Mild and Selective Hydrozirconation of Amides to Aldehydes Using Cp₂Zr(H)Cl:  Scope and Mechanistic Insight

Abstract

An investigation of the use of Cp 2 Zr(H)Cl (Schwartz's reagent) to reduce a variety of amides to the corresponding aldehydes under very mild reaction conditions and in high yields is reported. A range of tertiary amides, including Weinreb's amide, can be converted directly to the corresponding aldehydes with remarkable chemoselectivity. Primary and secondary amides proved to be viable substrates for reduction as well, although the yields were somewhat diminished compared to the corresponding tertiary amides. Results from NMR experiments suggested the presence of a stable, 18-electron zirconacycle intermediate that presumably affords the aldehyde upon water or silica gel workup. A series of competition experiments revealed a preference of the reagent for substrates in which the lone pair of the nitrogen is electron releasing and thus more delocalized across the amide bond by resonance. This trend accounts for the observed excellent selectivity for tertiary amides versus esters. Experiments regarding the solvent dependence of the reaction suggested a kinetic profile similar to that postulated for the hydrozirconation of alkenes and alkynes. Addition of panisidine to the reaction intermediate resulted in the formation of the corresponding imine mimicking the addition of water that forms the aldehyde.

Chemoselectivity and the Curious Reactivity Preferences of Functional Groups

“…Georg and co-workers noted that aldehydes formed prior to work-up are converted into alcohols immediately. [79] However, the absence of any alcohol products suggested the existence of a stable intermediate that collapses upon work-up; a process similar to that observed in the Weinreb reduction of amides to ketones.…”

Breaking Amides using Nickel Catalysis

“…16b In fact, the repertoire of reactions involving amide C–N bond cleavage that are generally considered useful to synthetic chemists is limited. Notable transformations include (a) the conversion of Weinreb amides to ketones using basic and pyrophoric reagents ( 7 → 8 ), 17 (b) the stoichiometric reduction of amides using Schwartz’s zirconium-based reagent ( 9 → 10 ), 18 and (c) the hydrolysis or esterification of amides ( 9 → 11 ), which often requires harshly acidic or basic reaction conditions, a large excess of the nucleophile, high temperatures, or a combination of these reaction parameters. 16a …”

Synthesis of a 2,4,6,8,10-dodecapentanoic acid thioester as a substrate for biosynthesis of heat stable antifungal factor (HSAF)

“…The Horner-Emmons reaction employed n- BuLi for convenience; this reaction could also have been conducted with a more easily handled base such as LDA. In contrast to the problems experienced during attempted reduction of the trienoate O -esters, reduction of the Weinreb amide with Schwartz’s reagent was accomplished in moderate yield but high selectivity 16 to furnish a dark red and moderately light-sensitive trienal ( 4 ). An iteration of the homologation and reduction sequence furnished tetraenal 6 .…”