Unsymmetrical diaryl sulfones and aryl vinyl sulfones through palladium-catalyzed coupling of aryl and vinyl halides or triflates with sulfinic acid salts

Article abstract of DOI:10.1021/jo0493469

The palladium-catalyzed reaction of sulfinic acid salts with a wide variety of aryl and vinyl halides or triflates provides unsymmetrical diaryl sulfones and aryl vinyl sulfones in good to excellent yields. The reaction is strongly influenced by the presence of ⁿBu₄NCl, and the use of Xantphos, a rigid bidentate ligand with a wide natural bite angle, was found to be crucial for the success of the reaction. With neutral, electron-rich, and electron-poor aryl iodides best results were obtained by using Pd ₂(dba)₃, Xantphos, Cs₂CO₃, and ⁿBu₄NCl, in toluene at 80 °C. Two general procedures were employed with aryl bromides and triflates: sodium p-toluenesulfinate, Pd₂(dba)₃, Xantphos, Cs₂CO₃, 120 °C, in toluene with ⁿBu₄NCl (procedure A: neutral, electron-rich, and slightly electron-poor aryl bromides or triflates) and without ⁿBu₄NCl (procedure B: electron-poor aryl bromides or triflates). With vinyl triflates best results were obtained at 60 °C omitting ⁿBu₄NCl.

Full text of DOI:10.1021/jo0493469

Un sym m etr ica l Dia r yl Su lfon es a n d Ar yl Vin yl Su lfon es th r ou gh
P a lla d iu m -Ca ta lyzed Cou p lin g of Ar yl a n d Vin yl Ha lid es or
Tr ifla tes w ith Su lfin ic Acid Sa lts
Sandro Cacchi,*,† Giancarlo Fabrizi,† Antonella Goggiamani,† Luca M. Parisi,† and
Roberta Bernini‡
Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive, Universita` degli
Studi “La Sapienza”, P. le A. Moro 5, 00185 Rome, Italy, and Dipartimento A.B.A.C., Universita` degli
Studi della Tuscia, Via S. Camillo De Lellis, 01100 Viterbo, Italy
sandro.cacchi@uniroma1.it
Received April 19, 2004
The palladium-catalyzed reaction of sulfinic acid salts with a wide variety of aryl and vinyl halides
or triflates provides unsymmetrical diaryl sulfones and aryl vinyl sulfones in good to excellent
yields. The reaction is strongly influenced by the presence of nBu4NCl, and the use of Xantphos, a
rigid bidentate ligand with a wide natural bite angle, was found to be crucial for the success of the
reaction. With neutral, electron-rich, and electron-poor aryl iodides best results were obtained by
n
using Pd2(dba)3, Xantphos, Cs2CO3, and Bu4NCl, in toluene at 80 °C. Two general procedures were
employed with aryl bromides and triflates: sodium p-toluenesulfinate, Pd2(dba)3, Xantphos, Cs2-
CO3, 120 °C, in toluene with nBu4NCl (procedure A: neutral, electron-rich, and slightly electron-
n
poor aryl bromides or triflates) and without Bu4NCl (procedure B: electron-poor aryl bromides or
n
triflates). With vinyl triflates best results were obtained at 60 °C omitting Bu4NCl.
In tr od u ction
HIV-1 reverse transcriptase and to represent an emerg-
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resistance problems of nucleoside inhibitors. They also
exhibit interesting chemical properties6 and are useful
intermediates in organic synthesis.7 Because of this,
diaryl sulfones are important synthetic targets, and
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compounds exhibiting important biological activities. For
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selective, and orally active cyclooxygenase-2 (COX-2)
inhibitors1 and to exhibit high antifungal and antibac-
terial activities.2 Diaryl sulfones have been shown to
possess antitumor activities.3 Recently, diaryl4 and aryl
heteroaryl5 sulfones have been shown to inhibit the
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† Universita` degli Studi “La Sapienza”.
‡ Universita` degli Studi della Tuscia.
