The A³ coupling (also known as A³ coupling reaction or the aldehyde-alkyne-amine reaction), coined by Prof.

Chao-Jun Li Chao-Jun "C.-J." Li is E. B. Eddy Professor of Chemistry and Canada Research Chair in Green Chemistry at McGill University, Montréal. He works on organic transformation applied to Green chemistry, including C-H activation, reactions in water and ...

of McGill University, is a type of

multicomponent reaction In chemistry, a multi-component reaction (or MCR), sometimes referred to as a "Multi-component Assembly Process" (or MCAP), is a chemical reaction where three or more compounds react to form a single product. By definition, multicomponent reaction ...

involving an

aldehyde In organic chemistry, an aldehyde () is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred to as an aldehyde but can also be classified as a formyl grou ...

, an

alkyne \ce \ce Acetylene \ce \ce \ce Propyne \ce \ce \ce \ce 1-Butyne In organic chemistry, an alkyne is an unsaturated hydrocarbon containing at least one carbon—carbon triple bond. The simplest acyclic alkynes with only one triple bond and n ...

and an

amine In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituen ...

which react to give a

propargyl In organic chemistry, the propargyl group is a functional group of 2-propynyl with the structure . It is an alkyl group derived from propyne (). The term propargylic refers to a saturated position ( ''sp''3-hybridized) on a molecular framework n ...

Catalyst CuFe2O4 for Multicomponent Reaction 2

The reaction proceeds via direct dehydrative condensation and requires a metal

catalyst Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...

, typically based on

ruthenium Ruthenium is a chemical element with the Symbol (chemistry), symbol Ru and atomic number 44. It is a rare transition metal belonging to the platinum group of the periodic table. Like the other metals of the platinum group, ruthenium is inert to ...

copper Copper is a chemical element with the symbol Cu (from la, cuprum) and atomic number 29. It is a soft, malleable, and ductile metal with very high thermal and electrical conductivity. A freshly exposed surface of pure copper has a pinkis ...

gold Gold is a chemical element with the symbol Au (from la, aurum) and atomic number 79. This makes it one of the higher atomic number elements that occur naturally. It is a bright, slightly orange-yellow, dense, soft, malleable, and ductile met ...

silver Silver is a chemical element with the Symbol (chemistry), symbol Ag (from the Latin ', derived from the Proto-Indo-European wikt:Reconstruction:Proto-Indo-European/h₂erǵ-, ''h₂erǵ'': "shiny" or "white") and atomic number 47. A soft, whi ...

. Chiral catalyst can be used to give an enantioselective reaction, yielding a chiral amine. The solvent can be water. In the

catalytic cycle In chemistry, a catalytic cycle is a multistep reaction mechanism that involves a catalyst. The catalytic cycle is the main method for describing the role of catalysts in biochemistry, organometallic chemistry, bioinorganic chemistry, materials s ...

the metal activates the alkyne to a

metal acetylide In organometallic chemistry, acetylide refers to chemical compounds with the chemical formulas and , where M is a metal. The term is used loosely and can refer to substituted acetylides having the general structure (where R is an organic side ...

, the amine and aldehyde combine to form an

imine In organic chemistry, an imine ( or ) is a functional group or organic compound containing a carbon–nitrogen double bond (). The nitrogen atom can be attached to a hydrogen or an organic group (R). The carbon atom has two additional single bo ...

which then reacts with the acetylide in a

nucleophilic addition In organic chemistry, a nucleophilic addition reaction is an addition reaction where a chemical compound with an electrophilic double or triple bond reacts with a nucleophile, such that the double or triple bond is broken. Nucleophilic additions di ...

. The reaction type was independently reported by three research groups in 2001 -2002; one report on a similar reaction dates back to 1953. 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 Crabbé reaction (or Crabbé allene synthesis, Crabbé–Ma allene synthesis) is an organic reaction that converts a terminal alkyne and aldehyde (or, sometimes, a ketone) into an allene in the presence of a soft Lewis acid catalyst (or stoichio ...

