Oxidative trifluoromethylthiolations of aryl boronic acids using a copper/O2-based protocol

Article abstract of DOI:10.1002/asia.201200347

All you need is air: A new protocol has been developed which can mediate the coupling of aryl and vinyl boronic acids at room temperature in high yields (see scheme, dtbpy=4,4'-di-tert-butyl-2,2'-bipyridine). The reactions take place using simple copper(II) salts under aerobic conditions and do not require the use of expensive silver oxidants.

Full text of DOI:10.1002/asia.201200347

DOI: 10.1002/asia.201200347
Oxidative Trifluoromethylthiolations of Aryl Boronic Acids Using a Copper/
O -Based Protocol
2
[
a]
Cheng-Pan Zhang and David A. Vicic*
The development of new protocols to prepare perfluor-
omethyl sulfides from substrates that could ultimately origi-
nate from aryl chlorides. Indeed, in the course of preparing
this manuscript, Qing and co-workers showed that CuSCN
[1]
oalkyl sulfides is of growing synthetic interest. Carbon–
sulfur bonds are prevalent in medicinally and agriculturally
[2]
[1d]
relevant molecules, and fluorination provides additional
mediates such a reaction [Eq. (3)]. Qingꢀs method allows
[1a,3]
functionality unique from the non-fluorinated forms.
for the coupling of a variety of aryl boronic acids bearing
additional functionality on the aryl groups, and proceeds
under relatively mild conditions. Although the protocol out-
lined in Equation (3) employs the use of a catalytic amount
(10%) of CuSCN, four mole equivalents of silver atoms are
required relative to the boronic acid for high conversions.
Additionally, a fivefold excess of the costly Me SiCF was
One motivation for the synthesis of perfluoroalkyl sulfides
is the high lipophilicities of these derivatives. The SCF3
functional group, for instance, has one of the highest
[4]
Hansch lipophilicity parameters for its size (p=1.44 ),
which makes it an appealing functional group to incorporate
into new library syntheses. Traditional methods to form per-
fluoroalkyl sulfides have involved, among other methods,
substitution of perchloroalkyl sulfides with fluoride sour-
3
3
also employed. Here, we present our own efforts to develop
copper-catalyzed oxidative trifluoromethylthiolations, and
offer a complementary protocol to that shown in Equa-
tion (3) which does not require the use of silver salts or
large excesses of Me SiCF in the presence of the organic
[
5]
ces, UV irradiation of thiophenols or disulfides with per-
[6]
fluoroalkyl iodides in liquid ammonia, and perfluoroalky-
[7]
lation of thiols using hypervalent iodine sources.
3
3
It has recently been shown that, in addition to the afore-
mentioned classical methods, Group 10 metals can mediate
trifluoromethylthiolations by cross-coupling aryl halides
coupling substrate.
[1b,c]
under quite mild conditions.
Buchwald and co-workers
found that a Brettphos-ligated palladium complex can con-
vert aryl bromides and iodides into aryl trifluoromethyl sul-
fides at 808C using AgSCF3 as the nucleophilic partner
[
Eq. (1); Cy=cyclohexyl, cod=1,5-cyclooctadiene, TMS=
[1b]
trimethylsilyl]. Vicic and co-workers found that the same
substrates undergo trifluoromethylthiolations at room tem-
perature using the less expensive and more conveniently
prepared [NMe4]
ACHTUNGTRENNUNG[ SCF ] nucleophile in combination with an
3
earth-abundant nickel bipyridine catalyst [Eq. (2); dmbpy=
[1c]
4
,4’-dimethyl-2,2’-bipyridine]. Both of these protocols rep-
resent significant advances to earlier known methods used
[1a]
to prepare aryl trifluoromethyl sulfides. However, neither
protocol was successful in the trifluoromethylthiolation of
aryl chlorides. Since aryl chlorides can be catalytically con-
[8]
verted to aryl boronic acids, we imagined that a copper-
catalyzed oxidative trifluoromethylthiolation reaction might
be an alternative approach to the formation of aryl trifluor-
[
a] C.-P. Zhang, D. A. Vicic
Department of Chemistry, University of Hawaii
Our initial search for conditions that could promote oxi-
dative trifluoromethylthiolations is presented in Table 1.
