Lewis Acid-Promoted Reaction of β,β-Difluorinated N,O-Acetal with Silylated Nucleophiles

Abstract

Lewis acid-promoted reaction of ethyl 3-ethoxy-2,2-difluoro-3-(dimethylamino)propionate (1) with some silylated nucleophiles afforded β,β-difluoroamines in good yields. The formation of iminium ion intermediate from 1 and BF3·OEt2 was confirmed by 19F and 13C NMR spectroscopy.

A Concise Enantioselective Synthesis of Fluorinated Pyrazolo-Piperidine GSK3901383A Enabled by an Organocatalytic Aza-Michael Addition

“…Dai et al have developed a copper-catalyzed ring opening cross-coupling of alkyl-substituted cyclopropanol with difluoroalkyl bromides [ 8 → 9 (Figure A)] . Few examples of accessing 3-amino derivatives are known, Kitazume et al have used Lewis acid-promoted addition of silylated nucleophiles to β,β-difluorinated N , O -acetals [ 10 → 11 (Figure B)]. , To date, no asymmetric variants of these reactions have been developed. Herein, we report the development of an enantioselective aza-Michael addition whereby iminium activation of a novel type of gem -difluoro-α,β-unsaturated acceptor 5 with an organocatalyst in the presence of 4-nitropyrazole forges the key C–N bond with high stereoselectivity (Figure C).…”

Regio- and Diastereoselective Vinylogous Mannich Addition of 3-Alkenyl-2-oxindoles to α-Fluoroalkyl Aldimines

“…6 In 1992, Tsukamoto and Kitazume reported the Lewis acid promoted reaction of fluorinated N,O-acetal with trimethylsilyloxyfuran (Scheme 1, a). 7 The Lewis acid catalyzed vinylogous Mannich addition of trimethylsilyloxyfuran to fluorinated aldimines was disclosed by Crousse and co-workers in 2004 (Scheme 1, a). 8 Shi's group realized the first enantioselective vinylogous Mannich reaction of fluorinated aldimines bearing a chiral auxiliary [(S)-1-phenylethyl group] and siloxyfurans under the catalytic environment of silver acetate and axially chiral phosphine-oxazoline ligand (Scheme 1, b).…”

Vinylogous Mannich‐Type Reaction Catalyzed by an Iodine‐Substituted Chiral Phosphoric Acid

“…A wide range of Lewis acids has been developed as catalysts for the reaction. [3,4] In contrast, the enantioselective, catalyzed-version of the vinylogous Mannich-type reaction has been little explored. Martin and co-workers reported the enantioselective synthesis of g-butenolide derivatives catalyzed by the TiA C H T U N G T R E N N U N G (O-i-Pr) 4 /(S)-BINOL system, [3f] but the enantioselectivities and the chemical yields were moderate.…”