Visible light-induced 3-sulfenylation of N-methylindoles with arylsulfonyl chlorides

Article abstract of DOI:10.1039/c2cc36866h

The synthesis of 1-methyl-3-(arylthio)-1H-indoles has been achieved by the photoredox reaction of N-methylindoles with readily available arylsulfonyl chlorides in moderate yields.

Full text of DOI:10.1039/c2cc36866h

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2012, 48, 11686–11688
www.rsc.org/chemcomm
COMMUNICATION
Visible light-induced 3-sulfenylation of N-methylindoles with arylsulfonyl
chloridesw
Min Chen, Zhi-Tang Huang and Qi-Yu Zheng*
Received 21st September 2012, Accepted 19th October 2012
DOI: 10.1039/c2cc36866h
The synthesis of 1-methyl-3-(arylthio)-1H-indoles has been achieved
by the photoredox reaction of N-methylindoles with readily
available arylsulfonyl chlorides in moderate yields.
Early in 1912, Ciamician predicted that photochemistry utilizing
sunlight could be prosperous in the not too distant future because
of its natural abundance and cleanliness.1 However, how to exploit
the energy from the sun is still a great challenge in this century.2
Recently, the visible light mediated photoredox reactions3 with Ru
(or Ir) poly-pyridine complexes4 as photosensitizers have attracted
significant interest from the research groups of MacMillan,5
Yoon,6 Stephenson7 and others.8 Among their elegant work,
it is very important to investigate potential compounds initiating
the photocatalysis cycle or generating highly reactive intermediates
via whatever oxidative or reductive quenching cycle.3a,e Until now,
the scope of reductive agents is limited, and only tertiary amines
have many applications. They can give rise to iminium inter-
mediates, which are prone to further functionalization.9 More-
over, indole derivatives,10 as intriguing motifs due to their
Scheme 1 Sulfonyl chlorides involved in photoredox reactions.
sulfonyl chloride with no collapse of the TsCl radical anion
fascinating bioactivities, can be deemed as enamines to some extent.
(Scheme 1b).7h Due to the interest in visible light induced reactions
of available starting materials, we herein accidentally discovered the
reaction of N-methylindoles and arylsulfonyl chlorides with not
only the release of chlorides but also the extrusion of oxygens,
generating 3-sulfenylated indoles14 (Scheme 1c).
They are rarely involved in initiating photoredox reactions,7d
though their redox potentials (E1/2 of N-methylindole = 0.79 V
vs. SCE)11 and unique electrochemical behaviors12 show that
they may serve as reductive quenchers.
On the other hand, oxidants also play an important role in
such photoredox catalyses, to construct C–C or C–X bonds in
the reactions of polyhalogen alkanes or halides.5b,7a,b,g However, to
the best of our knowledge, visible light induced reactions, in which
readily available sulfonyl chlorides13 participate, are still rare. One
example was reported by Nagib and MacMillan, which involves
visible light induced trifluoromethylation of arenes or heteroarenes
utilizing trifluoromethanesulfonyl chloride with first generation of
the CF3SO2Cl radical anion by oxidation of Ru(phen)32+* and
then release of SO2 and chloride (Scheme 1a).5c Another example
was discovered by Stephenson et al., which involves visible light-
mediated atom transfer radical addition of styrenes using p-toluene
Our initial work was the reaction of N-methylindole (1a)
with TsCl (2a) in the presence of 2 mol% Ru(bpy)3Cl2 in an Ar
atmosphere under visible light in acetonitrile, which afforded
23% of the product 1-methyl-3(p-tolylthio)-1H-indole (3a) with
the complete consumption of 1a (Table S1, entry 1, see ESIw).
The structure of 3a was confirmed by the X-ray analysis (Fig. 1).
Inspired by this result, we screened some bases which may serve
as deacid reagents, for removing HCl generated in the reaction.
Beijing National Laboratory for Molecular Sciences, CAS Key
Laboratory of Molecular Recognition and Function, Chinese Academy
of Sciences, Beijing 100190, China. E-mail: zhengqy@iccas.ac.cn;
Fax: +86 010 62554449; Tel: +86 010 62652811
w Electronic supplementary information (ESI) available: Detailed
experimental procedures and analytical data. CCDC 902004 (3a).
