Aryl sulfoxides via palladium-catalyzed arylation of sulfenate anions

Article abstract of DOI:10.1021/ol062315a

(Chemical Equation Presented) Palladium-catalyzed arylation of sulfenate anions generated from β-sulfinyl esters can take place under biphasic conditions. This hitherto unknown reaction provides a simple, mild, and efficient route to aryl sulfoxides in good yields. The development of a new pseudo-domino type I procedure involving a sulfinylation followed by a Mirozoki-Heck coupling is also described.

Full text of DOI:10.1021/ol062315a

ORGANIC
LETTERS
2006
Vol. 8, No. 26
5951-5954
Aryl Sulfoxides via Palladium-Catalyzed
Arylation of Sulfenate Anions
Guillaume Maitro, Sophie Vogel, Guillaume Prestat, David Madec,* and
Giovanni Poli*
UniVersite´ Pierre et Marie Curie-Paris 6, Laboratoire de Chimie Organique
(UMR CNRS 7611), Institut de Chimie Mole´culaire (FR 2769), Case 183,
4 Place Jussieu, F-75252, Paris Cedex 05, France
gioVanni.poli@upmc.fr; daVid.madec@upmc.fr
Received September 20, 2006
ABSTRACT
Palladium-catalyzed arylation of sulfenate anions generated from
â-sulfinyl esters can take place under biphasic conditions. This hitherto
unknown reaction provides a simple, mild, and efficient route to aryl sulfoxides in good yields. The development of a new pseudo-domino
type I procedure involving a sulfinylation followed by a Mirozoki−Heck coupling is also described.
The palladium-catalyzed arylation reaction represents a pri-
mary synthetic tool to generate carbon-carbon and carbon-
heteroatom bonds. In particular, the use of sulfur-based
nucleophiles1 such as sulfinates (RSO2-)2 and thiolates (RS-)3
allows the easy generation of aryl sulfones and aryl thioethers,
respectively. On the other hand, no related method allowing
the generation of aryl sulfoxides via arylation of a sulfenate
anion (RSO-) has, to our knowledge, so far been reported.
Although the sulfenate anion has been reported to be the
precursor of sulfoxides, sulfenic acids, sulfenate esters, and
thiols,4 its use remains sporadic probably due to its nonstraight-
forward preparation.5 In view of the importance of many
aryl sulfoxides for medicinal6 and pharmaceutical chemistry,
we decided to test this previously unknown type of coupling.
We recently described the synthesis of allylic sulfoxides
by palladium-catalyzed allylic alkylation of sulfenate anions
(Scheme 1),7 an original transformation that could be
successfully achieved generating the desired sulfinate anion
via â-sulfinyl ester enolate elimination8 under specifically
developed biphasic conditions.9
(4) (a) Hogg, D. R. Chemistry of Sulfenic Acids and Esters. The Chemistry
of Sulfenic Acids and their DeriVatiVes; Wiley-Interscience: Toronto, 1990;
pp 361-402. (b) Drabowicz, J.; Kielbasinski, P.; Mikolajczyk, M. The Chem-
istry of Sulfenic Acids, Esters and their DeriVatiVes; Patai, S., Ed.; John
Wiley & Sons: 1990; pp 351-429. (c) Katritzky, A. R.; Takahashi, I.;
Marson, C. M. J. Org. Chem. 1986, 51, 4914-4920. (d) O’Donnell, J. S.;
Schwan, A. L. Tetrahedron Lett. 2003, 44, 6293-6296. (e) Maezaki, N.;
Yoshigami, R.; Maeda, J.; Tanaka, T. Org. Lett. 2001, 3, 3627-3629. (f)
Maezaki, N.; Yagi, S.; Ohsawa, S.; Ohishi, H.; Tanaka, T. Tetrahedron
2003, 59, 9895-9906. (g) Maezaki, N.; Yagi, S.; Yoshigami, R.; Maeda, J.;
Suzuki, T.; Ohsawa, S.; Tsukamoto, K.; Tanaka, T. J. Org. Chem. 2003, 68,
5550-5558. (h) Maezaki, N.; Yagi, S.; Maeda, J.; Yoshigami, R.; Tanaka, T.
Heterocycles 2004, 62, 263-277. (i) Sandrinelli, F.; Perrio, S.; Beslin, P.
J. Org. Chem. 1997, 62, 8626-8627. (j) Sandrinelli, F.; Perrio, S.; Aver-
buch-Pouchot, M.-T. Org. Lett. 2002, 4, 3619-3622. (k) Sandrinelli, F.;
Fontaine, G.; Perrio, S.; Beslin, P. J. Org. Chem. 2004, 69, 6916-6919.
(5) For a review, see: O’Donnell, J. S.; Schwan, A. L. Sulfur Lett. 2004,
25, 183-211.
(1) (a) Prim, D.; Campagne, J.-M.; Joseph, D.; Andrioletti, B. Tetrahe-
dron 2002, 58, 2041-2075. (b) Kondo, T.; Mitsudo, T.-A. Chem. ReV. 2000,
100, 3205-3220.
(2) Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Paris, L. M.; Bernini, R. J.
Org. Chem. 2004, 69, 5608-5614.
(3) For precursor works, see: (a) Migita, T.; Shimizu, T.; Asami, Y.;
Shiobara, J.; Kato, Y.; Kosugi, M. Bull. Chem. Soc. Jpn. 1980, 53, 1385-
1389. (b) Foa`, M.; Santi, R.; Garavalia, F. J. Organomet. Chem. 1981, 206,
C29-C32. For recent examples, see: (c) Ferna´ndez-Rodr´ıguez, M. A.; Shen,
Q.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 2180-2181. (d) Ferna´ndez-
Rodr´ıguez, M. A.; Shen, Q.; Hartwig, J. F. Chem.-Eur. J. 2006, 12, 7582-
7596. (e) Itoh, T.; Mase, T. J. Org. Chem. 2006, 71, 2203-2206. (f) Moreau,
X.; Campagne, J.-M.; Meyer, G.; Jutand, A. Eur. J. Org. Chem. 2005,
3749-3760. (g) Mispelaere-Canivet, C.; Spindler, J.-F.; Perrio, S.; Beslin,
P. Tetrahedron 2005, 61, 5253-5259. (h) Itoh, T.; Mase, T. Org. Lett.
2004, 6, 4587-4590. (i) Murata, M.; Buchwald, S. L. Tetrahedron 2004,
60, 7397-7403.
(6) For reviews, see: (a) Legros, J.; Dehli, J. R.; Bolm, C. AdV. Synth.
Catal. 2005, 347, 19-31. (b) Bentley, R. Chem. Soc. ReV. 2005, 34, 609-
624.
(7) Maitro, G.; Prestat, G.; Madec, D.; Poli, G. J. Org. Chem. 2006, 71,
7449-7454.
10.1021/ol062315a CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/29/2006

