A3 coupling reaction

The A3 coupling (also known as A3 coupling reaction or the aldehyde-alkyne-amine reaction), coined by Prof. Chao-Jun Li of McGill University, is a type of multicomponent reaction involving an aldehyde, an alkyne and an amine which react to give a propargylamine.[1][2][3][4][5]

The reaction proceeds via direct dehydrative condensation[3] and requires a metal catalyst, typically based on ruthenium/copper, gold or silver.[3] Chiral catalyst can be used to give an enantioselective reaction, yielding a chiral amine. The solvent can be water.[3] In the catalytic cycle the metal activates the alkyne to a metal acetylide, the amine and aldehyde combine to form an imine which then reacts with the acetylide in a nucleophilic addition.[3] The reaction type was independently reported by three research groups in 2001 -2002;[6][7][8] one report on a similar reaction dates back to 1953.[9][10]

If the amine substituents have an alpha hydrogen present and provided a suitable zinc or copper catalyst is used, the A3 coupling product may undergo a further internal hydride transfer and fragmentation to give an allene in a Crabbé reaction.

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  5. ^ Rokade, Balaji V.; Barker, James; Guiry, Patrick J. (2019). "Development of and recent advances in asymmetric A3 coupling". Chemical Society Reviews. 48 (18): 4766–4790. doi:10.1039/C9CS00253G. PMID 31465045. S2CID 201665168.
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  10. ^ Cite error: The named reference Liu was invoked but never defined (see the help page).
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