Caldarelli, A. Ciavolella, A. Cirla, M. Colombo, F. Colotta, V. Croci, R. D'Alessio, M. D'Anello, A. Ermoli, F. Fiorentini, B. Forte, A. Galvani, P. Giordano, A. Isacchi, K. Martina, A. Molinari, J. K. Moll, A. Montagnoli, P. Orsini, F. Orzi, E. Pesenti, A. Pillan, F. Roletto, A. Scolaro, M. Tatò, M. Tibolla, B. Valsasina, M. Varasi, P. Vianello, D. Volpi, C. Santocanale and E. Vanotti, J. Med. Chem., 2010, 53, 7296.
6. Y. Arikawa, H. Nishida, O. Kurasawa, A. Hasuoka, K. Hirase, N. Inatomi, Y. Hori, J. Matsukawa, A. Imanishi, M. Kondo, N. Tarui, T. Hamada, T. Takagi, T. Takeuchi and M. Kajino, J. Med. Chem., 2012, 55, 4446.
7. D. M. Bailey, R. E. Johnson and U. J. Salvador, J. Med. Chem., 1973, 16, 1298.
8. (a) A. Hantzsch, Ber. Dtsch. Chem. Ges., 1890, 23, 1474; (b) L. Knorr, Ber. Dtsch. Chem. Ges., 1884, 17, 1635; (c) C. Paal, Ber. Dtsch. Chem. Ges., 1884, 17, 2756; (d) V. Amarnath, D. C. Anthony, K. Amarnath, W. M. Valentine, L. A. Wetterau and D. G. Graham, J. Org. Chem., 1991, 56, 6924.
9. (a) V. F. Ferreira, M. C. B. V. de Souza, A. C. Cunha, L. O. R. Pereira and M. L. G. Ferreira, Org. Prep. Proced. Int., 2001, 33, 411; (b) H. Cho, R. Madden, B. Nisanci and B. Torok, Green Chem., 2015, 17, 1088; (c) A. R. Bharadwaj and K. A. Scheidt, Org. Lett., 2004, 6, 2465; (d) G. Minetto, L. F. Raveglia and M. Taddei, Org. Lett., 2004, 6, 389; (e) P. B. Cranwell, M. O'Brien, D. L. Browne, P. Koos, A. Polyzos, M. Pena-Lopez and S. V. Ley, Org. Biomol. Chem., 2012, 10, 5774; (f) R. U. Braun, K. Zeitler and T. J. J. Müller, Org. Lett., 2001, 3, 3297.
10. V. Estevez, M. Villacampa and J. C. Menendez, Chem. Soc. Rev., 2010, 39, 4402.
11. (a) R. de la Campa, I. Ortín and D. J. Dixon, Angew. Chem., Int. Ed., 2015, 54, 4895; (b) Z.-L. He and C.-J. Wang, Chem. Commun., 2015, 51, 534; (c) M.-X. Zhao, H.-L. Bi, R.-H. Jiang, X.-W. Xu and M. Shi, Org. Lett., 2014, 16, 4566; (d) A. V. Lygin and A. de Meijere, Angew. Chem., Int. Ed., 2010, 49, 9094; (e) A. V. Gulevich, A. G. Zhdanko, R. V. A. Orru and V. G. Nenajdenko, Chem. Rev., 2010, 110, 5235.
12. (a) N. C. Misra, K. Panda, H. Ila and H. Junjappa, J. Org. Chem., 2007, 72, 1246; (b) J. L. Bullington, R. R. Wolff and P. F. Jackson, J. Org. Chem., 2002, 67, 9439; (c) D. H. R. Barton, J. Kervagoret and S. Z. Zard, Tetrahedron, 1990, 46, 7587.
13. (a) S. Kamijo, C. Kanazawa and Y. Yamamoto, J. Am. Chem. Soc., 2005, 127, 9260; (b) J. Liu, Z. Fang, Q. Zhang, Q. Liu and X. Bi, Angew. Chem., Int. Ed., 2013, 52, 6953; (c) M. Gao, C. He, H. Chen, R. Bai, B. Cheng and A. Lei, Angew. Chem., Int. Ed., 2013, 52, 6958; (d) O. V. Larionov and A. de Meijere, Angew. Chem., Int. Ed., 2005, 44, 5664; (e) A. V. Lygin, O. V. Larionov, V. S. Korotkov and A. de Meijere, Chem.–Eur. J., 2009, 15, 227; (f) C. Kanazawa, S. Kamijo and Y. Yamamoto, J. Am. Chem. Soc., 2006, 128, 10662.
14. (a) X. Qi, H. Xiang, Q. He and C. Yang, Org. Lett., 2014, 16, 4186; (b) I. Savych, T. Glasel, A. Villinger, V. Y. Sosnovskikh, V. O. Iaroshenko and P. Langer, Org. Biomol. Chem., 2015, 13, 729; (c) J. Yan, M. Cheng, F. Hu and Y. Hu, Org. Lett., 2012, 14, 3206; (d) X. Zhang, Q. He, H. Xiang, S. Song, Z. Miao and C. Yang, Org. Biomol. Chem., 2014, 12, 355.
15. (a) A. O. Fitton, J. R. Frost, H. Suschitzky and P. G. Houghton, Synthesis, 1977, 133; (b) A. O. Fitton, M. Kosmirak, H. Suschitzky and J. L. Suschitzky, Tetrahedron Lett., 1982, 23, 3953; (c) A. S. Plaskon, S. V. Ryabukhin, D. M. Volochnyuk, A. N. Shivanyuk and A. A. Tolmachev, Tetrahedron, 2008, 64, 5933; (d) P. D. Clarke, A. O. Fitton, M. Kosmirak, H. Suschitzky and J. L. Suschitzky, J. Chem. Soc., Perkin Trans. 1, 1985, 1747.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1412634. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra21915a

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