A mild and base-free synthesis of unsymmetrical diaryl sulfones from arylboronic acids and arylsulfonyl hydrazides

Article abstract of DOI:10.1055/s-0033-1341023

A mild and efficient synthesis of diaryl sulfones from arylboronic acids and arylsulfonyl hydrazides is described. Promoted by cupric acetate and in the absence of additional ligand and base, the cross-coupling reaction could afford a series of unsymmetrical diaryl sulfones in moderate to good yields at room temperature under neutral and ambient conditions. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1341023

LETTER
▌1163
lAetteMr ild and Base-Free Synthesis of Unsymmetrical Diaryl Sulfones from Aryl-
boronic Acids and Arylsulfonyl Hydrazides
Synthesis of Unsymmetrical Diaryl Sulfones
Xiang-mei Wu,* Yan Wang
Department of Chemistry, College of Science, Lishui University, Lishui, Zhejiang 323000, P. R. of China
Fax +86(578)2271250; E-mail: lswxm7162@163.com
Received: 08.01.2014; Accepted after revision: 24.02.2014
and the compatibility with numerous functional groups.
Abstract: A mild and efficient synthesis of diaryl sulfones from ar-
However, to the best of our knowledge, the C–S bond for-
ylboronic acids and arylsulfonyl hydrazides is described. Promoted
mation from arylboronic acids and arylsulfonyl hydra-
zides has not been explored so far. Herein, we wish to
by cupric acetate and in the absence of additional ligand and base,
the cross-coupling reaction could afford a series of unsymmetrical
diaryl sulfones in moderate to good yields at room temperature un- report a mild and efficient procedure to build diaryl sul-
der neutral and ambient conditions.
fones promoted by cupric acetate under ligand- and base-
free conditions.
Key words: diaryl sulfone, arylboronic acid, arylsulfonyl hydra-
zide, cross-coupling reaction, copper
Initially, the reaction was carried out between p-toluene-
sulfonyl hydrazide and phenylboronic acid, using 20
mol% of Cu(OAc)2·H2O as catalyst in THF under air at
60 °C. However, only small amount of the desired cross-
coupling product was found and at the same time, substan-
tial amount of biphenyl resulted from consumption of
phenylboronic acid and trace amount of di-p-tolyl sulfone
derived from the undesired homocoupling of p-toluene-
sulfonyl hydrazide were determined by GC–MS (Table 1,
entry 1). To our delight, after several attempts on the
amount of Cu(OAc)2·H2O, we found that stoichiometric
quantity of Cu(OAc)2·H2O (1.5 equiv) as reaction promot-
er was necessary and effective and the target product was
obtained in 65% yield (Table 1, entry 2). And the product
yield did not increase by using more than 1.5 equivalents
Cu(OAc)2·H2O, whereas it resulted in low yield of the cor-
responding product when less than 1.5 equivalents were
adopted. When a control experiment was proceeded in the
absence of Cu(OAc)2·H2O, it resulted in almost quantita-
tive recovery of the substrate. Comparison of different
copper sources indicated that Cu(OAc)2·H2O was superior
to the other copper(II) sources such as Cu(NO3)2·5H2O,
CuSO4·5H2O, CuCl2·2H2O, CuBr2·2H2O, and CuO. Indeed,
only modest yield was obtained when they were tested as
reaction promotor (Table 1, entries 3–7). In addition, it
was obvious that copper(I) source was also inferior to
Cu(OAc)2·H2O under the same conditions (Table 1, en-
tries 8–10). Then the effect of solvents was investigated,
and it was observed that the desired product was almost
not isolated in toluene and only about 20% of yield were
obtained in PEG-400 or ethylene glycol. And 62% of
yield were obtained when MeCN was used as a solvent
(Table 1, entries 11–14). Although the reaction was also
effective with polar aprotic solvents such as DMSO,
DMF, and NMP, the best result was obtained when EtOH
was used as a solvent (Table 1, entries 15–18). Generally,
the presence of base was found to be necessary or crucial
for the synthesis of aryl sulfones in previous reports, how-
ever, addition of bases such as Cs2CO3, K2CO3, K3PO4,
and Et3N did not improve the yield in this work (Table 1,
entries 19–22). Further studies to investigate the optimal
Diaryl sulfones are attractive synthetic targets due to their
promising biological properties such as antifungal, anti-
bacterial, or antitumor activities. For example, some of
them have been proven to be potent inhibitors of HIV-1
reverse transcriptase and consequently been identified as
an important class of compounds which can address the
toxicity and resistance problems of nucleoside inhibitors.1
Moreover, diaryl sulfones are exceptionally versatile
building blocks in organic synthetic chemistry.
Traditional approaches to the synthesis of diaryl sulfones
mainly include the oxidation of corresponding sulfides2
and the sulfonylation of suitable arenes in the presence of
strong acids,3 which generally suffer from narrow sub-
strate scope, mixture of isomeric products or sometimes
drastic reaction conditions. Recently, palladium- or cop-
per-catalyzed coupling reactions between aryl halides or
arylboronic acids and arylsulfinic acid salts or arylsulfo-
nyl chlorides have been developed as a milder alterna-
tive.4 Nevertheless, the high cost of palladium catalyst
limits the practical application and some sulfenylating
agents are sensitive to air and moisture. In addition, the
high reaction temperature and inorganic or organic base
were often necessary in these previously reported sys-
tems. Hence, improved methods, especially under mild
and neutral conditions, for the preparation of aryl sulfones
are still highly desirable from a synthetic practicality
viewpoint.
In recent years, the readily accessible arylsulfonyl hydra-
zides have attracted considerable attention in organic syn-
thesis as sulfonyl sources,5 arylating reagents,6 and very
recently as aryl thiol surrogates.7 On the other hand, aryl-
boronic acids have been widely used as precursors in var-
ious cross-coupling reactions due to the easy availability
SYNLETT 2014, 25, 1163–1167
Advanced online publication: 27.03.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1341023; Art ID: ST-2014-W0021-L
© Georg Thieme Verlag Stuttgart · New York