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10.1021/jo0493469 CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/16/2004
5608
J . Org. Chem. 2004, 69, 5608-5614

Unsymmetrical Diaryl Sulfones and Diaryl Vinyl Sulfones
SCHEME 1
numerous procedures for their preparation have been
described, including the oxidation of the corresponding
sulfides,8 the sulfonylation of arenes,9,10 the reaction of
organomagnesium halides11 or organolithium compounds12
with sulfonate esters, and the copper-mediated displace-
ment reaction of nonactivated aryl iodides with arene-
sulfinates.13 All these procedures, however, have their
own drawbacks: the oxidation process is limited by the
availability of sulfides, the sulfonylation approach suffers
from the formation of mixtures of isomeric products and
inefficiency with arenes bearing strongly electron-
withdrawing substituents, the employment of organo-
metallic reagents does not tolerate many functionalities,
and the copper-mediated displacement uses an excess of
copper iodide complicating the workup in large scale
preparations. Recently, a copper-catalyzed procedure for
the coupling of sulfinate salts and aryl iodides has been
developed.14 However, it does not achieve full conversion
of aryl bromides and sulfone products are obtained in low
yields when aryl bromides are used. Improved methods
for the preparation of sulfone derivatives are therefore
highly desirable.
SCHEME 2
which have been used extensively in organic synthesis.
In attempting to extend the target scope of the Caryl
-
heteroatom bond-forming technology and to develop a
new more convenient synthesis of unsymmetrical sul-
fones, we observed and previously communicated16 that
the palladium-catalyzed coupling of aryl halides or tri-
flates and arenesulfinates can provide an extremely
efficient route to unsymmetrical diaryl sulfones (Scheme
1).
We wish at this time to report full details on this very
useful straightforward synthetic approach to this class
of compounds.
Direct palladium-catalyzed replacement of the Caryl-X
(X ) I, Br, OTf) bond by a Caryl-SO2 bond is, to our
knowledge, unprecedented. This is in sharp contrast to
analogous processes involving the substitution of the
Caryl-X bond with an Caryl-heteroatom bond15 such as
Caryl-N, Caryl-PR2, Caryl-PO(OR)2, and Caryl-SR bonds,
Resu lts a n d Discu ssion
(8) (a) Schank, K. In The Chemistry of Sulfones and Sulfoxides;
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R. S.; Reddy, J . S.; Kumar, R.; Kumar, P. J . Chem. Soc., Chem.
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Aldea, R.; Alper, H. J . Org. Chem. 1995, 60, 8365. (f) Bosch, E.; Kochi,
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(9) Electrophilic aromatic substitution of arenes with arenesulfonic
acids in the presence of strong acids: (a) Graybill, B. M. J . Org. Chem.
1967, 32, 2931. (b) Ueda, M.; Uchiyama. K.; Kano, T. Synthesis 1984,
323.
(10) Electrophilic aromatic substitution of arenes with arenesulfonyl
halides: (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.
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Marquie´, J .; Laporterie, A.; Dubac, J .; Roques, N.; Desmurs, J .-R. J .
Org. Chem. 2001, 66, 421.
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 (Scheme 2). Reactions were carried out
using Pd2(dba)3 as the precatalyst and the following
reaction variables were examined: the presence or
absence of phosphine or carbene ligands, the base, the
added salt, the solvent, and the reaction temperature.
All the reactions were conducted on a 0.35 mmol scale
in 2 mL of solvent under argon, using 1.2 equiv of sodium
p-toluenesulfinate, 0.025 equiv of Pd2(dba)3, 0.05 equiv
of bidentate ligand or 0.1 equiv of monodentate ligand,
n
1.5 equiv of base, and 1.2 equiv of Bu4NCl or lithium
chloride (when added). Some results from that study are
summarized in Table 1.
Essentially no sulfone product was formed after 6 h at
80 °C in a variety of solvents (DMSO, DMF, DME,
dioxane, toluene), adding or omitting nBu4NCl, in the
presence or absence of Cs2CO3, K2CO3, or Li2CO3, with a
variety of monodentate and bidentate phosphine ligands
such as PPh3, (o-tol)3P, (2-furyl)3P, (p-MeO-C6H4)3P (tmpp),
[2,4,6-(MeO)3-C6H2]3P (ttmpp), (p-Cl-C6H4)3P, BINAP
[2,2′-bis(diphenylphosphino)-1,1′-binaphthyl], MOP [2-(di-
phenylphosphino)-2′-methoxy-1,1′-binaphthyl], dppp [1,1′-
bis(diphenylphosphino)propane], dppb [1,1′-bis(diphen-
ylphosphino)butane], and with 1,3-bis(2,4,6-trimethylphen-
yl)imidazolium chloride, which has been shown to gener-
ate in situ, in the presence of Cs2CO3 as the base, the
corresponding carbene ligand.17
(11) Gilman, H.; Beaver, N. J .; Meyers, C. H. J . Am. Chem. Soc.
