Unsymmetrical Diaryl Sulfones through Palladium-Catalyzed Coupling of Aryl Iodides and Arenesulfinates

Article abstract of DOI:10.1021/ol0271887

(Equation Presented) The palladium-catalyzed coupling of aryl iodides and arenesulfinates provides a simple and extremely efficient new route to unsymmetrical diaryl sulfones, usually isolated in high yield. The reaction tolerates a variety of functionalized aryl iodides, including those containing ether, ester, and nitro groups. The best results have been obtained by using Pd₂(dba)₃, Xantphos, Cs₂CO₃, and ⁿBu₄NCl in toluene at 80 °C.

Full text of DOI:10.1021/ol0271887

ORGANIC
LETTERS
2002
Vol. 4, No. 26
4719-4721
Unsymmetrical Diaryl Sulfones through
Palladium-Catalyzed Coupling of Aryl
Iodides and Arenesulfinates
Sandro Cacchi,* Giancarlo Fabrizi, Antonella Goggiamani, and Luca M. Parisi
Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente AttiVe,
UniVersita` degli Studi “La Sapienza”, P. le A. Moro 5, 00185 Rome, Italy
sandro.cacchi@uniroma1.it
Received October 28, 2002
ABSTRACT
The palladium-catalyzed coupling of aryl iodides and arenesulfinates provides a simple and extremely efficient new route to unsymmetrical
diaryl sulfones, usually isolated in high yield. The reaction tolerates a variety of functionalized aryl iodides, including those containing ether,
ester, and nitro groups. The best results have been obtained by using Pd2(dba)3, Xantphos, Cs2CO , and nBu4NCl in toluene at 80 °C.
3
Because of their chemical properties1 and biological activi-
ties,2 diaryl sulfones are important synthetic targets. Recently,
diaryl sulfones have been shown to inhibit the HIV-1 reverse
transcriptase and represent an emerging class of substances
able to address the toxicity and resistance problems of
nucleoside inhibitors.3
Known procedures for their preparation are based on the
oxidation of the corresponding sulfides,4 the electrophilic
aromatic substitution of arenes with arenesulfonic acids in
the presence of strong acids5 or with arenesulfonyl halides,6
and the reaction of organomagnesium halides7 or organo-
lithium compounds8 with sulfonate esters. All these proce-
dures have their own drawbacks: the oxidation process is
limited by the availability of sulfides; the electrophilic
approach suffers from the formation of mixtures of isomeric
products and inefficiency with arenes bearing strongly
electron-withdrawing substituents, and employment of or-
ganometallic reagents does not tolerate many functionalities.
Recently, a copper-mediated displacement reaction of non-
activated aryl iodides with arenesulfinates has been de-
scribed.9 However, an excess of copper iodide is required.
Improved methods for the preparation of diaryl sulfones is
therefore highly desirable.
(1) H. Fumio; 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.
(2) 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.; Carrupt, 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, Theresa M.; O’Neill, T. J.;
Liu, D.; Rands, E.; Culberson, J. C.; Lobell, R. B.; Koblan, K. S.; Kohl, N.
E.; Gibbs, J. B.; Oliff, A. I.; 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.
(3) (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.; Boyd, 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’Bnen, J. A.; Sardana, V. V.; Schleif, W. A.; Theoharides, A. D.;
Anderson, P. S. J. Med. Chem. 1993, 36, 1291. (c) Neamati, N.; Mazumder,
A.; Zhao, H.; Sunder, S.; Burke, Terrence, R., Jr.; Schultz, R. J.; Pommier,
Y. Antimicrob. Agents Chemother. 1997, 41, 385.
(4) Schank, K. In The Chemistry of Sulfones and Sulfoxides; Patai, S.,
Rappoport, Z., Stirling, C. J. M., Eds.; Wiley: New York 1988; Chapter 7.
(5) (a) Graybill, B. M. J. Org. Chem. 1967, 32, 2931. (b) Ueda, M.;
Uchiyama. K.; Kano, T. Synthesis 1984, 323.
(6) (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, 8616. (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.