For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c2cc36866h
Fig. 1 The crystal structure of 3a (C: gray; H: white; N: blue; S: yellow).
c
11686 Chem. Commun., 2012, 48, 11686–11688
This journal is The Royal Society of Chemistry 2012

View Article Online
However, the reactions rarely took place no matter which organic
or inorganic bases were added (Table S1, entries 2–6, ESIw). So we
turned to adjust the ratio of 1a/2a, and surprisingly found that
3 equiv. of 1a benefited the yield dramatically albeit a slightly
higher yield with more 1a (Table S1, entries 7–9, ESIw).
Table 2 Scope of indoles
Temperature had a little effect on the reactions (Table S1,
entries 10 and 11, ESIw). Moreover, the counteranion of
photocatalyst, PF6À, seemed to be beneficial to the yield
(Table S1, entry 12, ESIw). Further optimization of the reac-
tion was focused on the media. Other polar solvents such as
DMF, DMSO and NMP gave rise to no products, as did
mixed solvent or solvent with 4 A molecular sieves (Table S1,
entries 13–17, ESIw). Last, control experiments showed that a
photocatalyst and visible light were essential.
With the optimized reaction conditions in hand, we then
explored the scope of arylsulfonyl chlorides (Table 1). o-, m- or
p-Toluene sulfonyl chlorides and benzene sulfonyl chloride could be
utilized to give the corresponding products 3 in moderate yields
(Table 1, 3a–d). Steric hindrance of o-methyl made the reaction
sluggish, with longer reaction time and lower yield (Table 1, 3b).
Sulfenylating reagents 2 bearing both electron-donating (Table 1,
3h) as well as electron-withdrawing groups (Table 1, 3e–g)
generated products in almost the same yields. 1-Naphthyl
sulfonyl chloride could afford the product in just 45% yield
because of the steric hindrance effect (Table 1, 3i). This reaction
was available for heteroaryl sulfonyl chloride too (Table 1, 3j).
By varying the substituents on indoles 1, we further investigated
the scope of indoles (Table 2). N-methyl indoles bearing groups on
C-5 with either electron-donating or withdrawing groups could
react with 2h to provide sulfenylated products respectively (Table 2,
4a–c). Substitutions on various positions of the N-methylindole
a
Unless otherwise specified, all reactions were carried out with
1 (3 mmol), 2h (1 mmol), photocatalyst (2 mol%) in CH3CN, under 23 w
fluorescent light at 40 1C under the atmosphere of Ar for 12 h, and the
b
c
d
yield is isolated yield. 24 h. 48 h. 4 equiv. of free (N–H) indole
were used.
are also tolerated (Table 2, 4d–e). However, the reaction of Br
or Cl-substituted N-methyl indole was a little complex, and the
reason is unknown. Besides N-methyl indoles, other N-substituted
groups were also involved (Table 2, 4f–h). N-benzyl indole worked
well (Table 2, entry 4f), but N-Boc indole didn’t react at all
(Table 2, entry 4h), which may be explained by its high redox
potential (E1/2 of N-Boc indole = 1.6 V vs. SCE) and weak
nucleophilic ability, since no 4h was detected in the reaction of
3 mmol 1a, 3 mmol N-Boc indole and 1 mmol TsCl under
standard conditions. To our delight, when 4 equiv. of free
(N–H) indole reacted with TsCl, the corresponding product
was obtained in 33% yield (Table 2, entry 4g).
Table 1 Scope of arylsulfonyl chlorides
Although the Friedel–Crafts reaction of indoles with sulfonyl
chlorides in the presence of Lewis acid was well developed, the
sulfonylated product or related intermediates were not involved in
the reaction under discussion. This was confirmed by the reaction
of 1-methyl-3-tosyl-1H-indole under standard conditions with or
without 1a (Scheme 2a). The sulfenylation exclusively occurred at
C3 rather than C2 of N-methylindole, indicating that no routine
of radical addition to indoles occurred15 but nucleophilic attack
of electron-rich N-methylindoles did. As sulfenyl chlorides are
reactive sulfenylating agents especially for indoles,16 we deduced
that p-tolyl hypochlorothioite 11 was produced in this reductive
system somewhat similar to what You16a reported via multiple
steps SET. Although a detailed process of reduction of TsCl to
p-tolyl hypochlorothioite was not clear, partially reductive
intermediate 4-methylbenzene-1-sulfinic chloride (10) may be
generated. So the reaction of 10 with 1a was carried out, yielding
3a in 64% yield (Scheme 2b). Moreover, addition products with
other byproducts have been detected via GC-MS.17
a
Unless otherwise specified, all reactions were carried out with 1a
While the mechanism of this photoredox reaction was not very
clear, the hypothetical process may include: (i) 1a reductively
quenching 7 to generate highly reductive 8, (ii) 2a being reduced
to 9 by getting an electron from 8, (iii) three other steps of SET
(3 mmol), 2 (1 mmol), photocatalyst (2 mol%) in CH3CN, under 23 W
fluorescent light at 40 1C under the atmosphere of Ar for 12 h, and the
yield is isolated yield. 24 h.
