Transition-metal-free, visible-light induced cyclization of arylsulfonyl chlorides with o-azidoarylalkynes: a regiospecific route to unsymmetrical 2,3-disubstituted indoles

Article abstract of DOI:10.1039/c6cc10305g

A visible-light-catalyzed synthesis of unsymmetrical 2,3-diaryl-substituted indoles from arylsulfonyl chlorides and o-azidoarylalkynes at room temperature has been discovered. This transformation exhibits excellent substrate scope and functional group tolerance. The use of inexpensive eosin Y as the catalyst with easy operation makes this protocol very practical.

Full text of DOI:10.1039/c6cc10305g

ChemComm
View Article Online
View Journal
COMMUNICATION
Transition-metal-free, visible-light induced
cyclization of arylsulfonyl chlorides with
o-azidoarylalkynes: a regiospecific route to
unsymmetrical 2,3-disubstituted indoles†
Cite this:DOI: 10.1039/c6cc10305g
Received 29th December 2016,
Accepted 22nd February 2017
Lijun Gu,*a Cheng Jin,b Wei Wang,a Yonghui He,a Guangyu Yangc and Ganpeng Lia
DOI: 10.1039/c6cc10305g
rsc.li/chemcomm
A visible-light-catalyzed synthesis of unsymmetrical 2,3-diaryl- approach to activate chemical transformations.5 Many visible-
substituted indoles from arylsulfonyl chlorides and o-azidoarylalkynes light photoredox catalysts, such as Ru or Ir complexes and
at room temperature has been discovered. This transformation exhibits organic dye catalysts have been used to solve the problem of
excellent substrate scope and functional group tolerance. The use of poor visible light absorption efficiency.6 Visible-light photoredox
inexpensive eosin Y as the catalyst with easy operation makes this catalysts are capable of engaging in single-electron-transfer
protocol very practical.
(SET) events in their photoexcited states. Some groundbreaking
studies have reported unusual chemical reactions induced by
Polysubstituted indoles are not only common motifs in natural photoredox catalysis, in particular, SET-based photoredox
products and pharmaceuticals, but also useful building blocks activation processes.7
for the construction of highly complex target structures.1 The
Given the wide availability of arylsulfonyl chlorides with some
importance of indole motifs has initiated substantial research of them, such as p-toluenesulfonyl chloride, produced indust-
efforts directed towards the development of efficient synthetic rially on a multi-ton scale, they appear to be an attractive class
strategies to prepare this heteroarene.2,3 As important members of of compounds for the formation of aryl radicals.6d Recently,
the indole family, 2,3-disubstituted indole derivatives are core we developed a visible-light induced cyclization of arylsulfonyl
structures in some bioactive natural products.1f In this regard, chlorides with 2-isocyanobiphenyls for the synthesis of phenan-
there are many reports on the synthesis of 2,3-disubstituted indole thridines.8 We hypothesized that o-azidoarylalkynes may serve
derivatives.4 Generally, the complementary synthesis of indole as a platform to trap aryl radicals, a transformation that to our
derivatives with a predictable 2,3-substitution pattern meets with knowledge has not previously been described. Herein, we disclose
certain restrictions. For the case of unsymmetrical 2,3-diarylated our preliminary results on the visible-light-promoted transforma-
derivatives, the use of transition-metal catalysis has enabled some tion of arylsulfonyl chlorides and o-azidoarylalkynes used for the
elegant solutions to this problem. Recently, Zhang developed the synthesis of unsymmetrical 2,3-diaryl-substituted indoles at room
gold-catalyzed annulation of o-azidoarylalkynes with electron- temperature without the requirement for strong acids, strong
rich arenes for the synthesis of unsymmetrical 2,3-disubstituted bases or organometallic reagents. This new method offers rapid
indoles.4a Very recently, the group of Wan reported the rhodium- access to unsymmetrical 2,3-diaryl-substituted indoles from
catalyzed C–H annulation of nitrones with alkynes for the for- simple and readily available arylsulfonyl chlorides. The signifi-
mation of unsymmetrical 2,3-diaryl-substituted indoles.4g However, cance of the present finding is two-fold: (1) simple and readily
these reactions employ transition metals as the catalyst. To date, available eosin Y emerges as an efficient catalyst, rather than
the synthesis of unsymmetrical 2,3-diaryl-substituted indoles under a transition-metal catalyst, which is often expensive and is
visible-light irradiation has not been realized.
required to be completely removed from the products, especially
Harvesting of energy from visible light, the most abundant in the synthesis of pharmaceutical compounds, and (2) visible-
part of the solar spectrum, is a sustainable and cost-effective light is employed as a safe, renewable and inexpensive source of
chemical energy to facilitate the construction of unsymmetrical
a Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs
Commission & Ministry of Education, Yunnan Minzu University, Kunming,
Yunnan, 650500, China. E-mail: gulijun2005@126.com
b New United Group Company Limited, Changzhou, Jiangsu 213166, China
c Key Laboratory of Tobacco Chemistry of Yunnan Province,
2,3-diaryl-substituted indoles (Scheme 1).
As an initial test reaction, the simple benzenesulfonyl chloride
1a was treated with the o-azidophenylalkyne 2a and 1,4-cyclo-
hexadiene (1,4-CHD) in DMF in the presence of eosin Y and the
inorganic base Na2CO3 at room temperature for 14 h. The desired
Yunnan Academy of Tobacco Science, Kunming, Yunnan, 650106, China
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6cc10305g 2,3-diphenyl-1H-indole 3aa was obtained, albeit in a low yield
This journal is ©The Royal Society of Chemistry 2017
Chem. Commun.

