Synthesis of symmetric diaryl sulfones with dimethyl sulfate

Article abstract of DOI:10.1246/cl.2010.390

In this procedure dimethyl sulfate was used for preparation of symmetric diaryl sulfones. First, dimethyl sulfate was treated with pyridine, then activated by Tf₂O to generate SO₂ as the functional group for synthesis of diaryl sulfones. It is noticeable that this reaction was carried out in moderate conditions and products obtained in short times and good yields.

Full text of DOI:10.1246/cl.2010.390

doi:10.1246/cl.2010.390
390
Published on the web March 13, 2010
Synthesis of Symmetric Diaryl Sulfones with Dimethyl Sulfate
Mohammad Mehdi Khodaei* and Ehsan Nazari
Department of Chemistry and Nanoscience & Nanotechnology Research Center (NNRC),
Razi University, Kermanshah 67149, Iran
(Received January 5, 2010; CL-100011; E-mail: mmkhoda@razi.ac.ir)
In this procedure dimethyl sulfate was used for preparation
O
S
0 °C to RT
of symmetric diaryl sulfones. First, dimethyl sulfate was treated
with pyridine, then activated by Tf2O to generate SO2 as the
functional group for synthesis of diaryl sulfones. It is noticeable
that this reaction was carried out in moderate conditions and
products obtained in short times and good yields.
+ MeO
OMe
2-
SO4
N
O
N
+
2
OMe
O
Tf2O
Aryl sulfones are of great use in organic synthesis and
industry.1,2 Diaryl sulfones are important drugs active against
leishmaniasis, malaria, and infections in patients with AIDS
discoid lupus erythematosus.3,4 Various methods for the synthesis
of sulfones involve the oxidation of sulfides,5 sulfonylation of
arenes using an arylsulfonyl halide in the presence of Lewis
acids,6 and reaction of sulfonyl fluorides with organometallic
reagents.7 Catalysts such as AlCl3 and SbF5,8 BiCl3/triflic
acid,9 metal-exchanged k-10 Montmorillonites,10 Sn(OTf)2,11
In(OTf)3,12 Nafion-H,13 Zn-exchanged zeolites,14 and InCl3/
triflic acid15 have been used to promote Friedel-Crafts reactions.
Also, very recently Zhang et al. reported the sulfonylation of
aromatic compounds with sulfonamide using Tf2O.16
Most of the above procedures lead to unsymmetrical diaryl
sulfones and methods that lead to symmetric diaryl sulfones
via electrophilic aromatic substitution have been less reported.
Therefore, the development of new methods, especially those
leading to symmetric diaryl sulfone in situ electrophilic aromatic
substitution is highly desirable.
2
+
TfO
S
OTf
_
N
O
+
OTf
O
O
S
MeO
OMe
Scheme 1.
5 min. The reactions of xylene derivatives under the same
reaction conditions were also studied and the results for o- and
m-xylene were desirable, but in the case of p-xylene no product
was achieved. The reason for this fact may be arisen from the
steric effect and low activity of p-xylene. However, in the case
of m-xylene, the steric effect still exist but the position of the
reaction can be activated by two methyl groups. Also, some
active derivatives of anisole (Entries 5-8) were applied and their
reactions were performed and the corresponding products were
obtained in good yields.
In continuation of our studies on diaryl sulfone in situ
aromatic substitution,17 we would like to report the use of
dimethyl sulfate as the source of SO2 functional groups to
produce symmetric diaryl sulfone in situ with pyridine and triflic
anhydride (Tf2O).
Reaction of cumene under these conditions was unsuccess-
ful. However, when the temperature was increased to 80 °C,
methyl 4-isopropylbenzenesulfonate instead of the correspond-
1
ing diaryl sulfone was obtained that shows H NMR peaks at
The activity of dimethyl sulfate under these reaction
conditions was investigated with anisole as an aromatic model
compound (Scheme 1). First, dimethyl sulfate was treated with
pyridine to produce bis(N-methylpyridinium) sulfate [IR (neat)/
cm¹1 1205, 1049 (SO2). 1H NMR (DMSO-d6, 200 MHz): ¤ 4.32
(s, 3H), 8.05 (t, 2H), 8.52 (t, 1H), 8.93 (d, J = 5.3 Hz, 2H).
13C NMR (DMSO-d6, 50 MHz): ¤ 48.3, 128.1, 145.5, 145.9].
Then this salt was activated by Tf2O to create ditriflate sulfone
1.30 (d, 6H), 3.03 (m, 1H), 3.79 (OMe, s, 3H), 7.48 (d, 2H), and
7.85 (d, 2H). Activity of toluene was investigated in different
temperatures and various solvents, but no product was observed.
Among of heterocyclic aromatic compounds, thiophene and
indole were chosen and tested. The reaction of thiophene was
successful and di-2-thienyl sulfone was obtained in 90% yield
but the reaction of indole afforded a mixture of products.
Instead of dimethyl sulfate and pyridine, some inorganic
salts such as Na2SO4, (NH4)2SO4 were allowed to react with
Tf2O and anisole, but no reaction was observed. This means that
the reaction between dimethyl sulfate and pyridine produces the
organic salt [bis(N-methylpyridinium) sulfate] that can easily
react in organic media.
¹1
[IR (neat)/cm 1306, 1028 (SO2). 13C NMR (DMSO-d6, 50
MHz): ¤ 120.6 (CF3, q, J = 318.7 Hz) (The chemical shifts of
quartet are: 111.0, 117.4, 123.7, 130.1)] having two excellent
leaving groups, and finally anisole was added. The correspond-
ing sulfone, bis(4-methoxyphenyl) sulfone, was obtained after
15 min in 82% yield (Table 1). The amount of other isomers
were ignorable. To demonstrate the generality of this method, we
next investigated the scope of this reaction and the results are
summarized in Table 1.
In conclusion, we have described a novel approach to
produce symmetric diaryl sulfones via activation of dimethyl
sulfate with pyridine and Tf2O under mild conditions.18
It is shown in Table 1, the best result was obtained for
mesitylene and dimesityl sulfone achieving 95% yield after
The authors thank the Razi University Research Council for
financial assistance.
Chem. Lett. 2010, 39, 390-391
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

