An Improved Preparation of 3,5-Bis(trifluoromethyl)acetophenone and Safety Considerations in the Preparation of 3,5-Bis(trifluoromethyl)phenyl Grignard Reagent

Abstract

An improved and efficient bromination of 3,5-bis(trifluoromethyl)benzene was developed. A safe and reliable preparation of the potentially explosive 3,5-bis(trifluoromethyl)phenyl Grignard and 3-trifluoromethylphenyl Grignard reagents, from the precursor bromides, is described. Reaction System Screening Tool (RSST) and Differential Thermal Analysis (DTA) studies suggest these trifluoromethylphenyl Grignard reagents can detonate on loss of solvent contact or upon moderate heating. When prepared and handled according to the methods described herein, these Grignard reagents can be safely prepared and carried on to advanced intermediates.

Preparation of Polyfunctional Arylmagnesium, Arylzinc, and Benzylic Zinc Reagents by Using Magnesium in the Presence of LiCl

“…The formation of magnesium reagents containing a trifluoromethyl group is dangerous and difficult to perform, especially at temperatures between 30 and 50 8C. [18] By using Mg turnings in the presence of LiCl, Grignard reagents such as 2 g-j can be safely prepared within 30 min at 0 8C. After transmetalation to the corresponding zinc reagents and Negishi cross-coupling reactions with ethyl 4-iodobenzoate, the desired trifluoromethyl-substituted biphenyls 5 h-j were obtained in yields of 83-97 % (entries 6-8).…”

Propagation and Synchronization of Potential Oscillations in Multiple Liquid Membrane Systems

“…30 The NaTFPB salt was synthesized as reported previously. 29,[31][32][33] CTACl (Wako Pure Chemical Ind., No. 038-08402), picric acid (Nacalai Tesque Ind., No.…”

Preparation, Thermal Stability and Carbonyl Addition Reactions of 2,5-Difluorophenyl Lithium and 2,5-Difluorophenyl Grignard

“…9, 1646-1648 © Thieme Stuttgart · New York 2,5-Difluorophenyl lithium (2) has been previously accessed by bromine-lithium exchange reaction of 1-bromo-2,5-difluorobenzene with BuLi in THF. 7 Direct lithiation of 1,4-difluorobenzene by BuLi, 8a s-BuLi, 8b or the superbase combination BuLi/t-BuOK, 8c has also been reported, although no rigorous stability or assay data were documented in any of these preparations of 2.…”

“…We were particularly drawn to the potential use of 2,5-difluorophenyl Grignard reagent (1, X = Cl or Br) and 2,5-difluorophenyl lithium reagent (2). In this letter we document efficient preparations and thermal stability data of 1 and 2, as well as exemplifying the utility of organolithium 2 in the addition to aldehyde and ketone electrophiles.…”