1925, 47, 2047.
(12) Baarschers, W. H. Can. J . Chem. 1976, 54, 3056.
(13) Suzuki, H.; Abe, H. Tetrahedron Lett. 1995, 36, 6239.
(14) Baskin, J . M.; Wang, Z. Org. Lett. 2002, 4, 4423.
(15) For a recent review on the palladium-catalyzed reaction of aryl
halides with soft nonorganometallic nucleophiles, see: (a) Prim, D.;
Campagne, J . M.; J oseph, D.; Andrioletti, B. Tetrahedron 2002, 58,
2041. For some recent references on the substitution of Caryl-halogen
bonds with Caryl-N bonds, see: (b) Yin, J .; Buchwald, S. L. J . Am.
Chem. Soc. 2002, 124, 6043. (c) Maes, B. U. W.; Loones, K. T. J .;
J onckers, T. H. M.; Lemiere, G. L. F.; Dommisse, R. A.; Haemers, A.
Synlett 2002, 1995. (d) Urgaonkar, S.; Nagarajan, M.; Verkade, J . G.
J . Org. Chem. 2003, 68, 452. (e) Ferreira, I. C. F. R.; Queiroz, M.-J . R.
P.; Kirsch, G. Tetrahedron 2003, 59, 3737. For some recent references
on the substitution of Caryl-halogen bonds with Caryl-PR2 bonds, see:
(f) 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. For recent references on the substitution of Caryl-halogen
bonds with Caryl-SR bonds, see: (g) Menger, F. M.; Azov, V. A. J . Am.
Chem. Soc. 2002, 124, 11159. (h) Brown, M. J .; Carter, P. S.; Fenwick,
A. E.; Fosberry, A. P.; Hamprecht, D. W.; Hibbs, M. J .; J arvest, R. L.;
Mensah, L.; Milner, P. H.; O’Hanlon, P. J .; Pope, A. J .; Richardson, C.
M.; West, A.; Witty, D. R. Bioorg. Med. Chem. Lett. 2002, 12, 3171.
(16) (a) Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Parisi, L. M. Org.
Lett. 2002, 4, 4719. (b) Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Parisi,
L. M. Synlett 2003, 361.
(17) Zhang, C.; Huang, J .; Trudell, M. L.; Nolan, S. P. J . Org. Chem.
1999, 64, 3804.
J . Org. Chem, Vol. 69, No. 17, 2004 5609

Cacchi et al.
TABLE 1. Ba ses, Ad d itives, a n d Solven ts in th e
Rea ction of p-Iod oa n isole w ith Sod iu m
as dioxane and DME proved less satisfactory whereas
in DMSO and DMF yields were very low. In DMF,
formation of small amounts of the ester 4a (X ) p-OMe),
generated through the competitive O-arylation of the
ambident sulfinate anion, was also observed.
The use of Pd(OAc)2 (0.05 equiv) as the precatalyst was
also attempted and, in the presence of Xantphos, Cs2-
CO3, and nBu4NCl, in toluene at 80 °C, sulfone 3a was
isolated in a satisfactory 78% yield after 6 h. Interest-
ingly, employing Pd/C (5%) under the same conditions
afforded the desired sulfone in 69% yield after 20 h. Most
probably, the active species is a soluble Pd-Xantphos
complex which is formed via leaching of palladium into
solution.22 Accordingly, no sulfone product was observed
after 20 h when the same reaction was carried out
omitting Xantphos.
