Sulfonylation of aromatic compounds with methyl p-toluenesulfonate as a sulfonylating precursor

Article abstract of DOI:10.1007/s13738-011-0062-3

We have developed Friedel-Crafts (FC) sulfonylation of aromatic compounds with methyl p-toluenesulfonate as a sulfonylating precursor. In this procedure, methyl p-toluenesulfonate was treated and activated with pyridine to produce N-methylpyridinium p-toluenesulfonate as a sulfonylation reagent. Reactivity of this salt for the sulfonylation of mesitylene was investigated in the presence of three different promoters, such as triflic anhydride, dimethylsulfide ditriflate, and triphenylphosphine ditriflate (TPPD). All of the promoters show chemoselectivity and among them, TPPD presents a chemoselectivity in FC sulfonylation. Iranian Chemical Society 2012.

Full text of DOI:10.1007/s13738-011-0062-3

J IRAN CHEM SOC (2012) 9:507–512
DOI 10.1007/s13738-011-0062-3
ORIGINAL PAPER
Sulfonylation of aromatic compounds with methyl
p-toluenesulfonate as a sulfonylating precursor
M. M. Khodaei E. Nazari
•
Received: 13 September 2011 / Accepted: 2 December 2011 / Published online: 13 January 2012
Ó Iranian Chemical Society 2012
Abstract We have developed Friedel–Crafts (FC) sulf-
onylation of aromatic compounds with methyl p-toluene-
sulfonate as a sulfonylating precursor. In this procedure,
methyl p-toluenesulfonate was treated and activated with
pyridine to produce N-methylpyridinium p-toluenesulfo-
nate as a sulfonylation reagent. Reactivity of this salt for the
sulfonylation of mesitylene was investigated in the presence
of three different promoters, such as triflic anhydride,
dimethylsulfide ditriflate, and triphenylphosphine ditriflate
anti-HIV-1 agents [5, 6]. In addition, they are active
against malaria, leishmaniasis, and infections in patients
with discoid lupus erythematosus [7–9]. Typically, FC-
sulfonylations are performed using sulfonyl chloride in the
presence of a little more than 1 equivalent of Lewis acids,
such as anhydrous AlCl , TiCl , and FeCl [10–12]. Also,
3
4
3
it has been reported that sulfonic anhydrides can be used
for FC-sulfonylation [13, 14].
Over the last decade, FC-sulfonylation of aromatic
compounds with sulfonic acids has been developed in the
presence of various catalysts, such as Nafion-H [15],
Montmorillonite clay [16] and P O /SiO [17]. This
(
TPPD). All of the promoters show chemoselectivity and
among them, TPPD presents a chemoselectivity in FC
sulfonylation.
2
5
2
reaction with sulfonic acid under microwave irradiation
has been also reported [18]. Although these methods uti-
lize sulfonic acids as the cheapest and the most available
of all sulfonylating reagents, but most of these methods
suffer from disadvantages, such as using reflux condition,
long reaction times, and especially large amount of aro-
matic compound as both solvent and substrate. Very
recently, Yao et al. [19] have reported the sulfonylation of
aromatic compounds using sulfonamide as the new and
unusual sulfonylating reagent in the presence of triflic
Keywords Sulfonylation Á Arenes Á
Methyl p-toluenesulfonate Á Triphenylphosphine ditriflate Á
Sulfones
Introduction
Friedel–Crafts (FC) sulfonylation reactions are one of the
most important groups of aromatic electrophilic substitu-
tions [1, 2]. These reactions provide fundamental and
useful methods for the synthesis of aryl sulfones which are
important compounds in industry and organic synthesis [3].
Diaryl sulfones are especially important intermediates for
synthesizing pharmaceutical compounds [4] and are potent
anhydride (Tf O) at high temperature (120 °C) in long
2
reaction times. Therefore, there is still a considerable
interest in the developing of FC-sulfonylation of aromatic
compounds using other sulfonylating reagents such as
esters.
In contrast to FC-acylation with carboxylic ester [20–
24], FC-sulfonylation using sulfonic ester, which is more
stable and easier to handle than typical sulfonylating
reagents, such as sulfonic acid, sulfonic anhydride, and
sulfonyl chloride, was not developed. Thus, we herein
report our results describing the first method for the FC-
sulfonylation of aromatic compounds using methyl p-
toluenesulfonate as a sulfonylating precursor.
