Tetrafluoroborate

Carbene

Catalysis

Salt (chemistry)

Photochemistry

Electrophile

Difluorocarbene

Ylide

Reactive intermediate

Combinatorial chemistry

Organic chemistry

Reagent

Nucleophile

Phosphonium

Phosphonium salt

Chemistry

Ionic liquid

Sulfonium

Accounts of Chemical Research

ConspectusOwing to the special effects of the fluorine element, including high electronegativity and small atomic radius, the incorporation of a fluorinated group into organic molecules may modify their physical, chemical, and biological properties. Fluorine-containing compounds have found widespread application in a variety of areas, and thus, the development of efficient reagents and methods for the incorporation of fluorinated groups has become a subject of significant interest.Described in this Account are our recent discoveries in the chemistry of fluorinated ylides/carbenes and related intermediates generated from phosphonium/sulfonium salts. Initially, we obtained the (triphenylphosphonio) difluoroacetate, Ph3P+CF2CO2– (PDFA), which was proposed as a reactive intermediate but had never been successfully synthesized. PDFA, shelf-stable and easy to prepare, is not only a mild ylide (Ph3P+CF2–) reagent, but also an efficient difluorocarbene source. It can directly generate difluorocarbene, via the first generation of ylide Ph3P+CF2–, simply under warming conditions without the need for any additive. Interestingly, difluorocarbene chemistry was then discovered by using PDFA as a reagent. Difluorocarbene can be oxidized to CF2═O, can react with elemental sulfur to afford CF2═S, and can be trapped by NaNH2 or NH3 to give CN–. The development of these processes into synthetic tools allowed us to achieve various reactions, including the challenging 18F-trifluoromethylthiolation and cyanodifluoromethylation. It was found that a substituent on the cation of a phosphonium salt can be directly transferred as a nucleophile despite the cation's high electrophilicity. This transfer process is like an "umpolung" of the cation, which may provide more opportunities for the synthetic utilities of phosphonium salts. The investigation of this transfer process led us to find that iodophosphonium salts, active intermediates which can be easily generated, may efficiently promote deoxygenative functionalizations of aldehydes and alcohols. Dehydroxylative substitution of alcohols by this protocol permits the use of unprotected amines with higher pKa values as nucleophiles, which is an attractive feature compared with the Mitsunobu reaction. On the basis of the ylide-to-carbene process (Ph3P+CF2– → :CF2), we further developed sulfonium salts as precursors of fluorinated ylides and fluorinated methyl carbenes. In particular, the studies on difluoromethylcarbene, remaining largely unexplored, may deserve more attention. The discoveries may find utility in the synthesis of biologically active fluorine-containing molecules.

Fluorinated Ylides/Carbenes and Related Intermediates from Phosphonium/Sulfonium Salts