Rapid Dehydroxytrifluoromethoxylation of Alcohols

Abstract

SummaryThe CF3O functional group is a unique fluorinated group that has received a great deal of attention in medicinal chemistry and agrochemistry. However, trifluoromethoxylation of substrates remains a challenging task. Herein we describe the dehydroxytrifluoromethoxylation of alcohols promoted by a R3P/ICH2CH2I (R3P = Ph3P or Ph2PCH=CH2) system in DMF. P-I halogen bonding drives the reaction of R3P with ICH2CH2I in DMF to generate iodophosphonium salt (R3P+I I−) and a Vilsmeier-Haack-type intermediate, both of which could effectively activate alcohols, thus enabling a fast (15 min) trifluoromethoxylation reaction. A wide substrate scope and a high level of functional group tolerance were observed.

Facile Access to AgOCF3 and Its New Applications as a Reservoir for OCF2 for the Direct Synthesis of N−CF3, Aryl or Alkyl Carbamoyl Fluorides

“…This suggests that our practical preparation of AgOCF 3 at room temperature has no adverse impact on reactivity or stability; in fact, AgOCF 3 appears to be stable in the reaction medium even for extended periods of time. Similarly, our AgOCF 3 stock solution also performed well in reactions with alcohols to produce R‐OCF 3 at up to 100 °C reaction temperature (see Figure B); this otherwise known transformation relies on the generation of an iodophosphonium salt (R 3 IP + I − ) and Vilsmeier–Haack‐type intermediate which can activate alcohols to form the trifluoromethoxylated product through dehydration. Another popular reaction is the silver mediated transformation of α‐diazo esters into α‐OCF 3 esters .…”

Recent trends in dehydroxylative trifluoro-methylation, -methoxylation, -methylthiolation, and -methylselenylation of alcohols

“…In an attempt to further demonstrate the strength of this novel and interesting alkyl triuoromethyl ether synthesis, Lin and Xiao along with their co-workers documented an elegant Ph 3 P/ICH 2 CH 2 I-promoted triuoromethoxylation of aliphatic alcohols using AgOCF 3 as a nucleophilic triuoromethoxylating reagent, which allowed very rapid access to the corresponding dehydroxytriuoromethoxylated products. 25 Through exploration and optimization of this dehydroxylative functionalization, the authors identied that the reaction rate is highly dependent on the nature of solvent. Among several solvents tested (e.g., DMSO, DMF, NMP, and toluene), DMF was found to be the most effective.…”

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

“…Furthermore, the nucleophiles are required to be relatively acidic in the Mitsunobu reaction, meaning that unprotected amines with higher p K a values are not suitable nucleophiles . The R 3 P/ICH 2 CH 2 I-promoted process was further extended to other dehydroxylative reactions, such as trifluoromethoxylation (Scheme b), trifluoromethylthiolation (Scheme b), and fluoroalkylation (Scheme c) . Different phosphines R 3 P may be used in different reactions.…”