Tertiary amine synthesis via reductive coupling of amides with Grignard reagents

Abstract

A new iridium catalyzed reductive coupling reaction of Grignard reagents and tertiary amides affording functionalised tertiary amine products via an efficient and technically-simple one-pot, two-stage experimental protocol, is reported. The reaction - which can be carried out on gram-scale using as little as 1 mol% Vaska's complex [IrCl(CO)(PPh₃)₂] and TMDS as the terminal reductant for the initial reductive activation step - tolerates a broad range of tertiary amides from (hetero)aromatic to aliphatic (branched, unbranched and formyl) and a wide variety of alkyl (linear, branched), vinyl, alkynyl and (hetero)aryl Grignard reagents. The new methodology has been applied directly to bioactive molecule synthesis and the high chemoselectivity of the reductive coupling of amide has been exploited in late stage functionalization of drug molecules. This reductive functionalisation of tertiary amides provides a new and practical solution to tertiary amine synthesis.

Scheme 1. Reductive functionalisation of amides with carbon-centered nucleophiles.

Scheme 2. Scope with respect to the tertiary amide. Standard condition: amide 0.3 mmol, IrCl(CO)(PPh₃)₂ 1 mol%, TMDS 0.6 mmol, CH₂Cl₂ 3 mL, BnMgCl 0.6 mmol; isolated yields are given; Bpin = pinacol boronate; Boc = t-butyloxy carbonyl. ^a5 mol% of IrCl(CO)(PPh₃)₂ was used; ^bperformed at 0 °C for 6 h after the addition of BnMgCl (1.2 eq.); ^cPd/C catalysed hydrogenolysis of the N-benzyl group was performed on the tertiary amine product and overall yield is given.

Scheme 3. Scope with respect to the Grignard reagent. Standard condition: amide 0.3 mmol, IrCl(CO)(PPh₃)₂ 1 mol%, TMDS 0.6 mmol, CH₂Cl₂ 3 mL, RMgX 0.6 mmol; isolated yields are given. ^aPerformed on 1.01 g of amide with no additional optimisation; ^bGrignard reagent prepared by Mg/I exchange with i-PrMgBr; ^cwith 1.5 eq. Grignard reagent; ^dperformed at 0 °C for 6 h after Grignard reagent addition; ^eyield based on Grignard reagent (0.67 eq.).