α,β-Unsaturated acyl azoliums from N-heterocyclic carbene catalyzed reactions: observation and mechanistic investigation

Abstract

Catalytically generated acyl azoliums I and their α,β-unsaturated counterparts II are thought to be key reactive intermediates in a rapidly growing number of transformations promoted by N-heterocyclic carbene (NHC) catalysts.^[1] Acyl azoliums are invoked in the postulated catalytic cycles of nearly all of the new NHC-catalyzed reactions of α-functionalized aldehydes reported since 2004, in which they are generally assumed to possess the reactivity of an activated carboxylic acid, that is, analogous to an activated ester.^[2] In NHC-catalyzed processes, they are most often obtained through internal redox reactions of functionalized aldehydes but have also been prepared by oxidations of the Breslow intermediates^[3] or additions to ketenes.^[4] Acyl azoliums I are important intermediates in thiamine pyrophosphate (ThPP) dependent enzymatic reactions.^[5] Townsend et al. have recently proposed that unsaturated acyl azolium III is the key intermediate in clavulanic acid biosynthesis;^[6] despite careful efforts, III or its analogues II have never been characterized or independently synthesized. Here, we document the observation and characterization of α,β-unsaturated acyl azoliums 1 and 2 (Scheme 1) and demonstrate that their corresponding hemiacetals (1′ and 2”) are the kinetically important intermediates in both their acylation and annulation reactions.

Figure 1

¹H NMR investigation of α,β-unsaturated acyl azolium 1 generated from 3 and 4, and its methanolysis to 5 (the labeled H atoms correlate to the indicated signals in the spectra).

Figure 2

UV/Vis and ESI-HRMS characterizations of 1. Black: precatalyst + aldehyde; gray: acyl azolium.

Figure 3

Key NMR correlation assignments of acyl azolium 1.

Figure 4

Linear free-energy relationship (Hammett study) for NHC-catalyzed redox reaction with para-substituted ynals: ρ = − 0.69 (Z = CF₃, Cl, H, Me, or OMe as indicated in the plot). γ= −0.6901 x+0.0326, R²= 0.903.

Scheme 1

Various acyl azoliums and the hemiacetals.

Scheme 2

Reactions of a catalytically generated acyl azolium with various nucleophiles.

Scheme 3

Activation parameters, rate constants, and rate laws comparison between NHC-catalyzed redox and Claisen reactions.

Scheme 4

a) Differential activation parameters measurement from a competition experiment and b) the mechanistic rationale.

Scheme 5

Breakdown of hemiacetal V is the rate-limiting step in NHC-catalyzed redox esterifications of ynals.