p-Tolu en esu lfin a te in th e P r esen ce of P d 2(d ba )3 a n d
Xa n tp h os To Give p-Meth oxyp h en yl Tolyl Su lfon e 3a a
yield % of
time p-methoxyphenyl
entry solvent
base
salt
(h)
tolyl sulfone 3a b
1
2
3
toluene
toluene Cs2CO3
toluene
nBu4NCl
24
8
24
36
48
1
6
6
6
6
49
70
c
4d
5d
6
toluene Cs2CO3
toluene
toluene Cs2CO3 nBu4NCl
90e
70
58
76
55
7
8
9
10
toluene Li2CO3
toluene K2CO3
nBu4NCl
nBu4NCl
toluene Rb2CO3 nBu4NCl
toluene AcOK
nBu4NCl
11
12
13
14
15
16
17
18
19
20
toluene Cs2CO3 LiCl
48
24
4
2
2
24
24
24
24
24
31
toluene Cs2CO3 nBu4NCl
toluene Cs2CO3 nBu4NCl
80f
81g
79
DME
Cs2CO3 nBu4NCl
dioxane Cs2CO3 nBu4NCl
81
DMSO
DMF
DMF
DMF
DMF
Cs2CO3 nBu4NCl
Cs2CO3 nBu4NCl
Cs2CO3
9h
22i
29j
20k
21l
As indicated in Table 2, a wide variety of neutral,
electron-rich, and electron-poor aryl iodides were con-
verted into the corresponding unsymmetrical diaryl
sulfones, usually in high yields, under the best conditions
developed so far [Pd2(dba)3, Xantphos, Cs2CO3, nBu4NCl,
toluene, 80 °C]. The reaction tolerates important func-
tional groups, amenable to further functionalization. For
example, the high I/Br selectivity observed with p-
bromoiodobenzene (Table 2, entry 14) allows a ready
access to amino derivatives23 as shown in Scheme 3. The
aryl-sulfonyl-phenyl-piperidine motif is present in com-
pounds prepared as â3 adrenergic receptor agonists.24
Only p-iodoacetophenone, among the substrates that we
have investigated, produced a complex reaction mixture
(most probably as the result of ketone arylation pro-
cesses)25 that we have not further investigated (Table 2,
Li2CO3
nBu4NCl
nBu4NCl
a
Unless otherwise stated, reactions were carried out on a 0.35
mmol scale, under argon, in 2 mL of solvent using 1 equiv of
p-iodoanisole, 1.2 equiv of sodium p-toluenesulfinate, 0.025 equiv
of Pd2(dba)3, 0.05 equiv of Xantphos, 1.5 equiv of base, and 1.2
b
equiv of nBu4NCl or LiCl (when added). Yields are given for
isolated products. c p-Iodoanisole was recovered in 83% yield. In
d
the absence of Xantphos. e 81% in 6 h, under the same conditions,
g
h
with toluenesulfinic acid lithium salt. f At 40 °C. At 60 °C. p-
i
Iodoanisole was recovered in 70% yield. p-Iodoanisole was re-
j
covered in 45% yield. The ester 4a was isolated in 9% yield. p-
Iodoanisole was recovered in 52% yield. The ester 4a was isolated
k
in 4% yield. p-Iodoanisole was recovered in 47% yield. The ester
l
4a was isolated in 5% yield. p-Iodoanisole was recovered in 47%
yield. The ester 4a was isolated in 3% yield.
Only after switching to Xantphos [9,9-dimethyl-4,6-bis-
(diphenylphosphino)xanthene],18 a rigid bidentate ligand
with a wide natural bite angle,19 did the desired sulfone
product, 3a , form in moderate yield within 24 h at 80 °C
in the presence of nBu4NCl (Table 1, entry 1). Compound
3a was isolated in 70% yield in 8 h in the presence of
(20) For the influence of halide additives on Pd(0)-catalyzed reac-
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S.; Fedeli, W.; Ortar, G. Tetrahedron 1989, 45, 813. (d) Larock, R. C.;
Leung, W.-Y.; Stolz-Dunn, S. Tetrahedron Lett. 1989, 30, 6629. (e)
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Kennelly, T.; Brungard, N. L.; Farrauto, R. J . Appl. Catal. 1991, 70,
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II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.; Pergamon: New
York, 1995; Vol. 12, pp 797, 904. (f) Widenhoefer, R. A.; Buchwald, S.
L. Organometalllcs 1996, 15, 2755. (g) Ba¨ckvall, J . E. In Metal-
Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J ., Eds.;
Wiley-VCH: Weinheim, 1998; pp 339-385.
n
Cs2CO3 omitting Bu4NCl (Table 1, entry 2), whereas no
sulfone product was observed omitting both Cs2CO3 and
nBu4NCl (Table 1, entry 3). The yield increased to 90%
n
in 1 h by adding both Cs2CO3 and Bu4NCl20,21 (Table 1,
entry 6). At lower temperatures, 40 and 60 °C, 3a is still
isolated in high yield, but longer reaction times are
required (Table 1, entries 12 and 13). From these studies,
at least with our model reaction, it appears that the best
base for this substitution reaction is Cs2CO3. Lower
reaction rate and/or yield were observed with Li2CO3
(Table 1, entry 7), K2CO3 (Table 1, entry 8), Rb2CO3
(Table 1, entry 9) and AcOK (Table 1, entry 10). The use
n
of Bu4NCl is clearly superior to LiCl (Table 1, compare
entry 6 with entry 11). Use of more polar solvents such
(18) 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. For recent reviews on the use of Xantphos ligands in
transition metal-catalyzed reactions, see: van Leeuwen, P. W. N. M.;