(7) Gilman, H.; Beaver, N. J.; Meyers, C. H. J. Am. Chem. Soc. 1925,
47, 2047.
(8) Baarschers, W. H. Can. J. Chem. 1976, 54, 3056.
(9) Suzuki, H.; Abe, H. Tetrahedron Lett. 1995, 36, 6239.
10.1021/ol0271887 CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/06/2002

Here we report that aryl iodides form diaryl sulfones
through a novel palladium-catalyzed reaction employing a
straightforward procedure (Scheme 1).
Table 1. Bases and Salts in the Reaction of p-Iodoanisole and
Sodium p-Toluenesulfinate 1 in the Presence of Pd2(dba)3 and
Xantphos to Give p-Methoxyphenyl Tolyl Sulfone.a
T
time
(h)
yield
(%)b
entry Xantphos
Cs2CO3
Cs2CO3
salt
(°C)
Scheme 1
1
2
3
4
5
6
7
8
9
+
+
+
-
-
+
+
+
+
+
80
80
80
80
80
80
80
80
40
60
8
24
1
36
48
6
70
49
90c
nBu4NCl
nBu4NCl
Cs2CO3
Cs2CO3
K2CO3
Rb2CO3 nBu4NCl
Cs2CO3
Cs2CO3
Cs2CO3
nBu4NCl
58
76
31
80
81
6
LiCl
nBu4NCl
nBu4NCl
48
24
4
Direct palladium-catalyzed replacement of the aryl C-I
bond by a C-SO2 bond is, to our knowledge, unprecedented.
This is in sharp contrast to analogous processes involving
the substitution of the aryl C-I bond with an aryl C-het-
10
a Reactions were conducted on a 0.350 mmol scale in starting aryl iodides
in toluene (2 mL) under argon using the following molar ratio: 1:p-
iodoanisole:Pd2(dba)3:Xantphos:base:nBu4NCl or LiCl (when added) ) 1.2:
1:0.025:0.05:1.5:1.2. b Yields are given for isolated products. c p-Methoxy-
phenyl tolyl sulfone was isolated in 81% yield (6 h) by using lithium
p-toluenesulfinate.
11c,12
eroatom bond such as C-N,10 C-PR2,11 C-PO(OR)2
and C-SR13 bonds, which have been used extensively in
organic synthesis. We discovered that the palladium-
catalyzed coupling of aryl iodides and arenesulfinates
provides an extremely efficient route to unsymmetrical diaryl
sulfones.
product form in satisfactory yield within 8 h (Table 1, entry
1). The yield increased to 90% in 1 h by adding 1.2 equiv
of nBu4NCl (Table 1, entry 3). Lower reaction rate and yield
were observed with K2CO3 (Table 1, entry 6) and Rb2CO3
Initial attempts focused on exploring the feasibility of the
transformation. p-Iodoanisole and the commercially available
sodium p-toluenesulfinate were used as the model system.
Reactions were carried out using Pd2(dba)3 as the precatalyst,
K2CO3, Rb2CO3, or Cs2CO3 as the bases, and a variety of
phosphine and carbene ligands at temperatures ranging from
40 to 80 °C. However, no sulfone product was formed with
PPh3, (o-tol)3P, (2-furyl)3P, (p-MeO-C6H4)3P, [2,4,6-(MeO)3-
C6H2]3P, (p-Cl-C6H4)3P, BINAP, MOP, dppp, dppb, and
1,3-bis-(2,4,6-trimethylphenyl)imidazolium chloride.14
Only after switching to Xantphos [9,9-dimethyl-4,6-bis-
(diphenylphosphino)xanthene]15 did the desired sulfone
n
(Table 1, entry 7) or upon substituting LiCl for Bu4NCl
(Table 1, entry 8). Use of more polar solvents such as
DMSO, DMF, and DME proved to be unsuccessful. In DMF,
formation of small amounts of toluenesulfinic acid 4-meth-
oxyphenyl ester (derived from the competing O-arylation
process) was observed.