When excess copper(II) salts are used in the absence of any
additional oxidant, high yields of cross-coupled product
could be observed (Table 1, entry 1). However, low yields of
2
545 McCarthy Mall, Honolulu, HI 96822 (USA)
Fax : (+1)808-956-5908
E-mail: vicic@hawaii.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201200347.
Chem. Asian J. 2012, 00, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
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COMMUNICATION
[
a]
[1c]
Table 1. Identifying optimal conditions for copper-mediated trifluoromethylthiolation of aryl boronic acids.
duct. Sulfur- and oxygen-con-
taining heterocycles were also
reactive towards the oxidative
couplings (Table 2, entries 7
and 8). As was observed in our
screening conditions, the cou-
pling reactions will indeed take
place under a nitrogen atmos-
phere, as long as excess oxidant
is present (Table 2, entry 9),
[
b]
Entry
1
Cu salt ([Cu])
Ligand (L)
Oxidant
ArB(OH)
Cu]:L:Cs
2
:
A
H
U
G
E
N
N
3
]:
Yield [%]
[
2
3
Cu
Cu(OTf)
CuOTf
Cu(OTf)
Cu(OTf)
Cu(OTf)
CuCl
Cu(OAc)
CuO
Cu(acac)
Cu(OTf)
Cu(OTf)
Cu(OTf)
Cu(OTf)
Cu(OTf)
Cu(OTf)
Cu(OTf)
Cu(OTf)
Cu(OTf)
Cu(OTf)
Cu(OTf)
Cu(OTf)
Cu(OTf)
CuOTf
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(OTf)
2
dtbpy
dtbpy
dtbpy
dtbpy
dtbpy
dtbpy
dtbpy
dtbpy
dtbpy
dtbpy
dtbpy
dtbpy
dtbpy
–
–
–
1:2.4:2:2:1.2
1:1:1:1:1.2
1:1:1:1:1.2
1:1.3:1:1:1.2
1:1:0.5:0.5:1.2
1:1:0.3:0.3:1.2
1:1:1:1:1.2
1:1:1:1:1.2
1:1:1:1:1.2
1:1:1:1:1.2
1:1:1:1:1.2
1:1:1:1:1.2
1:1:1:1:1.2
1:1:1:1:1.2
1:1:1:1:1.2
1:1:1:1:1.2
1:1:1:1:1.2
1:1:1:1:1.2
1:1:1:1:1.2
1:1:1:1:1.2
1:1:0.5:0.5:1.2
1:1:0.4:0.4:1.2
1:1:0.3:0.3:1.2
1:1:1:1:1.2
90
37
trace
91
49
trace
20
0
0
0
59
0
50
75
73
34
0
68
60
18
61
47
6
[
c]
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
2
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
2
2
2
air
air
air
air
air
air
air
BQ
DDQ
ACHTUNGTRENNUNG
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
Finally, we set out to explore
if the conditions could also be
used to couple vinyl boronic
acids. Table 3 describes the pre-
liminary results of this study.
Both alkyl- and aryl-substituted
vinyl boronic acids could be
converted to trifluoromethylth-
ioethers, however the vinyl sub-
strate bearing the chlorine-sub-
stituted aryl group (Table 3, en-
tries 4 and 5) gave poor yields.