Kramer, P. C. J .; Reek, J . N. H.; Dierkes, P. Chem Rev. 2000, 100,
2741. Kramer, P. C. J .; van Leeuwen, P. W. N. M.; Reek, J . N. H. Acc.
Chem. Res. 2001, 34, 895.
(22) Nova´k, Z.; Szabo´, A.; Re´pa´si, J .; Kotschy, A. J . Org. Chem. 2003,
68, 3327.
(19) Casey, C. P.; Whiteker, G. T. Isr. J . Chem. 1990, 30, 299.
5610 J . Org. Chem., Vol. 69, No. 17, 2004

Unsymmetrical Diaryl Sulfones and Diaryl Vinyl Sulfones
TABLE 2. P a lla d iu m -Ca ta lyzed Syn th esis of Dia r yl
Su lfon es fr om Ar yl Iod id es 2 a n d Sod iu m
p-Tolu en esu lfin a te 1a
and industrial applications, was then attempted. Using
the reaction of sodium p-toluenesulfinate and 4-bromo
biphenyl as a model system, we were pleased to find that
the desired sulfone derivative 3o could be obtained in
87% isolated yield after 24 h under the same conditions
[Pd2(dba)3, Xantphos, Cs2CO3, nBu4NCl, in toluene],
increasing the temperature to 120 °C (Table 3, entry 2).
Even in this case the addition of nBu4NCl proved crucial
for the success of the reaction. Compound 3o was isolated
in only 18% yield when sodium p-toluenesulfinate and
4-bromobiphenyl were treated under the same conditions
omitting nBu4NCl (Table 3, entry 3; see also Table 4,
compare entries 3 and 5 with, respectively, entries 4 and
6).
diaryl sulfone 3
entry
aryl iodide 2
time (h)
yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
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-MeCO-C6H4-I
p-O2N-C6H4-I
1
1
24
6
1
24
1
1
1
5
24
3
24
1
6
7
1
90, a
88, b
96, c
93, d
85, e
90, f
89, g
90, h
81, i
46, j
67, k
65, l
When the procedure was extended to electron-poor aryl
bromides, a dramatic decrease in efficiency was observed.
In fact, subjecting m-nitrophenyl bromide to the same
conditions afforded the corresponding sulfone in only 20%
yield (Table 3, entry 6). In addition, the toluenesulfinic
acid ester 4t (X ) m-NO2) was isolated in 17% yield along
with n-butyl p-toluenesulfinate (15% yield), generated
through a nucleophilic substitution reaction involving
sodium p-toluenesulfinate and nBu4NCl. We then went
back and reexamined the influence on the reaction
outcome of some variables, such as ligands, the amounts
of sulfinate salts, and the added salts. Using other
bidentate phosphine ligands such as dppf [1,1′-bis-
(diphenylphosphino)ferrocene] only trace amounts of
sulfone were obtained and the yield of the ester 4t
increased to 43% (Table 3, entry 7). Increasing the
sulfinate salt to aryl bromide molar ratio produced only
a moderate increase of the yield (Table 3, entry 9) and
the employment of other ammonium salts did not provide
72, m
a
Reactions were conducted on a 0.35 mmol scale in starting
aryl iodides in toluene (2 mL) at 80 °C under argon using 1.2 equiv
of 1, 0.025 equiv of Pd2(dba)3, 0.05 equiv of Xantphos, 1.5 equiv of
b
Cs2CO3, and 1.2 equiv of nBu4NCl. Yields are given for isolated
products.
SCHEME 3
n
n
any beneficial effect. The use of both Bu4NBr and Bu4-
NI produced low yields of the sulfone derivative and
almost equimolar amounts of the sulfinic acid ester
(Table 3, entries 12 and 13). Surprisingly, the best result
in terms of yield and reaction time was obtained by
omitting the ammonium salt (Table 3, entry 14). None
of the sulfinic acid ester was observed under these
conditions and the sulfone derivative was isolated in 89%
yield. The negative effect of nBu4NCl on the reaction yield
observed with m-nitrophenyl bromide resulted to be quite
general with electron-poor aryl bromides and triflates.
