Synthesis of di(hetero)aryl sulfides by directly using arylsulfonyl chlorides as a sulfur source

Article abstract of DOI:10.1039/c1cc13633j

A new, efficient protocol for the synthesis of di(hetero)aryl sulfides is described. Cheap and easily available arylsulfonyl chlorides as a sulfur source reductively couple with electron-rich (hetero)arenes (e.g., indolizines, indoles, electron-rich benzenes, etc.) in the presence of triphenylphosphine to afford di(hetero)aryl thioethers in good yields.

Full text of DOI:10.1039/c1cc13633j

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2011, 47, 9188–9190
www.rsc.org/chemcomm
COMMUNICATION
Synthesis of di(hetero)aryl sulfides by directly using arylsulfonyl
chlorides as a sulfur sourcew
Qian Wu, Dongbing Zhao, Xurong Qin, Jingbo Lan and Jingsong You*
Received 18th June 2011, Accepted 28th June 2011
DOI: 10.1039/c1cc13633j
A new, efficient protocol for the synthesis of di(hetero)aryl
sulfides is described. Cheap and easily available arylsulfonyl
chlorides as a sulfur source reductively couple with electron-
rich (hetero)arenes (e.g., indolizines, indoles, electron-rich
benzenes, etc.) in the presence of triphenylphosphine to afford
di(hetero)aryl thioethers in good yields.
absence of a transition metal catalyst. To the best of our
knowledge, there are no examples describing metal-free synthesis
of di(hetero)aryl sulfides by directly using sulfonyl chlorides as
a sulfur source (Fig. 1).
Indolizines have been widely explored due to their biological
and pharmaceutical importance. In particular, 3-sulfenyl-
indolizines are ligands of the CRTH2 receptor, and valuable
in treatment of various respiratory diseases. Furthermore,
these sulfenyl-containing compounds can be subjected to
oxidation to form sulfone derivatives, which act as a foothold
in a variety of target bioactive molecules.14 Following our
interest in direct C–H functionalization of heteroarenes, we
herein would like to focus on sulfenylation of indolizines with
arylsulfonyl chlorides, which affords a variety of 3-sulfenyl-
indolizines.
Di(hetero)aryl sulfides are important building blocks for
creating molecules of medicinal interest, natural products
and functional materials. In the last decade, transition metal-
catalyzed Ullmann condensation and modified reactions of
aryl donors (e.g., aryl halides, aryl boronic acids, etc.) with
S-containing nucleophiles have been well developed, and
become one of the most powerful and reliable protocols for
the synthesis of di(hetero)aryl thioethers.1 An alternative
approach to di(hetero)aryl thioethers is the electrophilic
substitution of (hetero)arenes (especially electron-rich (hetero)-
arenes) by diverse sulfenylating agents such as quinone
mono-O,S-acetals,2 disulfides,3 sulfenyl halides,4,5 N-thioaryl-
phthalimides,6 and thiols in combination with N-chlorosuccinimide,
SelectfluorTM or iron (III) chloride.7–9 Despite significant
progress, the development of a new, direct and facile sulfenyl-
ation of (hetero)arenes to forge di(hetero)aryl thioethers is still
a highly desirable objective.
ð1Þ
In our initial work, we surprisingly observed that N-methyl-
morpholine (NMM) did mediate the reductive coupling of
p-tolylsulfonyl chloride 2a with methyl indolizine-1-carboxylate 1a
to afford methyl 3-(p-tolylthio)indolizine-1-carboxylate 3a in
50% yield in the absence of a transition metal catalyst (see
ESIw, Table S1) (eqn (1)). We assumed that NMM might
function as a reductive reagent in the sulfenylation process.