M. M. Khodaei (&) Á E. Nazari
Department of Chemistry and Nanoscience and Nanotechnology
Research Center (NNRC), Razi University,
67149 Kermanshah, Iran
e-mail: mmkhoda@razi.ac.ir
123

5
08
J IRAN CHEM SOC (2012) 9:507–512
Experimental
(d, J = 8.0 Hz, 2H), 8.09 (t, 2H), 8.54 (t, 1H), 8.96 (d,
1
3
J = 5.4 Hz, 2H).
d = 20.8, 47.9, 125.5, 127.7, 128.1, 137.7, 145.0, 145.6,
45.8]. These data easily confirmed the formation of
C NMR (50 MHz, DMSO-d6):
Chemical and apparatus
1
All the chemicals were obtained from Merck Company and
used as received. All products are known and characterized
N-methylpyridinium p-toluenesulfonate.
1
by a comparison of their melting points and spectral ( H
General procedure
1
3
NMR, C NMR) data with those reported in the literatures.
All yields refer to isolated products. NMR spectra were
recorded on Brucker Avance spectrophotometer (200 MHz)
To a solution of Ph PO (0.278 g, 1 mmol) in CH Cl
2
3
2
(1 mL), Tf O (0.16 mL, 1 mmol) was added at 0 °C and
2
in CDCl using TMS as an internal standard. Melting points
3
the solution allowed to stir for 10 min at room temperature.
N-methylpyridinium p-toluenesulfonate (0.266 g, 1 mmol)
was added to the reaction mixture and the mixture allowed
stirring for 30 min. Then, arene (1 mmol) was added to the
mixture and the solution was stirred again for appropriate
time (Table 1). Upon completion of the reaction, the
organic solvent was evaporated and the crude product was
purified by a column chromatography using ethyl acetate/
n-hexane (2:8) to afford an aromatic sulfone. The products
are all known compounds.
were achieved on Barnstead electrothermal melting point
(
apparatus) instrument.
p-Toluenesulfonic anhydride (Scheme 1, a): white solid,
1
mp 122–123 °C (lit [25] 129.5–131.5 °C). H NMR
(
CDCl , 200 MHz): d = 2.47 (s, 3H), 7.36 (d, J = 8.2 Hz,
3
1
3
2
H), 7.85 (d, J = 8.0 Hz, 2H).
0 MHz): d = 21.4, 128.3, 129.5, 132.8, 146.2.
Dimesitylmethane (Scheme 1, b): white solid, mp
C NMR (CDCl3,
5
1
1
2
6
1
32–133 °C (lit [26] 134.4–135.4 °C). H NMR (CDCl ,
3
00 MHz): d = 2.14 (s, 12H), 2.25 (s, 6H), 4.0 (s, 2H),
(2,4,6-Trimethyphenyl) p-tolyl sulfone (Table 1, entry
1
1): white solid, mp 115–116 °C (lit [27] 117 °C). H NMR
1
3
.84 (s, 4H). C NMR (CDCl , 50 MHz): d = 20.3, 20.4,
3
28.9, 134.4, 134.5, 136.3.
(CDCl , 200 MHz): d = 2.28 (s, 3H), 2.38 (s, 3H), 2.59 (s,
3
6
H), 6.92 (s, 2H), 7.24 (d, J = 8.2 Hz, 2H), 7.67 (d,
3
1
Preparation of N-methylpyridinium p-toluenesulfonate
J = 8.2 Hz, 2H). C NMR (CDCl , 50 MHz): d = 20.6,
3
21.1, 22.4, 125.9, 129.0, 131.7, 139.5, 140.2, 142.8, 143.0.
N-methylpyridinium p-toluenesulfonate (I) was obtained
from the reaction of methyl p-toluenesulfonate (1 mmol)
and pyridine (1 mmol) at room temperature under neat
conditions. Melting point for this salt is 133–134 °C and its
(2,5-Dimethylphenyl) p-tolyl sulfone (Table 1, entry 4):
1
white solid, mp 104–105 °C (lit [28] 108–110 °C). H
NMR (CDCl , 200 MHz): d = 2.37 (s, 3H), 2.40 (s, 6H),
3
1
7.08 (d, J = 7.7 Hz, H), 7.27 (d, J = 7.5 Hz, 2H), 7.69
(m, 3H), 8.02 (s, 1H).