Substitution of air with dioxy-
gen (Table 3, entry 3) improved
the yield of the biphenyl-substi-
tuted vinyl trifluoromethylth-
ioether substantially. Of all the
vinyl groups tested, the cyclo-
hexyl-substituted one afforded
the best yields with the stan-
2
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
2
[
[
[
d]
d]
d]
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
2
2
2
2
2
2
2
2
2
2
2
2
2
ACHTUNGTRENNUNG
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
A
H
U
G
R
N
N
(tBuO)
2
OMe
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
bpy
air
air
air
air
air
air
air
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
bpy
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
phen
terpy
dmbpy
ACHTUNGTRENNUNG
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
6
Me
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
bpy
bpy
6
,6’Me
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
dtbpy
dtbpy
dtbpy
dtbpy
O
O
O
O
2
2
2
2
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
43
[
a] All the reactions were run on 0.1 mmol scale in 4 mL of dry THF for 15 h. Abbreviations: OTf=CF
3
SO
bpy=4,4’-dimethoxy-2,2’-bi-
pyridine, bpy=2,2’-bipyridine, phen=1,10-phenanthroline, terpy=2’,2:6,2’’-terpyridine, dmbpy=4,4’-dimethyl-
3
,
OMe
OAc =acetate, acac=acetylacetonate, dtbpy=4,4’-di-tert-butyl-2,2’-bipyridine,
6
Me
6,6’Me
2
,2’-bipyridine,
none, DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone. [b] The yields were determined by F NMR spec-
troscopy using PhCF
as internal standard. [c] The same yields were obtained in DMF and THF. [d] Two equiv- dard protocol. To our knowl-
bpy=6-methyl-2,2’-bipyridine,
bpy=6,6’-dimethyl-2,2’-bipyridine, BQ=1,4-benzoqui-
1
9
3
alents of the oxidants were employed.
edge, the data shown in Table 3
represents the first time that
successful trifluoromethylthiola-
product are obtained when the amount of copper(II) salt is
scaled back to stoichiometric amounts (Table 1, entry 2),
suggesting that in entry 1 the copper is serving as both a cat-
alyst and as an oxidant. Upon optimizing the reaction for
amounts of reagents, ligand type, and oxidant type, the opti-
mal conditions ultimately proved to be those in Table 1,
entry 4. We note that simple ambient air was gratifyingly ob-
served to be the best oxidant for the coupling reaction. In-
terestingly, the phenanthroline ligand, which was effective in
the oxidative trifluoromethylthiolations involving silver oxi-
tion of vinyl boronic acids has been reported.
In conclusion, we present here a new protocol which
could oxidatively couple [NMe ][SCF ] with boronic acids to
AHCTUNGTRENNUNG
4
3
afford aryl- and vinyl-SCF products. There is a significant
3
advantage of the current conditions over those previously
reported in that no silver oxidants are required and simple
air can be used as the oxidant. With the absence of any
known procedure to form aryl trifluoromethyl sulfides di-
rectly from aryl chlorides, this method provides a work-
around to obtain the desired SCF products from intermedi-
3
[1d]
dants, was less effective than bipyridine ligands for the re-
actions carried out under aerobic conditions (Table 1, en-
tries 4 versus 16).
ate aryl boronic acids.
With the optimized conditions in hand, we then set out to
explore the scope of the copper-mediated aerobic trifluoro-
methylthiolations. Table 2 describes the effectiveness of the
protocol with a variety of aryl and heteroaryl boronic acids.
Both electron-poor and electron-donating aryl boronic acids
gave high yields of products (Table 2, entries 1–6, 9), with
the electron-withdrawing arenes slightly outperforming the
electron-donating ones. This reactivity contrasts the nickel-
mediated cross-coupling chemistry, in which electron-rich
aryl halides provided the highest yields of cross-coupled pro-
Experimental Section
General Procedure for the Oxidative Trifluoromethylthiolations
Example for Table 2, entry 4: Biphenyl-3-ylboronic acid (40 mg,
0.2 mmol), [NMe4]
0.2 mmol), 4,4’-di-tert-butyl-2,2’-bipyridine (55 mg, 0.2 mmol), and
Cs CO (80 mg, 0.25 mmol) were added into THF (6 mL) and taken out
from a glovebox. Dry air was introduced. The mixture was stirred at
room temperature overnight. Then Et O (50 mL) and H O (50 mL) were
added. The ether layer was separated, washed with H O (3ꢂ30 mL),
3 2
ACTHUNGTRENNUNG[ SCF ] (48 mg, 0.26 mmol), Cu ACHTUNGTERNNNU(G OTf) (72 mg,
2
3
2
2
2
dried over anhydrous Na
2
SO
4
, and evaporated under reduced pressure.
