Palladium-catalyzed direct α-arylation of methyl sulfones with aryl bromides

Article abstract of DOI:10.1021/ol400472v

A direct and efficient approach for palladium-catalyzed arylation of aryl and alkyl methyl sulfones with aryl bromides has been developed. The catalytic system affords arylated sulfones in good to excellent yields (73-90%).

Full text of DOI:10.1021/ol400472v

ORGANIC
LETTERS
2013
Vol. 15, No. 7
1690–1693
Palladium-Catalyzed Direct r‑Arylation
of Methyl Sulfones with Aryl Bromides
Bing Zheng,†,‡ Tiezheng Jia,‡ and Patrick J. Walsh*,‡
Department of Applied Chemistry, China Agricultural University, Beijing 100193,
P. R. China, and Roy and Diana Vagelos Laboratories, Penn/Merck Laboratory for
High-Throughput Experimentation, Department of Chemistry, University of Pennsylvania,
231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States
pwalsh@sas.upenn.edu
Received February 20, 2013
ABSTRACT
A direct and efficient approach for palladium-catalyzed arylation of aryl and alkyl methyl sulfones with aryl bromides has been developed.
The catalytic system affords arylated sulfones in good to excellent yields (73À90%).
Sulfones are present in a large number of pharmaceu-
ticals and biologically active compounds.1 They are also
found in natural products2 and Syngenta’s popular herbi-
cide mesotrione.3 Given the importance of sulfones, more
efficient and atom-economical approaches to their syn-
thesis are in demand.
Despite the recent interest in palladium-catalyzed aryla-
tion reactions,4,5 only limited success has been achieved
in the R-arylation of sulfones. This may be due to the high
pKa’s of sulfones, particularly in the absence of neighboring
electron-withdrawing substituents. In 2002, Beletskaya and
co-workers described the first example of R-arylation of
activated sulfones (Scheme 1, eq 1) using a palladium/
triphenylphosphine-based catalyst. Flourinated sulfones,
CF3SO2CH2R, with their increased acidity (pKa ∼20),
were also good substrates. Unfortunately, unactivated
substrates, suchasmethylphenylsulfone, werenotsuitable
for this method.6 In 2009, Niwa and co-workers reported a
protocol for the direct arylation of benzyl sulfones in
excellent yield (up to 99%, Scheme 1, eq 2). The pKa of
PhSO2CH2Ph in DMSO is 24. More challenging sub-
strates, such as PhSO2CH3 (pKa 29), did not react under
their conditions.7
† China Agricultural University.
‡ University of Pennsylvania.
(1) (a) Andrei, G.; Naesens, L.; Snoeck, R.; Stephens, C. E. Patent:
WO 2012/113920. (b) Caron, J. M. Patent: WO 2010/141956. (c)
Chakravarty, P. K.; Shao, P. P. Patent: WO 2010/036596. (d) Harrak,
Y.; Casula, G.; Basset, J.; Rosell, G.; Plescia, S.; Raffa, D.; Cusimano,
M. G.; Pouplana, R.; Pujol, M. D. J. Med. Chem. 2010, 53, 6560. (e)
Sasikumar, T. K.; Qiang, L.; Burnett, D. A.; Cole, D.; Xu, R.; Li, H.;
Greenlee, W. J.; Clader, J.; Zhang, L.; Hyde, L. Bioorg. Med. Chem.
Lett. 2010, 20, 3632. (f) Legros, L.; Dehli, J. R.; Bolm, C. Adv. Synth.
Catal. 2005, 347, 19.
(2) (a) Prinsep, M. R.; Blunt, J. W.; Munro, M. H. G. J. Nat. Prod.
1991, 54, 1068. (b) Chou, S.-S. P.; Wu, C.-J. J. Tetrahedron 2012, 68,
5025. (c) Chen, L.; Hua, Z.; Li, G.; Jin, Z. Org. Lett. 2011, 13, 3580.