1
NMR spectroscopic data are [ H NMR (200 MHz, DMSO-
d6): d = 2.26, 4.33, 7.09 (d, J = 7.8 Hz, 2H), 7.46
Results and discussion
O O O O
(
(
a)
b)
S
S
O
In our studies on FC-reactions [29–37], we have demon-
strated that a methyl-donor compound such as dimethyl
Me
Me
Me
9
0%
sulfate can be easily activated with pyridine and Tf O for
2
preparation of symmetrical diaryl sulfones [36]. Encouraged
by this success; we decided to use methyl p-toluenesulfonate
to react with pyridine for production of N-methylpyridinium
p-toluenesulfonate (I) as a new sulfonylating reagent
Compound I
Me Me
H2
C
+
Me
Me
Me Me
(Scheme 2).
78%
Reactivity of this salt was examined for the sulfonyla-
Me
Me
tion of mesitylene in the presence of three different pro-
moters in CH Cl as the solvent, and the results are shown
O O Me
S
(c)
2
2
in Scheme 1. It is noticeable that we utilized CH Cl as a
2
2
Me
Me
Me
non-nucleophilic solvent to create the homogeneous reac-
tion conditions, and also non-nucleophilic feature of this
solvent does not allow CH Cl to react with the promoters.
9
4%
2
2
Scheme 1 a Tf
(
2
2
O (1 mmol), mesitylene (1 mmol) in CH
1 mL), rt. b 1: DMSD (1 mmol), CH Cl (1 mL), time = 10 min.
: Mesitylene (1 mmol), rt, time = 24 h. c 1: TPPD (1 mmol),
Cl (1 mL). 2: Mesitylene (1 mmol), rt, time = 30 min
2 2
Cl
At first as shown in Scheme 1 (path a), when 1 equiv-
2
2
alent of Tf O was applied to promote I for the sulfonyla-
2
CH
2
2
tion of mesitylene, no sulfone product was observed, but
1
23

J IRAN CHEM SOC (2012) 9:507–512
509
Table 1 Friedel-Crafts sulfonylation of aromatic compounds with N-mthylpyridinium p-methytoluenesulfonate in the presence of TPPD
Ph
O O
S
O O
S
1
) Ph
P
2 2
OTf OTf, CH Cl
O
Ph
Ar
2
) ArH, 0 oC to rt
Me
N
Me
Me
a
ref
Entry
1
Aromatic
Time (h)
0.5
Product
Yield (%)
94
Mp (°C, observed)
Mp (°C, observed)
115–116
117 [27]
Me
Me
Me
O
O
S
Me
Me
Me
Me
Me
Me
2
1
85
51–52
52 [38]
Me
O
O
O
S
Me
Me
Me
3
4
1
1
74
68
113–114
104–105
117 [39]
Me
Me
O
Me
Me
S
108–110 [28]
Me
Me
O
O
S
Me
Me
Me
5
6
7
8
9
2
80
147–148
118–119
126–127
132–133
115–116
–
155 [27]
Me
O O
b
Me
S
o:p = 23:78
Me
2
85
119 [27]
O
S
O
S
a:b = 90:10
Me
3
55
126–127 [40]
132–134 [40]
115–117 [40]
–
O
O
Me
6
43
Br
Cl
O O
b
Br
Cl
S
o:p = 7:93
Me
6
40
O
O
b
S
o:p = 10:90
Me
1
0
24
–
0
NO2
a
b
c
Isolated yields
1
The ratio of ortho:para was determined with H NMR
1
The ratio of a:b was determined with H NMR
123

5
10
J IRAN CHEM SOC (2012) 9:507–512
Ph
O O
S
O O
S
O O
S
Ph P OTf OTf
Ph
OMe
N
O
O
RT, Neat
Me
Me
N
CH Cl
2 2
Me
N
Me
Me
I
Me
Scheme 2
O O
S
Ph
O P Ph
Ph
Me
Me
Me
O
10 min
Me
OTf
(i)
S
+
Tf O
2
S
Me
CH Cl
2
2
o
OTf
OTf
Neat, 0 C to RT
Me
Me
II
DMSD
Me
O O
S
Ph
Ph P O
Ph
Ph
1
5 min
Ph
Ph P O
Ph
(
ii)
+
Tf O
2
Ph P OTf OTf
+
o
CH Cl , 0 C to RT
Ph
2
2
Me
Me
Me
TPPD
Scheme 4
Scheme 3
p-toluenesulfonic anhydride was achieved in 90% yield.
