N‐Heterocyclic Carbene Catalyzed Enantioselective α‐Fluorination of Aliphatic Aldehydes and α‐Chloro Aldehydes: Synthesis of α‐Fluoro Esters, Amides, and Thioesters

Abstract

The asymmetric fluorination of azolium enolates that are generated from readily available simple aliphatic aldehydes or α-chloro aldehydes and N-heterocyclic carbenes (NHCs) is described. The process significantly expands the synthetic utility of NHC-catalyzed fluorination and provides facile access to a wide range of α-fluoro esters, amides, and thioesters with excellent enantioselectivity. Pyrazole was identified as an excellent acyl transfer reagent for catalytic amide formation.

Vitamin B1-catalyzed aerobic oxidative esterification of aromatic aldehydes with alcohols

“…Despite advances, these transformations commonly suffered from harsh reaction conditions, the use of costly metal catalysts, stoichiometric oxidants, and extra additives, which constitute drawbacks for large-scale applications and late-stage modifications. 11 Alternatively, N-heterocyclic carbenes (NHCs) derived from thiazolium ions have the capability to accomplish the oxidative esterification with the assistance of various oxidants, such as MnO 2 , 12 nitroarene, 13 TEMPO, 14 NFSI, 15 diphenoquinone, 16 azobenzene, 17 phenazine, 18 CCl 3 CN, 19 and O 2 /air ( Scheme 1B ). 20 From a viewpoint of green chemistry, a metal-free NHC-catalyzed one-pot esterification of aldehydes under air has become more sought after.…”

NHC-catalyzed enantioselective synthesis of β-trifluoromethyl-β-hydroxyamides

“…Among the most common reactive intermediates generated using NHCs, the azolium enolate has been widely used [27,28]. Methods to generate azolium enolates from a number of precursors have been reported, including the use of ketenes [29,30], α-functionalized aldehydes [31][32][33][34][35], enals [36][37][38], aryl esters [39][40][41][42], or aldehydes [43][44][45] in the presence of an oxidant. As representative examples of the use of azolium enolates in reactions with trifluoroacetophenone derivatives, Ye and co-workers have shown that using disubstituted ketenes as azolium enolate precursors and NHC precatalyst 1 allowed access to trifluoromethyl-substituted β-lactone products in a high yield, diastereo-, and enantioselectivity ( Figure 2A) [46].…”

[2.2]Paracyclophane-Based Isothiourea-Catalyzed Highly Enantioselective α-Fluorination of Carboxylic Acids

“…Among them, asymmetric fluorination of carbonyl compound is undoubtedly one of the most significant transformations. In contrast to asymmetric construction of α-fluoro aldehyde, ketone, or 1,3-dicarbonyl derivatives, the development of methods for highly enantioselective synthesis of α-fluoro carboxylic acid derivatives lags behind. Despite some elegant approaches developed in this context, there are still some limitations with existing methods such as the need to use high active carbonyl compounds (aldehydes and its analogies) ,, or unstable intermediates (ketenes) (Scheme a).…”