Synthesis of substituted imidazo[1,5-a]pyrazines via Mono-, Di-, and directed remote metalation strategies

Organic Letters

Volumn 11, Issue 22, 2009, Pages 5118-5121

  Board, Johnathan ^a   Wang, Jian Xin ^a   Crew, Andrew P ^b   Jin, Meizhong ^b   Foreman, Kenneth ^b   Mulvihill, Mark J ^b   Snieckus, Victor ^a  

^a QUEEN S UNIVERSITY   (Canada)

^b OSI PHARMACEUTICALS INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

IMIDAZO(1,5 A)PYRAZINE; IMIDAZO(1,5-A)PYRAZINE; IMIDAZOLE DERIVATIVE; METAL; PYRAZINE DERIVATIVE;

ARTICLE; CHEMICAL STRUCTURE; CHEMISTRY; CYCLIZATION; QUANTUM THEORY; STEREOISOMERISM; SYNTHESIS;

CYCLIZATION; IMIDAZOLES; METALS; MOLECULAR STRUCTURE; PYRAZINES; QUANTUM THEORY; STEREOISOMERISM;

EID: 70749153146     PISSN: 15237060     EISSN: None     Source Type: Journal    
DOI: 10.1021/ol901889e     Document Type: Article

References (36)

1. Wang, J.-X.; McCubbin, J. A.; Jin, M.; Laufer, R. S.; Mao, Y.; Crew, A. P.; Mulvihill, M. J.; Snieckus, V. Org. Lett. 2008, 10, 2923.
2. Queguiner, G.; Marsais, F.; Snieckus, V.; Epsztajn, J. Adv. Heterocycl. Chem. 1991, 52, 187.
3. Turck, A.; Pié, N.; Mongin, F.; Queguiner, G. Tetrahedron 2001, 57, 4489.
4. Whisler, M. C.; MacNeil, S.; Snieckus, V.; Beak, P. Angew. Chem., Int. Ed. 2004, 43, 2206.
5. Examples of such biological applications are; IGF-IR inhibitors, for example; (a) Mulvihill, M. J.; Ji, Q.-S.; Coate, H. R.; Cooke, A.; Dong, H.; Feng, L.; Foreman, K.; Rosenfeld-Franklin, M.; Honda, A.; Mak, G.; Mulvihill, K. M.; Nigra, A. I.; O'Connor, M.; Pirrit, C.; Steinig, A. G.; Siu, K.; Stolz, K. M.; Sun, Y.; Tavares, P. A. R.; Yao, Y.; Gibson, N. W. Bioorg. Med. Chem. 2008,16, 1359. c-SRC inhibition and treatment of acute ischemic stroke.
6. (b) Mukaiyama, H.; Nishimura, T.; Kobayashi, S.; Ozawa, T.; Kamada, N.; Komatsu, Y.; Kikuchi, S.; Oonota, H.; Kusama, H. Bioorg. Med. Chem. 2007, 15, 868. Corticotropin releasing hormone receptor ligands.
7. (c) Hartz, R. A.; Gilligan, P. J.; Nanda, K. K.; Tebben, A. J.; Fitzgerald, L. W.; Miller, K. Bioorg. Med. Chem. Lett. 2002, 12, 291.
8. Initial syntheses of imidazo[1,5-a]pyrazines; (a) Abushanab, E.; Bindra, A. P.; Goodman, L.; Peterson, H., Jr. J. Org. Chem. 1973, 38, 2049.
9. (b) Abushanab, E.; Bindra, A. P.; Lee, D. Y.; Goodman, L. J. Heterocycl. Chem. 1975, 12, 211.
10. (c) Abushanab, E.; Bindra, A. P.; Goodman, L. J. Heterocycl. Chem. 1975, 12, 207.
11. (d) Abushanab, E.; Bindra, A. P.; Lee, D. Y.; Goodman, L. J. Org. Chem. 1975, 40, 3373.
12. (e) Abushanab, E.; Lee, D. Y.; Goodman, L. J. Org. Chem. 1975, 40, 3376.
13. (f) Abushanab, E.; Lee, D. Y.; Goodman, L. J. Org. Chem. 1975, 40, 33792. Syntheses of more highly substituted imidazo[1,5-a]pyrazines.
