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 propargyl amine. [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.
One variation is called the decarboxylative A3 coupling. [11] In this reaction the amine is replaced by an amino acid. The imine can isomerise and the alkyne group is placed at the other available nitrogen alpha position. [11] [12] [13] This reaction requires a copper catalyst. The redox A3 coupling has the same product outcome but the reactants are again an aldehyde, an amine and an alkyne as in the regular A3 coupling. [11] [14] [15] [16]
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 propargyl amine. [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.
One variation is called the decarboxylative A3 coupling. [11] In this reaction the amine is replaced by an amino acid. The imine can isomerise and the alkyne group is placed at the other available nitrogen alpha position. [11] [12] [13] This reaction requires a copper catalyst. The redox A3 coupling has the same product outcome but the reactants are again an aldehyde, an amine and an alkyne as in the regular A3 coupling. [11] [14] [15] [16]