Transition Metal‐free gem‐difluorocyclopropanation of Alkenes with CF₃SiMe₃−NaI System: a Recipe for Electron‐deficient Substrates

Abstract

Reaction of various electron-deficient alkenes, as well as functionalized styrene derivatives with CF 3 SiMe 3 ÀNaI system is studied. Relative reactivity of the substrates is established. It is shown that many a,b-unsaturated esters can be difluorocyclopropanated efficiently under "slow addition protocol" conditions, which provides access to mono-and spirocyclic gem-difluorocyclopropyl-substituted carboxylic acids with good yields (36-79% for two steps) on up to 100 g scale.

N‐Difluorocyclopropyl‐Substituted Pyrazoles: Synthesis and Reactivity

“…0.8–1.2 equivalents of CF 3 SiMe 3 ; an induction period was observed. This is yet another fact showing that the reaction cannot be described simply as difluorocarbene cycloaddition;, in particular, some type of radical mechanism might be involved.…”

“…Unfortunately, other azole derivatives 9b–g were unreactive towards the Ruppert–Prakash reagent with the use of either “one‐batch” or “slow addition” protocol;, no conversion of 9b–g was observed. Although the reason behind this result is unclear, it might be addressed either to the presence of a nucleophilic nitrogen atom (especially in the case of 9b ) or to electronic effects (for other representatives).…”

“…While a number of papers describe synthetic approaches to the compounds having a gem ‐difluorocyclopropyl group attached to the carbon atom, as well as their chemical transformations,, the corresponding N ‐substituted analogues are much less studied. Most of them referred to the parent gem ‐difluorocyclopropylamine ( 5 ) or its derivatives (Scheme );, it should be noted that similar aliphatic amines (e.g.…”

“…In a recent paper by Xiao and co‐workers, a few N ‐difluorocyclopropyl‐substituted indole, benzimidazole and benzotriazole derivatives of general formula 7 were synthesized by N ‐alkylation of the corresponding heterocyclic anions with tosylate 8 . In the current work we describe an alternative approach to N ‐difluorocyclopropyl‐substituted azoles, which is based on the difluorocyclopropanation of the corresponding N ‐vinylazoles 9 with the CF 3 SiMe 3 –NaI system, which was initially developed by Hu, Prakash, Olah and co‐workers in 2011, and has been used by many other groups since then . Although this method appeared to be suitable only for the pyrazole derivatives, a wide range of functionalized compounds could be obtained, which are valuable low‐molecular‐weight building blocks for drug discovery and agrochemistry.…”

gem‐Difluorocyclopropanation of Alkenyl Trifluoroborates with the CF3SiMe3–NaI System

“…Because application of these reaction conditions to functionalized substrates is limited by their thermal stability and their susceptibility to side reactions at elevated temperatures, a selection of a TMSCF 3 –NaI system as a difluorocarbene equivalent was envisaged. The usage of TMSCF 3 , which is also referred as Ruppert–Prakash reagent, for gem ‐difluoromethylation reaction was first developed by Hu, Prakash and co‐workers, and was further adapted for preparation of gem ‐difluorocyclopropanes bearing diverse functional groups . Nonetheless, the addition of difluorocarbene equivalent derived from TMSCF 3 to alkenylboronic derivatives was unknown until the present study.…”