Practical method for the Cu-mediated trifluoromethylation of arylboronic acids with CF3 radicals derived from NaSO2CF3 and tert-butyl hydroperoxide (TBHP)

Article abstract of DOI:10.1021/ol3022726

A mild and practical protocol for the copper-mediated trifluoromethylation of aryl and heteroaryl boronic acids using NaSO₂CF₃ (Langlois' reagent) and TBHP is described. The reaction proceeds at room temperature under ambient conditions, and the products can be readily purified by extraction or column chromatography.

Full text of DOI:10.1021/ol3022726

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
Practical Method for the Cu-Mediated
Trifluoromethylation of Arylboronic Acids
with CF Radicals Derived from NaSO CF
000–000
3
2 3
and tert-Butyl Hydroperoxide (TBHP)
Yingda Ye, Stefan A. K €u nzi, and Melanie S. Sanford*
Department of Chemistry, University of Michigan, 930 North University Avenue,
Ann Arbor, Michigan 48109, United States
mssanfor@umich.edu
Received August 15, 2012
ABSTRACT
2 3
A mild and practical protocol for the copper-mediated trifluoromethylation of aryl and heteroaryl boronic acids using NaSO CF (Langlois’
reagent) and TBHP is described. The reaction proceeds at room temperature under ambient conditions, and the products can be readily purified by
extraction or column chromatography.
4
5
Trifluoromethyl-substituted arenes and heteroarenes
are increasingly important structural motifs in pharma-
1
ceuticals, agrochemicals, and organic materials. As a
K[CF B(OMe) ], CF H, S-(trifluoromethyl)diphenyl-
3 3 3
6
sulfonium triflate, Togni’s reagent, and Umemoto’s
8,9
reagent. However, most of these procedures are limited
7
result, the development of practical protocols to achieve
aromatic trifluoromethylation efficiently, selectively, and
cost effectively has been the subject of intense research
by the requirement for an inert atmosphere and/or dry
solvents. Further, the high cost and/or lack of bulk avail-
ability of many of these trifluoromethylating reagents
limits their usage on a large scale. Finally, these methods
commonly lead to competitive formation of protodeboro-
nated byproducts, which are challenging to separate from
the desired compounds.
2
effort. Over the past 3 years, a variety of Cu-mediated
and/or catalyzed methods have been reported for the
trifluoromethylation of aryl and heteroaryl boronic acids
ꢀ
þ
3
using “CF3 ” or “CF3 ” reagents, including TMSCF3,
We recently reported the Cu-catalyzed trifluoromethy-
lation of aryl boronic acids with CF I in the presence of a
3
(
1) (a) Schlosser, M. Angew. Chem., Int. Ed. 2006, 45, 5432. (b) M u€ ller,
K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881. (c) Hagmann, W. K.
J. Med. Chem. 2008, 51, 4359. (d) Kirk, K. L. Org. ProcessRes. Dev. 2008,
(
5) Nov ꢀa k, P.; Lishchynskyi, A.; Grushin, V. V. Angew. Chem., Int.
Ed. 2012, 51, 7767.
1
2, 305. (e) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem.
Soc. Rev. 2008, 37, 320.
2) (a) Tomashenko, O. A.; Grushin, V. V. Chem. Rev. 2011, 111,
475. (b) Furuya, T.; Kamlet, A. S.; Ritter, T. Nature 2011, 473, 470. (c)
Roy, S.; Gregg, B. T.; Gribble, G. W.; Le, V.-D. Tetrahedron 2011, 67,
(
(6) Zhang, C.-P.; Cai, J.; Zhou, C.-B.; Wang, X.-P.; Zheng, X.; Gu,
Y.-C.; Xiao, J.-C. Chem. Commun. 2011, 47, 9516.
(7) (a) Liu, T.; Shen, Q. Org. Lett. 2011, 13, 2342. (b) Liu, T.; Shao,
X.; Wu, Y.; Shen, Q. Angew. Chem., Int. Ed. 2012, 51, 540.
