Decarboxylative aldol reaction of α,α-difluoro-β-ketocarboxylate salt: a facile method for generation of difluoroenolate

Abstract

We developed a decarboxylative aldol reaction using a,a-difluoro-b-ketocarboxylate salt, carbonyl compounds, and ZnCl 2 /N,N,N 0 ,N 0 -tetramethylethylenediamine. The generation of difluoroenolate proceeded smoothly under mild heating to provide a,a-difluoro-b-hydroxy ketones in good to excellent yield (up to 99%). The a,a-difluoro-b-ketocarboxylate salt was bench stable and easy to handle under air, which realizes a convenient and environmentally friendly methodology for synthesis of difluoromethylene compounds.

β‐Keto Acids in Organic Synthesis

“…The Michael addition is one of the most important and fundamental methods for C–C bond construction. The utility of β ‐keto acids as ketone enolate equivalents in Michael addition has been well studied …”

“…Recently, Omote,[7a] Mao[7b] and Mai[7c] independently described the decarboxylative aldol reactions from α,α ‐difluoro‐ β ‐keto carboxylate salt[7a] or α,α ‐difluoro‐ β ‐keto acids. [7b], [7c] As reported by the Mao group,[7b] the convenient method could even be achieved in the absence of any base and metal catalysts (Scheme ).…”

“…Quintard and co‐workers[7d] extended the applicability of in situ generated α,α ‐difluoroaldehydes 13.2 in one‐pot synthesis of gem ‐difluorinated β ‐aldol building blocks 13.1 (Equation 13–1) (Scheme ).…”

“…The Ahmed group[7e] disclosed a series of base‐directed constructions of aldol or Knoevenagel products. A strong basic (potassium tert‐ butoxide, 10 mol‐%) would selectively promote the formation of α ‐hydroxy ketones 14.1 (Equation 14–1), while the pyridine (10 mol‐%) led to the decarboxylative elimination (Equation 14–2).…”

“…In 2018, Han and co‐workers[7i] presented a study on the quaternary ammonium salt‐catalyzed three‐component reaction of 2‐formyl benzoic acid 15.1 , β ‐keto acids, and ammonia (or primary amine) in an aqueous medium (Equation 15–1). It might involve a decarboxylative alkylation/lactamization sequence.…”