Site-Selective Copper(I)-Catalyzed Hydrogenation of Amides

Abstract

We present a bifunctional catalyst consisting of a copper(I)/N-heterocyclic carbene and an organocatalytic guanidine moiety that enables, for the first time, a copper(I)-catalyzed reduction of amides with H₂ as the terminal reducing agent. The guanidine allows for reactivity tuning of the originally weakly nucleophilic copper(I) hydrides - formed in situ - to be able to react with difficult-to-reduce amides. Additionally, the guanidine moiety is key for the selective recognition of "privileged" amides based on simple and readily available heterocycles in the presence of other amides within one molecule, giving rise to hitherto unknown site-selective catalytic amide hydrogenation. A substrate scope, mechanistic investigations, and a working hypothesis supported by computational analysis for site-selectivity are presented.

Scheme 1. Developing Bifunctional Catalysts for Site-Selective Amide Reduction

a) Overview of homogeneous hydrogenation of amides; b) catalytic ester hydrogenation with a bifunctional copper(I) catalyst – control of reactivity; c) concept: the guanidine subunit allows for molecular recognition of a privileged amide in the presence of other amides – control of site-selectivity.

Scheme 2. Privileged Amides in Catalytic Hydrogenation:^a,b a) Influence of Amine Moieties; b) Correlation of Electronic Predisposition of Amides 1a–1j vs Conversion; c) Hypothesized Transition State with Additional Hydrogen Bonding^c; d) Failed Substrates

All reactions were performed with 0.1 mmol of the corresponding benzamides 1a–1l. Conversion was determined by GC and GC/MS analysis and/or ¹H NMR analysis. Calculated transition state with selected bond lengths (distances are given in Å, DSD-BLYP-D3(BJ)/CBS/SMD(1,4-dioxane)//M06-L/6-31+G(d,p), SDD for Cu).

Scheme 3. Control Experiments Probing the Necessity for a Bifunctional Catalyst

Performed with 0.10 mmol of benzamide 1j, [IMesCuCl] 4 10 mol %, NaOtBu 1.3 equiv, 15-crown-5 1.5 equiv in 1,4-dioxane (1.0 mL), 100 bar H₂, 24 h. Performed with 0.05 mmol of benzamide 1j, [IMesCuCl] 4 10 mol %, [IPrGua] 5 1.1 equiv, NaOtBu 1.3 equiv, 15-crown-5 1.5 equiv in 1,4-dioxane (0.50 mL), 100 bar H₂, 24 h.

Scheme 4. Confounding Experiments on the Influence of the Catalyst Structure (a) and Hydride/Deuteride Transfer Pathway (b)

All reactions were performed with 0.1 mmol benzamide 1j. Conversion was determined by GC, GC/MS, and/or ¹H NMR analysis.

Scheme 5. Comparison of Chemoselectivity in Competition Experiments:, Bifunctional Catalyst vs Commonly Employed Stoichiometric Aluminum Hydrides

Conversion was determined by GC and GC/MS analysis and/or ¹H NMR analysis. Substrates 0.20 mmol, [CuGua] 3 10 mol %, NaOtBu 1.3 equiv, tridecane 10 mol %, 15-crown-5 1.5 equiv in 1,4-dioxane (2.0 mL) for 4 h at 70°C. Substrates 0.30 mmol, DiBAl–H (1.0 M in toluene, 4.0 equiv) in dry THF (3.0 mL) for 15 min at rt. Substrates 0.30 mmol, LiAlH₄ 4.0 equiv in dry THF (3.0 mL) for 15 min at rt.

Scheme 6. Site-Selective Amide Hydrogenations

Substrate (0.2 mmol); isolated yields are given. Substrate (0.3 mmol), [CuGua] 3 20 mol%, NaOtBu 2.5 equiv, in 1,4-dioxane (3.0 mL), 100 bar H₂, 24 h.