(3) (a) Cornes, D. Patent: WO 2002/100173. (b) Wichert, R. A.;
Beckett, T. H. WO 2002/019823.
(4) (a) Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119,
11108. (b) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119,
12382. (c) Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1740. (d) Culkin, D. A.; Hartwig, J. F.
Acc. Chem. Rev. 2003, 36, 234. (e) Bellina, F.; Rossi, R. Chem. Rev. 2010,
110, 1082. (f) Johansson, C. C. C.; Colacot, T. J. Angew. Chem., Int. Ed.
Subsequently, Zhou described a palladium-catalyzed
arylation of alkyl sulfones with aryl halides (Scheme 1,
eq 3).8 A broad scope and good yields were obtained.
(5) (a) Abd-El-Aziz, A. S.; De Denus, C. R. J. Chem. Soc., Perkin
Trans. 1 1993, 293. (b) Cho, G. Y.; Bolm, C. Org. Lett. 2005, 7, 1351. (c)
Gorelik, M. V.; Titova, S. P.; Kanor, M. A. Kano., Zh. Org. Khim. 1992,
28, 2294. (d) Kim, S. H.; Lee, H. S.; Kim, K. H.; Kim, J. N. Tetrahedron
Lett. 2009, 50, 6476. (e) Makosza, M.-L.; Lemek, T.; Kwast, A.; Terrier,
F. J. Org. Chem. 2002, 67, 394. (f) Mitin, A. V.; Kashin, A. N.;
Beletskaya, I. P. J. Organomet. Chem. 2004, 689, 1085. (g) Sakamoto,
T.; Katoh, E.; Kondo, Y.; Yamanaka, H. Chem. Pharm. Bull. 1990, 38,
1513. (h) Suzuki, H.; Qui, Y.; Inoue, J.; Kusume, K.; Ogawa, T. Chem.
Lett. 1987, 887. (i) You, J.; Verkade, J. G. J. Org. Chem. 2003, 68, 8003.
(j) You, J.; Verkade, J. G. Angew. Chem., Int. Ed. 2003, 42, 5051.
(6) (a) Kashin, A. N.; Mitin, A. V.; Beletskaya, I. P.; Wife, R.
Tetrahedron Lett. 2002, 43, 2539. (b) Renaud, P.; Bourquard, T.;
Carrupt, P.-A.; Gerster, M. Helv. Chim. Acta 1998, 81, 1048.
(7) Niwa, T.; Yorimitsu, H.; Oshima, K. Tetrahedron 2009, 65, 1971.
(8) Zhou, G.; Ting, P. C.; Aslanian, R. G. Tetrahedron Lett. 2010,51, 939.
2010, 49, 676. (g) Novak, P.; Martı
´
n, R. Curr. Org. Chem. 2011, 15, 3233.
(h) Magano, J.; Dunetz, J. R. Chem. Rev. 2011, 111, 2177.
r
10.1021/ol400472v
Published on Web 03/21/2013
2013 American Chemical Society

Their method, however, has several experimental drawbacks.
It requires multiple changes in temperature (À20 °C to rt
to À20 °C to 65 °C), generation of the lithiated sulfone must
be followed by transmetalation to ZnCl2, and the limiting
reagent was the aryl halide and not the sulfone. Thus, a more
atom-econimical and experimentally simpler method to
make these valuable compounds would be advantageous.
because the benzyl sulfone product is ∼4 orders of magni-
tude more acidic than the starting methyl sulfone.
Scheme 2. R-Arylation of Sulfoxides10c
Scheme 1. R-Arylation of Sulfones
We initiated optimization of the sulfone arylation em-
ploying conditions for the palladium-catalyzed arylation
of sulfoxides (Scheme 2). The sulfoxide arylation was
performed at 110 °C in cyclopentyl methyl ether (CPME)
with 10 mol % Pd(OAc)2 and 20 mol % of Kwong’s ligand
L.12 The first and most important variable to be optimized
in the sulfone arylation was the base, because the nature of
the base would impact the relative rates of the first and
second arylations. A screen of six bases [LiOtBu, NaOtBu,
KOtBu, LiN(SiMe3)2, NaN(SiMe3)2, and KN(SiMe3)2]
indicated that LiOtBu performed better for the aryaltion
(Table 1, entries 1À6) and provided the monoarylation
product with very good selectivity. Both NaOtBu and
KOtBu did not efficiently promote the arylation reaction
(Table 1, entries 2À3), with only trace products observed.
Significantly lower yields were obtained with the stronger
basesLiN(SiMe3), NaN(SiMe3), and KN(SiMe3) (Table1,
entries 4À6).
Table 1. Optimization of the Base for the R-Arylation
of Sulfones with the Bromobenzenea
We recently initiated a program in the catalytic func-
tionalization of weakly acidic sp3-hybridized CÀH bonds.9
Substrates reported to date include diphenylmethanes,10a,b
benzylic amines,9 and sulfoxides.10c Our R-arylation of
sulfoxides is the first example of this reaction and is
illustrated in Scheme 2. Given that the R-protons of
sulfones (pKa 29) are more acidic than those of sulfoxides
(pKa 33),11 we decided to explore the possibility of a
palladium-catalyzed deprotonative cross-coupling process
(DCCP) for the R-arylation of unactivated sulfones with
aryl bromides. We envisioned that one of the challenges
would be to minimize the amount of bis(arylation) formed,
time
(h)
temp
NMR
entry
base
solvent
(°C)
yield (%)
1
2
5
4
5
6
LiOtBu
12
12
12
12
12
12
CPME
CPME
CPME
CPME
CPME
CPME
110
110
110
110
110
75
70
NaOtBu
trace
trace
17
KOtBu
LiN(SiMe3)2
NaN(SiMe3)2
KN(SiMe3)2
23
36
a Reactions performed using 1 equiv of 1a, 2 equiv of 2a, Pd(OAc)2
(10 mol %), L (20 mol %), and 3 equiv of base on 0.1 mmol scale.
(9) (a) McGrew, G. I.; Temaismithi, J.; Carroll, P. J.; Walsh, P. J.
Angew. Chem., Int. Ed. 2010, 49, 5541. (b) Zhang, J.; Stanciu, C.; Wang,
B.; Hussain, M. M.; Da, C.-S.; Carroll, P. J.; Dreher, S. D.; Walsh, P. J.
J. Am. Chem. Soc. 2011, 133, 20552. (c) McGrew, G. I.; Stanciu, C.;
Zhang, J.; Carroll, P. J.; Dreher, S. D.; Walsh, P. J. Angew. Chem., Int.
Ed. 2012, 51, 11510.
(10) (a) Zhang, J.; Bellomo, A.; Creamer, A. D.; Dreher, S. D.;
Walsh, P. J. J. Am. Chem. Soc. 2012, 134, 13765. (b) Bellomo, A.;
Zhang, J.; Trongsiriwat, N.; Walsh, P. J. Chem. Sci. 2013, 4, 849. (c) Jia,
T.; Bellomo, A.; Baina, K. E.; Dreher, S. D.; Walsh, P. J. J. Am. Chem.
Soc. 2013, 135, 3740.
With LiOtBu as the base, four solvents (CPME, 2-MeTHF,
dioxane, and toluene), three concentrations (0.1, 0.2, and
0.3 M), and two temperatures (80 and 110 °C) were
screened (Table 2). Yields of 70% and 66% were obtained
in CPME and toluene, respectively (entries 1 and 4), while
(11) (a) Matthews, W. S.; Bares, J.; Bartmess, J. E.; Bordwell, F. G.;
Cornforth, F. J.; Drucker, G. E.; Margolin, Z.; McCallum, R. J.;
McCallum, G. J.; Vanier, N. R. J. Am. Chem. Soc. 1975, 97, 7006. (b)
Bordwell, F. G.; Branca, J. C.; Johnson, C. R.; Vanier, N. R. J. Org.
