Cu-mediated chemoselective trifluoromethylation of benzyl bromides using shelf-stable electrophilic trifluoromethylating reagents

Article abstract of DOI:10.1021/ol201205t

Copper-mediated chemoselective trifluoromethylation at the benzylic position by the use of shelf-stable electrophilic trifluoromethylating reagents 3 in good to high yields under mild conditions is described for the first time. The generality of this trifluoromethylation for a wide variety of benzyl bromides facilitates the rapid creation of structural diversity of medicinal candidates in drug discovery.

Full text of DOI:10.1021/ol201205t

ORGANIC
LETTERS
2011
Vol. 13, No. 14
3596–3599
Cu-Mediated Chemoselective
Trifluoromethylation of Benzyl Bromides
Using Shelf-Stable Electrophilic
Trifluoromethylating Reagents
Hiroyuki Kawai, Tatsuya Furukawa, Yoshinori Nomura, Etsuko Tokunaga, and Norio Shibata*
Department of Frontier Materials, Graduate School of Engineering,
Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya 466-8555, Japan
nozshiba@nitech.ac.jp
Received May 6, 2011
ABSTRACT
Copper-mediated chemoselective trifluoromethylation at the benzylic position by the use of shelf-stable electrophilic trifluoromethylating
reagents 3 in good to high yields under mild conditions is described for the first time. The generality of this trifluoromethylation for a wide variety
of benzyl bromides facilitates the rapid creation of structural diversity of medicinal candidates in drug discovery.
Direct introduction of a CF3 group into organic molecules
provides straight entrance to trifluoromethylated compounds
that are important building blocks in the synthesis of drug
and agrochemical candidates as well as other unique products
in material sciences.1 Among the many potential trifluoro-
methylated synthons for these purposes,2 a considerable
research effort has been focused on the synthesis of tri-
fluoromethyl-containing aromatic compounds such as
(trifluoromethyl)arenes,3 (trifluoromethoxy)arenes,4 and
(trifluoromethylthio)arenes5 (Figure 1). In contrast to the
long-standing interest in these trifluoromethyl-containing
arenes, (trifluoroethyl)arenes as well as their heteroaromatic
variants remain remarkably uncommon synthetic targets
despite their high potential utilities in various fields including
medicinal, biological, agricultural, and material chemistry.6
Figure 1. Trifluoromethyl-containing aromatic compounds.
(1) (a) Filler, R.; Kobayashi, Y. Biomedicinal Aspects of Fluorine
Chemistry; Elsevier Biomedical Press and Kodansya Ltd.: Amsterdam,
1982. (b) Welch, J. T.; Eswarakrishman, S. Fluorine in Bioorganic Chem-
istry; Wiley: New York, 1991. (c) Filler, R.; Kobayashi, Y.; Yagupolskii,
L. M. Organofluorine Compounds in Medicinal Chemistry and Biomedical
Applications; Elsevier: Amsterdam, 1993. (d) Kuhar, V. P.; Soloshonok,
V. A. Fluorine Containing Amino Acids: Synthesis and Properties; Wiley:
Chichester, UK, 1995. (e) Ojima, I.; MacCarthy, J. R.; Welch, J. T. Biomedical
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Although tremendous progress has been achieved in this
area, particularly for the trifluoromethylation of an aro-
matic ring,3 the preparation of (trifluoroethyl)arenes by
direct introduction of a trifluoromethyl group at the
benzylic position has been considerably less studied.7
Trifluoromethylation of benzyl bromide with [CuCF3]
generated from CF3I and Cu powder was initially exam-
ined by Kobayashi and co-workers in 1979.7a This method
requires a high reactiontemperatureina stainlesssteel tube
r
10.1021/ol201205t
Published on Web 06/13/2011
2011 American Chemical Society

