Copper-catalyzed aerobic oxidation and cleavage/formation of C-S bond: A novel synthesis of aryl methyl sulfones from aryl halides and DMSO

Article abstract of DOI:10.1039/c2cc32964f

With atmospheric oxygen as the oxidant, a novel copper(i)-catalyzed synthesis of aryl methyl sulfones from aryl halides and widely available DMSO is described. The procedure tolerates aryl halides with various functional groups (such as methoxy, acetyl, chloro, fluoro and nitro groups), which could afford aryl methyl sulfones in moderate to high yields. The copper-catalyzed aerobic oxidation and the cleavage/formation of C-S bond are the key steps for this transformation.

Full text of DOI:10.1039/c2cc32964f

View Online / Journal Homepage
Dynamic Article Links
ChemComm
Cite this: DOI: 10.1039/c2cc32964f
www.rsc.org/chemcomm
COMMUNICATION
Copper-catalyzed aerobic oxidation and cleavage/formation of C–S bond:
a novel synthesis of aryl methyl sulfones from aryl halides and DMSOw
Gaoqing Yuan,* Junhua Zheng, Xiaofang Gao, Xianwei Li, Liangbin Huang, Huoji Chen and
Huanfeng Jiang
Received 25th April 2012, Accepted 5th June 2012
DOI: 10.1039/c2cc32964f
With atmospheric oxygen as the oxidant, a novel copper(I)-
catalyzed synthesis of aryl methyl sulfones from aryl halides and
widely available DMSO is described. The procedure tolerates
aryl halides with various functional groups (such as methoxy,
acetyl, chloro, fluoro and nitro groups), which could afford aryl
methyl sulfones in moderate to high yields. The copper-catalyzed
aerobic oxidation and the cleavage/formation of C–S bond are
the key steps for this transformation.
Pd(0)- or Ni(0)-catalyzed synthesis of aryl sulfides. Herein, we
report an efficient method for the synthesis of aryl methyl
sulfones from aryl halides and DMSO via copper-catalyzed
aerobic oxidation and the cleavage/formation of C–S bonds
(Scheme 1). Various aryl methyl sulfones could be obtained in
moderate to good yields. To our knowledge, it is the first
example of using atmospheric oxygen as the oxidant and
widely available DMSO as the sulfur resource to prepare aryl
methyl sulfones.
With iodobenzene (1a) and DMSO (2a) as substrates, the
reaction parameters (catalysts, bases, ligand, solvents and
temperature) were first examined. The obtained results are
listed in Table 1. Under the same conditions, the catalytic
activity of Cu(I) compounds is much higher than that of Cu(II)
compounds (Table 1, entries 6–10). Among the examined
The synthesis of aryl (methyl) sulfones has attracted much
attention due to their promising antibacterial, antifungal and
1
antitumor activities. For example, some aryl methyl sulfones
(
DuP-697, Rofecoxib and Etoricoxib, shown in Fig. 1) have
been identified as very effective and specific cyclooxygenase-2
–4
2
inhibitors.
Very recently, some investigations have also
2 2 2
catalysts (Cu O, CuBr, CuI, Cu(OAc) and CuO), Cu O
shown that aryl sulfones derivatives are potent inhibitors of
several enzymes, such as HIV-1 reverse transcriptase, matrix
exhibits the best result and the isolated yield of phenyl methyl
5
sulfone (3a) could reach 92% (Table 1, entry 6). With Cu O as
2
metalloproteinase and g-secretase. In addition, aryl sulfones
as synthetic intermediates could achieve particular trans-
6
formations. So far, various synthetic routes have been developed
the catalyst, some inorganic and organic bases (K
3
PO
4
Á3H
2
O,
K CO , Cs CO , KOH, DBU and t-BuOK) were further
3
2
3
2
screened. The strong base KOH, especially t-BuOK, gave very
good results (Table 1, entries 5 and 6), while weak bases
K PO Á3H O, Cs CO and DBU afforded quite poor ones
to synthesize aryl sulfones, mainly including the oxidation of
7
sulfides, the coupling reaction of arylboronic acids (or aryl
8
halides) with sulfinic acid salts or arylsulfonyl chlorides, the
3
4
2
2
3
(
2 3
Table 1, entries 1, 3 and 4). Additionally, with K CO as the
sulfonylation of arenes with arenesulfonic acids or arene-
sulfonyl halides and the reaction of Grignard reagents or
base, or in the absence of the catalyst, strong base and ligand,
no target product was obtained (Table 1, entries 2 and 13–15).
These results clearly indicate that the catalyst, strong base and
9
organolithium compounds with sulfonate esters. Some novel
1
0
routes have been exploited in recent years as well. As for the
ligand are necessary for this transformation. Using Cu(AcAc)
(Cu(II) acetylacetonate) as the catalyst, 3a was also obtained in
9% yield even without adding acetylacetone (Table 1, entry 20).
2
oxidiation methods, although numerous types of oxidation
7
have been reported, convenient and environmentally benign
2
methods for the oxidation of sulfides or sulfoxides are still
required. Air is a green, safe and economical oxidant. Using
air as the oxidant still remains a challenge in this field.
In contrast to the development of catalytic C–O and C–N
If 1 equiv. of acetylacetone was added, the yield did not
obviously change (Table 1, entry 21), indicating that acetyl-
acetone only acts as the ligand (for details of ligands screening,
see Supporting Informationw). In addition, reaction temperature,
1
1
bond-forming method, there have been fewer investigations
1
2
on transition metal-catalyzed C–S bond formation. Also, the
majority of these investigations have mainly focused on the
School of Chemistry and Chemical Engineering, South China
University of Technology, Guangzhou, 510640, China.
E-mail: gqyuan@scut.edu.cn
w Electronic supplementary information (ESI) available: Experimental
section, characterization of all compounds, copies of H and C NMR
spectra for isolated compounds. See DOI: 10.1039/c2cc32964f
1
13
Fig. 1 Aryl methyl sulfones that are inhibitors.
This journal is c The Royal Society of Chemistry 2012
Chem. Commun.

View Online
Cu-catalyzed aerobic oxidation is probably one of key steps
for the formation of 3a.
Under the optimized reaction conditions, we further studied
the scope of the reaction with respect to aryl iodides and the
results are summarized in Table 2. Aryl iodide derivatives
bearing either an electron-withdrawing or electron-donating
group reacted smoothly with 2a to afford the corresponding
products in moderate to high yields. Generally, substrates with
electron-withdrawing groups were more reactive than those
with electron-donating groups (Table 2, entries 2–11). Steric
hindrance on the phenyl ring of aryl iodides has a significant
influence on the transformation. For instance, 3c could be
obtained in 71% yield, while the yield of 3e was only 43%
Scheme 1 Traditional methods versus our method.
a
Table 1 Optimization of reaction conditions
(
Table 2, entries 3 vs. 5). It is noteworthy that the iodobenzene
b
Yield (%)
Entry
Catalyst
Base
Solvent
derivatives with the p-acetyl- or chloro groups could also
be successfully transformed into the corresponding target
products (Table 2, entries 6 and 9). The results favor to
broaden the application of the present method.
1
2
3
4
5
6
7
8
9
Cu
Cu
Cu
Cu
Cu
2
2
2
2
2
O
O
O
O
O
O
K
K
Cs
DBU
KOH
3
PO
CO
CO
4
Á3H
2
O
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO : THF
DMF
20
2
3
NR
o5
10
85
96
2
3
The reaction of aryl bromides with 2a was further investigated. It
was found that aryl bromides were also able to react with 2a at
120 1C, affording the corresponding sulfones in moderate to good
yields (Table 2, entries 15–20). In particular, the beta-bromostyrene,
Cu
2
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
None
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
CuBr
CuI
Cu(OAc)
CuO
86
82
2
40
48
2
which has sp C–Br bond, could also be converted into the desired
10
11
12
13
14
15
16
17
18
19
20
21
22
23
c
Cu
Cu
2
O
O
40
70
product, although a higher reaction temperature and longer
reaction time were required (Table 2, entry 20). Unlike other
copper-catalyzed methodologies for the synthesis of aryl sulfones
from sulfinic acid salts and aryl iodides, the present method could
well achieve the conversion of aryl bromides.
d
2
none
NR
NR
Cu
Cu
Cu
Cu
Cu
Cu
2
2
2
2
2
2
O
O
O
O
O
O
e
NR
83
f
g
trace
trace
In order to probe the reaction mechanism, the isotopic
h
nitroethane
nitroethane
DMSO
DMSO
DMSO
DMSO
18
18
i
labeling experiments with H
Scheme 2, for details of isotopic labeling experiments, see SI).
The isotopic labeling studies demonstrated clearly that the
2
O and
2
O were performed
17
29
e
(
Cu(AcAc)
Cu(AcAc)
2
2
34
NRj
NR
j
Cu
2
O
additional oxygen atom of 3a originated from molecular O
2
CuO
a
a
Reaction conditions: 1a (0.25 mmol), 2a (2.0 mL), ligand acetyl-
acetone (1 equiv.), base (3 equiv.), catalyst (10 mol%) at 100 1C for
Table 2 Reactions of 2a with various aryl halides
b
c
d
e
2
f
0 h. Determined by GC. For 10 h. At 120 1C. Without ligand.
g h
Mix-solvent (2 mL, volume ratio 1 : 3). DMSO (1 equiv.). DMSO
i
1 equiv.). DMSO (10 equiv.). Under nitrogen atmosphere.
j
(
b
Yield (%)
Entry
Ar
X
1
3
time and solvents have a significant effect on the yield of 3a.
For example, when the temperature was raised from 100 1C to
1
2
3
4
5
6
7
8
Ar = Ph
Ar = p-MeO–C
Ar = p-Me–C
Ar = m-Me–C
Ar = o-Me–C H
Ar = p-Acetyl–C
Ar = m-F–C
Ar = p-F–C
Ar = p-Cl–C
Ar = p-NO
Ar = o-NO
Ar = o-Et–C
Ar = p-Et–C
Ar = p-Ph–C H
6
Ar = Ph
I
I
I
I
I
I
I
I
I
I
I
I
I
I
Br
Br
Br
Br
Br
Br
1a
1b
1c
1d
1e
1f
1g
1h
1i
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3a
3m
3o
3h
3i
92
53
71
46
43
52
85
95
73
78
72
40
58
67
92
65
62
68
52
50
6
H
4
1
20 1C, the yield was decreased from 96% to 70% (Table 1,
6
H
4
entries 6 and 12). Shortening the reaction time to 10 h led to
only 40% yield (Table 1, entry 11). If the reaction was
performed with pure DMF or nitroethane (2 mL) as the
solvent and 1 equiv. of DMSO as the substrate, only a trace
amount of 3a was observed (Table 1, entries 17 and 18). Even
with 10 equiv. of DMSO, the yield of 3a was still very low
6
H
4
6
4
6
H
4
6
H
H
H
–C
–C
4
6
4
9
10
6
4
2
6
H
H
4
4
1j
1k
1l
1
1
1
1
2
3
2
6
(
17%, Table 1, entry 19). Only when DMSO served as a
6
H
H
4
substrate as well as the solvent could 3a be obtained in high
yields (Table 1, entries 6 and 16). Moreover, it is worth noting
that 3a was not formed at all if the reaction was conducted
6
4
1m
1n
1o
1p
1q
1r
1s
1s
14
4
15
16
17
18
Ar = p-Et–C
Ar = 3,5-dimethyl–C
Ar = p-F–C
Ar = p-Cl–C
Ar = (E)-C
6 4
H
2
under a nitrogen atmosphere, even in the presence of Cu O
6 3
H
(
(
or CuO), t-BuOK, acetylacetone and DMSO as the solvent
Table 1, entries 22 and 23). Based on the catalytic results of
6
H
4
H
6 4
19
2
c
0
6
H
4
–CHQCH
3p
Cu(I) and Cu(II) (Table 1, entries 6, 10, 22 and 23), it could be
ruled out that the atmospheric oxygen is just needed to oxidize
the catalytic amount of Cu(I) into Cu(II). It seems that the
a
Reaction conditions: as shown in Table 1, entries 15–20 at 120 1C.
b
c
Isolated yield. At 130 1C for 36 h.
Chem. Commun.
This journal is c The Royal Society of Chemistry 2012

View Online
toxic or expensive compounds, as the oxidant and Cu
2
O as the
catalyst mean the present synthetic route shows a potential
application in organic and pharmaceutical synthesis.
We thank the National Natural Science Foundation of
China (No. 21172079) for financial support.
Notes and references
1
(a) M.-J. Langman, D.-M. Jensen, D.-J. Watson, S.-E. Harper,
P.-L. Zhao, H. Quan, J.-A. Bolognese and T.-J. Simon, J. Am.
Med. Assoc., 1999, 282, 1929; (b) D. Bachovchin, A. Zuhl,
A. Speers, M. Wolfe, E. Weerapana, S. Brown, H. Rosen and
B. Cravatt, J. Med. Chem., 2011, 54, 5229.
Scheme 2 Preliminary mechanistic studies.
instead of H O. Namely, the aerobic oxidation leads to the
2
3
K.-R. Gans, W. Galbraith, R.-J. Roman, S.-B. Haber, J.-S. Kerr,
W.-K. Schmidt, C. Smith, W.-E. Hewes and N.-R. Ackerman,
J. Pharmacol. Exp. Ther., 1990, 254, 180.
S.-P. Khanapure, D.-S. Garvey, D.-V. Young, M. Ezawa,
R.-A. Earl, R.-D. Gaston, X. Fang, M. Murty, A. Martino,
M. Shumway, M. Trocha, P. Marek, S.-W. Tam, D.-R. Janero
and L.-G. Letts, J. Med. Chem., 2003, 46, 5484.
R.-W. Friesen, C. Brideau, C.-C. Chan, S. Charleson,
´
D. Desch eˆ nes, D. Dube, D. Ethier, R. Fortin, J.-Y. Gauthier,
Y. Girard, R. Gordon, G.-M. Greig, D. Riendeau, C. Savoie,
Z. Wang, E. Wong, D. Visco, J.-L. Xu and R.-N. Young, Bioorg.
Med. Chem. Lett., 1998, 8, 2777.
(a) R.-D. Santo, R. Costi, M. Artico, R. Ragno, A. Lavecchia,
E. Novellino, E. Gavuzzo, L.-F. Torre, R. Cirilli, R. Cancio and
G. Maga, Chem. Med. Chem., 2006, 1, 82; (b) S.-A. Kolodziej, S.-L.
Hockerman, G.-A. DeCrescenzo, J.-J. McDonald, D.-A. Mischke,
G.-E. Munie, T.-R. Fletcher, N. Stehle, C. Swearingen and
D.-P. Becker, Bioorg. Med. Chem. Lett., 2010, 20, 3561.
2
SQO bond formation of aryl methyl sulfones. Furthermore,
under the standard conditions, it was found that the reaction
of dimethyl sulfone with iodobenzene (1a) could afford the
target product 3a in 18% yield, while phenyl methyl sulfoxide
could not be converted into 3a at all (Scheme 2). In addition,
we observed that aryl methyl sulfones were always formed
together with dimethyl sulfone, but without aryl methyl sulfoxide
in all of the synthetic experiments. Thus, we deduce that the
formation of aryl methyl sulfones may undergo the oxidation
of DMSO to dimethyl sulfone and the coupling reaction
4
5
of dimethyl sulfone with Ar–X (i.e., MeSOMe + O
2
-
MeSO Me, Ar–X + MeSO Me - ArSO Me). In order to
2
2
2
better understand the reaction mechanism, we separately
examined the effect of the catalyst, ligand and base on the
both processes. The results indicate that the oxidation process
only needs the catalyst and ligand, while the base t-BuOK is
necessary for the coupling reaction besides the catalyst and
ligand (see ESI, Tables 2 and 3). In the synthetic experiment of
6 (a) R.-J. Song, Y. Liu, Y.-Y. Liu and J.-H. Li, J. Org. Chem., 2011,
6, 1001; (b) G.-L. Duc, E. Bernoud, G. Prestat, S. Cacchi,
7
G. Fabrizi, A. Iazzetti, D. Madec and G. Poli, Synlett, 2011, 20, 2943.
(a) S. Oae, Organic Sulfur Chemistry, CRC Press, Boca Raton, FL,
1992, ch. 6; (b) M. Gonza-Nenuz, R. Mello, J. Royo, J.-V. Rıos
and G. Asensio, J. Am. Chem. Soc., 2002, 124, 9154; (c) N. Fukuda
and T. Ikemoto, J. Org. Chem., 2010, 75, 4629; (d) C.-A. Gamelas,
7
3
a, the by-product t-BuOMe was detected by GC-MS, but not
T. Lourenco, D. Costa, A.-L. Simplıcio, B. Royo and
´
À
EtSOMe. The t-BuO probably as the nucleophile plays a key
role in the cleavage of the C–S bond. Based on the experi-
mental results, a possible reaction mechanism was proposed in
C.-C. Romao, Tetrahedron Lett., 2008, 49, 4708; (e) S.-L. Jain,
B.-S. Rana, B. Singh, A.-K. Sinha, A. Bhaumik, M. Nandi and
B. Sain, Green Chem., 2010, 12, 374; (f) B. M. Choudary,
C. R. V. Reddy, B. V. Prakash, M. L. Kantam and B. Sreedhar,
Chem. Commun., 2003, 754.