1164
X.-m. Wu, Y. Wang
LETTER
reaction temperature appeared that almost the same result The substrate scope was found to be very general for the
was obtained even at room temperature. Moreover, the re- cross-coupling reaction under the optimized reaction con-
action was cleaner at room temperature than at 60 °C, ditions, and a range of diaryl sulfones was prepared in
which is consistent with the observation for the reaction of moderate to good yields as listed in Table 2. It is notewor-
boronic acids with sulfinic acid salts reported by Evans.8 thy that either an electron-donating or an electron-with-
Indeed, the homocoupling of p-toluenesulfonyl hydrazide drawing group such as methyl, methoxy, fluoro, chloro,
was advantageous at higher temperature. And the change bromo, acetyl, nitro, and trifluoromethyl was introduced
from air to oxygen did not affect the conversion, which into the diaryl sulfones without any problem by employ-
might improve its operational simplicity. Therefore, 1.5 ing arylboronic acid bearing such a group on the aromatic
equivalents of Cu(OAc)2·H2O in EtOH at room tempera- ring at para or meta position (Table 2, entries 1–15). In
ture under air for six hours was chosen as the optimal con- general, the expected product yields were higher with ar-
ditions for the synthesis of diphenyl sulfone from p- ylboronic acids bearing electron-donating substituents
toluenesulfonyl hydrazide and phenylboronic acid.
whereas the use of arylboronic acids containing electron-
withdrawing substituents led to the products in modest
isolated yields. Unfortunately, the same group at ortho po-
sition afforded a poor yield with the reaction mixture
probably due to the steric effect. Of particular interesting,
under the reaction conditions, bromo and chloro substitu-
ents on the arylboronic acid moiety did not participate in
the coupling reaction, which could allow for further func-
tionalization on the aromatic ring (Table 2, entries 6, 7,
and 10).
Table 1 Optimization of Reaction Conditionsa
Entry
Catalyst
Solvent
Yield (%)b
1c
2
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(NO3)2·5H2O
CuSO4·5H2O
CuCl2·2H2O
CuBr2·2H2O
CuO
THF
15
65
38
15
20
23
18
35
30
28
<5
20
22
62
78
70
68
57
76
74
70
62
THF
3
THF
4
THF
The scope of arylsulfonyl hydrazide was subsequently ex-
amined in the coupling reaction with phenylboronic acid
under the optimized reaction conditions. It was shown that
a variety of arylsulfonyl hydrazides could react smoothly
in this reaction, thus afforded the desired products in mod-
erate to good yields, no matter if bearing electron-donat-
ing or electron-withdrawing functional groups (Table 2,
entries 16–21). Similarly, the reaction of bromo- and chlo-
ro-substituted sulfonyl hydrazides exhibited excellent
chemoselectivity, that is, only the sulfonyl hydrazide
group occurred and the bromo and chloro groups were
well tolerated. According to our experimental results and
5
THF
6
THF
7
THF
8
CuI
THF
9
CuBr
THF
10
11
12
13
14
15
16
17
18
19d
20e
21f
22g
CuCl
THF
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
toluene
PEG-400
ethylene glycol
MeCN
EtOH
DMF
proposed mechanism reported in the literatures,4f,6c
a
probable and simple reaction pathway for the cross-cou-
pling of arylsulfonyl hydrazides and arylboronic acids to
prepare diaryl sulfones is given in Scheme 1.
Cu(OAc)2
Ar1SO2CuOAc
Ar1SO2NHNH2
DMSO
NMP
N2
Ar2B(OH)2
EtOH
EtOH
EtOH
EtOH
Ar1SO2CuAr2
Ar1SO2Ar2
Scheme 1 Plausible reaction pathway for the cross-coupling
In summary, we have developed an efficient and conve-
nient route to a variety of diaryl sulfones from readily
available arylsulfonyl hydrazides and arylboronic acids,
promoted by cupric acetate in the absence of additional li-
gand and base. The reaction conditions are mild and neu-
tral and avoid the use of excess reagents or additives.
a Reaction conditions: phenylboronic acid (1.2 mmol), p-toluenesulfo-
nyl hydrazide (1.0 mmol), catalyst (1.5 mmol), solvent (2.0 mL), r.t.,
6 h, in air.
b Isolated yield.
c Cu(OAc)2·H2O (0.2 mmol).
d Cs2CO3.
e K2CO3.
f K3PO4.
g Et3N.
Synlett 2014, 25, 1163–1167
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Unsymmetrical Diaryl Sulfones
1165
Table 2 Synthesis of Diaryl Sulfones from Various Arylboronic Acids and Arylsulfonyl Hydrazidesa,9
SO2NHNH2
O
O
Cu(OAc)2
EtOH, r.t.
S
Ar
+
ArB(OH)2
R
R
Entry
1
Arylboronic acid
R
Sulfone product
Yield (%)b
78
O
O
B(OH)2
S
Me
O
O
O
B(OH)2
B(OH)2
S
2
3
4
5
Me
Me
Me
Me
80
76
82
86
O
S
O
O
B(OH)2
S
O
O
B(OH)2
S
MeO
MeO
O
O
B(OH)2
S
6
7
Me
Me
Me
Me
Me
Me
Me
79
75
68
60
70
65
50
Cl
Cl
Cl
Cl
O
O
B(OH)2
B(OH)2
S
O
O
S
S
8
F
F
F
F
O
O
B(OH)2
B(OH)2
9
O
O
S
10
11
12
Br
Br
O
O
O
B(OH)2
B(OH)2
S
S
O
O2N
O2N
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1163–1167

