Unsymmetrical diaryl sulfones through palladium-catalyzed coupling of aryl boronic acids and arylsulfonyl chlorides

Article abstract of DOI:10.1021/ol049692c

A simple and efficient method for the synthesis of unsymmetrical diaryl sulfones using the palladium-catalyzed coupling of aryl boronic acids and arylsulfonyl chlorides has been developed. High product yields, a short reaction time, and mild reaction conditions are important features of this method.

Full text of DOI:10.1021/ol049692c

ORGANIC
LETTERS
2004
Vol. 6, No. 13
2105-2108
Unsymmetrical Diaryl Sulfones through
Palladium-Catalyzed Coupling of Aryl
Boronic Acids and Arylsulfonyl
Chlorides
B. P. Bandgar,* Sampada V. Bettigeri, and Jaywant Phopase
Organic Chemistry Research Laboratory, School of Chemical Sciences,
Swami Ramanand Teerth Marathwada UniVersity, Vishnupuri, Nanded-431 606, India
bandgar_bp@yahoo.com
Received February 21, 2004
ABSTRACT
A simple and efficient method for the synthesis of unsymmetrical diaryl sulfones using the palladium-catalyzed coupling of aryl boronic acids
and arylsulfonyl chlorides has been developed. High product yields, a short reaction time, and mild reaction conditions are important features
of this method.
Organosulfones are important intermediates in organic
synthesis1 because of their chemical properties2 and biologi-
cal activities.3 Diaryl sulfones are important synthetic targets
and widely used synthons for synthetic organic chemists due
to their many industrial applications.4 These are useful in
the practice of medicinal chemistry because the sulfone
functional group is found in numerous drugs, including the
recently developed selective COX-2 inhibitor Vioxx.5 Di-
phenyl sulfone is used as an intermediate for the synthesis
of 4,4′-diamino-diphenyl sulfone (DAPSONE), which is
effective for leprosy treatment.6 Recently, diaryl sulfones
have been shown to inhibit HIV-1 reverse transcriptase and
represent an emerging class of substances able to address
the toxicity and resistance problems of nucleoside inhibitors.7
Sulfones are generally prepared by oxidation of the
corresponding sulfides and sulfoxides or by a displacement
* Fax: 0091-2462-229245.
(1) Jensen F. R.; Goldman G. In Friedel-Crafts and Related Reactions;
Olah, G., Ed.; Wiley-Interscience: New York, 1964; Vol. III, pp 1319-
1367. (b) Simpkins, N. S. Sulfones in Organic Synthesis; Pergamon Press:
Oxford, 1993; and references therein.
(2) Fumino H.; Mitsuru, K. JP Patent 61271271, 1986; Chem. Abstr.
1986, 106, 61271271. Keiichi, S.; Toru, O.; Aki, S. JP Patent 04120050,
1992; Chem. Abstr. 1992, 117, 150703. Toshiaki, T.; Takeshi Y. JP Patent
2001260544, 2001; Chem. Abstr. 2001, 135, 264604.
(3) For some recent references, see for example: (a) Yoshihara, S.-i.;
Tatsumi, K. Drug Metab. Dispos. 1990, 18, 876. (b) Sato, H.; Clark, D. P.
Microbios 1995, 83, 145. Jones, T. R.; Webber, S. E.; Varney, M. D.; Reddy,
M. R.; Lewis, K. K.; Kathardekar, V.; Mazdiyasni, H.; Deal, J.; Nguyen,
D.; Welsh, K. M.; Webber, S.; Johnson, A.; Matthews, D. A.; Smith, W.
W.; Janson, C. A. Bacquet, R. J.; Howland, E. F.; Booth, C. L. J.; Ward,
R. W.; Herrmann, S. M.; White, J.; Bartlett, C. A.; Morse, C. A. J. Med.
Chem. 1997, 40, 677. (c) Caron, G.; Gaillard, P.; Carrut, P. A.; Testa, B.
HelV. Chim. Acta 1997, 80, 449. (d) Seydel, J. K.; Burger, H.; Saxena, A.
K.; Coleman, M. D.; Smith, S. N.; Perris, A. D. Quant. Struct.-Act. Relat.
1999, 18, 43. (e) Dinsmore, C. J.; Williams, T. M.; O’Neil, T. J.; Liu, D.;
Rands, E.; Culberson, J. C.; Lobell, R. B.; Koblan, K. S., Kohl, N. E.;
Gibbs, J. B.; Oliff, A. J.; Graham, S. L.; Hartman, G. D. Bioorg. Med.
Chem. Lett. 1999, 9, 3301. (f) Sun, Z. Y.; Botros, E.; Su, A. D.; Kim, Y.;
Wang, E.; Baturay, N. Z.; Kwon, C. H. J. Med. Chem. 2000, 43, 4160.
(4) Roy, K. M. In Ullmann’s Encyclopedia of Industrial Chemistry;
Gerhartz, W., Ed.; VCH: Weinheim, 1985; Vol. A 25, pp 487-501 and
references therein.
(5) Prasit, P.; Wang, Z.; Brideau, C.; Chem, C. C.; Charleson, S.;
Cromlish, W.; Ethier, D.; Evans, J. F.; Ford-Hutchinson, A. W.; Gauthier,
J. Y.; Gordon, R.; Guay, J.; Gresser, M.; Kargman, S.; Kennedy, B.; Leblanc,
Y.; Leger, S.; Mancini, J.; O’Neill, G. P.; Ouellet, M.; Percival, M. D.;
Perrier, H.; Riendeau, D.; Rodger, I.; Tagari, P.; Therien, M.; Vickers P.;
Wang, E.; Xu L.-J.; Young, R.-N.; Iamboni, R. Biorg. Med. Chem. Lett.
1999, 9, 1773.
(6) Repichet, S.; Le Roux, C.; Dubac, J. J. Org. Chem. 1999, 64, 6429.
(7) (a) McMahon, J. B.; Gulakowsky, R. J.; Welslow, O. S.; Schoktz,
R. J.; Narayanan, V. L.; Clanton, D. J.; Pedemonte, R.; Wassmundt, F. W.;
Buckheit, R. W., Jr.; Decker, W. D.; White E. L.; Bader, J. P.; Boyed, M.
R. Antimicrob. Agents Chemother. 1993, 37, 754. (b) Williams, T. M.;
Ciccarone, T. M.; MacTough, S. C.; Rooney, C. S.; Balani, S. K.; Condra,
J. H.; Emini, E. A.; Goldman, M. E.; Greenlee, W. J.; Kauffman, L. R.;
O’Brien, J. A.; Sardana, V. V.; Schleif, W. A.; Theoharides, A. D.;
Anderson, P. S. J. Med. Chem. 1993, 36, 1291. (c) Neamati, N.; Mazumdar,
A.; Zhao, H.; Sunder, S.; Burke, Terrence, R., Jr.; Schultz, R. J.; Pommier,
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10.1021/ol049692c CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/27/2004

