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

Abstract

Metrics & MoreArticle Recommendations CONSPECTUS: Owing 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, Ph 3 P + CF 2 CO 2 − (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 (Ph 3 P + CF 2 − ) reagent, but also an efficient difluorocarbene source. It can directly generate difluorocarbene, via the first generation of ylide Ph 3 P + CF 2 − , 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 CF 2  O, can react with elemental sulfur to afford CF 2 S, and can be trapped by NaNH 2 or NH 3 to give CN − . The development of these processes into synthetic tools allowed us to achieve various reactions, including the challenging 18 F-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 pK a values as nucleophiles, which is an attractive feature compared with the Mitsunobu reaction. On the basis of the ylide-tocarbene process (Ph 3 P + CF 2 − → :CF 2 ), 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.

TMSCF2Br‐Enabled Fluorination–Aminocarbonylation of Aldehydes: Modular Access to α‐Fluoroamides

“…Fluorinated ylides are common in organofluorine chemistry as reagents or reactive intermediates [16] . During the last few years, difluomethylene phosphonium ylides have found wide applications as nucleophilic fluoroalkylation reagents in the transformation of many electrophiles including carbonyl compounds [9g, 16b, 17] . In this context, we speculated that the nucleophilic aminodifluoromethylation of carbonyl compounds with difluorocarbene could be tamed by the addition reaction of difluomethylene ammonium ylides [18] in‐situ generated from tertiary amines and difluorocarbene followed by the selective removal of one alkyl substitute from the quaternary ammonium salt intermediates (Scheme 1C).…”

Recent Advances in the Synthesis of CF3‐ or HCF2‐Substituted Cyclopropanes

“…Due to the explosive nature of CF 3 CHN 2 , it is desirable to develop a safe and convenient trifluoromethylcarbene reagent. We have been interested in the development of fluorinated phosphonium/sulfonium salts as fluorinated carbene reagents [41] . Based on our previous observation that phosphonium ylide Ph 3 P + −CF 2 − could directly undergo a P−C bond cleavage to release difluorocarbene, [42] we originally thought that sulfonium ylide Ph 2 S + −CH − CF 3 may also be able to generate trifluoromethylcarbene via a S−C bond cleavage.…”

“…We have been interested in the development of fluorinated phosphonium/sulfonium salts as fluorinated carbene reagents. [41] Based on our previous observation that phosphonium ylide Ph 3 P + À CF 2 À could directly undergo a PÀ C bond cleavage to release difluorocarbene, [42] we originally thought that sulfonium ylide Ph 2 S + À CH À CF 3 may also be able to generate trifluoromethylcarbene via a SÀ C bond cleavage. However, deep investigations revealed that the bond cleavage cannot directly occur.…”

anti‐Markovnikov Iodofluorination of Alkenes

“…We previously used Selectfluor, one of the most commonly used “F + ” reagents, to achieve dehydroxylative fluorination of tertiary alcohols, allowing for the formation of tertiary C−F bonds [10] . In continuation of our research interest in fluorine incorporation, [11] we have now investigated the anti ‐Markovnikov iodofluorination of alkenes with Selectfluor. Compared with the above anti ‐Markovnikov methods, our protocol features convenient operations, simple reaction conditions, a wide substrate scope, and the installation of an iodine atom which provides possibilities for further transformations (Scheme 1, eq 3).…”