Inspired by these preliminary findings, we further screened a
series of other additives (e.g., i-Pr2NEt, Ph3N, n-Pr3N, DBU,
Arylsulfonyl chlorides have been widely used as the protecting
groups, sulfonylating agents,10 and leaving groups in C–C
bond formation.11,12 Quite recently, Beller and co-workers
reported a novel palladium-catalyzed synthesis of diaryl sulfides
via the direct C–H functionalization of electron-rich arenes
with arylsulfonyl cyanides.13 Due to an interest in the palladium-
catalyzed arylation of heteroarenes with sulfonyl chloride as a
leaving group, we herein accidentally discovered that inexpensive
and easily available arylsulfonyl chlorides can directly serve
as a sulfur source for sulfenylation of (hetero)arenes. More
surprisingly, this type of transformation even works well in the
Key Laboratory of Green Chemistry and Technology of Ministry of
Education, College of Chemistry, and State Key Laboratory of
Biotherapy, West China Medical School, Sichuan University,
29 Wangjiang Road, Chengdu 610064, PR China.
E-mail: jsyou@scu.edu.cn; Fax: +86 28-85412203
w Electronic supplementary information (ESI) available: Detailed
experimental procedures, analytical data. CCDC 819088. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c1cc13633j
Fig. 1 Scope of application of arylsulfonyl derivatives.
c
9188 Chem. Commun., 2011, 47, 9188–9190
This journal is The Royal Society of Chemistry 2011

View Article Online
Table 2 Synthesis of di(hetero)aryl sulfides with sulfonyl chloridesa,b
Fig. 2 ORTEP diagram of 3a. Thermal ellipsoids are shown at the
50% probability level.
NMI, Me3SiCl, HP(OPh)2, P(OEt)3, PPh3, etc.). Among the
additives investigated, inexpensive triphenylphosphine proved
to be more effective. Although NMI, i-Pr2NEt and n-Pr3N
gave slightly higher yields at 120 1C, the substrate 1a was
consumed completely in 24 h (Table S1, entries 2, 4, 6 and 10,
ESIw). The yield of 3a could be greatly improved up to 88% by
elevating the reaction temperature to 130 1C in the presence of
PPh3 (Table S1, entry 15, ESIw). Subsequently, a set of
solvents were explored, and toluene turned out to be the best
choice. Furthermore, we attempted to shorten the reaction
time and reduce the amount of triphenylphosphine and
p-tolylsulfonyl chloride, but the results were disappointing
(Table S1, entries 18–20, ESIw). Finally, the cross-coupling
reaction proceeded well when 3.0 equiv. of triphenylphosphine
and 3.0 equiv. of p-tolylsulfonyl chloride were employed in
toluene at 130 1C for 24 h. An X-ray analysis of single crystals
of 3a confirmed the selective sulfenylation at the C3-position
of 1a rather than the sulfonylation (Fig. 2).15
With optimized conditions now in hand, we first investigated
the scope of this protocol with respect to arylsulfonyl chlorides
as shown in Table 1. No matter if the substituents on the
aromatic ring were electron-withdrawing (except the nitro
group), electron-donating, or sterically bulky, all of them
afforded good to excellent yields. It was noteworthy that our
method could be applied to arylsulfonyl chlorides with the chloro
and bromo groups on the aromatic ring, which provided
a complementary platform for further functionalizations
a
Reactions were carried out using 1 (0.25 mmol), 2 (0.75 mmol), and
b
PPh3 (0.75 mmol) in toluene (1.5 mL) at 130 1C for 24 h. Isolated
yield based on 1. 140 1C. N-Pivaloyl-2-methylindole was used as
substrate. FeCl3 (20 mol%) was added.
c
d
e
through transition metal catalyzed-coupling reactions to create
more complex bioactive molecules (Table 1, 3c–d).14b
It was gratifying to find that a variety of indolizines could
couple with diverse arylsulfonyl chlorides in satisfactory yields
(Table 2). For example, the C1-substituted indolizines
smoothly furnished the sulfenylation of indolizines at the C3
position in good yields (4a–d, and 4g–j), whereas the
C2-occupied ones gave 1,3-bis-S-arylated products (4e–f). In
addition to indolizines, various indoles proceeded well under
optimized conditions (4k–m). Particularly noteworthy is that
the free (NH)-indole could be sulfenylated with arylsulfonyl
chlorides. Interestingly, the protection of indole with the pivaloyl
group could dramatically improve the yield of sulfenylindole
from 46% to 71%, but gave the free (NH)-indole derivative 4l,
which might be attributed to hydrochloride generated during
the transformation. We next determined that our protocol was
applicable to not only heteroarenes, but also electron-rich
arenes to some extent. For example, trimethoxybenzene
gave the diaryl sulfide 4n in an acceptable yield. Notably,
the addition of extra FeCl3 (20 mol%) could raise the yield of
4n up to 67%.
