Enantioselective Trifluoromethylation of Ketones with (Trifluoromethyl)trimethylsilane Catalyzed by Chiral Quaternary Ammonium Phenoxides

Abstract

Chiral quaternary ammonium phenoxides were prepared readily from commercially available cinchona alkaloids and employed as novel useful asymmetric organocatalysts. Among these chiral quaternary ammonium phenoxides, a cinchonidine-derived phenoxide that possesses a sterically hindered N(1)-3,5-bis[3,5-bis(trifluoromethyl)phenyl]benzyl group was the most effective for asymmetric trifluoromethylation. In the presence of a catalytic amount of Lewis bases, such as cinchonidine-derived quaternary ammonium phenoxides, catalyzed the reaction of various ketones with (trifluoromethyl)trimethylsilane to afford the corresponding trifluoromethylated adducts in high yields and with moderate to high enantioselectivities.

Chiral Ammonium Betaines as Ionic Nucleophilic Catalysts

“…In this respect, an anionic molecule could function as a potentially more nucleophilic catalyst for initiating the reaction, compared to the commonly utilized electronically neutral molecules, but it generates a rather stable intermediate bearing no charge (see below). [6] Acyl transfer reactions by means of nucleophilic catalysts are the fundamental molecular transformation in synthetic organic chemistry. [2,3] We recently introduced the chiral ammonium betaine 1 as a new, yet intriguing structural motif as an organic molecular catalyst.…”

“…[6] Acyl transfer reactions by means of nucleophilic catalysts are the fundamental molecular transformation in synthetic organic chemistry. Given that the aryloxylate functionality has a nucleophilic character, we envisioned that 1 could be evolved into a chiral nucleophile after appropriate structural manipulations.…”

“…Given that the aryloxylate functionality has a nucleophilic character, we envisioned that 1 could be evolved into a chiral nucleophile after appropriate structural manipulations. [6] Acyl transfer reactions by means of nucleophilic catalysts are the fundamental molecular transformation in synthetic organic chemistry. Among these reactions, the Steglich rearrangement, [7] which is the rearrangement of 5-oxazolyl carbonate into 4-carboxyazlactones, offers an attractive process for establishing a tetrasubstituted stereogenic center, and also serves as a model system for evaluating the efficiency of chiral nucleophilic catalysts (Scheme 1); [8,9] the pioneering work in this field was reported by Ruble and Fu for a synthetic analogue of DMAP.…”

Trifluoromethylation of Carbonyl Compounds

“…Significant progress has been made in the development of asymmetric trifluoromethylation reactions [56][57][58][59][60][61][62]. However, the direct enantioselective trifluoromethylation reaction remains a challenge as recently observed when chiral crown ethers were used to the enantioselective trifluoromethylation of aldehydes and ketones [62].…”

Nucleophilic trifluoromethylation of carbonyl compounds and derivatives

“…Mukaiyama et al developed a cinchona alkaloid derivative 59 with phenoxide as counteranion (Scheme 27) 53 based on the fact that metal alkoxides are efficient nucleophilic initiators of the Ruppert-Prakash reagent 1. Therefore, they demonstrated that this cinchonidinederived quaternary ammonium phenoxide 59 could catalyze the asymmetric trifluoromethylation of ketones and with 1 efficiently, affording the desired products in high yields and with up to 87% ee (Scheme 27, Table 3, entries 1-11).…”