View Article Online
Communication
ChemComm
Scheme 2 Control experiment.
reaction conditions were applicable to a wide range of aryl-
sulfonyl chlorides 1. The results showed that the cyclization
reaction could be realized in a good yield irrespective of the
nature and the position of the aryl substituents on the aryl-
sulfonyl chloride 1. In addition, a variety of functional groups
were tolerated and the efficiency of the reaction was not affected
in the presence of halides, ethers and alkyl groups. Notably, the
halogens F and Cl were tolerated under the reaction conditions,
thereby facilitating additional modification at the halogenated
positions. The application of naphthalene-1-sulfonyl chloride 1h
delivers the desired products in 64% yield (Table 2, entry 7). Apart
from benzenesulfonyl chloride 1a, thiophene-2-sulfonyl chloride
1i reacted smoothly with 2a and led to the corresponding product
3ai in 57% yield (Table 2, entry 8). To further explore the potential
of our methodology, trifluoro-methanesulfonyl chloride 1j was
subjected to the standard reaction conditions (Table 2, entry 9)
and the desired product was isolated in a low yield (31%).
Subsequently, we examined the generality of this visible-
light initiated cyclization reaction with respect to a range of
o-azidoarylalkynes 2 (Table 3). Gratifyingly, both electron-
donating and electron-withdrawing aromatic substituents were
tolerated in the terminal alkyne. We were pleased to find that
heteroaryl-substituted alkyne 2d was also a suitable substrate
and allowed the formation of 3da in 63% yield. It was found
that the reactions of 2e with 1a proceeded well and gave the
desired indole in 69% yield. However, the optimized reaction
conditions were not applicable to substrate 2f, which bears an
alkyl group in the terminal alkyne. To highlight the utility of
this transformation, representative 2-phenylethynyl arylazides
were selected to illustrate the tolerance for substituents on the
aryl ring of the 1-(azido)benzene moiety. Electron-withdrawing-
Scheme 1 The synthesis of unsymmetrically 2,3-diaryl substituted indoles
via the cyclization of o-azidoarylalkynes.
Table 1 Optimization of the reaction conditionsa
Entry
Catalyst
Solvent
Base
Yieldb (%)
1
Eosin Y
Eosin Y
Eosin Y
Eosin Y
Eosin Y
Eosin Y
Eosin Y
Eosin Y
Eosin Y
Rose Bengal
[Ru(bpy)3Cl2]
[Ir(ppy)3]
Eosin Y
Eosin Y
Eosin Y
None
DMF
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2HPO4
NaHCO3
K2CO3
36
58
30
Trace
9
74
53
32
15
12
Trace
19
26
33
0
2c
3
MeCN
DMSO
THF
4
5
6
7
8
9
10
11
12
13c
14d
15e
16
EtOAc
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
Et3N
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
0
a
Reaction conditions: 1a (0.35 mmol), 2a (0.3 mmol), base (0.3 mmol),
catalyst (3 mol%), solvent (2.0 mL), room temperature, Ar atmosphere,
1,4-CHD (0.45 mmol), 5 W blue LED (lmax = 455 nm) light for 14 h.
b
c
Isolated yield. Hantzsch ester (0.45 mmol) was used instead of 1,4-
d
e
CHD. Ph3SiH (0.45 mmol) was used instead of 1,4-CHD. Without
additional light.
(Table 1, entry 1). Extensive screening of the solvents revealed that group-substituted substrates 2g–2j were compatible with the
MeCN provided the best results (Table 1, entries 2–5). Switching domino sequence. Substrate 2 bearing electron-donating groups,
the base to Na2HPO4 resulted in a significant improvement in the such as methyl and methoxyl, proceeded smoothly in the reaction
yield. Other bases, such as NaHCO3, K2CO3 and Et3N, were less and gave the desired indoles in moderate to good yields (Table 3,
efficient than Na2HPO4 (Table 1, entries 6–9). It was found that entries 10 and 11). The visible-light initiated domino reactions
eosin Y was superior to other visible-light photoredox catalysts can tolerate some functional groups such as an alkyl group,
(Table 1, entries 10–12). To improve the reaction yield, different ethers and C–Cl bonds, which could be used for further modi-
hydrogen sources were added to the reaction (Table 1, entries 13 fication at the substituted positions.
and 14). However, no higher yield of 2a was observed. The
In order to gain some more information on the reaction
reaction did not take place in the absence of either the visible- mechanism, several control reactions were performed as shown
light photoredox catalysts or additional visible light (Table 1, in Scheme 2. When the reaction of 1a with 2a was carried out in
entries 15 and 16).
the presence of a stoichiometric amount of 2,2,6,6-tetramethyl-
With the best conditions in hand, the scope of the [eosin Y]- 1-piperidinyloxy (TEMPO, a well-known radical-capturing species),
facilitated, visible-light induced cyclization protocol was inves- the reaction was completely suppressed (Scheme 2). These results
tigated with regard to the scope of the arylsulfonyl chloride 1 suggest that a radical process may be involved in this transformation.
and o-azidoarylalkyne 2. As shown in Scheme 2, the optimal Furthermore, the product yield dropped significantly when no
Chem. Commun.
This journal is ©The Royal Society of Chemistry 2017