reaction of sodium arenesulfinate with an appropriate alkyl
halide.8 The electrophilic aromatic substitution of arenes with
arenesulfonic acids in the presence of strong acids9 or with
arenesulfonyl halides10 and the reaction of organomagnesium
halides11 or organolithium compounds12 with sulfonate esters
are known procedures for their preparation. Some metal
halides,1a zeolites,13 Bronsted acids,14 bismuth triflate,15
indium triflate,16 and Fe(III)-exchanged montmorillonite
clay17 have been successfully used for catalytic sulfonylation
of arenes. Lithium perchlorate18 and sodium perchlorate19
have been used as efficient catalysts under neutral conditions.
More recently, sulfones were prepared from sulfinic acid salts
and aryl iodides using copper20 and palladium catalysts.21
Each of the above methods has its own merit, while some
of these methods are plagued by limitations. Most of the
methods require drastic conditions. The electrophilic ap-
proach required strong protic or Lewis acids and suffers from
the formation of mixtures of isomeric products and inef-
ficiency with arenes bearing strongly electron-withdrawing
substituents. The application of organometallic reagents does
not tolerate the presence of many functional groups elsewhere
in the molecule. The well-known Suzuki reaction22 of aryl
iodides with an aryl sulfinate required more than stoichio-
metric amounts of copper iodide (1.5 equiv) and arene
sulfinate (1.6 equiv) in DMF at 110 °C. However, the use
of an excess amount of copper complicates the workup of
large-scale reactions. The recently developed copper-
catalyzed method20 for the coupling of aryl iodides and
sulfinic acid salts required high temperatures (110 °C) and
a longer reaction time (20 h) and afforded poor yields for
heterocyclic substrates. The palladium-catalyzed coupling
required not only drastic conditions but also addition of
In this communication, we report that diaryl sulfones are
prepared using palladium-catalyzed coupling of aryl boronic
acids with arylsulfonyl chlorides under mild conditions
(Scheme 1).
Scheme 1
The catalytic activity of the PdCl2 was investigated with
respect to the loadings. After many studies on coupling
reaction, we found that when less than 1.6 mol % PdCl2 was
applied, it resulted in no reaction or in low yield of the
corresponding product (Table 1, entries 2-5), whereas use
Table 1. Catalytic Effect of PdCl2 in the Coupling Reaction of
Phenyl Boronic Acid (1 mmol) with p-Toluenesulfonyl Chloride
(1 mmol) at 25 °C
entry
PdCl2 (mol %)
reaction time (min)
yield (%)
1
2
3
4
5
6
7
8
0
960
30
30
30
30
30
30
30
0
0
0
55
68
98
98
97
0.6
0.8
1.1
1.4
1.6
2.3
2.8
n
xantphos and Bu4NnCl,21 and the presence of substituents
close to the C-I bond was found to hamper the reaction.21
Consequently, there is an opportunity for further development
toward mild conditions, increased variation of the substituents
in the components, and better yields.
of more than 1.6 mol % did not improve the yield (Table 1,
entries 7, 8). When attempts were made to carry out coupling
reaction in the absence of catalyst (PdCl2), it resulted in
almost quantitative recovery of the substrate (Table 1,
entry1). A wide variety of electronically and structurally
diverse aryl boronic acids and aryl sulfonyl chlorides can
be cross-coupled efficiently under mild reaction conditions23
(Tables 2 and 3). The palladium-catalyzed coupling of aryl
boronic acids with aryl sulfonyl chlorides was found to be
an extremely efficient route for the synthesis of unsym-
metrical diaryl sulfones. Various substituted aryl boronic
(8) Block, E. In The Chemistry of Functional Groups; Patai, S., Ed.;
Wiley: New York, 1980; Suppl. E, Part 1, Chapter 13.
(9) (a) Graybill, B. M. J. Org. Chem. 1967, 32, 2931, (b) Ueda, M.;
Uchiyama, K.; Kano, T. Synthesis 1984, 323.
(10) (a) Truce, W. E.; Klinger, T. C.; Brand, W. W. In Organic Chemistry
of Sulfur; Oae, S., Ed.; Plenum Press: New York, 1977. (b) Nara, S. J.;
Harjani, J. R.; Salunkhe, M. M. J. Org. Chem. 2001, 66, 8666. (c) Frost,
C. G.; Hartley, J. P.; Whittle, A. J. Synlett 2001, 830. (d) Bandgar B. P.;
Kasture, S. P. Synth. Commun. 2001, 31, 1065.
(11) Gilman, H.; Beayer, N. J.; Meyers, C. H. J. Am. Chem. Soc. 1925,
47, 2047.
(12) Baarschers, W. H. Can. J. Chem. 1976, 54, 3056.
(13) Smeek J.; Fowler, J. S. J. Org. Chem. 1968, 33, 3422.
(14) Smith, K.; Ewart, G. M.; Randles, K. R. J. Chem. Soc., Perkin Trans.
1 1997, 9, 1085.
(15) Repichet, S.; LeRoux, C.; Dubac, J. J. Org. Chem. 1999, 64, 6479.
(16) Frost, C. G.; Hartley, J. P.; Whittle, A. J. Synlett 2001, 6, 830.
(17) Choudary, B. M.; Chowdary, N. S.; Kantam, M. L.; Kannan, R.
Tetrahedron Lett. 1999, 40, 2859.
(18) Bandgar, B. P.; Kamble, V. T.; Sadavarte, V. S.; Uppalla, L. S.
Synlett 2002, 5, 735.
(19) Bandgar, B. P.; Kamble V. T.; Fulse, D. B.; Deshmukh, M. V. New
J. Chem. 2002, 26, 1105.
(20) Baskin, J. M.; Wang, Z. Org. Lett. 2002, 4, 4423.
(21) Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Parisi, L. M. Org. Lett.
2002, 4, 4719.
(22) (a) Suzuki, H.; Abe, H. Tetrahedron Lett. 1995, 36, 6239. (b) Ulman,
A.; Urankar, E. J. Org. Chem. 1989, 54, 4691.
(23) Typical Procedure. To a mixture of benzene boronic acid (121
mg, 1 mmol), p-toluene-sulfonyl chloride (190 mg, 1 mmol), and K2CO3
(276 mg, 2 mmol) in acetone/water (3:1, 10 mL) at 0 °C was added
palladium chloride (3 mg, 0.016 mmol), and stirring was continued at room
temperature under a N2 atmosphere. The reaction was monitored by TLC.
After completion of the reaction after 30 min, the solvent was removed
under reduced pressure. Distilled water (10 mL) was added to the reaction
mixture, and the product was extracted with petroleum ether (40-60 °C)
and washed with water (2 × 10 mL). The removal of the solvent under
reduced pressure yielded the product, which was found to be pure with no
need for further purification. Phenyl p-tolyl sulfone: mp 120-121 °C (lit.12
1
119-122); IR (KBr) 1091, 1340, 1596, 2922, 3092 cm-1; H NMR (300
MHz, CDCl3) δ 2.5 (s, 3 H, Ar-CH3), 6.95 (d, 2 H, J ) 8.7 Hz, Ar-H),
7.4-7.43 (m, 5 H, Ar-H), 7.47 (d, 2 H, J ) 8.7 Hz, Ar-H); 13C NMR
(75 MHz, CDCl3) δ 21.5, 127.2, 127.5, 129.7, 129.9, 132.8, 138.5, 141.5,
143.7. Anal. Calcd for C13H12O2S: C, 61.21; H, 5.21; S, 13.80. Found: C,
61.11; H, 5.26; S, 13.69.
2106
Org. Lett., Vol. 6, No. 13, 2004

