Enantioselective Reductive Cyanation and Phosphonylation of Secondary Amides by Iridium and Chiral Thiourea Sequential Catalysis

Abstract

The combination of transition-metal catalysis and organocatalysis increasingly offers chemists opportunities to realize diverse unprecedented chemical transformations. By combining iridium with chiral thiourea catalysis, direct enantioselective reductive cyanation and phosphonylation of secondary amides have been accomplished for the first time for the synthesis of enantioenriched chiral a-aminonitriles and aaminophosphonates. The protocol is highly efficient and enantioselective, providing a novel route to the synthesis of optically active a-functionalized amines from the simple, readily available feedstocks. In addition, the reactions are scalable and the thiourea catalyst can be recycled and reused.

Asymmetric Deoxygenative Alkynylation of Tertiary Amides Enabled by Iridium/Copper Bimetallic Relay Catalysis

“…Inspired from Huang's elegant procedure for the reductive alkynylation of tertiary amides by Ir and Cu I sequential catalysis, [10a] and enantioselective reductive cyanation and phosphonylation of secondary amides by combination of iridium with chiral thiourea catalysis (Scheme 1 b), [10g] we envisioned that the combined use of two metal‐catalyzed processes, which are Ir catalyzed partial reduction and asymmetric alkynylation enable by a chiral Cu catalyst may achieve the enantioselectively deoxygenative alkynylation of amides (Scheme 1 c). [16, 17] For this goal, the following challenges must be addressed: 1) the residual reductant (usually a silane) and the Ir catalyst from the first catalytic cycle for deoxygenative transformation of the amide may interfere with the following Cu‐catalyzed asymmetric alkynylation step, e.g., hydrosilation reactions or the formation of Cu‐H species, 2) the second catalytic alkynylation reaction cycle has to be fast enough and highly enantioselective to give the desired tertiary amine product in a stereocontrolled manner, and 3) the competition reaction from addition of ligand‐free alkynylcopper species into the in situ formed iminium species can be problematic, which would lead to the formation of a racemic product.…”

Challenges and Breakthroughs in Selective Amide Activation

“…By employing different trapping nucleophiles, Huang, Wang et al. were able to capture the iminium ion with different nucleophiles in various asymmetric catalytic systems (Scheme 22A) [45] . Enantioselective reductive cyanation and phosphonylation reactions of secondary amides 134 were achieved using trimethylsilyl nitrile (TMSCN) or phosphites as the nucleophiles, in combination with chiral thiourea catalysts.…”