to prepare [CuCF3] species and removal of excess amounts
of copper in a glovebox. One year later, Yagupolskii’s
group achieved trifluoromethylation of benzyl bromide in
moderate yield using [CuCF3] generated from (CF3)2Hg.7b
In order to avoid the vigorous conditions, toxic material or
a troublesome procedure is necessary to promote the
reaction. Fuchikami and Urata devised the conditions
for the trifluoromethylation of benzyl bromide by the use
of Et3SiCF3 in the presence of a stoichiometric amount of
KF and CuI.7c The generation of reactive [CuCF3] and
related species were further examined by developing con-
ditions such as Me3SiCF3/KF/CuI in ionic liquid,7d
FO2SCF2CF2OCF2CO2Me/CuI,7e CF3Br/copper anode,7f
and Me3SiCF3/N-heterocyclic carbeneꢀCu complexes.7g,h
Although all the reported works describe the trifluoro-
methylation of benzyl halides, substrate generality is
unexplored.7 As part of our ongoing research programs
directed toward the development of efficient electrophilic
trifluoromethyl reagents,8 and methodologies for the intro-
duction of the trifluoromethyl group,9 we hypothesized
that benzyl bromides would reacted with [CuCF3] gener-
ated in situ from the reduction of electrophilic trifluoro-
methylating reagents. We have started our work, during
which time trifluoromethylations of aromatic ring (sp2
carbon) using shelf-stable electrophilic trifluoromethylat-
ing reagents such as (trifluoromethyl)diphenylsulfonium
salt were successively disclosed.10 However, no example
was reported for the trifluoromethyaltion at the benzylic
position (sp3 carbon). We herein report the copper-mediated
chemoselective trifluoromethylation reaction of a series of
benzyl bromides through in situ generated [CuCF3] species
from shelf-stable electrophilic trifluoromethylating reagents
311 and copper (Scheme 1). Reactive functional groups such as
ester, ketone, and imide are well retained under the condition,
while they are reacted under the conventional nucleophic
trifluoromethylation condition. To the best of our knowledge,
this is the first example for trifluoromethylation of benzyl
bromides using electrophilic trifluoromethylating reagents.
Scheme 1. Copper-Mediated Trifluoromethylation of Benzyl
Bromides with Electrophilic Trifluoromethylating Reagents
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We started our investigation with the reaction of
4-nitrobenzylbromide (1a) with a series of electrophilic
trifluoromethylating reagents 3 in the presenceofcopper in
DMF at 60 °C (Table 1). First, the trifluoromethylation of
1a with our trifluoromethylsulfoxinium salt 3a was at-
tempted; however, it gave a disappointing result, and only
a trace amount of desired product 2a was obtained (entry 1).
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Org. Lett., Vol. 13, No. 14, 2011
3597

