Nitrene Cyclization of 2-(Trichloromethyl)-5-phenylpyrimidines: Application to the Synthesis of 2-(Trichloromethyl)pyrimido[4,5-b]indoles and Related Heterocycles

Abstract

An aromatic C–H nitrene insertion of 2-(trichloromethyl)pyrimidines bearing a phenyl substituent at the C-5 position is described. Treatment of 4-chloro-5-phenyl-2-(trichloromethyl)pyrimidines with sodium azide in DMF or the reflux of 4-azido-5-phenyl-2-(trichloromethyl)pyrimidines in toluene provided 2-(trichloromethyl)pyrimido[4,5-b]indole derivatives in moderate yields. Excellent yields of this heterocyclic system were obtained through the aromatic C–H insertion with the Du Bois catalyst. This is an attractive approach for synthesizing pyrimido[4,5-b]indoles with a trichloromethyl substituent in the pyrimidine moiety.

Key words

nitrene insertion - 5-phenylpyrimidines - pyrimido[4,5-b]indoles - trichloromethylated heterocycles - Du Bois catalyst - intramolecular cyclization

Publication History

Received: 14 July 2023

Accepted after revision: 23 August 2023

Accepted Manuscript online:
23 August 2023

Article published online:
04 October 2023

• References

• 1 Nicolaou KC, Snyder SA. Classics in Total Synthesis II: More Targets, Strategies, Methods. Wiley-VCH; Weinheim: 2003
• 2 McGlacken GP, Fairlamb IJ. S. Nat. Prod. Rep. 2005; 22: 369
• 3 Shiri M. Chem. Rev. 2012; 112: 3508
• 4 Lancianesi S, Palmieri A, Petrini M. Chem. Rev. 2014; 114: 7108
• 5 Alex K, Tillack A, Schwarz N, Beller M. Angew. Chem. Int. Ed. 2008; 47: 2304
• 6 Pei T, Chen C.-y, Dormer PG, Davies IW. Angew. Chem. Int. Ed. 2008; 47: 4231
• 7 Wei Y, Deb I, Yoshikai N. J. Am. Chem. Soc. 2012; 134: 9098
• 8 Sharma U, Kancherla R, Naveen T, Agasti S, Maiti D. Angew. Chem. Int. Ed. 2014; 53: 11895
• 9 Showalter HD. H, Bridges AJ, Zhou H, Sercel AD, McMichael A, Fry DW. J. Med. Chem. 1999; 42: 5464
• 10 Tichý M, Pohl R, Xu HY, Chen Y.-L, Yokokawa F, Shi P.-Y, Hocek M. Bioorg. Med. Chem. 2012; 20: 6123
• 11 Okamoto A, Tanaka K, Fukuta T, Saito I. J. Am. Chem. Soc. 2003; 125: 9296
• 12 Okamoto A, Tanaka K, Nishiza K.-i, Saito I. Bioorg. Med. Chem. 2004; 12: 5875
• 13 Okamoto A, Kamei T, Saito I. J. Am. Chem. Soc. 2006; 128: 658
• 14 Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB, Fedorov O, Morse EM, Keates T, Hickman TT, Felletar I, Philpott M, Munro S, McKeown MR, Wang Y, Christie AL, West N, Cameron MJ, Schwartz B, Heightman TD, La Thangue N, French CA, Wiest O, Kung AL, Knapp S, Bradner JE. Nature 2010; 468: 1067
• 15 Waring MJ, Chen H, Rabow AA, Walker G, Bobby R, Boiko S, Bradbury RH, Callis R, Clark E, Dale I, Daniels DL, Dulak A, Flavell L, Holdgate G, Jowitt TA, Kikhney A, McAlister M, Méndez J, Ogg D, Patel J, Petteruti P, Robb GR, Robers MB, Saif S, Stratton N, Svergun DI, Wang W, Whittaker D, Wilson DM, Yao Y. Nat. Chem. Biol. 2016; 12: 1097
• 16 Traxler PM, Furet P, Mett H, Buchdunger E, Meyer T, Lydon N. J. Med. Chem. 1996; 39: 2285
• 17 Zhao Y, Bai L, Liu L, McEachern D, Stuckey JA, Meagher JL, Yang C.-Y, Ran X, Zhou B, Hu Y, Li X, Wen B, Zhao T, Li S, Sun D, Wang S. J. Med. Chem. 2017; 60: 3887
• 18 Tichý M, Pohl R, Tloušt’ová E, Weber J, Bahador G, Lee Y.-J, Hocek M. Bioorg. Med. Chem. 2013; 21: 5362
• 19 Xu G, Zheng L, Dang Q, Bai X. Synthesis 2013; 45: 743
• 20 Xu G, Zheng L, Wang S, Dang Q, Bai X. Synlett 2009; 3206
• 21 Nicodeme E, Jeffrey KL, Schaefer U, Beinke S, Dewell S, Chung C.-w, Chandwani R, Marazzi I, Wilson P, Coste H, White J, Kirilovsky J, Rice CM, Lora JM, Prinjha RK, Lee K, Tarakhovsky A. Nature 2010; 468: 1119