(8) Xu, J.; Luo, D.-F.; Xiao, B.; Liu, Z.-J.; Gong, T.-J.; Fu, Y.; Liu,
L. Chem. Commun. 2011, 47, 4300.
4
2161. (d) Wu, X.-F.; Neumann, H.; Beller, M. Chem.;Asian J. 2012, 7,
1744. (e) Besset, T.; Schneider, C.; Cahard, D. Angew. Chem., Int. Ed.
2012, 51, 5048. (f) Ye, Y.; Sanford, M. S. Synlett 2012, 23, 2005.
(g) Studer, A. Angew. Chem., Int. Ed. 2012, 51, 8950.
(9) For an example of fluorobutylation of arylboronic acids with
(
3) (a) Chu, L.; Qing, F.-L. Org. Lett. 2010, 12, 5060. (b) Senecal,
R
F
I, see: Qi, Q.; Shen, Q.; Lu, L. J. Am. Chem. Soc. 2012, 134, 6548.
(10) Ye, Y.; Sanford, M. S. J. Am. Chem. Soc. 2012, 134, 9034.
(11) (a) Nagib, D. A.; Scott, M. E.; MacMillan, D. W. C. J. Am.
T. D.; Parsons, A. T.; Buchwald, S. L. J. Org. Chem. 2011, 76, 1174. (c)
Jiang, X.; Chu, L.; Qing, F.-L. J. Org. Chem. 2012, 77, 1251. (d) Litvinas,
N. D.; Fier, P. S.; Hartwig, J. F. Angew. Chem., Int. Ed. 2012, 51, 536.
Chem. Soc. 2009, 131, 10875. (b) Pham, P. V.; Nagib, D. A.; MacMillan,
D. W. C. Angew. Chem., Int. Ed. 2011, 50, 6119. (c) Nagib, D. A.;
MacMillan, D. W. C. Nature 2011, 480, 224.
(4) Khan, B. A.; Buba, A. E.; Gooßen, L. J. Chem.;Eur. J. 2012, 18,
1
577.
1
0.1021/ol3022726 r XXXX American Chemical Society

1
photocatalyst and visible light (Scheme 1a). A key
0
the reaction scales well, proceeding in 85% isolated yield
on a 0.5 mmol scale.
feature of this transformation is the merger of CF • (gene-
3
1
1
rated via a photocatalysis cycle) with a Cuꢀaryl inter-
mediate. The high selectivity and mild conditions asso-
ciated with this process led us to consider more practical
a
Table 1. Optimization of the Trifluoromethylation of 1
potential sources of CF • to use in Cu-mediated boronic
3
acid trifluoromethylation. Several reports have shown that
the combination of NaSO CF (Langlois’ reagent) and
2
3
TBHP generates trifluoromethyl radicals at room tem-
1
2,13
perature in the presence of ambient air and moisture.
This in situ generated CF • has been shown to react with
3
b
entry
copper salt
solvent
yield
electron-rich arenes and heterocycles to afford mixtures of
2,13
c,d
1
1
CuOAc
CuOAc
CuOAc
CuOAc
CuCl
DCM/H
DCM/H
2
O
O
18%
47%
60%
71%
80%
<1%
isomeric CꢀH trifluoromethylation products.
We rea-
soned that in the presence of a Cu salt, the CF • generated
d
2
2
3
d
3
2
MeOH/H O
from NaSO CF and TBHP could instead be harnessed
2
e
3
4
MeOH/DCM/H
MeOH/DCM/H
MeOH/DCM/H
2
O
2
O
2
O
to achieve site selective trifluoromethylation of a boronic
acid (Scheme 1b). We report herein the feasibility of this
approach and the development of a general, mild, and
practical protocol for Cu-mediated trifluoromethylation
e
5
e
6
ꢀ
a
General conditions: substrate 1 (1 equiv, 0.05 mmol), [Cu] (1 equiv),
b
2 3
NaSO CF (3 equiv), TBHP (5 equiv) at 23 °C for 12 h. Yields
19 c d
determined by F NMR analysis. 0.2 equiv of CuOAc. Solvent
of aryl boronic acids with NaSO CF and TBHP.
