Generic placeholder image

Letters in Organic Chemistry

Editor-in-Chief

ISSN (Print): 1570-1786
ISSN (Online): 1875-6255

Letter Article

A Short Synthesis of the Plant Alkaloid 4-Methyl-2,6-naphthyridine

Author(s): Alexandra Kamlah and Franz Bracher*

Volume 16, Issue 12, 2019

Page: [931 - 934] Pages: 4

DOI: 10.2174/1570178616666181116110647

Price: $65

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

[1]
Bracher, F.; Mink, K. Liebigs Ann. Chem., 1995, 645-647.
[2]
Janot, M.; Guilhem, J.; Contz, O.; Venera, G.; Clonga, E. Ann. Pharm. Fr., 1979, 37, 413-420.
[3]
Lotter, M.; Schilling, J.; Reimann, E.; Bracher, F. Arch. Pharm. (Weinheim), 2006, 339, 677-679.
[4]
Ripperger, H. Phytochemistry, 1978, 17, 1069-1070.
[5]
Lotter, M.; Bracher, F. Sci. Pharm., 2009, 77, 1-7.
[6]
Bracher, F. Archiv der. Pharm. (Weinheim), 1989, 322, 511-512.
[7]
Larghi, E.L.; Bohn, M.L.; Kaufman, T.S. Tetrahedron, 2009, 65, 4257-4282.
[8]
(a)Bracher, F.; Tremmel, T. Mini Rev. Org. Chem., 2017, 14, 92-98.
(b)Dai, J.; Li, N.; Wang, J.; Schneider, U. Molecules, 2016, 21, 493.
[9]
(a)Bracher, F. Liebigs Annalen der. Chem., 1989, 87-88.
(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.
[10]
(a)Plodek, A.; Bracher, F. Mar. Drugs, 2016, 14, 26.
(b)Sharma, V.; Sharma, P.C.; Kumar, V. J. Adv. Res., 2015, 6, 63-71.
[11]
(a)Harkiss, K.J.; Swift, D. Tetrahedron Lett., 1970, 11, 4773-4774.
(b)Harkiss, K.J. Planta Med., 1972, 21, 84-88.
(c)Brooker, S.E.; Harkiss, K.J. Planta Med., 1974, 26, 305-310.
[12]
Taurins, A.; Li, R.T. Can. J. Chem., 1974, 52, 843-848.
[13]
(a)Bracher, F. Archiv der. Pharm. , 1989, 322, 293-294.
(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.
[14]
Reviews: (a)Litvinov, V.P.; Roman, S.V.; Dyachenko, V.D. Russ. Chem. Rev., 2000, 69, 201-220.
(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.
[15]
(a)Giacomello, G.; Gualtieri, F.; Riccieri, F.M.; Stein, M.L. Tetrahedron Lett., 1965, 6, 1117-1121.
(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.
[16]
Numata, A.; Kondo, Y.; Sakamoto, T. Synthesis, 1999, 306-311.
[17]
Kamlah, A.; Lirk, F.; Bracher, F. Tetrahedron, 2016, 72, 837-845.
[18]
Jones, K.; Escudero-Hernandez, M.L. Tetrahedron, 1998, 54, 2275-2280.
[19]
Vismara, E.; Fontana, F.; Minisci, F. Gazz. Chim. Ital., 1987, 117, 135-136.
[20]
(a)Estévez, C.; Venemalm, L.; Alvarez, M.; Joule, J.A. Tetrahedron, 1994, 50, 7879-7888.
(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.
[21]
Sakamoto, T.; Kondo, Y.; Yasuharu, A.; Yamanaka, H. Heterocycles, 1990, 31, 219-221.
[22]
(a)Crestey, F.; Hooyberghs, G.; Kristensen, J.L. Tetrahedron, 2012, 68, 1417-1421.
(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.
[23]
Whelligan, D.K.; Thomson, D.W.; Taylor, D.; Hoelder, S. J. Org. Chem., 2010, 75, 11-15.
[24]
(a)Innocenti, P.; Woodward, H.; O’Fee, L.; Hoelder, S. Org. Biomol. Chem., 2015, 13, 893-904.
(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.

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy