Copper(I)-Catalyzed Ketone, Amine, and Alkyne Coupling for the Synthesis of 2-Alkynylpyrrolidines and -piperidines

Abstract

A Cu(I)-catalyzed coupling of a ω-chloro ketone, a primary amine, and an alkyne is described. This protocol allows for the synthesis of α-quaternary carbons in 2-alkynyl-substituted N-heterocycles. The key step is the in situ generation of a cyclic ketiminium species, which has enhanced reactivity for alkynylation compared to acyclic ketiminium species.

Zn-Catalyzed Multicomponent KA2 Coupling: One-Pot Assembly of Propargylamines Bearing Tetrasubstituted Carbon Centers

“…31 Only by using a different approach, in combination with Cu 2 O catalysis, ω-chloro ketones, primary amines, and alkynes could be coupled to furnish 2-alkynyl heterocycles. 32 As expected, the rapidly increasing interest in this reaction has also given rise to various heterogeneous catalytic systems focusing on catalyst recyclability, such as those based on Cu 2 O nanoparticles on titania, 33a nano Cu 2 O–ZnO, 33b Cu 2 O/nano-CuFe 2 O 4 , 33c CuO/Fe 2 O 3 nanoparticles, 33d Cu(II)-hydromagnesite, 33e polystyrene-supported, N -phenylpiperazine-CuBr 2 , 33f Ag-doped nanomagnetic γ-Fe 2 O 3 @DA core–shell hollow spheres, 33g Cu(II)@furfural imine-decorated Halloysite, 33h CuI on Amberlyst A-21, 33i Fe 2 O 3 @SiO 2 -IL/Ag hollow spheres, 33j semi-heterogeneous, magnetically recoverable graphene oxide-supported CuCl 2 , 33k and polystyrene-supported N-heterocyclic carbene–Au(III). 33l…”

The Use of Calcium Carbide as Acetylene Source in a Three‐Component Coupling with ω‐Chlorinated Ketones and Primary Amines

“…In recent research, we investigated the three‐component coupling of ω‐chlorinated ketones, primary amines and terminal alkynes . To obtain terminal propargylamines, we envisioned to replace the terminal alkynes by calcium carbide.…”

“…The use of tertiary substituents on the primary amine, such as tert ‐butyl, dimethylpropynyl or adamantyl, did not lead to the intended products 4 af , 4 ag or 4 ah , respectively, but gave the δ‐amino ketones 4 af ′, 4 ag ′ and 4 ah ′, respectively, in low yields. From previous work we know that steric hindrance around the reacting electrophilic iminium species complicates the addition of nucleophilic species. Therefore, the reaction temperature was increased to 90 °C, but even then the products 4 af , 4 ag and 4 ah were not obtained.…”

“…In recent research, we investigated the three-component coupling of w-chlorinated ketones, primary amines and terminal alkynes. [28] To obtain terminal propargylamines, we envisioned to replacet he terminal alkynes by calcium carbide. For the optimisation of the coupling of 6-chlorohexan-2-one (1a), n-propylamine (2a)a nd calcium carbide( 3), first aC u I catalysti n MeCN was tested.…”

Multicomponent Mannich‐Like Reactions of Organometallic Species

“…Tehrani and co-workers described an original example of KA 2 -coupling. [124] In their approach, an iminium species was generated by consecutive condensation of a primary amine 2d with an ω-halo ketone 3l and nucleophilic substitution. Subsequent Cu-catalyzed alkyne addition led to the expected pyrrolidines and piperidines 104 in good yields (Scheme 48).…”