Next we attempted the same reaction using S-(trifluo-
romethyl)benzothiophenium salt 3b, and desired product
2a was obtained in 35% yield (entry 2), which was im-
proved to 54% by the use of S-(trifluoromethyl)diphen-
ylsulfonium salt 3c (entry 3), although its analogue 3d gave
a slightly inferior result (entry 4, 42%). Umemoto’s re-
agent, S-(trifluoromethy1)dibenzothiophenium salt 3e
proved to be equally effective, affording 2a in 52% yield
(entry 5). Hypervalent iodine(III)ꢀCF3 reagent 3f pro-
vided no desired 2a under the same reaction condition
(entry 6). These results might provide one possibility that
trifluoromethylation proceeds thorough the reaction of
benzyl bromide and reductively generates [CuCF3] species
via single electron transfer from copper to the cationic
sulfur in 3, and a mechanism by the electrophilic trifluor-
omethylation of Cu-benzyl spices could be ruled out, although
further work is necessary to substantiate a detailed mechan-
ism. The solvent was next screened for further improvement of
yields. While DMI, CH2(CH2Cl)2, DMSO, and HMPA did
not effectively improve yield, NMP proved to be a better
solvent in the reaction to provide 2a at 81% (entries 7ꢀ12).
were nicely converted into trifluoromethyl compounds
2aꢀd in 56ꢀ81% yields. This method can tolerate the
coexistenceof botha fluorineatom and a nitro group on an
aromatic ring. It is known that fluorine acts as a leaving
group on the aromatic substitution reaction if a strong
electron-withdrawing group is attached on the aromatics.
Fortunately, 2-fluoro-6-nitrobenzyl bromide was con-
verted into 2e in 61% yield, and none of the aromatic
trifluoromethylation was observed. Moreover, the reac-
tion of benzyl bromides having electron-withdrawing cya-
no (1f), ester (1g), and acetyl (1h) and electron-donating
tert-butyl (1i) and methoxy (1j) groups on the aromatic
rings provided the desired products 2fꢀj in 58;82% yield.
It should be noted that the benzyl position was chemoselec-
tively trifluoromethylated, and carbonyl moieties in ester 2g
and ketone 2h survived well under the reaction conditions,
while the conventional nucleophilic trifluoromethylation
using Me3SiCF3 generally occurs at carbonyl carbons.1f
Neutral and sterically demanding 2-(bromomethyl)napht-
halene (1k) and 9-(bromomethyl)phenanthrene (1l) also
afforded 2kꢀl in 77% and 79% yield, respectively, under
the same reaction conditions. Trifluoromethylation of
methoxy BINOL derivative 1m, which has a bromomethyl
group at the 3-position, nicely proceeded to give
Table 1. Optimization of CF3þ Reagents 3 and Solvents for
Copper-Mediated Trifluoromethylation of Benzyl Bromidesa
entry
CF3þ reagent
solvent
DMF
yieldb (%)
1
2
3a
3b
3c
3d
3e
3f
trace
35
54
42
52
nr
DMF
3
DMF
4
DMF
5
DMF
6
DMF
7
3c
3c
3c
3c
3c
3c
DMI
10
nr
8
CH2(CH2Cl)2
DMSO
HMPA
DMF/NMP (1/1)
NMP
9
11
10
11
12
52
73
81
a The reaction of 1a with 3 (2.0 equiv) was carried out in the presence
of Cu (3.0 equiv) at 60 °C. b Isolated yield.
With optimal conditions in hand, the scope of copper-
mediated trifluoromethylation of benzyl bromides with 3c
was explored with a variety of substrates selected in order
to establish the generality of the process (Figure 2). The
results were almost independent of the position of the
aromatic ring, as well as the nature and number of the
substituents. For instance, o-, m-, and p-nitrobenzyl bro-
mides 1aꢀc and dinitro-substituted benzyl bromide 1d
(11) (a) Yagupolskii, L. M.; Kondratenko, N. V.; Timofeeva, G. N.
J. Org. Chem. USSR 1984, 20, 103. (b) Yang, J.-J.; Kirchmeier, R. L.;
Shreeve, J. M. J. Org. Chem. 1998, 63, 2656. (c) Umemoto, T.; Ishihara,
S. Tetrahedron Lett. 1990, 31, 3579. (d) Umemoto, T.; Adachi, K. J. Org.
Chem. 1994, 59, 5692. (e) Eisenberger, P.Gischig, S.; Togni, A. Chem.;
Eur. J. 2006, 12, 2579. (f) Umemoto, T. Chem. Rev. 1996, 96, 1757.
(g) Shibata, N.; Matsnev, A.; Cahard, D. Beilstein J. Org. Chem. 2010, 6.
Figure 2. Copper-mediated trifluoromethylation of benzyl bro-
mides 1 with 3c.
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Org. Lett., Vol. 13, No. 14, 2011

