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.

Decarboxylative A3 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]

References
  1. 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 Waterdoi:10.1021/ja0359299
  2. 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
  3. Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications 2009 Li, Jie Jack
  4. 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
  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.
  6. 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
  7. 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
  8. 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
  9. Guermont, J. P. Bull. Soc. Chim. Fr. 1953, 386.
  10. Recent advances on diversity oriented heterocycle synthesis via multicomponent tandem reactions based on A3 coupling Yunyun Liu ARKIVOC 2014 (i) 1-20
  11. The redox-A3 reaction Daniel Seidel Org. Chem. Front., 2014, 1, 426 doi:10.1039/c4qo00022f
  12. "Copper-Catalyzed Decarboxylative Coupling of sp3-Hybridized Carbons of α-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
  13. 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
  14. 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
  15. 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
  16. 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
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