An Approach to the Synthesis of Pyrimido[b]azepines via Ruthenium-Catalyzed Ring-Closing Metathesis

Abstract

A highly efficient approach to the synthesis of a series of pyrimido[b]azepines has been developed with 5-allyl-2,4,6-trichloropyrimidine as the starting material in six or seven steps via a ring-closing metathesis (RCM) reaction. The absolute configuration of the key intermediate pyrimido[4,5-b]azepine was ascertained by X-ray crystal structure analysis.

Key words

RCM - pyrimido[b]azepines - pyrimido[4,5-b]azepine-2,4-dione - Grubbs catalyst - inhibitors of HIV-1 RT

• References

• 1 Szántay C, Bölcskei H, Gács-Baitz E. Tetrahedron 1990; 46: 1711
• 2a Loison S, Cottet M, Orcel H, Adihou H, Rahmeh R, Lamarque L, Trinquet E, Kellenberger E, Hibert M, Durroux T, Mouillac B, Bonnet D. J. Med. Chem. 2012; 55: 8588
• 2b Kometani T, Shiotani S. J. Med. Chem. 1978; 21: 1105
• 3a Aoyama A, Endo-Umeda K, Kishida K, Ohgane K, Noguchi-Yachide T, Aoyama H, Ishikawa M, Miyachi H, Makishima M, Hashimoto Y. J. Med. Chem. 2012; 55: 7360
• 3b Acques E, Di Chiara G. Eur. J. Pharmacol. 1999; 383: 275
• 4 Rosowsky A, Cody V, Galitsky N, Fu H, Papoulis AT, Quenner SF. J. Med. Chem. 1999; 42: 4853
• 5 Akritopoulou-Zanze I, Braje W, Djuric SW, Wilson NS, Turner SC, Kruger AW, Relo AL, Shekhar S, Welch DS, Zhao HY. US Patent Appl. Publ. US 20110118231 A1 20110519, 2011 ; Chem. Abstr. 2011, 154, 615137.
• 6 Jain AK, Thomas NS, Panchaqnula R. J. Control. Release 2002; 79: 93
• 7 Watthey JW, Stanton JL, Desai M, Babiarz JE, Finn BM. J. Med. Chem. 1985; 28: 1511
• 8 Zhong YL, Pipik B, Lee J, Kohmura Y, Okada S, Igawa K, Kadowaki C, Takezawa A, Kato S, Conlon DA, Zhou H, King AO, Reamer RA, Gauthier DR, Askin D. Org. Process Res. Dev. 2008; 12: 1245
• 9 Ikemoto T, Ito T, Nishiguchi A, Miura S, Tomimatsu K. Org. Process Res. Dev. 2005; 9: 168
• 10 Protter AA, Chakravarty S. Patent WO 2012112961 A1, 2012 ; Chem. Abstr. 2012, 157, 400665.
• 11 Brown DJ, Evans RF, Cowden WB, Fenn MD In The Chemistry of Heterocyclic Compounds . Vol. 52; Taylor EC. Wiley; New York: 1994: 49-238
• 12 Li G, Wang XW, Tian C, Zhang TB, Zhang ZL, Liu JY. Tetrahedron Lett. 2012; 53: 5193
• 13 Wang XW, Lou QH, Guo Y, Xu Y, Zhang ZL, Liu JY. Org. Biomol. Chem. 2006; 4: 3252
• 14a Takahata H, Nakano M, Tomiguchi A, Yamazaki T. Heterocycles 1982; 17: 413
• 14b Takahata H, Nakano M, Tomiguchi A, Yamazaki T. Chem. Pharm. Bull. 1985; 33: 4299
• 15a Donohoe TJ, Fishlock LP, Lacy AR, Procopiou PA. Org. Lett. 2007; 9: 953
• 15b Bajracharya GB, Nakamura I, Yamamoto Y. J. Org. Chem. 2005; 70: 892
• 15c Lovely CJ, Chen Y, Ekanayake EV. Heterocycles 2007; 74: 873
• 16a Muñiz K, Hövelmann CH, Streuff J. J. Am. Chem. Soc. 2007; 130: 763
• 16b Fonvielle M, Therisod H, Hemery M, Therisod M. Bioorg. Med. Chem. Lett. 2007; 17: 410
• 17 Farshori NN, Banday MR, Zahoor Z, Rauf A. Chin. Chem. Lett. 2010; 21: 646
• 18a Grubbs RH, Chang S. Tetrahedron 1998; 54: 4413
• 18b Fürstner A. Angew. Chem. Int. Ed. 2000; 39: 3012
• 18c Trnka TM, Grubbs RH. Acc. Chem. Res. 2001; 34: 18
• 18d Felpin FX, Lebreton J. Eur. J. Org. Chem. 2003; 3693
• 19 Fustero S, Sanchez-Roselló M, Jiménez D, Sanz-Cervera JF, Del Pozo C, Aceña JL. J. Org. Chem. 2006; 71: 2706
• 20 Fustero S, Esteban E, Sanz-Cervera JF, Jiménez D, Mojarrad F. Synthesis 2006; 4087
• 21a Sutton AE, Seigal BA, Finnegan DF, Snapper ML. J. Am. Chem. Soc. 2002; 124: 13390
• 21b Schmidt B. J. Mol. Catal. A: Chem. 2006; 254: 53
• 21c Schmidt B. Eur. J. Org. Chem. 2004; 1865
• 22 Ishikawa I, Khachatrian VE, Melic-Ohanjanian RG, Kawahara N, Mizuno Y, Ogura H. Chem. Pharm. Bull. 1992; 40: 846
• 23 Bennasar ML, Roca T, Monerris M, García-Díaz D. J. Org. Chem. 2006; 71: 7028
• 24 Kundu NG, Das B, Spears CP, Majumdar A, Kangs SI. J. Med. Chem. 1990; 33: 1975
• 25 Pontikis R, Benhida R, Aubertin AM, Grierson DS, Monneret C. J. Med. Chem. 1997; 40: 1845
• 26 CCDC-930092 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.