trifluoromethylated product 2m in 75% yield. It should be
noted that bis(bromomethyl)-substituted naphthalene 1n
was also a suitable substrate for the copper-mediated
trifluoromethylation reaction with 3c (4.0 equiv) in the
presence of Cu (6.0 equiv), affording a double trifluoro-
methylated adduct 2n in 83% yield. Methoxy-BINOL
derivative 1o with a bis(bromomethyl) group at the 3,30-
position and BINOL derivative 1p having a bis-
(bromomethyl) group at the 2,20-position also gave double
trifluoromethylated adducts 2o and 2p in 77% and 55%
yield, respectively. These chiral compounds, 2m, 2o, and 2p,
are attractive as chiral ligands for organic synthesis. 2-Bro-
momethylquinoline (1q) containing an exposed basic nitro-
gen was converted to the corresponding trifluoromethyl
compound 2q in 83% yield. Heteroaromatic, N-Boc-pro-
tected bromomethylindole (1r) afforded the desired adduct
2r in moderate yield (45%). Trifluoromethylation of 1-(3-
bromoprop-1-ynyl)-4-nitrobenzene 1s proceeded under the
same conditions to furnish 2s in 36%, which is the first
example of the trifluoromethylation of propargyl halides.
We were next interested in the trifluoromethylation of
phthalimide derivatives. Phthalimides are one of the key
structural motifs frequently encountered in biologically
active molecules and pharmaceuticals on the market, de-
spite their rare occurrence in nature.12 Our group has been
engaged in the design and development of thalidomide
derivatives for more than a decade13 since we required
trifluoroethyl analogues of thalidomide for anticancer
research, particularly focusing on multiple myeloma since
methyl analogues of thalidomide indicate the interesting
biological activity (Figure 3).14 To begin with, we examined
the trifluoromethylation of N-phenylphthalimide deriva-
tive 1t. Under the same reaction conditions using 3c, Cu in
NMP, the desired trifluoromethylated compound 2t was
obtained in 86%, chemoselectively. The two electrophilic
carbonyl groups attached to the nitrogen atom, imide
moiety, in 1t were retained without suffering from nucleo-
philic addition.15 In contrast, a complex mixture was
obtained including only 13% of 2t under previously re-
ported conditions developed by Fuchikami7c using Et3-
SiCF3/KF/CuI. Encouraged by these results, our target
trifluoroethyl thalidomide was nicely synthesized using our
chemoselective trifluoromethylation method at the benzylic
Figure 3. Thalidomide and (trifluoroethyl)thalidomides.
Scheme 2. Trifluoromethylations of Phtalimide Derivatives
position of 3c to provide thalidomide derivative 6 in 71%
yield (Scheme 2).
In summary, we developed copper-mediated chemoselective
trifluoromethylation at the benzylic position through the use of
shelf-stable electrophilic trifluoromethylating reagents 3bꢀe in
good to high yields under mild conditions for the first time.
Reactive carbonyl carbons including ester, ketone as well as
imide are well retained under our chemoselective benzylic
trifluoromethylation conditions. The method can be applic-
able to the trifluoromethylation of heteroarene derivatives as
well as double-trifluoromethylation reactions of chiral BINOL
derivatives. The generality of this trifluoromethylation for a
wide variety of benzyl bromides facilitates the rapid creation of
structural diversity of medicinal candidates in drug discovery
represented by thalidomide drugs. This methodology remains
a limitation in the trifluoromethylation of primary benzyl
bromides and requires essentially a stoichiometric amount of
copper metal. Hence, we are now focusing on developing the
trifluoromethylation of secondary benzyl bromides and cata-
lytic variants of this trifluoromethylation reaction.
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Acknowledgment. This study was financially supported
in part by Grants-in-Aid for Scientific Research (B21390030,
22106515) and the Asahi Glass Foundation.
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Supporting Information Available. Experimental proce-
dures and spectra data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(14) Man, H.-W.; Muller, G. W. WO9947512, 1999.
(15) Nucleophilic trifluoromethylation of imides easily proceeds with
Me3SiCF3. See ref 9a, for example.
Org. Lett., Vol. 13, No. 14, 2011
3599