The reason for this observation may have arisen from this
fact that there is a hard–soft interaction between p-tolu-
enesulfonate anion and N-methylpyridinium cation. This
hard–soft interaction intensifies the nucleophilic ability of
p-toluenesulfonate anion in comparison with mesitylene;
so, p-toluenesulfonate anion reacts rapidly with itself and it
does not allow mesitylene to react. Thus, in order to pre-
pare the desired product (sulfones), we decided to apply
other promoters with oxophile atoms such as sulfur and
phosphorous.
ditriflate (TPPD) and diphosphonium triflate salt [42–44].
These salts were shown to be a powerful dehydrating agent
and also a promising reagent for the conversion of car-
boxylic acids to anhydrides [45] esters, amides [42, 45]
and also the conversion of sulfonic acids to sulfonamides
[46]. We decided to utilize TPPD as the promoter for
FC-sulfonylation of mesitylene with N-methylpyridinium
p-toluenesulfonate.
To prepare 1 mmol of TPPD, 1 mmol of Tf O was
2
added dropwise to 1 mmol of Ph PO in 1 mL of CH Cl at
3
2
2
0 °C and the solution allowed to stir at room temperature
for 15 min (Scheme 3, (ii)). Then mesitylene (1 mmol) and
N-methylpyridinium p-toluenesulfonate (1 mmol) were
added to the reaction mixture. After 30 min, we observed
quiet satisfactory results in FC-sulfonylation of mesitylene
and (2,4,6-trimethylphenyl)phenyl sulfone was achieved in
94% yield (Scheme 1, path 3).
Early studies by Hendrickson and Schwartzman [41]
established that Tf O adds to dimethylsulfoxide to form the
2
relatively unstable, air, oxygen, and water-sensitive
dimethylsulfide ditriflate (DMSD). To produce 1 mmol of
DMSD, one equivalent of Tf O was added dropwise to
2
1
mmol of Me SO at 0 °C and the mixture allowed to stir
2
at room temperature. After 10 min, a white solid formed as
DMSD (Scheme 3, (i)).
A possible reaction mechanism is presented in
Scheme 4 in which N-methylpyridinium p-toluenesulfo-
nate was initially reacted with TPPD to produce interme-
In the second attempt, 1 mmol of N-methylpyridinium
p-toluenesulfonate was added to the solution of 1 mmol of
DMSD as the promoter in 1 mL of CH Cl at room tem-
diate II having Ph PO as an inert and excellent leaving
3
2
2
group. As a result II reacted with mesitylene and Ph PO
3
perature and the reaction mixture allowed stirring for
was sent out and desirable sulfone was produced. It seems
that TPPD acts as both a promoter and a scavenger for
N-methylpyridinium p-toluenesulfonate.
1
2
5 min. Finally, 1 mmol of mesitylene was added and after
4 h, dimesityl methane was obtained in 78% (Scheme 1,
path b). In the absence of either N-methylpyridinium
p-toluenesulfonate or DMSD, the reaction was not carried
out which implies that the presence of these compounds is
necessary to perform the reaction.
It is noteworthy that when trifluoroacetic anhydride
(TFAA) and Ph PO were used instead of Tf O and Ph PO
3
2
3
in the reaction of mesitylene with N-methylpyridinium
p-methyl toluenesulfonate, the reaction was not completed
even after 3 h.
In continuation with more accurate search on reported
literatures, we observed that triphenylphosphine oxide
reacts exothermically with Tf O in CH Cl to give white
The activity of TPPD as a promoter for FC-sulfonylation
of different aromatic compounds with N-methylpyridinium
p-methyltoluenesulfonate was examined and the results are
2
2
2
precipitates of the corresponding triphenylphosphine
1
23

J IRAN CHEM SOC (2012) 9:507–512
511
summarized in Table 1. These results show that this novel
method afforded diaryl sulfones in good to excellent yields.
