Fei Wang, T. Luo, Jinbo Hu
Jul 25, 2011
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Angewandte Chemie
Abstract
Difluorocyclopropanes and difluorocyclopropenes are becoming an important class of compounds in organofluorine chemistry. Introduction of a fluorine atom onto a cyclopropane ring is known to alter the structure and reactivity of the molecule because of the high electronegativity and small size of the fluorine atom, and consequently the increase in the C F bond polarity. Fluorine substituents also raise the biological activity, the bioavailability, and in some cases the potency of known biologically active molecules. The difluoromethylene group is also considered as a bioisostere for an oxygen atom in biological studies. Recently, a unique application of difluorocyclopropanes to trap the 1,3-diradical formed during the mechanochemical activation of the polybutadiene backbone was reported. Besides biological and polymeric applications, difluorocyclopropanes are synthetically useful substrates for a variety of reactions such as thermal rearrangements, bimolecular reactions, carbocation, carbanion, and radical chemistry. The synthesis of difluorocyclopropanes and difluorocyclopropenes can be achieved in various ways. However, a [2+1] cycloaddition reaction of difluorocarbene to an alkene or an alkyne has proven to be the most efficient method to date. 5] This result has led to considerable efforts in developing reagents that can act as a source of difluorocarbene. Owing to the interaction of the lone pairs of electrons on the fluorine substituents with the carbene center, difluorocarbene is a relatively stabilized carbene species (with a singlet ground state) and is therefore less reactive than other dihalocarbenes. This could be one of the reasons why difluorocarbenes do not react well with electron-poor alkenes. Higher temperatures are often required for the generation as well as efficient reactions of difluorocarbene with alkenes. Some of the reagents used previously include sodium chlorodifluoroacetate (or sodium bromodifluoroacetate), PhHgCF3 [8] and Me3SnCF3 [9] (Seyferth reagents), FSO2CF2CO2SiMe3 (TFDA), and Zn/CF2Br2. [11] However, most of these reagents suffer from disadvantages such as harsh reaction conditions, high toxicity, lack of commercial availability, and/ or low product yields. Recently, Hu and co-workers reported that TMSCF2Cl can act as an efficient difluorocarbene precursor under chloride-ion catalysis at 110 8C. However, TMSCF2Cl is not commercially available and its preparation requires the use of ozone-depleting CBrClF2. [13] For substrates that are thermally unstable, the abovementioned methods and reagents could be a serious limitation, and development of better difluorocarbene precursors that can generate difluorocarbenes at lower temperatures is required. There are only few reports that discuss difluorocarbene generation at room temperature with Ph3P/CF2Br2, [15] or at low temperatures (below 78 8C) with bis(trifluoromethyl) cadmium, which is a highly pyrophoric reagent, as a source. Again, the use of cadmium or phosphines and the lack of commercial availability of these reagents is a severe limitation. Trifluoromethyltrimethylsilane (Me3SiCF3 or TMSCF3), commonly known as the Ruppert–Prakash reagent, is readily available and is the most widely used nucleophilic trifluoromethylating agent for a variety of