Combes quinoline synthesis
The Combes quinoline synthesis is a chemical reaction, which was first reported by Combes in 1888. Further studies and reviews of the Combes quinoline synthesis and its variations have been published by Alyamkina et al.,[1] Bergstrom and Franklin,[2] Born,[3] and Johnson and Mathews.[4]
The Combes
Conrad-Limpach synthesis and the Doebner reaction
.
It involves the condensation of unsubstituted anilines (1) with β-diketones (2) to form substituted quinolines (4) after an acid-catalyzed ring closure of an intermediate Schiff base (3).[5][6]
Mechanism
The
tautomerizes to form an enamine that gets protonated via the acid catalyst, which is commonly concentrated sulfuric acid (H2SO4). The second major step, which is also the rate-determining step, is the annulation of the molecule. Immediately following the annulation, there is a proton transfer, which eliminates the positive formal charge on the nitrogen atom. The alcohol is then protonated, followed by the dehydration of the molecule, resulting in the end product of a substituted quinoline
.
Regioselectivity
The formation of the
regioisomer
as the product.
Importance of Quinoline Synthesis
There are multiple ways to synthesize
HIV-1 integrase inhibitors. They also looked at how the substituent placement on the quinoline
derivatives affected the primary anti-HIV inhibitory activity.
See also
- Conrad-Limpach reaction
- Doebner reaction
- Doebner-Miller reaction
- Skraup synthesis
References
- S2CID 94147793.
- ^ Bergstrom, F.W.; Franklin, E.C. (1944). Hexacyclic Compounds: Pyridine, Quinoline, and Isoquinoline in Heterocyclic Nitrogen Compounds. California: Department of Chemistry, Stanford University. p. 156.
- .
- .
- ^ Combes, A (1888). Bull. Soc. Chim. Fr. 49: 89.
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(help) - .
- ISBN 978-3-642-01053-8.
- doi:10.1002/poc.1433.
- ^ "Quinolines". Sigma-Aldrich. Sigma-Aldrich Co. LLC. Retrieved 7 December 2013.
- ^ Luo, Z.G.; Zeng, C.C; Wang, F.; HE, H.Q.; Wang, C.X. (2009). "Synthesis and Biological Activities of Quinoline Derivatives as HIV-1 Integrase Inhibitors". Chem. Res. Chinese Universities. 25: 841–845.
Further reading
- Alyamkina, E.A.; Yamashkin, S.A.; Artayeva, N.N.; Yurovskaya, M.A. (2010). "Using of 4-amino-2-phenylindoles in the synthesis of pyrroloquinolines by the Combes Reaction". Moscow University Chemistry Bulletin. 65 (5): 335–340. S2CID 94147793.
- Bergstrom, F.W. and Franklin, E.C. Hexaacylic Compounds: Pyridine, Quinoline, and Isoquinoline In Heterocyclic Nitrogen Compounds. California: Department of Chemistry, Stanford University, 1944, 156.
- Born, J.L. (1972). "The mechanism of formation of benzo[g]quinolines via the Combes reaction". J. Org. Chem. 37 (24): 3952–3953. .
- Johnson, W.S.; Mathews, F.J. (1944). "Cyclization studies in the benzoquinoline series". J. Am. Chem. Soc. 66 (2): 210–215. .
- Luo, Z.G; Zeng, C.C.; Wang, F.; HE; Wang, C.X. (2009). "Synthesis and biological activities of quinoline derivatives as HIV-1 integrase inhibitors". Chem. Res. Chinese Universities. 25: 841–845.
- Misani, F.; Bogert, M.T. (1945). "The search for superior drugs for tropical diseases. III. Further experiments in the quinoline group". J. Org. Chem. 10 (5): 458–463. PMID 21004582.
- Roberts, E.; Turner, E.E. (1927). "The factors controlling the formation of some derivatives of quinoline, and a new aspect of the problem of substitution in the quinoline series". J. Chem. Soc.: 1832–1857. .
- Sloop, J.C. (2009). "Quinoline formation via a modified Combes reaction: examination of kinetics, substituent effects, and mechanistic pathways". J. Phys. Org. Chem. 22 (2): 110–117. doi:10.1002/poc.1433.