2
3
e
ratio = 5:2. Solvent ratio = 5:5:4.
While electron-neutral and -rich boronic acids underwent
trifluoromethylation in excellent yields under the optimal
conditions from Table 1 (vide infra), several electron-
deficient derivatives did not. For example, (4-cyanophenyl)-
boronic acid (2) reacted to afford 2a in only 36% yield
Scheme 1. Cu-Mediated Trifluoromethylation of Aryl Boronic
Acids Using in Situ Generated CF Radical
3
(Table 2). We reasoned that the lower yield might be
due to slower transmetalation of the electron-deficient
boronic acid. Consistent with this proposal, the addition
of 1 equiv of NaHCO (which is expected to accelerate
3
transmetalation) led to an increase in yield to 46%.
Further evaluation of different Cu sources showed that
the substitution of CuCl with (MeCN) CuPF resulted in
Our initial studies focused on the CuOAc-mediated
0
4
6
the best yield of 2a (59%).
reaction of [1,1 -biphenyl]-4-ylboronic acid (1) with Na-
SO CF and TBHP at room temperature in DCM/H O.
With 0.2 equiv of CuOAc, the desired trifluoromethylated
2
3
2
1
4
a
product (1a) was formed in 18% yield. The yield in-
creased to 47% in the presence of 1 equiv of CuOAc.
Optimization of the solvent (to a 5:5:4 mixture of MeOH,
Table 2. Optimization for Electron-Poor Boronic Acids
DCM and H O) resulted in a further increase in yield to
2
1
1%. Finally, an extensive evaluation of copper salts
5
7
revealed that CuCl provides an 80% yield of 1a on a 0.05
1
6
mmol scale. There are several important features of this
protocol that highlight its practicality. First, the reactions
are all set up on the benchtop, without any purification of
commercial solvents and reagents. Second, protodeboro-
nation is not observed under these conditions, and the
only detectable byproduct is 4-hydroxybiphenyl. Third,
b
entry
copper salt
CuCl
base
yield
c
1
ꢀ
36%
46%
42%
38%
49%
59%
c
2
CuCl
NaHCO
ꢀ
3
d
3
(MeCN)
(MeCN)
(MeCN)
(MeCN)
4
CuPF
4
CuPF
4
CuPF
4
CuPF
6
6
6
6
d,e
4
ꢀ
d
5
NaHCO
NaHCO
3
d,e
6
3
(
12) Langlois, B. R.; Laurent, E.; Roidot, N. Tetrahedron Lett. 1991,
2, 7525.
13) Ji, Y.; Brueckl, T.; Baxter, R. D.; Fujiwara, Y.; Seiple, I. B.; Su,
S.; Blackmond, D. G.; Baran, P. S. Proc. Natl. Acad. Sci. U.S.A. 2011,
08, 14411.
14) When substoichiometric Cu was used under these conditions, the
3
a
General conditions: substrate 2 (1 equiv, 0.05 mmol), [Cu] (1 equiv),
CF
(3 equiv), TBHP (5 equiv) at 23 °C for 12 h.
Yields determined by F NMR analysis. Solvent = MeOH/DCM/
(
base (1 equiv), NaSO
2
3
b
19
c
1
d
e
H
2
O (5:5:4 ratio). Solvent = MeOH. 4 equiv of TBHP.
(
major side product was the corresponding phenol (derived from sub-
stitution of the CꢀB bond with a CꢀOH bond).
(
(
15) See Supporting Information for full optimization details.
16) Notably, less than 1% of the trifluoromethylated product 1a was
With these two sets of conditions in hand, we next
explored the full substrate scope of Cu-mediated
observed when CuOAc was excluded from the optimal conditions.