PPh3, dppe, or binap, did not allow generation of the cor-
responding sulfoxide (entries 2-4). Replacement of Pd2dba3
for Pd(OAc)2 as the palladium source lowered the yield to
62% (entry 5), thereby confirming the major role of the
Pd2dba3/xantphos combination for sulfur nucleophiles in
palladium catalysis. Finally, an experiment performed in
liquid-solid biphasic conditions, with Cs2CO3 as base,
afforded the corresponding sulfoxide in a limited 42% yield
(entry 6). It is interesting to note the absence of O-arylation
products, despite the ambident nature of the sulfenate anion.
With the optimized reaction conditions in hand, we inves-
tigated the scope and limitations of this transformation by
treating the p-tolyl sulfenate precursor 1a with a variety of
substituted aryl iodides (Table 2).
Scheme 1
From this result, we advanced the hypothesis that sulfenate
anions could be suitable nucleophiles for palladium-catalyzed
arylation reactions as well, so as to unveil a new route toward
arylsulfoxides.10 This proved to be the case, and we report
herein our results.
Table 2. Scope of the Reactiona
The Pd-catalyzed arylation reaction between the in situ gen-
erated p-tolyl sulfenate anion and p-iodoanisole was chosen as
the model reaction for preliminary experiments (Table 1).
Table 1. Optimization of the Reaction Conditionsa
entry catalytic system base (equiv)
solvent
yield (%)b
1
2
3
4
5
6
Pd2dba3/xantphos KOH (20)
toluene/H2O
toluene/H2O
toluene/H2O
toluene/H2O
toluene/H2O
70
-
-
-
62
42
c
Pd2dba3/PPh3
Pd2dba3/dppe
Pd2dba3/binap
KOH (20)
KOH (20)
KOH (20)
Pd(OAc)2/xantphos KOH (20)
Pd2dba3/xantphos Cs2CO3 (4) toluene
a Reagents and reaction conditions: p-iodoanisole (1.2 equiv), â-sulfinyl
ester, Pd2dba3 (5 mol %) or Pd(OAc)2 (10 mol %), ligand (10 mol %),
KOH (50% aqueous solution) in a 1:1 toluene/H2O system or Cs2CO3 in
toluene at 70 °C. b Yields are given for isolated products. c The reaction
was carried out by using 20 mol % of PPh3.
Much to our satisfaction, treatment of the two substrates
with Pd2dba3 (5 mol %), xantphos11 as the ligand (10 mol
%), and KOH (20 equiv) in 1:1 toluene/H2O gave, after 4 h
at 70 °C, the expected p-tolylsulfinyl anisole 2a in 70%
yield (Table 1, entry 1). The use of other ligands, such as
(8) Caupe`ne, C.; Boudou, C.; Perrio, S.; Metzner, P. J. Org. Chem. 2005,
70, 2812-2815.
(9) (a) Madec, D.; Prestat, G.; Martini, E.; Fristrup, P.; Poli, G.; Norrby,
P.-O. Org. Lett. 2005, 7, 995-998. (b) Maitro, G.; Prestat, G.; Madec, D.;
Poli, G. Synlett 2006, 1055-1058.
(10) (a) Drabowicz, J.; Kielbasinski, P.; Mikolajczyk, M. Synthesis of
Sulfoxides. In Syntheses of Sulphones, Sulfoxides and Cyclic Sulfides; Patai,
S., Rappoport, Z., Eds.; John Wiley & Sons: Chichester, 1994; pp 109-
254. (b) Procter, D. J. J. Chem. Soc., Perkin Trans. 1 2000, 835-871. (c)
Procter, D. J. J. Chem. Soc., Perkin Trans. 1 2001, 335-354.
(11) (a) Kranenburg, M.; van der Burgt, Y. E. M.; Kamer, P. C. J.; van
Leeuwen, P. W. N. M.; Goubitz, K.; Fraanje, J. Organometallics 1995, 14,
3081-3089. (b) Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Reek, J. N.
H. Acc. Chem. Res. 2001, 34, 895-904.
a Reagents and reaction conditions: aryl halide (1.2 equiv), â-sulfinyl
ester, Pd2dba3 (5 mol %), xantphos (10 mol %), KOH (50% aqueous
solution) in 1:1 toluene/H2O at 70 °C. b Yields are given for isolated
products. c Diastereomeric dl/meso ratio of >90:10 determined by 1H NMR.
5952
Org. Lett., Vol. 8, No. 26, 2006