Scheme 3. O
2
and Ar–X are first activated by the ligand-
1
3,14
catalyst to form intermediates A and B, respectively.
Then,
8 (a) M.-B. Jeremy and Z. Wang, Org. Lett., 2002, 4, 4423;
b) M.-K. Kantam, B.-N. Sreedhar and R. Chakravarti, Synlett,
2008, 10, 1455; (c) W. Zhu and D.-W. Ma, J. Org. Chem., 2005,
0, 2696; (d) A. Kar, I.-A. Sayyed, W.-F. Lo, H.-M. Kaiser,
(
the activated O
2
can oxidize DMSO to dimethyl sulfone.
À
Under the nucleophilic attack of the t-BuO , the cleavage of
the C–S bond of dimethyl sulfone generates reactive inter-
mediate C (together with t-BuOMe), followed by the reaction
with previously formed intermediate B to afford the desired
7
M. Beller and M.-K. Tse, Org. Lett., 2007, 9, 3405; (e) F. Huang
and R.-A. Batey, Tetrahedron, 2007, 63, 7667; (f) C. Beaulieu,
D. Guay, Z. Wang and D.-A. Evans, Tetrahedron Lett., 2004,
4
5, 3233; (g) S. Cacchi, G. Fabrizi, A. Goggiamani and
aryl methyl sulfone with the release of the ligand-catalyst and
À
L.-M. Parisi, Org. Lett., 2002, 4, 4719; (h) B.-P. Bandgar,
S.-V. Bettigeri and J. Phopase, Org. Lett., 2004, 6, 2105.
X
ions. The detailed mechanism needs to be studied further.
In conclusion, we have developed a novel method for the
9 (a) B.-M. Graybill, J. Org. Chem., 1967, 32, 2931; (b) S.-J. Nara,
J.-R. Harjani and M.-M. Salunkhe, J. Org. Chem., 2001, 66, 8616;
synthesis of aryl methyl sulfones from aryl halides and DMSO.
The copper-catalyzed aerobic oxidation and the cleavage/
formation of C–S bond play an important role in the
formation of aryl methyl sulfones. Using the air, instead of
(
0
c) C.-G. Frost, J.-P. Hartley and A.-J. Whittle, Synlett, 2001,
6, 830; (d) H. Gilman, N.-J. Beaver and C.-H. Meyers, J. Am.
Chem. Soc., 1925, 47, 2047; (e) W.-H. Baarschers, Can. J. Chem.,
976, 54, 3056.
0 (a) X. Zhao, E. Dimitrijevic and V.-M. Dong, J. Am. Chem. Soc.,
009, 131, 3466; (b) X.-W. Feng, J. Wang, J. Zhang, J. Yang,
1
1
1
1
2
N. Wang and X.-Q. Yu, Org. Lett., 2010, 12, 4408; (c) J.-P. Wu,
J. Emeigh and X.-P. Su, Org. Lett., 2005, 7, 1223.
1 (a) A. Klapars, J.-C. Antilla, X. Huang and S.-L. Buchwald, J. Am.
Chem. Soc., 2001, 123, 7727; (b) N.-J. Turner, Chem. Rev., 2011,
111, 4073; (c) F. Monnier and M. Taillefer, Angew. Chem., Int. Ed.,
009, 48, 6954.
2
2 (a) I.-P. Beletskaya and V.-P. Ananikov, Chem. Rev., 2011,
1
2
11, 1596; (b) H. Huang, J. Li, C. Lescop and Z. Duan, Org. Lett.,
011, 13, 5252.
1
1
3 E. A. Lewis and W. B. Tolman, Chem. Rev., 2004, 104, 1047.
4 C. He, S. Guo, L. Huang and A.-w. Lei, J. Am. Chem. Soc., 2010,
132, 8273.
Scheme 3 A plausible reaction mechanism.
This journal is c The Royal Society of Chemistry 2012
Chem. Commun.