N-Heterocyclic Carbene-Catalyzed Intramolecular Aldehyde-Nitrile Cross Coupling: An Easy Access to 3- Aminochromones † Seenuvasan Vedachalam, Jing Zeng, Bala Kishan Gorityala, Meraldo Antonio, and Xue-Wei Liu* DiVision of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological UniVersity, Singapore 637371 xuewei@ntu.edu.sg Received November 22, 2009 ABSTRACT An immense effort has been made to develop an efficient strategy for the carbon-carbon bond formation between aldehyde and nitrile intramolecularly using an N-heterocyclic carbene catalyst to derive 3-aminochromone derivatives in good to excellent yields (80-95%). Chromone is one of the most common heterocyclic motifs found in pharmaceutically active compounds. 1 One of the most important subfamilies of chromone is 3-aminochromone, whose derivatives show interesting therapeutic effects. 2 From previous research efforts, a wide variety of functionalized 3-aminochromone derivatives have been identified to possess anti-inflammatory (T-614)(I), 3 antirheumatic (I), 4 leukemic B-cells apoptosis (II), 5 and antimutagenic (II) activities. 6 They were found to be effective in the selective inhibition † Dedicated to Professor Charles E. McKenna on the occasion of his 65th birthday. (1) (a) Gobbi, S.; Cavalli, A.; Rampa, A.; Belluti, F.; Piazzi, L.; Paluszcak, A.; Hartmann, R. W.; Recanatini, M.; Bisi, A. J. Med. Chem. 2006, 49, 4777–4780. (b) Nutley, B. P.; Smith, N. F.; Hayes, A.; Kelland, L. R.; Brunton, L.; Golding, B. T.; Smith, G. C. M.; Martin, N. M. B.; Workman, P.; Raynaud, F. I. Br. J. Cancer. 2005, 93, 1011–1018. (c) Boumendjel, A.; Nicolle, E.; Moraux, T.; Gerby, B.; Blanc, M.; Ronot, X.; Boutonnat, J. J. Med. Chem. 2005, 48, 7275–7281. (d) Ahmed-Belkacem, A.; Pozza, A.; Mun ˜oz-Martı ´nez, F.; Bates, S. E.; Castanys, S.; Gamarro, F.; Di Pietro, A.; Pe ´rez-Victoria, J. M. Cancer Res. 2005, 65, 4852–4860. (e) Morris, J.; Wishka, D. G.; Lin, A. H.; Humphrey, W. R.; Wiltse, A. L.; Gammill, R. B.; Judge, T. M.; Bisaha, S. N.; Olds, N. L.; Jacob, C. S.; Bergh, C. L.; Cudahy, M. M.; Williams, D. J.; Nishizawa, E. E.; Thomas, E. W.; Gorman, R. R.; Benjamin, C. W.; Shebusk, R. J. J. Med. Chem. 1993, 36, 2026–2032. (f) Horie, T.; Tominaga, H.; Kawamura, Y.; Hada, T.; Ueda, N.; Amano, Y.; Yamamoto, S. J. Med. Chem. 1991, 34, 2169– 2176. (2) Dauzonne, D.; Folle ´as, B.; Martinez, L.; Chabot, G. G. Eur. J. Med. Chem. 1997, 32, 71–82. (3) (a) Sawada, T.; Hashimoto, S.; Tohma, S.; Nishioka, Y.; Nagai, T.; Sato, T.; Ito, K.; Inoue, T.; Iwata, M.; Yamamoto, K. Immunopharmacol. 2000, 49, 285–294. (b) Inaba, T.; Tanaka, K.; Takeno, R.; Nagaki, H.; Yoshida, C.; Takano, S. Chem. Pharm. Bull. 2000, 48, 131–139. (4) (a) Tanaka, K.; Yamamoto, T.; Aikawa, Y.; Kizawa, K.; Muramoto, K.; Matsuno, H.; Muraguchi, A. Rheumatology 2003, 42, 1365–1371. (b) Kuriyama, K.; Higuchi, C.; Tanaka, K.; Yoshikawa, H.; Itoh, K. Biochem. Biophys. Res. Commun. 2002, 299, 903–909. (c) Aikawa, Y.; Yamamoto, M.; Yamamoto, T.; Morimoto, K.; Tanaka, K. Inflammation Res. 2002, 51, 188–194. (d) Kawakami, A.; Tsuboi, M.; Urayama, S.; Matsuoka, N.; Yamasaki, S.; Hida, A.; Aoyagi, T.; Furuichi, I.; Nakashima, T.; Migita, K.; Kawabe, Y.; Nakashima, M.; Origuchi, T.; Eguchi, K. J. Lab. Clin. Med. 1999, 133, 566–574. (e) Aikawa, Y.; Tanuma, N.; Shin, T.; Makino, S.; Tanaka, K.; Matsumoto, Y. J. Neuroimmunol. 1998, 89, 35–42. ORGANIC LETTERS 2010 Vol. 12, No. 2 352-355 10.1021/ol9026232  2010 American Chemical Society Published on Web 12/21/2009