ashfeld redn ol 2010

Titanocene-Catalyzed Conjugate Reduction of r , β-Unsaturated Carbonyl Derivatives Andrew D. Kosal and Brandon L. Ashfeld* Department of Chemistry and Biochemistry, UniVersity of Notre Dame, Notre Dame, Indiana 46556 [email protected] Received October 21, 2009 ABSTRACT A titanocene-catalyzed conjugate reduction of r , β-unsaturated carbonyl derivatives has been developed. A series of carbonyl compounds including aldehydes, ketones, esters, and amides proved viable in the reduction process providing an efficient, chemoselective method for the catalytic reduction of unsaturated carbonyl derivatives. The chemoselective 1,4-reduction of R , β-unsaturated carbonyl derivatives is an important tactic in organic synthesis. 1 In recent years, a number of significant advances have been made toward the development of efficient and economical protocols for achieving this transformation with substantial emphasis placed on the use of transition metal catalysts. As a result, a number of metals have been shown to facilitate the conjugate reduction of R , β-unsaturated carbonyls, including palladium, 2 rhodium, 3 magnesium, 4 and others, 5 of which copper hydrid e comple xes are quite possibly the most widely utilized and have arguably demonstrated the greatest synthetic utility. 6 A number of alkali and lanthan ide metal-based rea gen ts hav e shown use ful lev els of rea cti vit y, but the procedures often suffer from chemoselectivity issues. 7 In many ways, concerns associated with synthetic inef- ficiency, the high cost of chemical research, and the need for hazardous reaction conditions can be alleviated through the use of transition metals in a catalytic fashion. To the best of our knowledge, there has yet to be discovered a (1) (a) Mahoney, W. S.; Brestensk y, D. M.; Stryker, J. M. J. Am. Chem. Soc. 1988, 110 , 291. (b) Haskel, A.; Keinan, E. Palladium-catalyzed 1,4- reduction (conjugate reduction). In Handbook of Organopalladium Chem- istry for Organic Synthesis; Negishi, E.-i., de Meijere, A., Eds.; Wiley: New York , 2002; Vol. 2, p 2767. (c) Shibata, I. Organomet. News 2004, 53. (d) Nishiyama, H. Kagaku (Kyoto, Jpn.) 2005, 60 , 72. (2) (a) Four, P.; Guibe, F. Tetrahedron Lett. 1982, 23, 1825. (b) Keinan, E.; Green spoon, N. Tetrahedr on Lett. 1985, 26 , 135 3. (c) Keinan, E.; Green spoo n, N. J. Am. Chem. Soc. 1986, 108, 731 4. (d) Otsuka, H.; Shirakawa, E.; Hayashi, T. Chem. Commun. 2007, 1819. For examples of enantioselective conju gate redu ctions catalyzed by pallad ium, see :(e) Tsuchiya, Y.; Hamashima, Y.; Sodeoka, M. Org. Lett. 2006, 8 , 4851. (f) Monguchi, D.; Beemelmanns, C.; Hashizume, D.; Hamashima, Y.; Sodeoka, M. J. Organomet. Chem. 2008, 693, 867. (3) (a) Evans, D. A.; Fu, G. C. J. Org. Chem. 1990, 55, 5678. (b) Wang, Z.; Zou, G.; Tang, J. Chem. Commu n. 2004, 1192. For example s of ena nti ose lect ive conjug ate red uct ions cata lyz ed by rho diu m, see: (c) Kanazawa, Y.; Nishiyama, H. Synlett 2006, 3343. (4) (a) You n, I. K.; Yon, G. H.; Pak , C. S. Tetrahedron Lett. 1986, 27 , 2409. (b) Hudlicky, T.; Sinai-Zingde, G.; Natchus, M. G. Tetrahedron Lett. 1987, 28, 5287. (c) Hutchins, R. O.; Suchismita; Zipkin, R. E.; Taffer, I. M.; Sivakumar, R.; Monaghan, A.; Elisseou, E. M. Tetrahedron Lett. 1989, 30, 55. (5) (a) Keinan, E.; Perez, D. J. Org. Chem. 1987, 52 , 2576. (b) Hays, D. S.; Scholl, M.; Fu, G. C. J. Org. Chem. 1996, 61, 6751. (c) Magnus, P.; Waring, M. J.; Scott, D. A. Tetrahedron Lett. 2000, 41 , 9731. (6) (a) Tsuda, T.; Fujii, T.; Kawasaki, K.; Saegusa, T. J. Chem. Soc., Chem. Commun. 1980, 1013. (b) Mahoney, W. S.; Stryker, J. M. J. Am. Chem. Soc. 1989, 111, 8818. (c) Lipshutz, B. H.; Keith, J.; Papa, P.; Vivian, R. Tetrahedron Lett. 1998, 39, 4627. (d) Chiu, P. Synthesis 2004, 2210. (e) Kim, D.; Park, B.-M.; Yun, J. Chem. Commun. 2005, 1755. For examples of enanti oselec tive conjugate reductio ns catalyz ed by coppe r, see: (f) Appella, D. H.; Moritani, Y.; Shintani, R.; Ferreira, E. M.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 9473. (g) Mori tani, Y.; Appella, D. H.; Jurkauskas, V.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122 , 6797. (h) Jurkauskas, V.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 2892. (i) Czekelius, C.; Carreira, E. M. Angew. Chem., Int. Ed. 2003, 42 , 4793. (j) Hughes, G.; Kimura, M.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125 , 11253. (k) Lipshutz, B. H.; Servesko, J. M. Angew. Chem., Int. Ed. 2003, 42, 4789. (l) Czekelius, C.; Carreira, E. M. Org. Lett. 2004, 6 , 4575. (m) Lipsh utz, B. H.; Serves ko, J. M.; Petersen , T. B.; Papa, P. P.; Lover, A. A. Org. Lett. 2004, 6 , 1273. (n) Rainka, M. P.; Milne, J. E.; Buchwald, S. L. Angew. Chem., Int. Ed. 2005, 44 , 6177. (o) Lipshutz, B. H.; Tanaka, N.; Taft, B. R.; Lee, C.-T. Org. Lett. 2006, 8 , 1963. (p) Llamas, T.; Arraya ´s, R. G.; Carretero, J. C. Angew. Chem., Int. Ed. 2007, 46 , 3329. ORGANIC LETTERS 2010 Vol. 12, No. 1 44-47 10.1021/ol9024315 © 2010 American Chemical Society Published on Web 12/07/2009

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