A variety of aryl donors of this type afforded sulfone
products in low yields in the presence of nBu4NCl (Table
4, entries 19, 21, 27, 30, 32, and 35) or, in any case, lower
than without nBu4NCl (Table 4, entry 15).
Therefore, two general procedures were employed
when the reaction was extended to include other aryl
bromides and triflates:26 procedure A (with neutral,
electron-rich, and slightly electron-poor aryl bromides or
triflates)ssodium p-toluenesulfinate, Pd2(dba)3, Xant-
phos, Cs2CO3, nBu4NCl, 120 °C, toluene; procedure B
(with electron-poor aryl bromides or triflates)ssodium
p-toluenesulfinate, Pd2(dba)3, Xantphos, Cs2CO3, 120 °C,
toluene. Under these conditions, the reaction gives
unsymmetrical diaryl sulfones in good to high yields with
entry 16). Lowering the temperature to 60 °C resulted
in a substantial slower reaction. No sulfone product was,
however, formed after 20 h, p-iodoacetophenone was
recovered in only 5% yield, and formation of significant
amount of tar was observed. The presence of substituents
close to the C-I bond was found to hamper the reaction
(Table 2, entries 3, 6, and 11).
Extension of the procedure to include aryl bromides
and triflates, a target of obvious interest for academic
(23) For some reviews on the substitution of the Caryl-X bond with
a Caryl-N bond, 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. See also: (h) Prim, D.; Campagne,
J .-M.; J oseph, D.; Andrioletti, B. Tetrahedron 2002, 58, 2041.
(24) Sum, F.-W.; Malamas, M. S. WO 2002006274, 2002; Chem.
Abstr. 2002, 136, 134678.
(26) For other reactions in which electron-rich and electron-poor
substrates require different conditions, see, for example: (a) Wolfe, J .
P.; Wagaw, S.; Marcoux, J .-F.; Buchwald, S. L. Acc. Chem. Res. 1998,
31, 805. (b) Yin, J .; Buchwald, L. S. Org. Lett. 2000, 2, 1101. (c)
Reference 23c. (d) Rutherford, J . F.; Rainka, M. P.; Buchwald, S. L. J .
Am. Chem. Soc. 2002, 124, 15168.
(25) 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.
J . Org. Chem, Vol. 69, No. 17, 2004 5611

Cacchi et al.
TABLE 3. Op tim iza tion for Neu tr a l a n d Electr on -P oor Ar yl Br om id esa
entry
aryl bromide
ligand
salt
base
T (°C)
time (h)
yield %b
S/O arylation ratio
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
p-Ph-C6H4-Br
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
dppf
nBu4NCl
nBu4NCl
Cs2CO3
Cs2CO3
Cs2CO3
100
120
120
120
120
120
120
120
120
120
120
120
120
120
120
24
2
3o
3t
11
87
4o
24
24
24
24
24
24
24
24
24
22
27
8
18c
nBu4NCl
m-O2N-C6H4-Br
nBu4NCl
nBu4NCl
nBu4NCl
nBu4NCl
nBu4NCl
nBu4NCl
nBu4NBr
nBu4NI
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
20
4t
17d
43
1.17
traces
traces
27f
26
27
19
dppf
30e
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
30
33g
20
22
0.87
0.82
0.93
1.23
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
28
89
24
73h
a
Unless otherwise stated, reactions were carried out on a 0.35 mmol scale under an argon atmosphere using 1 equiv of bromide, 1.2
equiv of sodium p-toluenesulfinate, 0.025 equiv of Pd2(dba)3, 0.05 equiv of ligand, 1.5 equiv of Cs2CO3, and 1.2 equiv of ammonium salt
b
dn
in 2 mL of toluene at 120 °C. Yields are given for isolated products. c 4-Bromobiphenyl was recovered in 74% yield. Butyl
p-toluenesulfinate was isolated in 15% yield. e The reaction was carried out by using Pd(OAc)2. f 1/aryl bromide ) 2:1. In DMF. The
reaction was carried out using p-Me-C6H4-SO2Li.
g
h
aromatic methyl ketones,28 favoring the formation of
SCHEME 4
enolate nucleophiles, can account for this result.
