Novel C-H functionalization of arenes: Palladium-catalyzed synthesis of diaryl sulfides

Article abstract of DOI:10.1039/c0cc04405a

A novel protocol for the direct arylthiolation of electron-rich arenes is described. Applying arylsulfonyl cyanides in the presence of catalytic amounts of Pd allows for a straightforward synthesis of diaryl sulfides.

Full text of DOI:10.1039/c0cc04405a

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COMMUNICATION
Novel C–H functionalization of arenes: palladium-catalyzed synthesis of
diaryl sulfidesw
Pazhamalai Anbarasan, Helfried Neumann and Matthias Beller*
Received 14th October 2010, Accepted 5th January 2011
DOI: 10.1039/c0cc04405a
A novel protocol for the direct arylthiolation of electron-
rich arenes is described. Applying arylsulfonyl cyanides in the
presence of catalytic amounts of Pd allows for a straightforward
synthesis of diaryl sulfides.
interesting, e.g. as serotonin transporter (SERT) ligands
(Fig. 2),6 and retinoid analogs for the specific binding and
transactivation of retinoid X receptors (RXR).7
Most synthetic approaches to diaryl sulfides are based on
the formation of C–S bonds through nucleophilic reaction of
metal thiolates with aryl halides.8 On the other hand, the
reduction of aryl sulfones or aryl sulfoxides was also adopted
for their synthesis.9 However, these methods are often limited
by their harsh conditions, low regioselectivity, narrow
preparative scope, and use of toxic reagents. Therefore, the
development of milder transition metal-catalyzed reactions for
the synthesis of diaryl sulfides is of actual interest.10
Arylsulfonyl motifs are widely used in organic synthesis as the
protecting group, activating the leaving group, substrates for
the introduction of sulfur, etc.1 The conventional way of
introducing sulfur via arylsulfonyl derivatives includes Lewis
acid mediated arylsulfonylation of electron-rich arenes2 and
arylsulfonylation under strong acidic conditions.3 More
recently, these traditional methods were complemented by
Cu- and Pd-catalyzed arylsulfonylations.4 In general, in these
reactions arylsulfonyl chlorides, anhydrides or amides are
employed leading to the formation of diarylsulfones (Fig. 1,
left side). Here, we disclose an alternative approach towards
diaryl sulfides. To the best of our knowledge such direct
synthesis of diaryl sulfides employing arylsufonyl derivatives
as sulfur source has not been described yet (Fig. 1, right side).
Diaryl sulfide (diaryl thioether) scaffolds are found in
pharmaceutically important natural products such as the
Lissoclinotoxin and Lissoclibadin class of natural products
(Fig. 2).5 In addition, non-natural diaryl sulfides are also
In the last few years, we developed novel methodologies for
the synthesis of functionalized arenes under electrophilic
conditions.11 During the course of our investigations on the
direct cyanation of substituted benzenes with p-toluenesulfonyl
cyanide in the presence of palladium salts,12 serendipitously,
we observed the formation of diaryl sulfide (Table 1).
Table 1 Optimization of reaction conditions for the synthesis of
diaryl sulfide Aa
Fig. 1 Catalytic reactions of arylsulfonyl derivatives with arenes.
Entry Metal (mol%) Solvent
Yieldb (%) Ratio of A : B
1
2
3
4
5
6
7
8
Pd(OAc)2 (10) CF3COOH 47
3 : 1
—
—
—
Pd(OAc)2 (10) CH3COOH
Pd(OAc)2 (10) CF3SO3H
Pd(OAc)2 (10) HCOOH
—
—
—
—
6
—
CF3COOH
CF3COOH
—
AuCl3 (10)
HAuCl4 (10)
FeCl3 (10)
5 : 1
9 : 2
13 : 1
2 : 1
26 : 1
6 : 1
51 : 1
CF3COOH 11
CF3COOH 14
9c
10d
11d,e
12
Pd(OAc)2 (10) CF3COOH 61
Pd(OAc)2 (10) CF3COOH 81
Pd(OAc)2 (10) CF3COOH 47
Fig. 2 Examples of therapeutically important diaryl sulfides.
Pd(OAc)2 (5)
CF3COOH 78
Leibniz-Institut fur Katalyse e.V. an der Universitat Rostock,
¨
¨
a
Albert-Einstein-Straße 29a, 18059 Rostock, Germany.