4-Iodotoluene reacted with 1a to give the corresponding
symmetrical sulfoxide 3a in 81% yield (entry 1). p-, m-, and
o-iodoanisoles afforded the corresponding isomeric sulfox-
ides 2a, 4a, and 5a with 70%, 63%, and 79% yields,
respectively (entries 2-4). Starting from p-iodoacetophenone,
the reaction afforded sulfoxide 6a in 58% yield (entry 5),
whereas sulfoxide 7a was isolated in 82% yield from
p-iodonitrobenzene (entry 6). An excellent coupling yield
(96%) was obtained using p-iodotrifluoromethyl benzene as
the substrate (entry 7). Reaction of 2-iodothiophene produced
the corresponding coupling product 9a in 82% yield (entry
8). Conversely, under the same conditions, 4-bromotoluene
did not allow generation of the expected sulfoxide 3a (entry
9). This difference in reactivity between bromides and iodides
was exploited in the reaction of 4-bromo-iodobenzene, which
afforded the corresponding monosulfoxide 10a without
concomitant formation of the bis-sulfoxide product (entry
10). Reaction between 1,2-diiodobenzene and excess sulfenate
precursor gave the bis-sulfoxide 11a in 45% yield and g90:
10 (dl/meso) ratio (entry 11).
Table 3. Scope of the Reactiona
The above diastereomeric ratio assignment was evaluated
on the basis of the spectroscopic data previously reported
for the dl diastereomer12 and confirmed by the synthesis of
the corresponding and hitherto unknown meso product 11a′.
This was achieved by double palladium-catalyzed coupling
between 1,2-diiodobenzene and excess p-thiocresol, followed
by oxone-mediated thioether-to-sulfoxide oxidation13
(Scheme 2).
a Reagents and reaction conditions: aryl halide (1.2 equiv), â-sulfinyl
ester substrate, Pd2dba3 (5 mol %), xantphos (10 mol %), KOH (50%
aqueous solution) in 1:1 toluene/H2O at 70 °C. b Yields are given for isolated
products. c The corresponding formally demethoxylated byproduct was
isolated in 28% yield. d The corresponding formally demethoxylated
byproduct was isolated in 37% yield.
Scheme 2
phonium ion mediated aryl scrambling of the arylpalladium-
(II) complex.14
More disappointingly, alkyl sulfenates afforded the cor-
responding alkyl sulfoxides 13d and 14d in moderate 42%
and 35% yields, respectively (entries 5 and 6). Finally, the
use of (Z)-1-iodohex-1-ene gave the (Z)-vinyl-sulfoxide 15a
in 33% yield (entry 7); the same reaction starting from the
(E)-isomer afforded only degradation products.
To take advantage of the chemoselectivity of the sulfiny-
lation of 4-bromo-iodobenzene (Table 2, entry 10) and of
the tert-butyl acrylate concomitantly released during sulfenate
generation, the possible enchainment of a pseudo-domino
type I15 sulfinylation/Mirozoki-Heck sequence was envi-
sioned. After some experimentation, we found that perform-
The reaction was next studied on various â-sulfinyl esters
(Table 3). Starting from 2-naphthylsulfenate precursor 1b,
reaction with p-iodotoluene or p-iodoanisole afforded the
corresponding diaryl sulfoxides 13b or 14b in 79% and 45%
respective yields (entries 1 and 2). Benzyl sulfenates could
also be satisfactorily coupled (entries 3 and 4). It should be
noted that the modest yields of the couplings involving
p-iodoanisole (entries 2 and 4) were due to the formation of
coupling byproducts (28% and 37% yields, respectively)
carrying a phenyl ring instead of the p-methoxy moiety.
These formally demethoxylated byproducts are very likely
the result of phenyl transfer from xantphos, due to phos-
(14) This side reaction is known to plague Pd-catalyzed cross-couplings
when electron-rich aryl halides and/or nucleophiles are used. (a) Kong, K.-
C.; Cheng, C.-H. J. Am. Chem. Soc. 1991, 113, 6313-6315. (b) Kwong,
F. Y.; Lai, C. W.; Yu, M.; Chan, K. S. Tetrahedron 2004, 60, 5635-5645
and references cited therein.
(15) (a) Poli, G.; Giambastiani, G. J. Org. Chem. 2002, 67, 9456-9459.
(b) Lemaire, S.; Prestat, G.; Giambastiani, G.; Madec, D.; Pacini, B.; Poli,
G. J. Organomet. Chem. 2003, 687, 291-300. (c) Prestat, G.; Poli, G.
Chemtracts - Org. Chem. 2004, 17, 97-103.
(16) Kanda, H.; Nakatsu, R.; Asai, A.; Yamashita, N. Patent JP
2003137861, 2003.
(12) Tokunoh, R.; Sodeoka, M.; Aoe, K.-I; Shibasaki, M. Tetrahedron
Lett. 1995, 36, 8035-8038.
(13) Greenhalgh, R. P. Synlett 1992, 235-236.
Org. Lett., Vol. 8, No. 26, 2006
5953