Table 1 Scope of arylsulfonyl chloridesa,b
a
Reactions were carried out using indolizine 1a (0.25 mmol), aryl-
sulfonyl chloride 2 (0.75 mmol), and PPh3 (0.75 mmol) in toluene
The sulfonyl chlorides as electrophilic reagents have
been described, especially in the presence of a Lewis acid or
b
(1.5 mL) at 130 1C for 24 h. Isolated yield based on 1a.c140 1C.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 9188–9190 9189

View Article Online
In conclusion, we have developed a new, efficient organo-
mediated-sulfenylation of (hetero)arenes (e.g., indolizines,
indoles, electron-rich benzenes, etc.) to prepare di(hetero)aryl
thioethers by directly using inexpensive and easily available
arylsulfonyl chlorides as an alternative sulfur source in
combination with cheap triphenylphosphine. We believe that
this methodology would provide a useful complement for the
sulfenylation of electron-rich (hetero)arenes.
Fig. 3 Proposed mechanism for sulfenylation of (hetero)arenes.
This work was supported by grants from the National NSF
of China (No. 21025205, 20972102 and 21021001), PCSIRT
(No. IRT0846), 973 Program (2011CB8086600). We thank the
Centre of Testing & Analysis, Sichuan University for NMR,
X-ray, ICP-MS, and AAS measurements.
transition-metal catalyst.10 It is noteworthy that no sulfonyl-
ating product was observed. In order to get some mechanistic
insights, the reaction mixture was further investigated. Under
the standard conditions, the coupling of 1a with 2a produced
3a in 88% yield with a concomitant quantitative amount of
triphenylphosphine oxide (Ph3PO) and 0.30 equiv. of 1, 2-di-p-
tolyldisulfide (based on 1a). These results suggested that
arylsulfonyl chloride was subjected to reduction by triphenyl-
phosphine, which abstracted oxygen from arylsulfonyl chloride to
generate the corresponding RS+ equivalent (Fig. 3).
Notes and references
1 For review on Ullmann condensation and modified reactions, see:
(a) S. V. Ley and A. W. Thomas, Angew. Chem., Int. Ed., 2003,
42, 5400; (b) F. Monnier and M. Taillefer, Angew. Chem., Int. Ed.,
2009, 48, 6954; (c) I. P. Beletskaya and V. P. Ananikov, Chem.
Rev., 2011, 111, 1596.
A point worthy of note is that the reduction of sulfonyl
chlorides with triphenylphosphine or other reductive reagents
to yield sulfenyl chlorides,12 arylthiols16 or disulfides through a
possible ArSX (X = Cl, I) intermediate17 is known in the
literature (for extra experimental data, see ESIw, VI), and
sulfenyl chlorides, disulfides and arylthiols may all serve as
effective sulfenylating agents.3–5 Fortunately, the controlled
experiments gave the direct evidence of the plausible mechanism
(eqn (2)). Benzenesulfenyl chloride (PhSCl) coupled with 1a to
give the desired product 3g in 82% yield with 0.28 equiv.
of diaryldisulfide as the side product under the standard
conditions, whereas both diphenyl disulfide (PhSSPh) and
arylthiol (ArSH) failed to react with 1a. In the absence of
indolizine, benzenesulfenyl chloride coupled to each other to
form diphenyl disulfide as a competitive reaction in 85% yield
in toluene at 130 1C for 24 h (see ESIw, VI).17,18 These results
implied that sulfenyl chlorides might act as a selective source
of RS+ equivalents.
2 M. Matsugi, K. Murata, K. Gotanda, H. Nambu, G. Anilkumar,
K. Matsumoto and Y. Kita, J. Org. Chem., 2001, 66, 2434.
3 (a) X.-L. Fang, R.-Y. Tang, P. Zhong and J.-H. Li, Synthesis,
2009, 4183; (b) S. Zhang, P. Qian, M. Zhang, M. Hu and J. Cheng,
J. Org. Chem., 2010, 75, 6732.
4 I. V. Koval’, Russ. J. Gen. Chem., 1995, 64, 731.
5 (a) M. Raban and L.-J. Chern, J. Org. Chem., 1980, 45, 1688;
(b) P. Hamel, J. Org. Chem., 2002, 67, 2854; (c) Y. Chen,
C.-H. Cho and R. C. Larock, Org. Lett., 2009, 11, 173.