E-mail: matthias.beller@catalysis.de; Fax: +49 381-1281-5000
w Electronic supplementary information (ESI) available: Experimental
details and characterization of synthesized diaryl sulfides. See DOI:
10.1039/c0cc04405a
Reaction conditions: mesitylene (1 equiv.), TsCN (2 equiv.), metal
b
(x mol%), solvent (1 mL), rt, 1 h. GC yield. 5 eq. of mesitylene was
c
d
used and the yield is based on TsCN. Mesitylene was added after
e
10 min. 1.2 eq. of TsCN was used.
c
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For this unusual reductive arylthiolation we found no
precedent in the literature. Hence, we studied the reaction of
mesitylene with p-toluenesulfonyl cyanide (TsCN) more closely.
An initial screening of the influence of different solvents
and palladium precursors revealed that the model reaction
proceeded best in trifluoroacetic acid (TFA) with Pd(OAc)2.
Here, at room temperature a mixture of diaryl sulfide A and
diaryl sulfone B is obtained in 47% yield in a ratio of 3 : 1
(Table 1, entry 1). To improve the selectivity and yield, various
acids and metals as solvents and catalysts, respectively, were
examined (Table 1, entries 2–8). Less acidic formic acid and
acetic acid or more acidic trifluoro-methanesulfonic acid
resulted in the decomposition of TsCN (Table 1, entries 2–4).
Notably, no product is observed in the absence of Pd(OAc)2
and the reaction resulted only in recovering the starting
materials (Table 1, entry 5).
Table 2 Synthesis of diaryl sulfides: scope and limitationsa
Entry Arene
Product
Yieldb (%)
1
72
2
76
3
57
Replacement of Pd(II) with other metals such as Au(III) and
Fe(III) afforded only small amounts of A and B (Table 1,
entries 6–8).13 Alternatively, introduction of mesitylene into
the reaction mixture after pre-formation of the reagents for
10 min increased the yield to 81%, along with a dramatically
improved selectivity to 26 : 1 for A and B, respectively
(Table 1, entry 10). Apparently, the reaction of TsCN with
palladium in TFA generates a highly reactive species which
then affords the observed diaryl sulfide in excellent yield and
selectivity. Reducing the ratio of mesitylene to TsCN to 1 : 1.2
furnished the products in 47% yield with moderate selectivity
(Table 1, entry 11). Interestingly, decreasing the loading of
catalyst to 5 mol% also gave similar results (Table 1, entry 12).
Based on these results we envision the following mechanism
for the direct arylthiolation of mesitylene with 4-tolylsulfonyl
cyanide (Fig. 3): initially, palladium-mediated activation
of TsCN proceeds in the acidic medium. Rearrangement and
elimination of CF3CO2CN gave the respective sulfinate.
Subsequent trifluoroacetylation forms a cationic sulfur species
which can react either with mesitylene directly or with the
palladated arene. Final reduction with the in situ-generated
sulfinate leads to the observed diaryl sulfide.14 The present
4c
43 (1 : 3)d
5
6
7
58
44
39
8e
66
61
37
9
10
11f
55
57
12
13
33
41
14
a
Reaction conditions: arene (1 mmol), ArSO2CN (2 mmol), Pd(OAc)2
b
c
(5 mol%), TFA (1 mL), rt, 1 h. Isolated yield. 21% of diaryl-
d
thiolated product. Ortho : para ratio. 10% of diarylthiolated
e
f
product. 6% of diarylthiolated product.
Fig. 3 Proposed mechanism.
c
3234 Chem. Commun., 2011, 47, 3233–3235
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proposal is supported by the following observations: (1) the
presence of palladium in the reaction mixture is a prerequisite
for the arylthiolation to occur; (2) addition of mesitylene after
pre-formation of the active species increases the yield and
selectivity; (3) in order to observe yields >50% an arylsulfonyl
cyanide to arene ratio >1 : 1.2 is necessary. Furthermore,
we were able to obtain the same products in good yield
(>70%) by replacement of the arylsulfonyl cyanide with
sodium 4-tolylsulfinate in the presence of trifluoroacetic
anhydride. Notably, no reaction is observed without this
anhydride.14
Notes and references
1 (a) T. W. Greene and P. G. M. Wuts, Protective Groups in
Organic Synthesis, Wiley-Interscience, New York, 3rd edn, 1999;
(b) R. J. Cremlyn, An introduction to organosulfur chemistry, John
Wiley and Sons, Chichester, 1996.
2 For selected references: (a) K. P. Borujeni and B. Tamami, Catal.
Commun., 2007, 8, 1191; (b) G. A. Olah, T. Mathew and
G.
K.
