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] 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.

[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.

The imine can isomerise and the alkyne group is placed at the other available nitrogen alpha position.