Under the best conditions developed so far [Pd2(dba)3,
Xantphos, Cs2CO3, nBu4NCl, toluene, 80 °C],16 the reaction
proceeds very smoothly and, as shown in Table 2, appears
to tolerate a variety of functional groups in the aryl iodides,
including ether, ester, and nitro groups. Unsymmetrical diaryl
sulfones were isolated usually in high yields with many
neutral, electron-rich, and electron-poor aryl iodides. Only
p-iodoacetophenone, among the substrates that we have
investigated, produced a complex reaction mixture (most
probably as a result of ketone arylation processes)17 that we
have not further investigated. The presence of substituents
(10) For some reviews, see: (a) Hartwig, J. F. Synlett 1997, 329. (b)
Baranano, D.; Mann, G.; Hartwig, J. F. Curr. Org. Chem. 1997, 1, 287. (c)
Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852. (d) Wolfe, J. P.; Wagaw, S.;
Marcoux, J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805. (e) Hartwig,
J. F. Angew. Chem., Int. Ed. 1998, 37, 2046. (f) Hartwig, J. F. Pure Appl.
Chem. 1999, 71, 1417. (g) Yang, B. H.; Buchwald, S. L. J. Organomet.
Chem. 1999, 576, 125.
(11) (a) Herd, O.; Hessler, A.; Hingst, M.; Tepper, M.; Stelzer, O. J.
Organomet. Chem. 1996, 522, 69. (b) Herd, O.; Hessler, A.; Hingst, M.;
Machnitzki, P.; Tepper, M.; Stelzer, O. Catal. Today 1998, 42, 413. (c)
Machnitzki, P.; Nickel, T.; Stelzer, O.; Landgrafe, C. Eur. J. Inorg. Chem.
1998, 1029. (d) Kraatz, H.-B.; Pletsch, A. Tetrahedron: Asymmetry 2000,
11, 1617. (e) Machnitzki, P.; Tepper, M.; Wenz, K.; Stelzer, O.; Herdtweck,
E. J. Organomet. Chem. 2000, 602, 158. (f) Hessler, A.; Kottsieper, K.
W.; Schenk, S.; Tepper, M.; Stelzer, O. Z. Naturforsch. B 2001, 56, 347.
(g) Brauer, D. J.; Hingst, M.; Kottsieper, K. W.; Liek, C.; Nickel, T.; Tepper,
M.; Stelzer, O.; Sheldrick, W. S. J. Organomet. Chem. 2002, 645, 14.
(12) (a) Hirao, T.; Masunaga, T.; Ohshiro, Y.; Agawa, O. Synthesis 1981,
56. (b) Xu, Y.; Zhang, J. J. Chem. Soc., Chem. Commun. 1986, 1606. (c)
Casalnuovo, A. L.; Calabrese, J. C. J. Am. Chem. Soc. 1990, 112, 4324.
(13) (a) Harayama, H.; Nagahama, T.; Kozera, T.; Kimura, M.; Fugami,
K.; Tanaka, S.; Tamaru, Y. Bull. Chem. Soc. Jpn. 1997, 70, 445. (b) Kato,
K.; Ono, M.; Akita, H. Tetrahedron Lett. 1997, 38, 1805. (c) Shopfer, U.;
Schlapbach, A. Tetrahedron 2001, 57, 3069. (d) Menger, F. M.; Azov, V.
A. J. Am. Chem. Soc. 2002, 124, 11159.
(16) Typical Procedure for the Preparation of Unsymmetrical Diaryl
Sulfones. In a Carousel Tube Reaction (Radley Discovery), to a solution
of sodium p-toluenesulfinate (0.075 g, 0.420 mmol) and p-iodoanisole (0.082
g, 0.350 mmol) in 2.0 mL of toluene under argon were added Pd2(dba)3
(0.008 g, 0.009 mmol), Xantphos (0.010 g, 0.018 mmol), Cs2CO3 (0.171
g, 0.525 mmol), and nBu4NCl (0.117 g, 0.420 mmol). The mixture was
warmed at 80 °C and stirred for 1 h. After cooling, the reaction mixture
was diluted with ethyl acetate, washed with water, dried over Na2SO4, and
concentrated under reduced pressure. The reaction mixture was purified by
chromatography (silica gel, 35 g; 80/20 v/v n-hexane/ethyl acetate) to give
0.0825 g of p-methoxyphenyl p-tolyl sulfone (90% yield): mp 103-4 °C;
IR (KBr) 2925, 1320, 1152; 1H NMR (CDCl3) δ 7.57-7.44 (m, 4H), 7.25
(d, J ) 8.9 Hz, 2H), 6.98 (d, J ) 8.8 Hz, 2H); 3.86 (s, 3H); 2.40 (s, 3H);
13C NMR (CDCl3) δ 159.0, 138.1, 136.4, 133.8, 129.5, 128.0, 126.7, 114.2,
55.4, 21.1. Anal. Calcd for C14H14O3S: C, 64.10; H, 5.38. Found: C, 64.01;
H, 5.36.