• 22 Anand P, Brown JD, Lin CY, Qi J, Zhang R, Artero PC, Alaiti MA, Bullard J, Alazem K, Margulies KB, Cappola TP, Lemieux M, Plutzky J, Bradner JE, Haldar SM. Cell 2013; 154: 569
• 23 Li B, Guo S, Zhang J, Zhang X, Fan X. J. Org. Chem. 2015; 80: 5444
• 24 Kumar AS, Nagarajan R. Org. Lett. 2011; 13: 1398
• 25 Kumar AS, Amulya Rao PV, Nagarajan R. Org. Biomol. Chem. 2012; 10: 5084
• 26 Majumder S, Bhuyan PJ. J. Iran. Chem. Soc. 2014; 11: 993
• 27 Molina P, Fresneda PM. J. Chem. Soc., Perkin Trans. 1 1988; 1819
• 28 Dotzauer B, Grünert R, Bednarski PJ, Lanig H, Landwehr J, Troschütz R. Bioorg. Med. Chem. 2006; 14: 7282
• 29 Zhang Y.-M, Razler T, Jackson PF. Tetrahedron Lett. 2002; 43: 8235
• 30 Venugopalan B, Desai PD, De Souza NJ. J. Heterocycl. Chem. 1988; 25: 1633
• 31 Freeman AW, Urvoy M, Criswell ME. J. Org. Chem. 2005; 70: 5014
• 32 Qu Z, Wang P, Chen X, Deng G.-J, Huang H. Chin. Chem. Lett. 2021; 32: 2582
• 33 Semenova NA, Katvalyan GT, Mistryukov EA. Tetrahedron Lett. 1976; 17: 445
• 34 Plé N, Turck A, Heynderickx A, Quéguiner G. J. Heterocycl. Chem. 1994; 31: 1311
• 35 Hyatt JA, Swenton JS. J. Org. Chem. 1972; 37: 3216
• 36 Hyatt JA, Swenton JS. J. Heterocycl. Chem. 1972; 9: 409
• 37 Lemir ID, Argüello JE, Lanterna AE, Scaiano JC. Chem. Commun. 2020; 56: 10239
• 38 Akiyama T, Wada Y, Yamada M, Shio Y, Honma T, Shimoda S, Tsuruta K, Tamenori Y, Haneoka H, Suzuki T, Harada K, Tsurugi H, Mashima K, Hasegawa J.-y, Sato Y, Arisawa M. Org. Lett. 2020; 22: 7244
• 39 Kondo Y, Watanabe R, Sakamoto T, Yamanaka H. Chem. Pharm. Bull. 1989; 37: 2933
• 40 Verhaeghe P, Azas N, Hutter S, Castera-Ducros C, Laget M, Dumètre A, Gasquet M, Reboul J.-P, Rault S, Rathelot P, Vanelle P. Bioorg. Med. Chem. 2009; 17: 4313
• 41 Verhaeghe P, Azas N, Gasquet M, Hutter S, Ducros C, Laget M, Rault S, Rathelot P, Vanelle P. Bioorg. Med. Chem. Lett. 2008; 18: 396
• 42 Liu X.-P, Narla RK, Uckun FM. Bioorg. Med. Chem. Lett. 2003; 13: 581
• 43 Sielecki TM, Johnson TL, Liu J, Muckelbauer JK, Grafstrom RH, Cox S, Boylan J, Burton CR, Chen H, Smallwood A, Chang C.-H, Boisclair M, Benfield PA, Trainor GL, Seitz SP. Bioorg. Med. Chem. Lett. 2001; 11: 1157
• 44 Verhaeghe P, Rathelot P, Gellis A, Rault S, Vanelle P. Tetrahedron 2006; 62: 8173
• 45 Kato T, Katagiri N, Wagai A. Tetrahedron 1978; 34: 3445
• 46 Castera-Ducros C, Azas N, Verhaeghe P, Hutter S, Garrigue P, Dumètre A, Mbatchi L, Laget M, Remusat V, Sifredi F, Rault S, Rathelot P, Vanelle P. Eur. J. Med. Chem. 2011; 46: 4184
• 47 Lechuga-Eduardo H, Olivo HF, Romero-Ortega M. Eur. J. Org. Chem. 2014; 5910
• 48 Seballos-Resendiz A, Lechuga-Eduardo H, Barroso-Flores J, Martinez-Otero D, Romero-Ortega M. Synthesis 2016; 48: 2205
• 49 Romero-Ortega M, Aviles A, Cruz R, Fuentes A, Gómez RM, Plata A. J. Org. Chem. 2000; 65: 7244
• 50 Guzmán A, Romero M, Talamás FX, Villena R, Greenhouse R, Muchowski JM. J. Org. Chem. 1996; 61: 2470
• 51 Trujillo-Lagunas ML, Medina-Mercado I, Zaragoza-Galicia I, Olivo HF, Romero-Ortega M. Synthesis 2019; 51: 530
• 52 Temple CJr, McKee RL, Montgomery JA. J. Org. Chem. 1965; 30: 829
• 53 CCDC 2259760 (2a) contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures
• 54 Taber DF, Raman K. J. Am. Chem. Soc. 1983; 105: 5935
• 55 Taber DF, Petty EH, Raman K. J. Am. Chem. Soc. 1985; 107: 196
• 56 Hashimoto S.-i, Watanabe N, Ikegami S. J. Chem. Soc., Chem. Commun. 1992; 1508
• 57 Stokes BJ, Dong H, Leslie BE, Pumphrey AL, Driver TG. J. Am. Chem. Soc. 2007; 129: 7500
• 58 Espino CG, Fiori KW, Kim M, Du Bois J. J. Am. Chem. Soc. 2004; 126: 15378
• 59 Rodriguez-Cárdenas E, Sabala R, Romero-Ortega M, Ortiz A, Olivo HF. Org. Lett. 2012; 14: 238