This synthesis of unsymmetrical sulfones presumably
proceeds via the following basic steps (the ligand has been
omitted for clarity): (a) oxidative addition of the organic
halide or triflate to Pd(0), (b) selective nucleophilic
displacement of the halide or triflate of the resultant
organopalladium intermediate 8 by the sulfur atom of
the ambident sulfinate anion to give the sulfonylpalla-
dium intermediate 9, and (c) reductive elimination of a
Pd(0) species to give the sulfone product and regenerate
the palladium catalyst (Scheme 5).
SCHEME 5
Xantphos has been proved to be crucial for the success
of the reaction. Though the reasons for such a beneficial
influence of this ligand are not straightforward to eluci-
date and we have not investigated this point, it is likely
that the close proximity of the oxygen to the palladium
center (with the possibility of assisting the displacement
of the leaving group from palladium)29 and/or the known
ability of chelating diphosphines with large bite angle
to promote the product-forming reductive elimination
step30 play an important role.
many neutral, electron-rich and electron-poor aryl and
heteroaryl bromides or triflates and tolerates a variety
of functional groups, including ether, cyano, aldehyde,
and nitro groups. The best results obtained during this
study are summarized in Table 4.
n
As to the role of Bu4NCl in controlling the reaction
outcome, it is conceivable that this ammonium salt acts
as a source of chloride ions,31 whose effect is to stabilize
palladium species as proposed by Amatore and J utand.20q
Furthermore, the large ammonium cation can stabilize
halide ligated zerovalent or divalent palladium-centered
complexes.32 nBu4NCl is superior to LiCl in this respect.
However, the fact that with electron-poor aryl bromides
the best results in terms of yield and S/ O arylation ratio
Finally, the procedure was extended to vinyl triflates
to prepare aryl vinyl sulfones (Scheme 4). Vinyl sulfones
have been recently shown to act as inhibitors of SrtA, a
transpeptidase required for cell wall protein anchoring
and virulence in Staphylococcus aureus.27 Our prepara-
tive results are shown in Table 5. Even in this case,
n
omitting Bu4NCl appears to play a beneficial effect on
the reaction outcome (Table 5, compare entry 1 with
entry 2). Reactions were run at 60 °C. At 80 °C complex
reaction mixtures were obtained, at least with 4-phenyl-
cyclohex-1-en-1-yl triflate, the compound we used as the
model triflate. Interestingly, the vinyl triflate 6f, contain-
ing an acetyl fragment at the C-17, gave the correspond-
ing sulfone derivative in 70% yield (Table 5, entry 7)
though the reaction failed with p-iodoacetophenone (Table
2, entry 16), most probably because of ketone arylation
processes.25 The higher acidity of the methyl protons of
(28) The pKa values for acetophenone and acetone in dimethyl
sulfoxide solutions are, respectively, 24.7 and 26.5: Bordwell, F. G.
Acc. Chem. Res. 1988, 21, 456.
(29) Guari, Y.; van Stijdonck, G. P. F.; Boele, M. D. K.; Reek, J . N.
H.; Kamer, P. C. J .; Van Leeuwen, P. W. N. M. Chem. Eur. J . 2001, 7,
475.
(30) For
a recent review on wide bite angle diphosphines in
transition-metal catalysis, see: Kamer, P. C. J .; Van Leeuwen, P. W.
N. M.; Reek, J . N. H. Acc. Chem. Res. 2001, 34, 895.
(31) For
a recent review on halide effects in transition metal
catalysis, see: Fagnou, K.; Lautens, M. Angew. Chem., Int. Ed. 2002,
41, 26.
(27) Frankel, B. A.; Bentley, M.; Kruger, R. G.; McCafferty, D. G.
(32) Amatore, C.; J utand, A.; Suarez, A. J . Am. Chem. Soc. 1993,
115, 9531.
J . Am. Chem. Soc. 2004, 126, 3404.