Chem. 1980, 45, 3884.
(12) (a) So, C. M.; Lau, C. P.; Kwong, F. Y. Org. Lett. 2007, 9, 2795.
(b) Lee, H. W.; Lam, F. L.; So, C. M.; Lau, C. P.; Chan, A. S. C.; Kwong,
F. Y. Angew. Chem., Int. Ed. 2009, 48, 7436.
Org. Lett., Vol. 15, No. 7, 2013
1691

reactions in 2-MeTHF and dioxane gave trace product
(entries 2 and 3). When the concentration was increased to
0.2 M, the yield climbed to 88% in toluene (entry 5) and
73% in CPME(entry 7). A lower yield (70%) was observed
at 0.3 M in toluene (entry 6). Unfortunately, despite
significant effort, reducing the palladium loading from
10 to 5 mol % at 110 °C resulted in a drop in the yield
from 88% to 68% (compare entries 5 and 8). Finally, when
the reaction temperature was decreased to 80 °C, the yield
fell to 50%, despite increasing the reaction time to 24 h
(entry 9).
Table 3. Substrate Scope of Aryl Bromides in the R-Arylation of
Methyl Phenyl Sulfonea
time
(h)
isolated
entry
ArÀBr
product
yield (%)
1
2
3
4
5
6
7
8
PhÀBr
12
12
12
12
12
12
36
24
3a
3b
3c
3d
3e
3f
86
82
78
90
83
81
80
73
3-MeÀC6H4ÀBr
4-MeOÀC6H4ÀBr
4-tBuÀC6H4ÀBr
4-FÀC6H4ÀBr
Table 2. Optimization of the Conditions of the R-Arylation of
Sulfonesa
4-ClÀC6H4ÀBr
3-CF3ÀC6H4ÀBr
1-naphthylÀBr
3g
3h
a Reactions performed using 1 equiv of 1a, 2 equiv of 2, Pd(OAc)2
(10 mol %), L (20 mol %), and 3 equiv of LiOtBu on a 0.2 mmol scale
for 12 h.
concn
(M)
temp
time
(h)
NMR
entry
solvent
(°C)
yield (%)
3-(methylsulfonyl)pyridine was performed in toluene at
90 °C (due to decomposition of starting materials at
110 °C) and provided the product (4i) in 70% yield after
24 h (Table 4, entry 8).
Dialkyl sulfones are more challenging substrates due to
their higher pKa (∼3113). Nonetheless, under the optimized
conditions, alkyl methyl sulfones underwent coupling at
the less sterically hindered methyl group in similar yields to
other substrates examined (83À84%, entries 9 and 10).
1
2
3
4
5
6
7
8b
9
CPME
dioxane
2-MeTHF
Tol
0.1
0.1
0.1
0.1
0.2
0.3
0.2
0.2
0.2
110
110
80
12
12
12
12
12
12
12
12
24
70
5
4
110
110
110
110
110
80
66
88
70
73
68
50
Tol
Tol
CPME
Tol
Tol
a Reactions performed using 1 equiv of 1a, 2 equiv of 2a, Pd(OAc)2
(10 mol %), L (20 mol %), and 3 equiv of LiOtBu on 0.1 mmol scale.
b Pd(OAc)2 (5 mol %) and L (10 mol %).
Table 4. Substrate Scope of Sulfones in the R-Arylation of
Benzene Bromidea
The optimal yield in our study was obtained at 110 °C in
toluene using LiOtBu as the base and a catalyst system
generated in situ from 10 mol % Pd(OAc)2 and 20 mol %
L. With optimized conditions in hand, the scope of aryl
bromides was examined (Table 3). In general, good to
excellent yields (73À90%) were observed for the arylation
ofmethylphenylsulfone(1a) with arylbromides. Electron-
donating (82À90% yield, entries 2À4) and electron-
withdrawing groups (80À83% yield, entries 5À7) were
welltolerated. 1-Bromonaphthalene gavethedesired prod-
uct in 73% yield after 24 h (entry 8). Under the optimized
conditions, the ratio of mono- to bis-arylation was well
controlled (10À20:1) in the reactions of Table 3.
