A General Approach to Various Five‐ and Six‐Membered gem‐Difluoroheterocycles: Application to the Synthesis of Fluorinated Analogues of Sedamine

Abstract

A new synthesis of a group of O‐, S‐ and N‐heterocycles with a gem‐difluoro group in position β to the heteroatom has been developed, starting from easily accessible gem‐difluoro propargylic derivatives. This tandem process involves a base‐induced isomerization followed by an intramolecular 1,4 hetero‐Michael addition. This methodology is suitable for the preparation of five‐ and six‐membered heterocycles and it has been successfully applied to the synthesis of the 3,3‐difluoro analogues of (±)‐sedamine III, (±)‐allosedamine V, (±)‐norallosedamine II, and (±)‐norsedamine IV.

Synthesis of Novel Cyclic Nitrones with gem‐Difluoroalkyl Side Chains Through Cascade Reactions

“…The reactions with nitromethane, or 2‐nitropropane, in the presence of DBU afforded in fair to good yields the nitro intermediates 4a – e and 5a – e respectively. In agreement with previous results, the first step of this domino process is likely the base‐mediated isomerization of the propargylic alcohols into the corresponding (non‐isolated) enones 3'a – e which are trapped in situ by the nitroalkane anions to give the desired molecules 4 or 5 …”

“…In order to prepare the first series of representative nitrones, we started from the known, gem ‐difluoro propargylic derivative 1 . After reaction with n BuLi at –90 °C, followed by addition of different aldehydes 2a – e , the gem ‐difluorinated alcohols 3a – e were obtained (Scheme , Table ).…”

“…In order to expand the strategy to fused bicyclic nitrones, we started from the known, gem ‐difluorinated propargylic compound 22 . After reaction with n BuLi and different aromatic aldehydes, the propargylic alcohols 23a – e were obtained in good yields (Table ).…”

Fluorine in pheromones: Synthesis of fluorinated 12-dodecanolides as emerald ash borer pheromone mimetics

“…A key reaction involved DAST treatment of propargylic ketone 13 to generate difluoromethylene 14, following previously developed protocols [18]. Orthogonal deprotection allowed release of alcohol 15 which was oxidised to carboxylic acid 16.…”

“…The difluoromethylene groups were introduced also by DAST reaction of a propargyl ketone [18] in a sequential manner to generate the orthogonally protected diacetylene 47, with both difluoromethylene groups installed. The p-methoxybenzyl group (PMB) was removed and replaced by TIPS and then a key hydrogenation step, using palladium on carbon cleaved the terminal benzyl ether with concomitant saturation of both acetylene bonds, to generate aliphatic alcohol 50.…”