After the success of mesitylene in performing of the
reaction and to show the generality of the method, different
isomers of xylene were utilized under these reaction con-
ditions; the best result was obtained for meta isomer and
the corresponding sulfone was produced after 1 h in 85%
yield (Table 1, entry 2), whereas in the case of ortho and
para isomers, lower yields were obtained (Table 1, entries
5. T.M. Willams, T.M. Ciccarone, S.C. MacTough, C.S. Rooney,
S.K. Balani, J.H. Condra, E.A. Emini, M.E. Goldman, W.J.
Greenlee, L.R. Kauffman, J.A. Brien, P.S. Anderson, J. Med.
Chem. 36, 1291 (1993)
6. M. Artico, R. Silvestri, E. Pagnozzi, B. Bruno, E. Novellino, G.
Greco, S. Massa, A. Ettorre, G. Loi, F. Scintu, P. La Colla, J.
Med. Chem. 43, 1886 (2000)
7
. R.C. Hastings, S.G. Franzblau, Ann. Rev. Pharmacol. Toxicol.
8, 231 (1966)
8. G. Wozel, Int. J. Dermatol. 28, 17 (1989)
2
9. J.S. Lo, R.E. Berg, K.J. Tomecki, Int. J. Dermatol. 28, 497 (1989)
0. W.E. Truce, T.C. Klinger, W.W. Brand, in Organic Chemistry of
Sulfur, ed. by S. Oae (Plenum Press, New York, 1977)
1. M. Ueda, K. Uchiyama, T. Kano, Synthesis 4, 323 (1984)
1
3
and 4). This observation may have arisen from this fact
that the reaction site in m-xylene is activated with two
methyl groups. When toluene was reacted with N-meth-
ylpyridinium p-toluenesulfonate in the presence of TPPD,
the corresponding sulfone was produced in 80% yield with
an ortho:para ratio of 23:78.
1
12. B.M. Graybill, J. Org. Chem. 32, 2931 (1967)
13. S. Re
J. Org. Chem. 64, 6479 (1999)
´
pichet, C. Le Roux, P. Hernandez, J. Dubac, J.R. Desmurs,
1
4. B.M. Choudary, N.S. Chowdari, M.L. Kantam, J. Chem. Soc.
Perkin Trans. 1, 2689 (2000)
Naphthalene was also sulfonylated under the above
conditions and produced the corresponding product in 85%
yield. In the case of benzene, (p-tolyl)phenyl sulfone was
achieved after 3 h in 55% yield. Also, deactivated arenes
such as chlorobenzene and bromobenzene were success-
fully sulfonylated and obtained results have shown high
p-selectivity in these compounds (Table 1, entries 8 and 9).
However, the reactions of nitrobenzene, benzaldehyde, and
acetophenone were unsuccessful even after 24 h.
15. G. A. Olah, T. Mathew, G. K. S. Parakash, Chem. Commun.
(2001) 1696
1
6. B.M. Choudary, N.S. Chowdari, M.L. Kantam, J. Chem. Soc.
Perkin Trans 1, 2689 (2000)
1
7. B.M. Mirjalali, M.A. Zolfigol, A. Bamoniri, L. Khazdooz, Bull.
Korean Chem. Soc. 24, 1009 (2003)
18. H. Z. Li, L.W. Xiao, H.Y. Li, K. F. Wang, X. Li, J. Chem. Res.
S) 493 (2003)
(
1
2
9. B. Yao, Y. Zhang, Tetrahedron Lett. 49, 5385 (2008)
0. R.R. Poondra, P.M. Fischer, N.J. Turner, J. Org. Chem. 69, 6920
(2004)
Triphenylphosphine ditriflate shows chemoselectivity in
all of the FC-sulfonylation reactions.
