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SCHEME 1. Retr osyn th etic An a lysis
An Im p r oved P r ep a r a tion of
3,5-Bis(tr iflu or om eth yl)a cetop h en on e a n d
Sa fety Con sid er a tion s in th e P r ep a r a tion
of 3,5-Bis(tr iflu or om eth yl)p h en yl
Gr ign a r d Rea gen t
J ohnnie L. Leazer, J r.,*,† Raymond Cvetovich,†
Fuh-Rong Tsay,† Ulf Dolling,† Thomas Vickery,‡ and
Donald Bachert‡
Department of Process Research and Department of
Chemical and Engineering Research and Development,
Merck Research Laboratories, P.O. Box 2000,
Rahway, New J ersey 07065
SCHEME 2. Br om in a tion of
john_leazer@merck.com
1,3-Bis(tr iflu or om eth yl)ben zen e (3)
Received December 23, 2002
Abstr a ct: An improved and efficient bromination of 3,5-
bis(trifluoromethyl)benzene was developed. A safe and reli-
able preparation of the potentially explosive 3,5-bis(trifluoro-
methyl)phenyl Grignard and 3-trifluoromethylphenyl Grig-
nard reagents, from the precursor bromides, is described.
Reaction System Screening Tool (RSST) and Differential
Thermal Analysis (DTA) studies suggest these trifluoro-
methylphenyl 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.
sion to 2, and present key safety considerations associ-
ated with the highly reactive and potentially explosive
trifluoromethylphenyl Grignard reagents.
Literature methods for the bromination of 3 to give
bromide 4 utilize either N-bromosuccinimide (NBS) or
1,3-dibromo-5,5-dimethylhydantoin (DBH) in concen-
trated sulfuric acid or trifluoroacetic acid.3 The yields are
quoted in the 90% range for bromide 4 with bis-bromi-
nated (5 and 6) and isomeric byproducts (7, 8, and 9)
amounting to 5-10 mol %3 as the byproducts (Scheme
2). Attempts to reproduce these procedures gave incon-
sistent results with significant amounts (>30 mol %) of
byproducts 5-9, later determined to result from inad-
equate mixing of the biphasic bromination reaction
mixture.
To circumvent the selectivity issues, the use of cosol-
vents to solubilize both the starting materials and
products was examined. Addition of acetic acid to a
sulfuric acid slurry of 3 and DBH resulted in increased
reaction selectivity for bromide 4 (>98%). Similar effects
were also observed when using NBS in HOAc/H2SO4
mixtures to brominate 3. When using HOAc/H2SO4
mixtures in the DBH system, bis-bromination of 3,
producing bromides 5 and 6, was observed only after 3
was completely consumed. In HOAc/H2SO4 mixtures,
little if any bis-bromination occurred after 3 was com-
The novel neurokinin 1 receptor antagonist MK869 has
shown clinical efficacy in the treatment of depression and
chemotherapy-induced emesis.1 As part of a program
directed toward the synthesis of MK869, we required a
practical synthesis of chiral benzyl alcohol 1.1a,2 It was
envisioned that 1 could be obtained by a chiral reduction
of 3,5-bis(trifluoromethyl)acetophenone 2.1a Acetophen-
one 2 could in turn arise from 3,5-bis(trifluoromethyl)-
benzene 3 by a highly regioselective bromination followed
by coupling of the corresponding Grignard reagent with
Ac2O. In this note we describe a highly regioselective
bromination of 3, a safe and scalable preparation of the
corresponding Grignard reagent 10, as well as its conver-
† Department of Process Research.
‡ Department of Chemical and Engineering Research and Develop-
ment.
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10.1021/jo026903n CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/09/2003
J . Org. Chem. 2003, 68, 3695-3698
3695