time
(h)
isolated
entry
R
product
yield (%)
1
2
2-MeÀC6H4 (1b)
3-MeOÀC6H4 (1c)
4-MeOÀC6H4(1d)
4-FÀC6H4 (1e)
4-ClÀC6H4 (1f)
4-CF3ÀC6H4 (1g)
1-naphthyl (1h)
3-pyridyl (1i)
12
12
12
12
24
12
24
24
12
12
4b
4c
4d
4e
4f
86
85
81
82
81
84
83
70
83
84
3
4
5
6
4g
4h
4i
7
8
We next explored the scope of substituted methyl sul-
fones with bromobenzene (Table 4). Electron-donating
and -withdrawing substituents at the ortho, meta, and para
positions of the sulfone were compatible with the reaction,
giving yields in excess of 80% (entries 1À6). Both 3- and
4-methoxy substituted aryl sulfones provided the prod-
uct in good yields (81À85%, entries 2À3). Sulfones with
electron-withdrawing groups underwent coupling in 81À84%
yield (entries 4À6). The 1-naphthyl derivative 1h gave
the product in 83% yield (entry 7). The reaction with
9
c-hexyl (1j)
4j
10
tert-butyl (1k)
4k
a Reactions performed with 1 equiv of 1, 2 equiv of 2a, Pd(OAc)2
(10 mol %), L (20 mol %), and 3 equiv of LiOtBu on a 0.2 mmol scale.
We evaluated the scalability of coupling by performing
the reaction withbromobenzene ona 6 mmol (0.94g) scale.
(13) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
Org. Lett., Vol. 15, No. 7, 2013
1692

Scheme 3. R-Arylation of Methyl Phenyl Sulfone on Gram Scale
Scheme 4. R-Arylation of Benzyl Phenyl Sulfone (3a)
The desired product was afforded in 83% yield (1.16 g,
Scheme 3).
Coupling of the more acidic benzyl phenyl sulfone
(3a) was investigated with 4-tert-butylbromobenzene (2d)
(Scheme 4). We examined six bases [LiOtBu, NaOtBu,
KOtBu, LiN(SiMe3)2, NaN(SiMe3)2, and KN(SiMe3)2]
for this reaction and found that KOtBu gave the best re-
sults. The catalyst loading could be reduced to 2.5 mol %
Pd(OAc)2 and 5 mol % of L with the more acidic substrate.
Furthermore, the reaction could be conducted at lower
temperature (75 °C). Under these conditions, the diaryl-
methyl phenylsulfone (5a) was isolated in 81% yield. The
excellent reactivity observed in this arylation is attributed
to the change in base and solvent.
It is noteworthy that weakly acidic alkyl methyl sulfones,
with pKa’s as high as 31 in DMSO, also proved to be good
substrates under our optimized conditions. The challeng-
ing nature of this transformation, however, requires the
use of 10 mol % catalyst. Future directions include use of a
recently developed additive approach10b to identify more
efficient catalysts and milder reaction conditions.
Acknowledgment. We thank the National Science
Foundation [CHE-0848460 (GOALI) and 1152488]
for financial support. B. Z. thanks the China Scholarship
Council [2011635137] for financial support.
In summary, we report the first deprotonative cross-
coupling process for the direct monoarylation of aryl
methyl and alkyl methyl sulfones with aryl bromides.
The catalyst afforded products with good to excellent
yields (73À90%). Importantly, very high selectivity for
the monoarylation products is observed, despite the in-
creased acidity and reactivity of the benzyl sulfone moiety.
Supporting Information Available. Procedures, charac-
terization data for all new compounds. This material
is available free of charge via the Internet at http://pubs.
acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 7, 2013
1693