(14) 1,3-Bis-(2,4,6-trimethylphenyl)imidazolium chloride has been shown
to generate in situ, in the presence of Cs2CO3 as the base, the corresponding
carbene ligand: Zhang, C.; Huang, J.; Trudell, M. L.; Nolan, S. P. J. Org.
Chem. 1999, 64, 3804.
(15) Kranenburg, M.; van der Burgt, Y. E. M.; Kramer, P. C. J.; van
Leeuwen, P. W. N. M.; Goubitz, K.; Fraanje, J. Organometallics 1995, 14,
3081.
(17) (a) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem.
Soc. 2000, 122, 1360. (b) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc.
1999, 121, 1473. (c) Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Zappia, G.
Org. Lett. 2001, 3, 2539.
4720
Org. Lett., Vol. 4, No. 26, 2002

Scheme 2
Table 2. Palladium-Catalyzed Synthesis of Diaryl Sulfones
from Aryl Iodides 2 and Sodium p-Toluenesulfinate 1
time
(h)
diaryl sulfone
entry
Ar1I 2
3 yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
p-MeO-C6H4-I
m-MeO-C6H4-I
o-MeO-C6H4-I
p-Me-C6H4-I
m-Me-C6H4-I
o-Me-C6H4-I
3,5-Me2-C6H3-I
PhI
p-F-C6H4-I
m-F-C6H4-I
o-F-C6H4-I
p-Cl-C6H4-I
m-CF3-C6H4-I
p-Br-C6H4-I
p-EtO2C-C6H4-I
p-O2N-C6H4-I
1
1
24
6
1
24
1
1
1
5
24
3
90
88
96
93
85
90
89
90
In conclusion, we have developed an efficient and
straightforward procedure for the preparation of unsym-
metrical diaryl sulfones. The methodology can tolerate many
important functional groups, and diaryl sulfones are usually
isolated in high yield. Further work is in progress along this
line.
81
46
67
65
72
24
1
6
Acknowledgment. Work carried out in the framework
of the National Project “Stereoselezione in Sintesi Organica.
Metodologie ed Applicazioni” was supported by the Min-
istero dell’Universita` e della Ricerca Scientifica e Tecno-
logica, Rome. The authors are also greatly indebted to the
University “La Sapienza” for financial support of this
research.
1
a Reactions were conducted on a 0.350 mmol scale in starting aryl iodides
in toluene (2 mL) at 80 °C under argon using the following molar ratio:
1:2:Pd2(dba)3:Xantphos:Cs2CO3:nBu4NCl ) 1.2:1:0.025:0.05:1.5:1.2. b Yields
are given for isolated products.
close to the C-I bond was found to hamper the reaction
Supporting Information Available: Experiments con-
ducted to evaluate the influence of ligands and solvents on
the reaction outcome, typical experimental procedure for the
preparation of unsymmetrical diaryl sulfones, and charac-
terization data for all compounds listed in Table 2. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(Table 2, entries 3, 6, and 11).
A possible rationale for the presented synthesis of diaryl
sulfones involves the following basic steps (the ligand has
been omitted for clarity): (a) oxidative addition of aryl iodide
to Pd(0), (b) nucleophilic displacement of iodide to give an
arylsulfonylpalladium intermediate, and (c) reductive elimi-
nation of a Pd(0) species to give the sulfone product (Scheme
2).
OL0271887
Org. Lett., Vol. 4, No. 26, 2002
4721