Difluorocarbene as a Building Block for Consecutive Bond-Forming Reactions

Alexander D Dilman, Vitalij V Levin

Acc Chem Res. 2018 May 15;51(5):1272-1280.

PMID: 29664601

Abstract:

Compounds containing a difluoromethylene unit have gained increasing attention due to their utility in drug design. Classic methods for the synthesis of these compounds rely on either harsh deoxofluorination reactions or laborious functional group manipulation sequences. In 2013, we proposed a method for assembling gem-difluorinated molecules from a difluorocarbene, a nucleophile, and an electrophile. In this process, a difluorocarbene can be considered an equivalent of a bipolar CF2 unit. Performing consecutive bond-forming reactions by sequential attachment of a nucleophile and an electrophile to a difluorocarbene provides the opportunity for the synthesis of a wide variety of organofluorine compounds. Silicon reagents were the most effective sources of the difluoromethylene fragment, and among them (bromodifluoromethyl)trimethylsilane (Me3SiCF2Br) is the reagent of choice. Mildly basic activators such HMPA, DMPU, bromide and acetate ions can initiate the decomposition of the silane with concomitant generation of a difluorocarbene. Organozinc reagents can be employed as nucleophiles, and the CF2 fragment can insert into the carbon-zinc bond. Primary and secondary benzyl and alkyl organozinc compounds work well. Generally, organozinc reagents tolerate a variety of functional groups. The resulting fluorinated organozinc species can be coupled with heteroatom- or carbon-centered electrophiles. Halogenation of the carbon-zinc bond leads to compounds with bromo- or iododifluoromethyl fragments, which are difficult to access by other means, whereas protonation of that bond generates a valuable difluoromethyl group. Despite the decrease in the reactivity of the carbon-zinc bond caused by the adjacent fluorines, organozinc compounds can effectively participate in copper-catalyzed cross-couplings with allylic and propargyl halides, 1-bromoalkynes, and S-acyl dithiocarbamates. Difluorocarbene can be inserted into the carbon-silicon bond of trimethylsilyl cyanide, and the resulting silane can react with aldehydes and imines to furnish difluorinated nitriles. Interactions of difluorocarbene with heteroatom nucleophiles, such as phosphines or halide ions, are reversible, but the adduct can be trapped by an electrophile. The use of halide ions allows the direct nucleophilic bromo- and iododifluoromethylation of aldehydes and iminium ions. The combination of triphenylphosphine with difluorocarbene generates a difluorinated phosphorus ylide, which can interact with a wide range of π-electrophiles (aldehydes, ketones, acyl chlorides, azomethines, and Michael acceptors) to provide gem-difluorinated phosphonium salts. In the latter species, the carbon-phosphorus bond can be readily cleaved under basic conditions, affording the difluoromethylation products. Primary products resulting from three-component couplings can subsequently be used for further transformations. Single-electron reduction of carbon-phosphorus or carbon-iodine bonds can be conducted under photocatalytic conditions to generate gem-difluorinated radicals. These radicals can be trapped by silyl enol ethers leading to β,β-difluorinated ketones as the primary products. Fluorinated radicals can also undergo intramolecular attacks adjacent to an aromatic ring or a double bond.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP115262016	(Bromodifluoromethyl)trimethylsilane		115262-01-6	Price