Direct Reductive Amination of Carbonyl Compounds Catalyzed by a Moisture Tolerant Tin(IV) Lewis Acid

Abstract

Despite the ever-broadening applications of main-group 'frustrated Lewis pair' (FLP) chemistry to both new and established reactions, their typical intolerance of water, especially at elevated temperatures (>100 °C), represents a key barrier to their mainstream adoption. Herein we report that FLPs based on the Lewis acid ⁱPr₃SnOTf are moisture tolerant in the presence of moderately strong nitrogenous bases, even under high temperature regimes, allowing them to operate as simple and effective catalysts for the reductive amination of organic carbonyls, including for challenging bulky amine and carbonyl substrate partners.

Keywords: catalytic hydrogenation; reductive amination; tin; water tolerance; ‘frustrated Lewis pairs’.

Scheme 1

Detrimental effects of hydroxylic species upon catalytic activity of B(C₆F₅)₃. R=alkyl, H; LB=Lewis base. [a] Brønsted acidification of H₂O via coordination to B(C₆F₅)₃. [b] Thermally induced protodeboronation. Quoted pK _a relates to aqueous conditions (est.).3

Scheme 2

Examples of previous moisture‐tolerant FLP hydrogenation systems relevant to this work.

Scheme 3

ⁱPr₃SnOTf‐catalysed hydrogenation of imines under ‘wet’ conditions. [a] 10 mol% Col added. 10 bar refers to initial pressure at RT. All reactions were prepared on the open bench and degassed before pressurisation. Percentages are in situ conversions determined by ¹H NMR spectroscopy (see SI for full details).

Scheme 4

Scaled‐up reductive amination of benzaldehyde with aniline catalysed by 1. 50 bar refers to final pressure at 150 °C (35 bar at RT). The reaction was prepared on the open bench and sparged with N₂ before pressurisation with H₂ (see SI). The in situ conversion was determined by ¹H NMR spectroscopic analysis (see SI), while the yield was calculated from the mass of isolated pure product.