Table 2. Palladium-Catalyzed Synthesis of Diaryl Sulfones from Aryl Boronic Acids and Aryl Sulfonyl Chlorides at 25 °C
acids were subjected to coupling with arylsulfonyl chlorides,
and the results are presented in Table 2. When boronic acids
with electron-donating substituents were subjected to the
coupling, the rate of the coupling process was increased
(Table 2, entries 2, 3, 5, 6) as compared to unsubstituted
aryl boronic acids (Table 2, entries 4, 6). It is important to
mention that, in general, the time required for coupling in
the present method is short as compared to the reported
methods. It is worth mentioning that only cross-coupled
products were obtained and that self-coupling of boronic
acids or formation of diarylsulfide was not observed even
in trace amounts under these reaction conditions, which
demonstrates the superiority of this method over the existing
methods.24,25
atmosphere. When attempts were made to carry out reactions
in the absence of the nitrogen atmosphere, the cross-coupling
reactions did not proceed even after the reaction mixture was
stirred for a longer period of time (16 h). However, the
reaction mixture became black in color.
More recently, Dabbaka and Vogel reported palladium-
catalyzed Suzuki-Miyaura cross-couplings of sulfonyl chlo-
rides and boronic acids25 as well as palladium-catalyzed Stille
It is important to note that the coupling proceeds smoothly
in the absence of ligand. The present procedure worked very
well in the case of ortho-substituted boronic acids as well
as heterocyclic boronic acids, resulting in excellent yields
of products in a short reaction time (Table 3). Mild reaction
conditions and short reaction times in an acetone-water
cosolvent system are important advantages of this method
over the reported ones. When acetone or water alone was
used as a solvent, there was no reaction, even after stirring
the reaction mixture for a longer time (16 h). All cross-
coupling reactions have been carried out under a nitrogen
Figure 1.
Org. Lett., Vol. 6, No. 13, 2004
2107