View Article Online
ChemComm
Communication
Table 2 Scope of the arylsulfonyl chloride 1a
Table 3 Scope of the o-azidoarylalkyne 2a
Yieldb (%)
84
Entry
1
Arylsulfonyl chloride 1
Indole 3
Yieldb (%)
74
Entry
1
Azidoarylalkyne 2
Indole 3
2
3
77
63
2
3
68
71
4
69
4
5
70
62
5
6
0
67
7
51
58
70
74
6
68
64
8
7
8
9
10
57
31
11
66
9
a
Reaction conditions: 1a (0.35 mmol),
2
(0.3 mmol), Na2HPO4
(0.3 mmol), eosin Y (3 mol%), MeCN (2.0 mL), room temperature, Ar
a
Reaction conditions:
1 (0.35 mmol), 2a (0.3 mmol), Na2HPO4
atmosphere, 1,4-CHD (0.45 mmol), 5 W blue LED light (lmax = 455 nm)
(0.3 mmol), eosin Y (3 mol%), MeCN (2.0 mL), room temperature, Ar
atmosphere, 1,4-CHD (0.45 mmol), 5 W blue LED (lmax = 455 nm) light
for 14 h. Isolated yield.
b
for 14 h. Isolated yield.
b
of Phꢀ to the alkynyl moiety of 2a forms intermediate A, which
photocatalyst was present in the reaction and/or under dark immediately undergoes the intramolecular cyclization of the alkenyl
conditions (Scheme 3). radical with the azido moiety to produce the N-radical intermediate B
Based on these observations, we proposed a rationale for this with extrusion of N2 gas. H-Atom abstraction from 1,4-CHD will form
visible-light initiated cyclization reaction.8–10 We reasoned that SET the desired product 3aa and generate the radical C, which closes the
+
reduction of benzenesulfonyl chloride 1a will occur upon photo- photoredox cycle by SET with PCꢀ .
catalyst excitation using visible light irradiation, delivering the
In conclusion, we have demonstrated a facile, transition-metal-
+
phenyl radical (Phꢀ) and [eosin Y]ꢀ . Subsequently, the addition free and direct annulation approach for access to a variety of
This journal is ©The Royal Society of Chemistry 2017
Chem. Commun.

