Identifying a Highly Active Copper Catalyst for KA² Reaction of Aromatic Ketones

Abstract

The well-established A(3) coupling reaction of terminal alkynes, aldehydes, and amines provides the most straightforward approach to propargylic amines. However, the related reaction of ketones, especially aromatic ketones, is still a significant challenge. A highly efficient catalytic protocol has been developed for the coupling of aromatic ketones with amines and terminal alkynes, in which Cu(I) , generated in situ from the reduction of CuBr2 with sodium ascorbate, has been identified as the highly efficient catalyst. Since propargylic amines are versatile synthetic intermediates and important units in pharmaceutical products, such an advance will greatly stimulate research interest involving the previously unavailable propargylic amines.

Manganese‐Catalyzed Multicomponent Synthesis of Tetrasubstituted Propargylamines: System Development and Theoretical Study

“…This result is of outmost importance, since, thus far, only one other example has been reported in the literature. [68] Specifically, we screened aromatic ketones bearing both electron-withdrawing (EWGs) and electron-donating groups (EDGs). When 4-methoxy-acetophenone was used, propargylamine 4 j was isolated in 34% isolated yield.…”

“…Furthermore, this observation agrees with the existing literature, in which the use of highly electron-deficient alkynes is rarely reported in similar studies, due to the decreased nucleophilicity of the respective acetylides. [68] Finally, 1-octyne was successfully employed, in combination with piperidine and cyclohexanone, affording propargylamine 4 w in 70% isolated yield. Therefore, under these conditions, both simple and more elaborate aliphatic alkynes (e. g. 2methylbut-3-yn-2-ol) can be derivatized.…”

“…[67] The same research group was the first to report the successful integration of aromatic ketones, in the KA 2 coupling, which was mediated by a catalytic system based on CuBr 2 , along with the use of Ti(OEt) 4 and sodium ascorbate. [68] Naturally, the increasing interest in this reaction and its potential has led to the development of a multitude of heterogeneous catalytic systems. Some leading examples include the use of Cu 2 O nanoparticles on titania, [69] nano Cu 2 O-ZnO, [70] Cu 2 O/nano-CuFe 2 O 4 , [71] CuO/Fe 2 O 3 nanoparticles, [72] Cu(II)-hydromagnesite, [73] polystyrene-supported, N-phenylpiperazine-CuBr 2 , and highly active, polymer-supported bipyridine-CuBr 2 , [74] Cu(II) @furfural imine-decorated Halloysite, [75] CuI on Amberlyst A-21, [76] as well as semi-heterogeneous, magnetically recoverable graphene oxide-supported CuCl 2.…”

Copper‐Catalyzed Synthesis of Tetrasubstituted Allenes from Quaternary Ammonium Salts and Grignard Reagents

“…Considering our previous report on KA 2 reactions (three‐component coupling reaction of ketone–amine–alkyne to produce secondary propargylamines) for the efficient synthesis of propargylic amines, we attempted to apply the reaction of propargylic amines and Grignard reagents to generate tetrasubstituted allenes. However, the reaction failed to yield the desired product [Eq.…”

Eco‐friendly magnetic clinoptilolite containing Cu(0) nanoparticles (CuNPs/MZN): as a new efficient catalyst for the synthesis of propargylamines via A3 and KA2 coupling reactions

“…Recently, Ti (OEt) 4 was employed as Lewis acid for neat KA 2 coupling reaction of acyclic and cyclic aliphatic ketones under solvent free and green conditions to enhance the activity of the substrates, yields, and lowering the reaction times . In order to employ aromatic ketones in KA 2 coupling reactions, new reaction conditions based on CuBr 2 /sodium ascorbate and Ti (OEt) 4 catalytic system have been reported …”