21. K. Gewald, O. Calderon, H. Schaefer, U. Hain, Liebigs Ann.
Chem. 1390 (1984)
2
2
2
2
2. H.W. Pinnick, S.P. Brown, E.A. McLean, L.W. Zoller, J. Org.
Chem. 46, 3758 (1981)
3. Y. Nishimito, S.A. Babu, M. Yasuda, A. Baba, J. Org. Chem. 73,
9465 (2008)
4. J.P. Hwang, G.K. Suria Prakash, G.A. Olah, Tetrahedron 56,
Conclusions
7
5. L. Field, J. Am. Chem. Soc. 74, 394 (1952)
199 (2000)
In summary, we have developed FC-sulfonylation of aro-
matic compounds with methyl p-toluenesulfonate as a new
sulfonylating precursor. Performing of the reaction under
mild reaction conditions at room temperature and sulf-
onylation of deactivated benzene such as chlorobenzene
are remarkable features of the present procedure. Tri-
phenylphosphine ditriflate shows chemoselectivity in all of
the FC-sulfonylation reactions.
26. C.M. Welch, H.A. Smith, J. Am. Chem. Soc. 73, 4391 (1951)
27. B.M. Graybill, J. Org. Chem. 32, 2931 (1967)
2
2
8. H. Drews, S. Meyerson, J. Am. Chem. Soc. 83, 3871 (1961)
9. P. Salehi, M.M. Khodaei, M.A. Zolfigol, S. Sirouszadeh, Bull.
Chem. Soc. Jpn. 76, 1863 (2003)
30. P. Salehi, M.M. Khodaei, M.A. Zolfigol, S. Zeinoldini, Synth.
Commun. 33, 1367 (2003)
3
3
3
3
3
1. M.M. Khodaei, A. Alizadeh, E. Nazari, Tetrahedron Lett. 48,
199 (2007)
2. A. Alizadeh, M.M. Khodaei, E. Nazari, Tetrahedron Lett. 48,
805 (2007)
3. A. Alizadeh, M.M. Khodaei, E. Nazari, Bull. Korean Chem. Soc.
8, 1854 (2007)
4. K. Bahrami, M.M. Khodaei, F. Shahbazi, Tetrahedron Lett. 49,
931 (2008)
5. K. Bahrami, M.M. Khodaei, F. Shahbazi, Chem. Lett. 37, 844
2008)
4
Acknowledgments The authors thank the Razi University Research
Council for financial support of this work.
6
2
3
References
(
1
2
3
4
. F.R. Jensen, G. Goldman, in Friedel-Crafts and Related Reac-
tions, ed. by G. Olah (Wiley-Interscience, New York, 1964)
. R. Taylor, in Comprehensive Chemical Kinetics, eds. by C.
H. Bamford, C. F. H. Tipper (Elsevier, New York, 1972)
. K.M. Roy, in Ullmann’s Encyclopedia of Industrial Chemistry,
ed. by W. Gerhartz (VCH, Weinheim, 1985)
. J.B. McMahan, R.J. Gulakowsky, O.S. Weislow, R.J. Schoktz,
V.L. Narayanan, D.J. Clanton, R. Pedemonte, F.W. Wassmundt,
R.W.J. Buckheit, W.D. Decker, E.L. White, J.P. Bader, M.R.
Boyd, Antimicrob. Agents Chemother. 37, 754 (1993)
36. M.M. Khodaei, E. Nazari, Chem. Lett. 39, 390 (2010)
37. M.M. Khodaei, E. Nazari, Bull. Korean Chem. Soc. 32, 1784
(2011)
38. E.M. Shamis, M.M. Dashevskii, Zh. Org. Khim. 2, 280 (1966)
39. S. Meyerson, H. Drews, E.K. Fields, Anal. Chem. 36, 1294
(1964)
40. R.P. Singh, R.M. Kamble, K.L. Chandra, P. Saravanan, V.K.
Singh, Tetrahedron 57, 241 (2001)
41. J.B. Hendrickson, S.M. Schwartzman, Tetrahedron Lett. 16, 273
(1975)
123

5
4
12
J IRAN CHEM SOC (2012) 9:507–512
2. J.B. Hendrickson, S.M. Schwartzman, Tetrahedron Lett. 16, 277
45. J.B. Hendrickson, M.S. Hussoin, J. Org. Chem. 54, 1144 (1989)
46. S. Caddick, J.D. Wilden, D.B. Judd, J. Am. Chem. Soc. 126, 1024
(2004)
(1975)
43. D. Crich, H. Dyker, Tetrahedron Lett. 30, 475 (1989)
44. A. Aaberg, T. Gramstad, S. Husebye, Tetrahedron Lett. 20, 2263
(1979)
1
23