b
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 11686–11688 11687

View Article Online
4 For selected references, see (a) S. Campagna, P. Francesco,
G. Bergamini, V. Balzani, C. Inorganica and C. Analitica, Top.
Curr. Chem., 2007, 280, 117; (b) H. B. Ross, M. Boldaji,
P. D. Rillema, C. B. Blanton and R. P. White, Inorg. Chem.,
1989, 28, 1013; (c) D. P. Rillema, D. G. Taghdiri, D. S. Jones,
C. D. Keller, L. A. Worl, T. J. Meyer and H. A. Levy, Inorg.
Chem., 1987, 26, 578.
5 For selected references, see (a) A. McNally, C. K. Prier and
D. W. C. MacMillan, Science, 2011, 334, 1114; (b) D. A.
Nicewicz and D. W. C. MacMillan, Science, 2008, 322, 77;
(c) D. A. Nagib and D. W. C. MacMillan, Nature, 2011, 480, 224;
(d) P. V. Pham, D. A. Nagib and D. W. C. MacMillan, Angew.
Chem., Int. Ed., 2011, 50, 6119; (e) D. A. Nagib, M. E. Scott and
D. W. C. MacMillan, J. Am. Chem. Soc., 2009, 131, 10875.
6 For selected references, see (a) J. Du and T. P. Yoon, J. Am. Chem.
Soc., 2009, 131, 14604; (b) J. Du, L. R. Espelt, I. A. Guzei and
T. P. Yoon, Chem. Sci., 2011, 2, 2115; (c) M. A. Ischay, M. S. Ament
and T. P. Yoon, Chem. Sci., 2012, 3, 2807; (d) M. A. Ischay,
M. E. Anzovino, J. Du and T. P. Yoon, J. Am. Chem. Soc., 2008,
130, 12886; (e) M. A. Ischay, Z. Lu and T. P. Yoon, J. Am. Chem. Soc.,
2010, 132, 8572; (f) S. Lin, M. A. Ischay, C. G. Fry and T. P. Yoon,
J. Am. Chem. Soc., 2011, 133, 19350.
Scheme 2 Control experiments.
7 For selected literature, see (a) C. Dai, J. M. R. Narayanam and
C. R. J. Stephenson, Nat. Chem., 2011, 3, 140; (b) J. M. R.
Narayanam, J. W. Tucker and C. R. J. Stephenson, J. Am. Chem.
Soc., 2009, 131, 8756; (c) A. G. Condie, J. C. Gonzalez-Gomez and
C. R. J. Stephenson, J. Am. Chem. Soc., 2010, 132, 1464;
(d) L. Furst, J. M. R. Narayanam and C. R. J. Stephenson, Angew.
Chem., Int. Ed., 2011, 50, 9655; (e) J. D. Nguyen, J. W. Tucker,
M. D. Konieczynska and C. R. J. Stephenson, J. Am. Chem. Soc.,
2011, 133, 4160; (f) J. W. Tucker, J. M. R. Narayanam, P. S. Shah
and C. R. J. Stephenson, Chem. Commun., 2011, 47, 5040;
(g) J. W. Tucker, J. D. Nguyen, J. M. R. Narayanam,
S. W. Krabbe and C. R. J. Stephenson, Chem. Commun., 2010,
46, 4985; (h) C. J. Wallentin, J. D. Nguyen, P. Finkbeiner and
C. R. J. Stephenson, J. Am. Chem. Soc., 2012, 134, 8875.
8 For selected references, see (a) Y. Miyake, K. Nakajima and
Y. Nishibayashi, J. Am. Chem. Soc., 2012, 134, 3338; (b) J. Xuan,
Y. Cheng, J. An, L.-Q. Lu, X.-X. Zhang and W.-J. Xiao, Chem.
Commun., 2011, 47, 8337; (c) Y.-Q. Zou, L.-Q. Lu, L. Fu,
N.-J. Chang, J. Rong, J.-R. Chen and W.-J. Xiao, Angew. Chem.,
Int. Ed., 2011, 50, 7171; (d) Y.-Q. Zou, J.-R. Chen, X.-P. Liu,
L.-Q. Lu, R. L. Davis, K. A. Jørgensen and W.-J. Xiao, Angew.