391
Table 1. Synthesis of symmetric diaryl sulfone with dimethyl
sulfate
References and Notes
1
a) F. R. Jansene, G. Gpldman, in Friedel-Crafts and Related
Reaction, ed. by G. Olah, Wiley Interscience, New York,
1964, Vol. III, p. 1319. b) N. S. Simpkins, Sulfones in
Organic Synthesis, Pergamon Press, Oxford, 1993.
K. M. Roy, in Ullmann’s Encyclopedia of Industrial
Chemistry, ed. by W. Gerhartz, VCH, Weinheim, 1985,
Vol. A25, p. 485.
Entry
Aromatic
OMe
Product
Time/min Yield/%a
O
S
O
O
O
2
3
1
15
83
95
88
85
88
90
87
90
90
40
MeO
OMe
R. C. Hastings, S. G. Franzblau, Annu. Rev. Pharmacol.
Toxicol. 1988, 28, 231.
O
S
4
5
G. Wozel, Int. J. Dermatol. 1989, 28, 17.
2
3
5
K. Schank, in The Chemistry of Sulfones and Sulfoxides, ed.
by S. Patai, Z. Rappoport, C. M. J. Stirling, Wiley, New
York, 1998, Chap. 7.
O
S
6
7
a) W. E. Truce, T. C. Klinger, W. W. Brand, in Organic
Chemistry of Sulfur, ed. by S. Oae, Plenum Press, New York,
1977. b) M. Ueda, K. Uchiyama, T. Kano, Synthesis 1984,
323. c) B. M. Graybill, J. Org. Chem. 1967, 32, 2931.
a) Y. Shirota, T. Nagai, N. Tokura, Tetrahedron 1969, 25,
3193. b) L. L. Frye, E. L. Sullivan, K. P. Cusack, J. M.
Funaro, J. Org. Chem. 1992, 57, 697.
10
10
10
15
10
15
5
O
O
S
4
8
9
G. A. Olah, S. Kobayashi, J. Nishimura, J. Am. Chem. Soc.
1973, 95, 564.
S. Répichet, C. L. Roux, J. Dubac, Tetrahedron Lett. 1999,
40, 9233.
OMe
OMe
OMe
MeO
MeO
O
O
S
OMe
5
10 B. M. Choudary, N. S. Chowdari, M. L. Kantam, J. Chem.
Soc., Perkin Trans. 1 2000, 2689.
11 R. P. Singh, R. M. Kamble, K. L. Chandra, P. Saravanan,
V. K. Singh, Tetrahedron 2001, 57, 241.
12 C. G. Frost, J. P. Hartley, A. J. Whittle, Synlett 2001, 830.
13 G. A. Olah, T. Mathew, G. K. Prakash, Chem. Commun.
2001, 17, 1696.
14 P. Laidlaw, D. Bethell, S. M. Brown, G. Watson, D. J.
Willock, G. J. Hutchings, J. Mol. Catal. A: Chem. 2002,
178, 205.
15 V. Garzya, I. T. Forbes, S. Lauru, P. Maragni, Tetrahedron
Lett. 2004, 45, 1499.
16 B. Yao, Y. Zhang, Tetrahedron Lett. 2008, 49, 5385.
17 a) A. Alizadeh, M. M. Khodaei, E. Nazari, Tetrahedron Lett.
2007, 48, 6805. b) K. Bahrami, M. M. Khodei, F. Shahbazi,
Tetrahedron Lett. 2008, 49, 3931.
18 General procedure: To a 25 mL flask, dimethyl sulfate
(0.5 mmol, 0.05 mL) and pyridine (1 mmol, 0.08 mL) were
added at 0 °C and allowed the mixture stirred at room
temperature for 30 min. Then Tf2O (1 mmol, 0.16 mL) and
aromatic compound (1 mmol) were added to the mixture and
after the appropriate time (Table 1), 10 mL of water was
added. The resulting pricipated crude product was purified
by recrystaliziation from a mixture of dichloromethane and
n-hexane (1:2). Selected spectroscopic data: [Bis(4-methoxy-
phenyl) sulfone, Entry 1]. 1H NMR (CDCl3, 200 MHz): ¤
3.83 (s, 3H), 6.94 (d, J = 8.3 Hz, 2H), 7.84 (d, J = 8.3 Hz,
2H). 13C NMR (CDCl3, 50 MHz): ¤ 55.9, 114.4, 129.5,
133.8, 163.1. [Bis(3,4-dimethylphenyl) sulfone, Entry 3].
1H NMR (CDCl3, 200 MHz): ¤ 2.22 (s, 6H), 2.30 (s, 6H),
6.95 (s, 2H), 7.10 (d, J = 8 Hz, 2H), 7.99 (d, J = 8 Hz, 2H).
13C NMR (CDCl3, 50 MHz): ¤ 19.9, 21.3, 126.6, 130.1,
133.2, 136.2, 137.5, 144.0.
OMe
MeO
O
OMe
O
S
6
OMe
OMe
MeO
MeO
OMe
OMe
O
O
S
7
OMe
O
O
O
S
8
OMe
MeO
O
S
9
S
S
S
O
S
10
60
OMe
O
aIsolated product.
Chem. Lett. 2010, 39, 390-391
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/