Decarboxylative A3 reaction

One variation is called the decarboxylative A³ coupling. In this reaction the amine is replaced by an

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

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

References

{{Reflist, 3, refs= W.-J. Yoo, L. Zhao, C.-J. Li, Aldrichimica Acta 2011, 44, 43–51. ''The A3-coupling (aldehyde-alkyne-amine) reaction: a versatile method for the preparation of propargylamines''; C. Wei, C.-J. Li, J. Am. Chem. Soc. 2002, 124, 5638-5639. ''Enantioselective Direct Addition of Alkynes to Imines Catalyzed by Copper(I)pybox Complex in Water and in Toluene'' {{doi, 10.1021/ja026007t; C. Wei, C.-J. Li, J. Am. Chem. Soc. 2003, 125, 9584-9585. ''A Highly Efficient Three-Component Coupling of Aldehyde, Alkyne, and Amines via C-H Activation Catalyzed by Gold in Water''{{doi, 10.1021/ja0359299 ''A walk around the A3-coupling'' Vsevolod A. Peshkov , Olga P. Pereshivkoa and Erik V. Van der Eycken Chem. Soc. Rev., 2012,41, 3790-3807 {{doi, 10.1039/C2CS15356D ''Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications'' 2009 Li, Jie Jack ''The Development of A3-Coupling (Aldehyde-Alkyne-Amine) and AA3-Coupling (Asymmetric Aldehyde-Alkyne-Amine)'' Chunmei Wei, Zigang Li, Chao-Jun Li Synlett 2004(9): 1472-1483 {{doi, 10.1055/s-2004-829531 Sakaguchi, S., Kubo, T. and Ishii, Y. (2001), ''A Three-Component Coupling Reaction of Aldehydes, Amines, and Alkynes.'' Angew. Chem. Int. Ed., 40: 2534–2536. {{doi, 10.1002/1521-3773(20010702)40:13<2534::AID-ANIE2534>3.0.CO;2-2 ''Direct Addition of TMS-acetylene to Aldimines Catalyzed by a Simple, Commercially Available Ir(I) Complex'' Christian Fischer and Erick M. Carreira Organic Letters 2001 3 (26), 4319-4321 {{doi, 10.1021/ol017022q ''Highly efficient Grignard-type imine additions via C–H activation in water and under solvent-free conditions'' Chao-Jun Li and Chunmei Wei Chem. Commun., 2002, 268-269 {{doi, 10.1039/B108851N ''The redox-A3 reaction'' Daniel Seidel Org. Chem. Front., 2014, 1, 426 {{doi, 10.1039/c4qo00022f "Copper-Catalyzed Decarboxylative Coupling of sp3-Hybridized Carbons of -Amino Acids" Hai-Peng Bi, Liang Zhao, Yong-Min Liang, and Chao-Jun Li Angew. Chem. Int. Ed. 2009, 48, 792-795 {{doi, 10.1002/anie.200805122;''Aldehyde- and Ketone-Induced Tandem Decarboxylation-Coupling (Csp3−Csp) of Natural α-Amino Acids and Alkynes'' Hai-Peng Bi, Qingfeng Teng, Min Guan, Wen-Wen Chen, Yong-Min Liang, Xiaojun Yao, and Chao-Jun Li The Journal of Organic Chemistry 2010 75 (3), 783-788 {{doi, 10.1021/jo902319h ''Nontraditional Reactions of Azomethine Ylides: Decarboxylative Three-Component Couplings of α-Amino Acids'' Chen Zhang and Daniel Seidel Journal of the American Chemical Society 2010 132 (6), 1798-1799 {{doi, 10.1021/ja910719x Das, D., Sun, A. X. and Seidel, D. (2013), ''Redox-Neutral Copper(II) Carboxylate Catalyzed α-Alkynylation of Amines.'' Angew. Chem. Int. Ed., 52: 3765–3769. {{doi, 10.1002/anie.201300021 ''CuI-Catalyzed C1-Alkynylation of Tetrahydroisoquinolines (THIQs) by A3 Reaction with Tunable Iminium Ions'' Qin-Heng Zheng, Wei Meng, Guo-Jie Jiang, and Zhi-Xiang Yu Organic Letters 2013 15 (23), 5928-5931 {{doi, 10.1021/ol402517e Lin, W., Cao, T., Fan, W., Han, Y., Kuang, J., Luo, H., Miao, B., Tang, X., Yu, Q., Yuan, W., Zhang, J., Zhu, C. and Ma, S. (2014), ''Enantioselective Double Manipulation of Tetrahydroisoquinolines with Terminal Alkynes and Aldehydes under Copper(I) Catalysis.'' Angew. Chem. Int. Ed., 53: 277–281. {{doi, 10.1002/anie.201308699 Guermont, J. P. Bull. Soc. Chim. Fr. 1953, 386. ''Recent advances on diversity oriented heterocycle synthesis via multicomponent tandem reactions based on A3 coupling'' Yunyun Liu ARKIVOC 2014 (i) 1-20 Organic reactions Multiple component reactions