Chem., Int. Ed., 2012, 51, 784; (e) G. Zhao, C. Yang, L. Guo,
H. Sun, C. Chen and W. Xia, Chem. Commun., 2012, 48, 2337;
(f) Y. Su, L. Zhang and N. Jiao, Org. Lett., 2011, 13, 2168.
9 D. B. Freeman, L. Furst, A. G. Condie and C. R. J. Stephenson,
Org. Lett., 2012, 14, 94.
Scheme 3 Proposed mechanism.
generating key intermediate 11,18 and (iv) 11 attacking 1a to
produce 12, which was finally transformed into the major
product 3a (Scheme 3).
In conclusion, we have developed a method to synthesize
1-methyl-3-(arylthio)-1H-indoles by the photoredox reactions
of N-methylindoles with readily available arylsulfonyl chlorides
in moderate yields. Further study on the photoredox of aryl-
sulfonyl chlorides is ongoing.
10 R. B. Van Order and H. G. Lindwall, Chem. Rev., 1942, 30, 69.
11 S. Marguet, P. Hapiot and P. Neta, J. Phys. Chem., 1994, 98, 7136.
12 A. Berlina and A. Canavesi, Tetrahedron, 1996, 52, 7947.
13 K. Bahrami, M. M. Khodaei and M. Soheilizad, J. Org. Chem.,
2009, 74, 9287.
14 (a) W. Ge and Y. Wei, Green Chem., 2012, 14, 2066; (b) Z. Li,
J. Hong and X. Zhou, Tetrahedron, 2011, 67, 3690; (c) Y. Maeda,
M. Koyabu, T. Nishimura and S. Uemura, J. Org. Chem., 2004,
69, 7688; (d) M. Tudge, M. Tamiya, C. Savarin and G. R. Humphrey,
Org. Lett., 2006, 8, 565.
Financial support from the Major State Basic Research Devel-
opment Program of China (2011CB808602) is acknowledged.
Notes and references
1 G. Ciamician, Science, 1912, 36, 385.
2 N. S. Lewis, Science, 2007, 315, 798.
15 L. Furst, B. S. Matsuura, J. M. R. Narayanam, J. W. Tucker and
C. R. J. Stephenson, Org. Lett., 2010, 12, 3104.
3 For selected references, see (a) K. Zeitler, Angew. Chem., Int. Ed.,
2009, 48, 9785; (b) F. Teply, Collect. Czech. Chem. Commun., 2011,
76, 859; (c) J. Xuan and W.-J. Xiao, Angew. Chem., Int. Ed., 2012,
51, 6828; (d) J. M. R. Narayanam and C. R. J. Stephenson, Chem.
Soc. Rev., 2011, 40, 102; (e) J. W. Tucker and C. R. J. Stephenson,
J. Org. Chem., 2012, 77, 1617; (f) T. P. Yoon, M. A. Ischay and
J. Du, Nat. Chem., 2010, 2, 527; (g) L. Shi and W.-J. Xia, Chem.
Soc. Rev., DOI: 10.1039/c2cs35203f.
16 (a) Q. Wu, D. Zhao, X. Qin, J. Lan and J. You, Chem. Commun.,
2011, 47, 9188; (b) Y. Chen, C. H. Cho and R. C. Larock, Org.
Lett., 2009, 11, 173; (c) P. Hamel, J. Org. Chem., 2002, 67, 2854;
(d) M. Raban and L. J. Chern, J. Org. Chem., 1980, 45, 1688.
17 For GC-MS scheme and other byproducts, see ESIw.
18 The detailed process is not clear now. And reductive agents
providing electrons may not only be 1a but also 5 or other
oligomers, for the system consist of only 3 equiv. of 1a.
c
11688 Chem. Commun., 2012, 48, 11686–11688
This journal is The Royal Society of Chemistry 2012