Cleavage of Carbon−Carbon Bonds through the Mild Release of Trifluoroacetate: Generation of α,α-Difluoroenolates for Aldol Reactions

Abstract

The selective cleavage of carbon-carbon bonds is a significant challenge in synthetic chemistry, yet this strategy can be a powerful way to generate reactive intermediates. We have discovered that, through the facile release of trifluoroacetate which occurs by C-C bond scission, difluoroenolates can be generated under very mild reaction conditions. Unlike existing reactions, this method is not limited to a small group of fluorinated building blocks. We have applied this process to the aldol reaction to install difluoromethylene groups.

Synthesis of α,α-difluoro-β-amino carbonyl-containing sulfonamides and related compounds

“…In this regard, the recent discovery by Colby group (Scheme 1), presents a major methodological development in this area. It was shown [14] that under the action of organic bases, pentafluoro-ketone hydrate 3 easily underwent haloform-type decomposition reaction [15] to generate free a,a-difluoroenolates [4].…”

“…In particular, only four reports by Colby [14,16] and Wolf [17] groups described synthesis of types 5 and 6 compounds by aldol additions and halogenation of the in situ generated difluoroenolates 4.…”

“…Pentafluorob-di-ketone hydrates were synthesized according to literature [14]. All experiments were monitored by thin layer chromatography (TLC).…”

Detrifluoroacetylative Generation of Halogenated Enolates: Practical Access to Perhalogenated Ketones and Alkenes

“…6 Prager and Ogden demonstrated almost 50 years ago that the cleavage of hexafluoroacetone and its ester derivatives with excess of base, metal salts and other additives produces fluorinated carbanions suitable for C-C bond formation. 7 The full potential of this concept in aldol reactions with difluoroenolates generated in situ from a bench-stable trifluoroacetyl-derived precursor was first demonstrated by Colby et al 8 This seminal work has led to a variety of interesting applications and developments reported by Prakash, 9 Colby, 10 Zhu, 11 Soloshonok and Han, 12 Hong and Wang, 13 Fang and Wu, 14 and our group. 15 Inspired by the successful halogenation of difluoroenolates prepared by detrifluoroacetylation in the presence of excess of lithium salts and triethylamine, 16 we initiated the synthesis of a small series of 1-aryl 2-chloro-2,4,4,4-tetrafluoro-butan-1,3-dione hydrates.…”

Cleaving Carbon-Carbon Bonds by the Release of Trifluoroacetate to Remodel Molecules and Assemble Fluorinated Structures

“…3 Aldol reactions with aldehydes were accomplished under exceeding mild conditions using LiBr and Et 3 N. The reactions provided excellent yields and were completed nearly instantaneous at room temperature (the typical reaction time is three minutes). The powerful reactivity can be tempered by lowering the temperature to -78°C, and reaction times are only extended to 30 minutes.…”