14. (g) Albert, A.; Ohta, K. J. Chem. Soc. (C) 1970, 11, 1540.
15. (h) Davey, D. D. J. Org. Chem. 1987, 52, 4379.
16. (i) Chattopadhyay, G.; Ray, S. J. Chem. Res. Synop. 1992, 5, 170.
17. (j) Marchand, E.; Morel, G. Tetrahedron Lett. 1993, 34, 2319.
18. (k) Trček, T.; Meden, A.; Verček, B. Synlett 2000, 10, 1458.
19. (l) Eltsov, O. S.; Mokrushin, V. S.; Tkachev, A. V. Russ. Chem. Bull., Int. Ed. 2004, 53, 2293.
20. (m) Trček, T.; Verček, B. Synthesis 2006, 20, 3437.
21. (n) Mulvihill, K. M.; Castelhano, A. L. US Patent 2007/0129547 Al.
22. The N-protected imidazole C2-TMS system is moderately unstable towards nucleophilic attack at silicon even when generated in situ, and its isolation can be highly problematic due to hydrolysis; Carpenter, A. J.; Chadwick, D. J. Tetrahedron 1986, 42, 2351.
23. For previous work on benzamide dianions, see; Mills, R. J.; Horvath, R. F.; Sibi, M. P.; Snieckus, V. Tetrahedron Lett. 1985, 26, 1145.
24. Zhao, Z.; Jaworski, A.; Piel, I.; Snieckus, V. Org. Lett. 2008, 10, 2617.
25. Denmark, S. E.; Sweis, R. F. Metal-Catalysed Cross-Coupling Reactions; de Meijere, A., Diederich, F., Eds.; Wiley-VCH; Weinheim, Germany, 2004; Vol.1, Chapter 4, p 163.
26. For successful results of such an expectation in furan and thiophene amide directed ortho metalation derived dianions, see; Doadt, E. G.; Snieckus, V. Tetrahedron Lett. 1985, 26, 1149.
27. 2 quench experiment, even when excess base was used.
28. See Supporting Information.
29. 2, see Kantlehner, W.; Kapassakalidis, J. J. Synthesis 1981, 6, 480. with LDA, see Bhasin, K. K.; Singh, J.; Singh, K. N. Phosphorus, Sulfur Silicon Relat. Elem. 2002, 177, 597. with "BuLi, see Andrews, I. P; Lewis, N. J.; McKillop, A.; Wells, A. S. Heterocycles 1996, 43, 1151.) usually occurs at the alkyl group.
30. Ayers, P. W.; Anderson, J. S. M.; Bartolotti, L. J. Int. J. Quantum Chem. 2004, 101, 520.
31. The general applicability of this approach to predict metalation sites is being actively explored.
32. Fu, J.-M.; Snieckus, V. Can. J. Chem. 2000, 78, 905.
33. Zhao, Z.; Snieckus, V. Org. Lett. 2005, 7, 2523.
34. The structure was confirmed by single crystal X-ray analysis, see Supporting Information.
35. Under the same reaction conditions, the C8-C1 analogue 7a gave only a chromatographically inseparable mixture (silica gel flash chromatography) of at least three compounds, presumably due to complications, in part, resulting from the greater reactivity of the C8-C1 over C8-OMe group.
36. Generation of an imidazo[1,2-a]pyrazine dilithiated species, as evidenced by the formation of dideuterated product upon DCl quench, has been previously reported, see; Vitse, O.; Bompart, J.; Subra, G.; Viols, H.; Escale, R.; Chapat, J. P.; Bonnet, P. A. Tetrahedron 1998, 54, 6485.