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Prakash,
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1696;
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Soc., Perkin Trans. 1, 2000, 2689; (d) R. P. Singh, R. M. Kamble,
K. L. Chandra, P. Saravanan and V. K. Singh, Tetrahedron, 2001, 57,
241; (e) S. Repichet, C. Le Roux and J. Dubac, Tetrahedron Lett.,
1999, 40, 9233; (f) B. M. Choudary, N. S. Chowdari, M. L. Kantam
and R. Kannan, Tetrahedron Lett., 1999, 40, 2859; (g) K. Bahrami,
M. M. Khodei and F. Shahbazi, Tetrahedron Lett., 2008, 49, 3931.
3 For selected references see: (a) B. Yao and Y. Zhang, Tetrahedron
Lett., 2008, 49, 5385; (b) A. Alizadeh, M. M. Khodaei and
E. Nazari, Tetrahedron Lett., 2007, 48, 6805.
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R. E. P. Mangindaan, H. Rotinsulu, H. Kobayashi and
M. Namikoshi, J. Nat. Prod., 2007, 70, 439; (b) T. Oda,
T. Fujiwara, H. Liu, K. Ukai, R. E. P. Mangindaan,
M. Mochizuki and M. Namikoshi, Mar. Drugs, 2006, 4, 15;
(c) H. Liu, T. Fujiwara, T. Nishikawa, Y. Mishima, H. Nagai,
T. Shida, K. Tachibana, H. Kobayashi, R. E. P. Mangindaane and
M. Namikoshia, Tetrahedron, 2005, 61, 8611.
After having identified suitable conditions for the model
reaction (Table 1, entry 12), we tested a number of arenes with
two arylsulfonyl cyanides to explore the scope of this new
methodology (Table 2). Arylthiolation of mesitylene with
TsCN yielded the corresponding diaryl sulfide in 72% isolated
yield (Table 2, entry 1). A similar result is obtained with
pentamethylbenzene (Table 2, entry 2). More simple substrates
such as anisole and m-xylene underwent smooth reaction to
afford the diaryl sulfides in 61% and 57% yield, respectively
(Table 2, entries 9 and 3). It is interesting to note that the ortho
to para selectivity in both cases is found to be excellent.
However, arylthiolation of 3,5-dimethylanisole furnished a
mixture of ortho- and para-arylthiolated products in a 1 : 3
ratio (Table 2, entry 4). Substituted diaryl sulfides (from
3,5-dimethoxytoluene and 1,3,5-trimethoxybenzene) were also
readily synthesized employing the present conditions (Table 2,
entries 5 and 6). Moreover, 1,3-dimethoxybenzene as well as
3-methylanisole are arylthiolated in 39% and 66% yield
(Table 2, entries 7 and 8). From a synthetic point of view it
is interesting to note that aryl bromides can be used as
substrates for the arylthiolation reaction. Thus, arylthiolation
of 5-bromo-1,3-dimethoxybenzene and 3-bromoanisole with
TsCN gave a moderate yield of the corresponding brominated
diaryl sulfide (Table 2, entries 10 and 11). Additionally,
9,9-dimethylxanthene, a heterocyclic arene was arylthiolated
in 57% yield (Table 2, entry 12). Finally, benzenesulfonyl
cyanide was utilized in place of TsCN.15 Consequently,
arylthiolation of simple arenes such as mesitylene and anisole
with benzenesulfonyl cyanide afforded the respective diaryl
sulfides in moderate yield (Table 2, entries 13 and 14).
In summary, a novel C–H functionalization methodology
for the synthesis of diaryl sulfides from arenes has been
developed. This palladium-catalyzed reaction utilizes aryl-
sulfonyl cyanide as sulfur source, which is the key for the
success of the present strategy. Different mono- and
diarylthiolations proceed under mild conditions with moderate
to excellent chemo- and regioselectivity.
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of AlCl3 see: (b) G. Dougherty and P. D. Hammond, J. Am. Chem.
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12 L. R. Reddy, B. Hu, M. Prashad and K. Prasad, Angew. Chem.,
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13 Here formation of chloromesitylene was observed as a major product.
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This work has been funded by the Alexander-von-
Humboldt-Stiftung, the BMBF, and the DFG (Leibniz
Prize). We thank Mrs S. Leiminger, Drs W. Baumann,
C. Fischer, and Mrs S. Buchholz (all LIKAT) for analytical
support.
15 For the synthesis and application of arylsulfonyl cyanides see for
example: Z. P. Demko and K. B. Sharpless, Angew. Chem., Int.
Ed., 2002, 41, 2110.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 3233–3235 3235