10.1021/ol400444g r XXXX American Chemical Society ORGANIC LETTERS XXXX Vol. XX, No. XX 000–000 Indoles Synthesized from Amines via Copper Catalysis Ronald Besandre, Miguel Jaimes, and Jeremy A. May* Department of Chemistry, University of Houston, 136 Fleming Building, Houston, Texas 77204-5003, United States jmay@uh.edu Received February 16, 2013 ABSTRACT N-Substituted indoles are synthesized from primary amines through a tandem reaction sequence. Initial condensation of the amine with an R-(o-haloaryl)ketone or aldehyde is followed by intramolecular aryl amination catalyzed by CuI. A variety of anilines and alkyl amines, including those with significant steric demands, are converted to indoles in high yields and with varying indole substitution. Methods for indole synthesis are important in natural product synthesis 1 and medicinal chemistry. 2 Consequently, a myriad of methods for their synthesis have been reported. 3 A noticeably underexploited synthetic strategy is to build indoles from amines. 3b Such an approach would allow for indoles with large and/or complex N-substituents, which are difficult to introduce to existing indoles, to be built from the appropriate amines. 4 An implementation of this approach could use readily available R-aryl ketones 2 5 via a tandem 6 imine formation/N-arylation sequence (Scheme 1). 7 While a few examples of palladium-catalyzed indole for- mation similar to this approach have been disclosed, 8,9 few reports use copper-catalyzed arylation of imines to form indoles, 10,11 even though copper catalysis offers advan- tages over palladium. 12 The few examples of copper cata- lysis do not use the facile formation of imines from R-aryl ketones and aldehydes to set up CÀN bond formation, but require more roundabout syntheses of enamines via con- densations or conjugate additions that limit substrate scope. 13 Attempts at initial copper-catalyzed amino-arylation to form aniline 3, which would be followed by dehydrative cyclization to indole 6, produced only benzofurans 4. 14 (1) (a) McInnes, A. G.; Taylor, A.; Walter, J. A. J. Am. Chem. Soc. 1976, 98, 6741. (b) Kikuchi, T.; Kadota, S.; Nakamura, K.; Nishi, A.; Taga, T.; Kaji, T.; Osaki, K.; Tubaki, K. Chem. Pharm. Bull. 1982, 30, 3846. (c) Saito, T.; Suzuki, Y.; Koyama, K.; Natori, S.; Iitaka, Y.; Kinoshita, T. Chem. Pharm. Bull. 1988, 36, 1942. (d) Yamada, A.; Kitamura, H.; Yamaguchi, K.; Fukuzawa, S.; Kamijima, C.; Yazawa, K.; Kuramoto, M.; Wang, G. Y. S.; Fujitani, Y.; Uemura, D. Bull. Chem. Soc. Jpn. 1997, 70, 3061. (e) Levy, L. M.; Cabrera, G. M.; Wright, J. E.; Seldes, A. M. Phytochemistry 2000, 54, 941. (f) Nakao, Y.; Kuo, J.; Yoshida, W. Y.; Kelly, M.; Scheuer, P. J. Org. Lett. 2003, 5, 1387. (g) Fujimoto, H.; Sumino, M.; Okuyama, E.; Ishibashi, M. J. Nat. Prod. 2004, 67, 98. (h) Takayama, H.; Mori, I.; Kitajima, M.; Aimi, N.; Lajis, N. H. Org. Lett. 2004, 6, 2945. (i) Li, G.-Y.; Li, B.-G.; Yang, T.; Yan, J.-F.; Liu, G.-Y.; Zhang, G.-L. J. Nat. Prod. 2006, 69, 1374. (j) Zhou, H.; He, H. P.; Wang, Y. H.; Hao, X. J. Helv. Chim. Acta 2010, 93, 1650. (k) Schallenberger, M. A.; Newhouse, T.; Baran, P. S.; Romesberg, F. E. J. Antibiot. 2010, 63, 685. (2) (a) Testa, B.; Murset Rossetti, L. Helv. Chim. Acta 1978, 61, 2530. (b) Watanabe, M.; Koike, H.; Ishiba, T.; Okada, T.; Seo, S.; Hirai, K. Bioorg. Med. Chem. 1997, 5, 437. (c) Yutilov, Y. M.; Smolyar, N. N.; Volchkov, A. S. Pharm. Chem. J. 2000, 34, 661. (d) Ivanov, Y. I.; Afanas’ ev, A. Z.; Bachurin, S. O. Pharm. Chem. J. 2001, 35, 353. (e) Yamamoto, A.; Ichihara, K.; Hoshi, K. J. Pharm. Pharmacol. 2001, 53, 227. (f) Miller, C. P.; Collini, M. D.; Tran, B. D.; Harris, H. A.; Kharode, Y. P.; Marzolf, J. T.; Moran, R. A.; Henderson, R. A.; Bender, R. H. W.; Unwalla, R. J.; Greenberger, L. M.; Yardley, J. P.; Abou-Gharbia, M. A.; Lyttle, C. R.; Komm, B. S. J. Med. Chem. 2001, 44, 1654. (g) Likhosherstov, L. M.; Novikova, O. S.; Zheltova, A. O.; Shibaev, V. N. Russian Chem. Bull. 2005, 54, 1294. (3) (a) Sundberg, R. J. Indoles; Academic Press: 1996; p 175. (b) Taber, D. F.; Tirunahari, P. K. Tetrahedron 2011, 67, 7195. (c) Cacchi, S.; Fabrizi, G. Chem. Rev. 2011, 111, PR215. (d) Vicente, R. Org. Biomol. Chem. 2011, 9, 6469. (4) (a) Ackermann, L.; Barf€ usser, S.; Potukuchi, H. K. Adv. Synth. Catal. 2009, 351, 1064. (b) Ball, C. J.; Willis, M. C. Eur. J. Org. Chem. 2012, 2013, 425. (5) (a) Willis, M. C.; Taylor, D.; Gillmore, A. T. Org. Lett. 2004, 6, 4755. (b) Liao, X.; Stanley, L. M.; Hartwig, J. F. J. Am. Chem. Soc. 2011, 133, 2088. (c) Nielsen, D. K.; Doyle, A. G. Angew. Chem., Int. Ed. 2011, 50, 6056. (d) Huang, X.; Maulide, N. J. Am. Chem. Soc. 2011, 133, 8510. (e) Huang, D. S.; DeLuca, R. J.; Hartwig, J. F. Org. Synth. 2011, 88, 4. (6) (a) Denmark, S. E.; Thorarensen, A. Chem. Rev. 1996, 96, 137. (b) Zou, B.; Yuan, Q.; Ma, D. Angew. Chem., Int. Ed. 2007, 46, 2598. (7) (a) Hesse, S.; Kirsch, G. Synthesis 2007, 2007, 1571. (b) Schultz, D.; Wolfe, J. Synthesis 2012, 44, 351.