The Ketone-Amine-Alkyne (KA 2 ) coupling reaction: Transition metal-catalyzed synthesis of quaternary propargylamines Leandros P. Zorba, Georgios C. Vougioukalakis ⇑ Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, 15771 Athens, Greece article info Article history: Received 11 June 2020 Accepted 8 September 2020 Available online xxxx Keywords: Catalysis Sustainable catalysis Green chemistry Multicomponent reaction One pot reaction A 3 coupling KA 2 coupling Propargylamines Aldehydes Ketones Amines Alkynes Copper Zinc Manganese Gold Silver abstract ‘‘Green chemistry” and sustainable catalysis are increasingly attracting significant attention, in both industry and academia. Multicomponent reactions aim towards ‘‘greener” chemical transformations, mostly due to their step economy. The A 3 coupling is a widely-studied multicomponent reaction, bringing together aldehydes, amines, and alkynes in a one pot manner, towards tertiary propargylamines, which are highly useful compounds with a variety of applications. The majority of reported synthetic protocols towards propargylamines require the preceding preparation of other starting materials, resulting in the need for increased time investment and cost, as well as encompassing a negative environmental impact. On the other hand, the A 3 reaction requires simple, widely-available starting materials and can be com- pleted in one step, making it immensely superior to the conventional approaches. This transformation is carried out by transition metal-based catalysts, which generate the necessary metal acetylides and merge them with the in situ generated aldimines/aldimine cations. Unfortunately, though, due to stereochemical and electronic reasons, ketimines/ketimine cations are way less reactive than their aldimine/aldimine cation counterparts, against nucleophilic attack, making their use in analogous transformations more challenging. This is why only 10 years have passed since the first KA 2 reaction was reported (i.e. the one-pot coupling of a ketone with an amine and an alkyne towards quaternary propargylamines). The present review article provides a brief introduction to multicomponent reactions, the existing conven- tional synthetic routes towards propargylamines, and the A 3 coupling reaction. A detailed, critical discus- sion of all KA 2 homogeneous and heterogeneous catalytic protocols, the mechanisms proposed, as well as the difficulties encountered and the strategies employed to circumvent them follows. Ó 2020 Elsevier B.V. All rights reserved. Contents 1. Introduction .......................................................................................................... 00 1.1. Multicomponent reactions ......................................................................................... 00 1.2. Propargylamines: A valuable family of compounds ..................................................................... 00 1.3. The A 3 coupling reaction: Multicomponent, single-step synthesis of tertiary propargylamines .................................. 00 2. The KA 2 coupling reaction: Challenging, but highly-useful ..................................................................... 00 2.1. Homogeneous KA 2 catalytic systems ................................................................................. 00 2.2. Heterogeneous KA 2 catalytic systems ................................................................................ 00 2.3. KA 2 -related catalytic systems ....................................................................................... 00 3. Conclusion and perspectives ............................................................................................. 00 Declaration of Competing Interest ........................................................................................ 00 Acknowledgments ..................................................................................................... 00 References ........................................................................................................... 00 https://doi.org/10.1016/j.ccr.2020.213603 0010-8545/Ó 2020 Elsevier B.V. All rights reserved. ⇑ Corresponding author. E-mail address: vougiouk@uoa.gr (G.C. Vougioukalakis). Coordination Chemistry Reviews xxx (xxxx) xxx Contents lists available at ScienceDirect Coordination Chemistry Reviews journal homepage: www.elsevier.com/locate/ccr Please cite this article as: L.P. Zorba and G.C. Vougioukalakis, The Ketone-Amine-Alkyne (KA 2 ) coupling reaction: Transition metal-catalyzed synthesis of quaternary propargylamines, Coordination Chemistry Reviews, https://doi.org/10.1016/j.ccr.2020.213603