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Chem. Asian J. 0000, 00, 0 – 0
ÝÝ These are not the final page numbers!

Oxidative Trifluoromethylthiolations
Table 2. Copper-mediated trifluoromethylthiolation of aryl boronic acids
at room temperature.
The crude product was purified by flash chromatography column to give
41 mg of the desired product (0.16 mmol, 81%).
[
a]
Acknowledgements
[
b]
Entry
1
ArB(OH)
2
ArSCF
3
Yield [%]
91
D.A.V. thanks the Office of Basic Energy Sciences of the U. S. Depart-
ment of Energy (DE-FG02-07ER15885).
2
3
93 (91)
75 (73)
Keywords: copper · cross-coupling · fluorine · sulfur
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[
c]
9
[
7
a] Reactions were run on 0.2 mmol scale in 6 mL THF, except entries 1,
, and 9 (0.1 mmol scale in 4 mL THF). 1.3 equivalents [NMe [SCF ] rel-
ative to ArB(OH) was employed except entry 9. [b] The yields were de-
termined by F NMR spectra using PhCF as internal standard. Yields of
isolated product are given in parentheses. [c] 2.4 equivalents [NMe
[SCF ], 1.2 equivalent Cs CO , and two equivalents Cu(OTf) and dtbpy
were employed in this reaction. The reaction was conducted at room
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4
]
A
H
U
G
R
N
U
G
3
2
1
9
3
4
]
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
3
2
3
A
H
U
G
R
N
U
G
2
temperature overnight in N
was used as the oxidant.
2 2
atmosphere. The excessive Cu ACHTUNRTGENNGNU( OTf) itself
1
977, 13, 1057–1061.
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[
7
Table 3. Copper-mediated trifluoromethylthiolation of vinyl boronic
acids at room temperature.
[
a]
1
[
1
Received: April 16, 2012
Published online: && &&, 0000
[
b]
Entry
1
ArB(OH)
2
ArSCF
3
Yield [%]
70
2
3
57
[
c]
52, 74
16
4
[
d]
5
33
[
a] All the reactions were run on 0.2 mmol scale in 6 mL THF. 1.3 equiva-
lents [NMe [SCF ] relative to ArB(OH) was employed. [b] The yields
were determined by F NMR spectra using PhCF as internal standard.
4
]
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
3
2
1
9
3
Yields of isolated products are given in parentheses. [c] Oxygen was em-
ployed instead of air. [d] The reaction was run at 508C.
Chem. Asian J. 2012, 00, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
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These are not the final page numbers! ÞÞ

COMMUNICATION
Cross-Coupling
Cheng-Pan Zhang,
David A. Vicic*
&&&& — &&&&
All you need is air: A new protocol
has been developed which can mediate
the coupling of aryl and vinyl boronic
acids at room temperature in high
yields (see scheme, dtbpy=4,4’-di-tert-
butyl-2,2’-bipyridine). The reactions
take place using simple copper(II)
salts under aerobic conditions and do
not require the use of expensive silver
oxidants.
Oxidative Trifluoromethylthiolations
of Aryl Boronic Acids Using
a Copper/O -Based Protocol
2
&
&
&4
&
www.chemasianj.org
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 0000, 00, 0 – 0
ÝÝ These are not the final page numbers!