Abstract
A new synthesis of the 2,6-naphthyridine alkaloid 4-methyl-2,6-naphthyridine from Antirrhinum majus has been developed. Key steps are a regioselective oxidation of 3-bromo-4,5- dimethylpyridine to the corresponding 4-formyl derivative, and the annulation of the second pyridine ring by Suzuki-Miyaura cross-coupling using (E)-2-ethoxyvinylboronic acid pinacol ester as a masked acetaldehyde equivalent. This protocol gives the alkaloid in four steps starting from commercially available 3,4-dimethylpyridine in 15% overall yield. This annulation protocol should be useful for the synthesis of other condensed pyridines as well.
Keywords: Alkaloid, naphthyridine, oxidation, annulation, Suzuki-Miyaura coupling, enol ether.
Graphical Abstract
(b)Dai, J.; Li, N.; Wang, J.; Schneider, U. Molecules, 2016, 21, 493.
(b)Pan, E.; Cao, S.; Brodie, P.J.; Callmander, M.W.; Randrianaivo, R.; Rakotonandrasana, S.; Rakotobe, E.; Rasamison, V.E.; TenDyke, K.; Shen, Y.; Suh, E.M.; Kingston, D.G.I. J. Nat. Prod., 2011, 74, 1169-1174.
(b)Sharma, V.; Sharma, P.C.; Kumar, V. J. Adv. Res., 2015, 6, 63-71.
(b)Harkiss, K.J. Planta Med., 1972, 21, 84-88.
(c)Brooker, S.E.; Harkiss, K.J. Planta Med., 1974, 26, 305-310.
(b)Bracher, F. Liebigs Annalen der. Chem., 1990, 205-206.
(c)Bracher, F. Heterocycles, 1989, 29, 2093-2095.
(d)Bracher, F. Liebigs Ann. Chem., 1992, 1205-1207.
(e)Plodek, A.; Bracher, F. Tetrahedron Lett., 2015, 56, 1445-1447.
(f)Melzer, B.; Plodek, A.; Bracher, F. J. Org. Chem., 2014, 79, 7239-7242.
(g)Bontemps, N.; Delfourne, E.; Bastide, J.; Francisco, C.; Bracher, F. Tetrahedron, 1997, 53, 1743-1750.
(h)Bracher, F. Pharmazie, 1993, 48, 521-523.
(i)Bracher, F.; Papke, T. Liebigs Ann., 1996, 115-116.
(b)Litvinov, V.P. Adv. Heterocycl. Chem., 2006, 91, 189-300.
(c)Haraburda, E.; Lledo, A.; Roglans, A.; Pla-Quintana, A. Org. Lett., 2015, 17, 2882-2885.
(d)Engelhardt, H.; Arnhof, H.; Carotta, S.; Hofmann, M.H.; Kerenyi, M.; Scharn, D. New Phenylpyrazolylacetamide Compounds and Derivatives as Cdk8/Cdk19 Inhibitors. WO2017202719 (A1), November 30 2017.
(b)Van Den Haak, H.J.W.; Van Der Plas, H.C.; Van Veldhuizen, B. J. Heterocycl. Chem., 1981, 18, 1349-1352.
(c)Sakamoto, T.; Kondo, Y.; Yamanaka, H. Chem. Pharm. Bull. , 1985, 33, 626-633.
(b)Roberts, D.; Joule, J.A.; Bros, M.A.; Alvarez, M. J. Org. Chem., 1997, 62, 568-577.
(c)Dombeck, F.; Bracher, F. Die Pharmazie - An International. Journal of Pharmaceutical Sciences, 2006, 61, 387-390.
(b)Petersen, I.N.; Crestey, F.; Jensen, A.A.; Indurthi, D.C.; Pedersen, H.; Andreasen, J.T.; Balle, T.; Kristensen, J.L. ACS Med. Chem. Lett., 2015, 6, 472-475.
(b)Hoelder, S.; Blagg, J.; Solanki, S.; Woodward, H.; Naud, S.; Bavetsias, V.; Sheldrake, P.; Innocenti, P.; Cheung, J.A. Preparation of isoquinoline and pyrido[3,4- d]pyrimidine derivatives as Mps1 inhibitors. WO2014037750 (A1), March 13 2014.