5612 J . Org. Chem., Vol. 69, No. 17, 2004

Unsymmetrical Diaryl Sulfones and Diaryl Vinyl Sulfones
TABLE 4. Syn th esis of Un sym m etr ica l Dia r yl Su lfon es
th r ou gh th e P a lla d iu m -Ca ta lyzed Rea ction of Sod iu m
p-Tolu en esu lfin a te 1 w ith Ar yl a n d Heter oa r yl Br om id es
or Tr ifla tes 2a
TABLE 5. Syn th esis of Vin yl Ar yl Su lfon es 7 th r ou gh
th e P a lla d iu m -Ca ta lyzed Rea ction of Sod iu m
p-Tolu en esu lfin a te 1 w ith Vin yl Tr ifla tes 6a
a
Unless otherwise stated, reactions were carried out on a 0,35
mmol scale under the following conditions: 1.0 equiv of bromide
or triflate, 1.2 equiv of sodium p-toluenesulfinate, 0.025 equiv of
Pd2(dba)3, 0.05 equiv of Xantphos, 1.5 equiv of Cs2CO3, toluene,
b
60 °C, under argon. Yields are given for isolated products. c In
d
the presence of 1.2 equiv of nBu4NCl. The starting triflate was
recovered in 66% yield.
n
have been obtained in the absence of Bu4NCl, whereas
its presence is required to achieve the best results with
electron-rich aryl bromides, appears to call for further
considerations.
The rationalization that may be advanced to account
for the observed dichotomy of behavior has its origin in
n
differential ion-pairing effects. In the presence of Bu4-
NCl, a tetrabutylammonium sulfinate salt can be gener-
ated in situ, which is expected to exist as a relatively
loose ion-pair in toluene. Furthermore, addition of a salt
increases the solvent polarity and a more polar solvent
can favor the formation of a loose ion pair. With arylpal-
ladium bromides containing electron-poor aryl fragments,
a charge controlled reaction may become an important
reaction pathway. In fact, the palladium atom of the
arylpalladium intermediate possesses a substantial cat-
ionic character (the effect of the electron-withdrawing
substituent on the aromatic ring combines with the
electron-withdrawing effect of bromine) and can show a
tendency to react with the more electronegative site of
the ambident sulfinate nucleophile.33 Sulfinate esters
may form as significant side products. In the absence of
nBu4NCl, sodium sulfinate is likely to exist as a tight ion-
a
Reaction conditions (0.35 mmol scale, 2 mL of toluene):
(procedure A) 1.0 equiv of organic bromide or triflate, 1.2 equiv of
sodium p-toluenesulfinate, 0.025 equiv of Pd2(dba)3, 0.05 equiv of
Xantphos, 1.5 equiv of Cs2CO3, 1.2 equiv of nBu4NCl, toluene, 120
°C, under argon; (procedure B) same molar ratios, solvent, and
temperature of procedure A omitting nBu4NCl. Yields are given
b
for isolated products. c Figures in parentheses refer to isolated
sulfinic esters 4.
J . Org. Chem, Vol. 69, No. 17, 2004 5613

Cacchi et al.
pair. The oxygen is shielded by the associated metal atom
and the reaction of the ambident sulfinate nucleophile
with the palladium intermediate involves preferentially
the sulfur atom. In this case, sulfones are by far the main
reaction products. In general, a similar reasoning can
account for the behavior of aryl and vinyl triflates.
With aryl iodides, the presence of iodide in the coor-
dination sphere of palladium most probably limits the
cationic character of palladium and the reaction of the
sulfinate anion with the arylpalladium intermediate is
primarily controlled by the softer character of the sulfur
atom, in the presence or absence of nBu4NCl, with
electron-rich and electron-poor aryl iodides.
providing an attractive complement to existing methods.
Sulfones are usually isolated in good to high yields and,
although substituents close to the oxidative addition site
hamper the reaction, the method merits attention due
to the tolerance of a wide range of substituents, the
simplicity of the experimental procedure, and the use of
readily available starting materials.
Ack n ow led gm en t. This work was carried out in the
framework of the National Project “Stereoselezione in
Sintesi Organica. Metodologie ed Applicazioni” sup-
ported by the Ministero dell’Universita` e della Ricerca
Scientifica e Tecnologica, Rome. We are also greatly
indebted to the University “La Sapienza” for financial
support of this research.
To sum up, it seems that this new palladium-catalyzed
transformation is a useful route for the synthesis of
unsymmetrical diaryl sulfones and aryl vinyl sulfones,
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedure and a complete description of product characterization.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(33) For the behavior of the ambident sulfinate anion with hard and
soft electrophiles, see: (a) Meek, J . S.; Fowler, J . S. J . Org. Chem. 1968,
33, 3422. See also: (b) Grossert, J . S.; Dubey, P. K.; Elwood, T. Can.
J . Chem. 1985, 63, 1263. (c) Schank, K.; Weber, A. Synthesis 1970,
367.
J O0493469
5614 J . Org. Chem., Vol. 69, No. 17, 2004