Table 3. Palladium-Catalyzed Coupling of Ortho-Substituted Aryl Boronic Acids, Heteroaryl Boronic Acids, and Aryl Sufonyl
Chlorides at 25 °C
cross-coupling of sulfonyl chlorides and organostannanes26
at high temperatures and using long reaction times. However,
the results were very interesting and contrast the results
presented here. Vogel described both Stille and Suzuki-type
cross-couplings of boronic acids with sulfonyl chlorides, but
the products were biaryls after extrusion of SO2. However,
the present results demonstrate simple cross-couplings
without extrusion of SO2. Desulfitative coupling required
higher temperatures than the simple coupling. After pal-
ladium insertion into the SO2-Cl bond, if conditions are not
adapted for a competitive desulfitation, the sulfur can be
retained in the Suzuki coupling. The present procedure
involved mild reaction conditions (0-25 °C) as compared
to procedure applied by Vogel (110 °C).25 A probable
catalytic cycle for Suzuki-Miyaura cross-couplings of
boronic acids and sulfonyl chlorides to prepare diaryl
sulfones is given in Figure 1. Work is in progress in our
laboratory to develop mild procedures for various Suzuki-
Miyaura cross-couplings.
Supporting Information Available: Experimental pro-
cedures, characterization of unknown compounds, and refer-
ences to known procedures and known physical constants
of products. This material is available free of charge via the
Internet at http://pubs.acs.org.
(24) Manas, M. M.; Perez, M.; Pleixats, R. J. Org. Chem. 1996, 61,
2346.
(25) Dabbaka, S. R.; Vogel, P. Org. Lett. 2004, 6, 95.
(26) Dabbaka, S. R.; Vogel, P. J. Am. Chem. Soc. 2003, 125, 15292.
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