B
Org. Lett., Vol. XX, No. XX, XXXX

trifluoromethylation with NaSO CF and TBHP. As
2
3
shown in Scheme 2, arenes bearing electron-donating
alkyl, alkoxy, or phenoxy substituents reacted in excellent
yield under the CuCl-mediated conditions (conditions a).
Trifluoromethylation of electron-deficient substrates (eg,
cyano, trifluoromethyl, and carbonyl-substituted aryl
boronic acids) afforded the desired trifluoromethylated
products in good to excellent yield in the presence of
Scheme 2. Substrate Scope of Copper-Mediated Trifluoro-
methylation of Aryl Boronic Acids
a
1
7
(
MeCN) CuPF and NaHCO (conditions b). Interest-
4 6 3
ingly, the reaction of (4-iodophenyl)boronic acid resulted
in exclusive trifluoromethylation of the CꢀB bond, leaving
the CꢀI linkage intact. Sterically hindered boronic acid
derivatives, which are generally challenging substrates for
1
8
Cu-mediated cross-couplings, afforded good to excellent
yields in this transformation (cf., products 6a, 8a, 14a,
2
0a, and 23a). Moreover, the reaction is compatible with
diverse functional groups, including enolizable ketones,
esters, amides, and phenols. Finally, heteroaryl boronic
acids based on pyridine, quinoline, thiophene, and furan
afforded moderate to excellent yields. Notably, trifluoro-
methylation of the CꢀB bond outcompeted free radical
CꢀH trifluoromethylation in all of these substrates.
As noted above, most previously reported boronic acid
trifluoromethylation protocols employ inert atmosphere
conditions and dry solvents. Even under these controlled
conditions, significant quantities (2ꢀ10%) of protode-
boronated products are commonly observed and are very
challenging to separate and purify from the desired Arylꢀ
CF products. In contrast, all of the trifluoromethyla-
3
tion reactions in Scheme 2 were insensitive to ambient
air and moisture and were set up on the benchtop with-
out purification of commercial reagents or solvents.
Despite the presence of water, protodeboronation of
the boronic acid was not detected under these condi-
tions. This makes product isolation extremely straight-
forward, as the major side product (the corresponding
hydroxylated arene) is readily removable by extraction or
column chromatography.
a
b
Isolated yield. Reaction conditions: substrate (1 equiv, 0.5 mmol),
CuCl (1 equiv), NaSO
H
2
CF
3
(3 equiv), TBHP (5 equiv) in DCM/MeOH/
c
2
O (5:5:4 ratio) at 23 °C for 12 h. Reaction conditions: substrate
(
1 equiv), (MeCN)
4
CuPF
6
(1 equiv), NaSO CF
2
3
(3 equiv), NaHCO
3
d
(1 equiv), TBHP (4 equiv) in MeOH at 23 °C for 12 h. Yields determined
by F NMR analysis.
1
9
In conclusion, this paper describes a practical copper-
mediated trifluoromethylation of a variety of aryl and
heteroaryl boronic acids using readily available Na-
SO CF and TBHP. These reagents are believed to react
synthetic advance for the selective preparation of trifluoro-
methylated compounds.
2
3
Acknowledgment. We thank the NIH NIGMS (GM-
73836) for financial support of this work. We also thank
in situ to generate CF • as the active trifluoromethylating
3
0
reagent. The reactions are easy to set up under ambient
conditions, and product purification is similarly straight-
forward. As a result, this protocol represents a significant
Professor Phil Baran (Scripps Research Institute) for
providing a sample of Zn(SO CF ) for evaluation.
2
3 2
Supporting Information Available. Experimental and
spectroscopic data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.
org.
(
17) For products 15a and 16a, the isolated material contained ∼4%
of the corresponding chloroarene as an inseparable byproduct. Ele-
mental analysis of all of the reagents showed that the chlorine is an
impurity in the NaSO
details.
2 3
CF . See Supporting Information for complete
(
18) Hassan, J.; S ꢀe vignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M.
Chem. Rev. 2002, 102, 1359.
The authors declare no competing financial interest.
Org. Lett., Vol. XX, No. XX, XXXX
C