Combes quinoline synthesis

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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
.

The Combes quinoline synthesis
The Combes quinoline synthesis

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

Combes Quinoline Synthesis Mechanism
Combes Quinoline Synthesis 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.

Quinoline structure

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

References

  1. S2CID 94147793
    .
  2. ^ 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.
  3. .
  4. .
  5. ^ Combes, A (1888). Bull. Soc. Chim. Fr. 49: 89. {{cite journal}}: Missing or empty |title= (help)
  6. .
  7. .
  8. .
  9. ^ "Quinolines". Sigma-Aldrich. Sigma-Aldrich Co. LLC. Retrieved 7 December 2013.
  10. ^ 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