6 M. Tudge, M. Tamiya, C. Savarin and G. R. Humphrey, Org.
Lett., 2006, 8, 565.
7 K. M. Schlosser, A. P. Krasutsky, H. W. Hamilton, J. E. Reed and
K. Sexton, Org. Lett., 2004, 6, 819.
8 J. S. Yadav, B. V. S. Reddy and Y. J. Reddy, Tetrahedron Lett.,
2007, 48, 7034.
9 J. S. Yadav, B. V. S. Reddy, Y. J. Reddy and K. Praneeth,
Synthesis, 2009, 1520.
10 (a) B. M. Graybill, J. Org. Chem., 1967, 32, 2931; (b) S. J. Nara,
J. R. Harjani and M. M. Salunkhe, J. Org. Chem., 2001, 66, 8616;
(c) X. Zhao, E. Dimitrijevic and V. M. Dong, J. Am. Chem. Soc.,
2009, 131, 3466.
11 For selected examples of arylsulfonyl chlorides used in C–C bond
formation, see: (a) N. Kamigata, M. Yoshikawa and T. Shimizu,
J. Fluorine Chem., 1998, 87, 91; (b) S. R. Dubbaka and P. Vogel,
Chem.–Eur. J., 2005, 11, 2633; (c) C. M. R. Volla and P. Vogel,
Angew. Chem., Int. Ed., 2008, 47, 1305.
12 S. R. Dubbaka and P. Vogel, J. Am. Chem. Soc., 2003, 125,
15292.
ð2Þ
13 P. Anbarasan, H. Neumann and M. Beller, Chem. Commun., 2011,
47, 3233.
14 For the pharmaceutical and bioactive importance of sulfenylated
indolizines and sulfonyl derivatives, see: (a) G. Hynd, N. C. Ray,
H. Finch, D. Middlemiss, M. C. Cramp, P. M. Blaney,
K. Williams, Y. Griffon, T. K. Harrison and P. Crackett, WO
2006/136859, 2006; (b) G. Hynd, J. G. Montana, H. Finch,
T. Harrison and J. Kulagowski, US 2010/0093751, 2010;
(c) J. Gubin, H. Vogelaer, H. Inion, C. Houben, J. Lucchetti,
J. Mahaux, G. Rosseels, M. Peiren, M. Clinet, P. Polster and
P. Chatelain, J. Med. Chem., 1993, 36, 1425.
15 CCDC 819088 (3a)w.
16 E. V. Bellale, M. K. Chaudhari and K. G. Akamanchi, Synthesis,
2009, 3211.
17 (a) G. A. Olah, S. C. Narang, L. D. Field and G. F. Salem, J. Org.
Chem., 1980, 45, 4792; (b) G. A. Olah, S. C. Narang, L. D. Field
and R. Karpeles, J. Org. Chem., 1981, 46, 2408; (c) G. W. Kabalka,
M. S. Reddy and M.-L. Yao, Tetrahedron Lett., 2009, 50,
7340.
In addition, the ICP-MS and/or AAS analysis indicated that
the contents of Pd and Cu were less than the detection limits of
1.0 ppb in the samples of 1a, 2a, and Ph3P, and the contents of
Fe were less than 30 ppb, which indicated that the reactions
observed could be considered as a metal-free process (ESIw,
Table S2).
Although the mechanism was not well understood at this
stage, on the basis of the above observations, we proposed
that a plausible mechanism could consist of (i) reduction of
sulfonyl chloride with Ph3P to IM, and (ii) electrophilic attack
of IM on the electron-rich (hetero)arene to give di(hetero)aryl
sulfide with the release of the acidic HCl gas that was detected
at the end of the reaction (Fig. 3).5b The diaryl disulfide
observed in the reaction system could be attributed to the
coupling of reactive sulfenyl chloride to each other.17
18 T. G. Back, S. Collins and M. V. Krishna, Can. J. Chem., 1987,
65, 38.
c
9190 Chem. Commun., 2011, 47, 9188–9190
This journal is The Royal Society of Chemistry 2011