N-Heterocyclic Carbene/Carboxylic Acid Co-Catalysis Enables Oxidative Esterification of Demanding Aldehydes/Enals, at Low Catalyst Loading

Abstract

We report the discovery that simple carboxylic acids, such as benzoic acid, boost the activity of N-heterocyclic carbene (NHC) catalysts in the oxidative esterification of aldehydes. A simple and efficient protocol for the transformation of a wide range of sterically hindered α- and β-substituted aliphatic aldehydes/enals, catalyzed by a novel and readily accessible N-Mes-/N-2,4,6-trichlorophenyl 1,2,4-triazolium salt, and benzoic acid as co-catalyst, was developed. A whole series of α/β-substituted aliphatic aldehydes/enals hitherto not amenable to NHC-catalyzed esterification could be reacted at typical catalyst loadings of 0.02-1.0 mol %. For benzaldehyde, even 0.005 mol % of NHC catalyst proved sufficient: the lowest value ever achieved in NHC catalysis. Preliminary studies point to carboxylic acid-induced acceleration of acyl transfer from azolium enolate intermediates as the mechanistic basis of the observed effect.

Keywords: acylation; carbenes; cooperative catalysis; esterification; oxidation.

Scheme 1

Acyl donor intermediates formed in NHC catalysis via a) internal redox reaction and b) external redox reaction.

Scheme 2

NHC‐catalyzed oxidative esterification of aliphatic aldehydes/enals.

Figure 1

Kinetic studies on the effect of (a) base, (b) DMAP/BzOH, and (c) BzOH, as the co‐catalysts of C1 in the reaction of 1 a and 2 a. Yields were determined by GC using dodecane as internal standard. A) Effect of bases: C1 (1.0 mol %), BzOH (10 mol %), base (2 mol %). B) Effect of DMAP/BzOH: C1 (0.5 mol %), DMAP (2 mol %), BzOH (10 mol %). C) Effect of BzOH: C1 (0.5 mol %), DMAP (0.5 mol %), BzOH (X mol %).

Figure 2

Substrate scope of the oxidative esterification of aliphatic aldehydes and alcohol nucleophiles. Yields refer to isolated products.

Figure 3

Scope of the oxidative esterification of aldehydes with methanol as alcohol component. Yields refer to isolated products.

Figure 4

Scope of the oxidative esterification of enals. Yields refer to isolated products. *The lower yield of the isolated methyl ester 5 ex (74 %) is due to its volatility, as the prenal substrate 5 e was completely consumed with clean conversion. When changing to n‐propanol, the resulting ester 5 ey could be isolated in 93 % yield.

Scheme 3

SIPr‐derived acetyl azolium triflate 6 a, benzoyl azolium chloride 6 b, acetyl azolium enolate 7, and the effect of BzOH on the reaction of 7 with BnOH (2 a) or methanol (2 x) [Dipp: 2,6‐di(2‐propyl)phenyl].