1166
X.-m. Wu, Y. Wang
LETTER
Table 2 Synthesis of Diaryl Sulfones from Various Arylboronic Acids and Arylsulfonyl Hydrazidesa,9 (continued)
SO2NHNH2
O
O
Cu(OAc)2
EtOH, r.t.
S
Ar
+
ArB(OH)2
R
R
Entry
13
Arylboronic acid
R
Sulfone product
Yield (%)b
52
O
O
O
F3C
B(OH)2
F3C
F3C
S
S
Me
Me
Me
O
F3C
B(OH)2
14
15
45
48
CF3
CF3
O
O
B(OH)2
S
Ac
Ac
O
O
B(OH)2
S
16
17
18
19
H
73
75
57
83
O
O
B(OH)2
S
H
O
O
F
B(OH)2
F
S
H
O
O
O
O
B(OH)2
B(OH)2
B(OH)2
S
S
S
OMe
OMe
O
O
20
21
F
66
70
F
Cl
Cl
a Reaction conditions: arylboronic acid (1.2 mmol), arylsulfonyl hydrazide (1.0 mmol), Cu(OAc)2 (1.5 mmol), EtOH (2.0 mL), r.t., 6 h, in air.
b Isolated yield.
Acknowledgment
References and Notes
We thank the Natural Science Foundation of Zhejiang Province
(NO. LY13B020005) for financial support.
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ungIifoop
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Synlett 2014, 25, 1163–1167
© Georg Thieme Verlag Stuttgart · New York

LETTER
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(9) General Procedure
Arylboronic acids (1.2 mmol), arylsulfonyl hydrazides (1.0
mmol), cupric acetate (1.5 mmol), and EtOH (2.0 mL) were
taken in a 25 mL two-neck flask. The reaction mixture was
stirred at r.t. for 6 h in air. The solution was evaporated under
reduced pressure and H2O (20 mL) was added, and then the
mixture was extracted with EtOAc (4 10 mL). The extracts
were combined and washed with brine (3 10 mL), dried over
MgSO4, filtered, evaporated, and purified by chromatog-
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EtOAc–hexane (v/v = 1:5 to 1:10). The products were
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Typical Data for Representative Compound: p-Ethyl-
phenyl p-Tolyl Sulfone (Table 2, Entry 4)
1H NMR (300 MHz, CDCl3): δ = 7.85–7.81 (m, 4 H), 7.31–
7.27 (m, 4 H), 2.68–2.66 (m, 2 H), 2.38 (s, 3 H), 1.22 (m, 3
H). 13C NMR (75 MHz, CDCl3): δ = 144.0, 139.1, 139.0,
129.9, 128.7, 127.6, 28.8, 21.6, 15.1. GC–MS (EI): m/z =
260 [M+]. Anal Calcd for C15H16O2S C: 69.20; H, 6.19.
Found: C, 69.12; H, 6.15.
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Synlett 2014, 25, 1163–1167

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