Direct Dehydroxytrifluoromethoxylation of Alcohols

Abstract

The first example of a direct dehydroxytrifluoromethoxylation of alcohols has been developed. This method generated an alkyl fluoroformate in situ from alcohols, followed by nucleophilic trifluoromethoxylation with trifluoromethyl arylsulfonate (TFMS) as the trifluoromethoxylation reagent. The reaction is operationally simple and scalable, and it proceeds under mild reaction conditions to provide access to a wide range of trifluoromethyl ethers from alcohols. In addition, this method is suitable for the late-stage trifluoromethoxylation of complex small molecules.

Concise and Additive‐Free Click Reactions between Amines and CF3SO3CF3

“…The carbamoyl fluoride of as econdary amine (e.g., 7a)w as an unreactive reagent for secondarya liphatic amines (e.g., 6a), aromatica mines (e.g., 1a), alcohols (e.g., 10), phenols( e.g., 12), benzenethiols (e.g., 14), and thiols (e.g., 16)a te ither room temperature or 60 8C( conditions A, Scheme 1). The addition of NEt 3 to the reactionm ixturesa tr oom temperature overnight could not form the condensed products (8,9,11,13,15,a nd 17)e ither (conditions B, Scheme 1). However,t he carbamoyl fluoride was reactive to primarya liphatic amines because the reactiono f7a with 1ab at room temperature for 1h gave 18 in 92 %y ield (Scheme 1).…”

“…[9] The similare mployment of trifluoromethyl arylsulfonates and trifluoromethyl benzoate as À OCF 3 sources has also been fully discussed. [11,12] Nonetheless,t he application of trifluoromethyl sulfonates in other reactions, rather than trifluoromethoxylation and sulfonylation, has rarely been studied. [8] Furthermore,c lick chemistry is ac hemical concept that was first introduced by Sharpless and co-workersi n2 001, and has been extensively used in biology,m edicine, and materials sciences.…”

“…[13c,d] It is known that trifluoromethanolates are thermally unstable and tend to undergo a-fluorine eliminationt of orm difluorophosgenea nd fluoridea bove À30 8C. [9][10][11] Because 2a is an easily accessible À OCF 3 source, whichc an be initiated by various nucleophiles, [8g, 9] we have wondered whether it could be used as al iquid reservoir of difluorophosgenea nd ac lick reagent for amines to prepareu reas and carbamoyl fluorides under metal-and additive-free conditions.…”

A Radical Revolution for Trifluoromethoxylation

“…Thev olatility of this reagent (b.p. 2 1 8 8C), however,c reates practical challenges while its high cost precludes large-scale applications.T oa ddress this issue,T ang and co-workers have introduced aseries of TFMS reagents 2.U nlike their volatile counterparts,T FMS species are easy to handle and have been successfully employed in as ynthetically attractive deoxytrifluoromethoxylation of aliphatic alcohols [6] and in the first enantioselective trifluoromethoxylation process (Scheme 1c). [7] Them ore convenient access to À OCF 3 anions should stimulate the field of nucleophilic trifluoromethoxylation although aless expensive synthetic route towards TFMS reagents that does not use electrophilic trifluoromethylation agents will be required for large-scale applications.Indeed, during the submission of this manuscript, Hu and co-workers reported arelated benzoatederived reagent that can be prepared using relatively inexpensive potassium fluoride.…”

Eine radikale Revolution für die Trifluormethoxylierung

“…[5] Ein breiteres Spektrum an Strategien ist dringend Schema 1. a) Oft genutzte Synthesewege fürtrifluormethoxylierte Verbindungen. [6] sondern ermçglichten darüber hinaus auch die erste enantioselektive Tr ifluormethoxylierung (Schema 1c). c) Asymmetrische Bromtrifluormethoxylierung von Alkenen unter Verwendung von TFMS-Reagentien; (DHQD) 2 PHAL = 1,4-Bis[(S)-[(2R,4S,5R)-5-ethylchinuclidin-2-yl]-(6-methoxy-4-chinolyl)methoxy]phthalazin.…”