ing the reaction in DMF at 130 °C, and in the presence of
Cs2CO3 as the base, allowed isolation of the desired sulfinyl-
substituted cinnamate 16 in 32% yield (Scheme 3). Despite
Scheme 4
Scheme 3
In conclusion, we have reported the first palladium-
catalyzed arylation of sulfenate anions under biphasic condi-
tions, thereby disclosing a new synthetic route toward aryl
sulfoxides. This methodological work was further enriched
by the development of a pseudo-domino type I sulfinylation/
Mirozoki-Heck sequence wherein the Pd(0) catalyst is
formally shared by the two mechanistically independent
catalytic cycles.
its moderate yield, this new arylation reaction could be a
straightforward method for the preparation of a telomerase
inhibitor for human kidney cancer.16
We propose for this new one-pot, two C-C bond forming
coupling the following mechanism (Scheme 4). Base-
mediated deprotonation of the â-sulfinyl ester first gives the
corresponding ester enolate. The following retro-Michael
reaction generates the sulfenate anion and the acrylate ester,
which are ready to enter the first (sulfinylation) and the
second (Mirozoki-Heck) catalytic cycles, respectively.
Transmetalation between the sulfenate anion and the arylpal-
ladium(II) complex generated from oxidative addition of Pd-
(0) to the aryl iodide gives, after reductive elimination, the
corresponding bromoaryl sulfoxide and releases Pd(0).
Oxidative addition of Pd(0) to the bromoaryl sulfoxide
expelled from the first catalytic cycle starts the second one.
Then, carbo-palladation of the acrylate ester by the newly
formed arylpalladium(II) complex, followed by dehydropal-
ladation, generates the final sulfinyl cinnamate.
Enantioselective Pd-catalyzed sulfinylation reactions are
presently under investigation and will be reported in due
course.
Acknowledgment. The support and sponsorship con-
certed by CNRS and COST Action D24 “Sustainable
Chemical Processes: Stereoselective Transition Metal-Ca-
talysed Reactions” are kindly acknowledged.
Supporting Information Available: General procedures
and spectroscopic data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL062315A
5954
Org. Lett., Vol. 8, No. 26, 2006