View Article Online
Communication
ChemComm
Angew. Chem., Int. Ed., 2011, 50, 1338; (m) H. G. Wang, C. Grohmann,
C. Nimphius and F. Glorius, J. Am. Chem. Soc., 2012, 134, 19592; (n) L. Y.
Zheng and R. M. Hua, Chem. – Eur. J., 2014, 20, 2352; (o) N. Isono and
M. Lautens, Org. Lett., 2009, 11, 1329; (p) S. P. Breazzano, Y. B. Poudel
and D. L. Boger, J. Am. Chem. Soc., 2013, 135, 1600; (q) P. Y. Tao and
Y. X. Jia, Chem. Commun., 2014, 50, 7367; (r) J. Bonnamour and C. Bolm,
Org. Lett., 2011, 13, 2012; (s) Q. Nguyen, T. Nguyen and T. G. Driver,
J. Am. Chem. Soc., 2013, 135, 620; (t) C. J. Wu, Q. Y. Meng, T. Lei,
J. J. Zhong, W. Q. Liu, L. M. Zhao, Z. J. Li, C. H. Tung and L. Z. Wu,
ACS Catal., 2016, 6, 4635.
4 Selected examples for the synthesis of 2,3-disubstituted indoles see:
(a) B. Lu, Y. D. Luo, L. Z. Liu, L. W. Ye, Y. Z. Wang and L. M. Zhang,
Angew. Chem., Int. Ed., 2011, 50, 8358; (b) D. R. Stuart, M. Bertrand-
Laperle, K. M. N. Burgess and K. Fagnou, J. Am. Chem. Soc., 2008,
130, 16474; (c) Y. Wei, I. Deb and N. Yoshikai, J. Am. Chem. Soc.,
2012, 134, 9098; (d) L. Fra and K. Muniz, Chem. – Eur. J., 2016,
22, 4351; (e) Y. Hoshino, Y. Shibata and K. Tanaka, Adv. Synth.
Catal., 2014, 356, 1577; ( f ) G. Y. Zhang, H. Yu, G. P. Qin and
H. M. Huang, Chem. Commun., 2014, 50, 4331; (g) H. Yan, H. L.
Wang, X. C. Li, X. Y. Xin, C. X. Wang and B. S. Wan, Angew. Chem.,
Int. Ed., 2015, 54, 10613.
5 For selected reviews on visible-light photoredox catalysis, see:
(a) J. Xuan and W. J. Xiao, Angew. Chem., Int. Ed., 2012, 51, 6828;
(b) T. P. Yoon, M. A. Ischay and J. Du, Nat. Chem., 2010, 2, 527;
(c) C. K. Prier, D. A. Rankic and D. W. MacMillan, Chem. Rev., 2013,
113, 5322; (d) K. Zeitler, Angew. Chem., Int. Ed., 2009, 48, 9785;
(e) L. Shi and W. Xia, Chem. Soc. Rev., 2012, 41, 7687; ( f ) I. Ghosh,
Scheme 3 Plausible reaction mechanism.
unsymmetrical 2,3-diaryl-substituted indoles via a visible-light
initiated cascade cyclization process with predictable regio-
selectivity upon the reaction of a variety of arylsulfonyl chlorides
with various 2-alkynyl arylazides. These reactions exhibit excellent
substrate scope and functional group tolerance. The use of
inexpensive eosin Y as the catalyst with easy operation makes
this protocol very practical. Further investigations on the
mechanism of the reaction and its application are ongoing in
our laboratory.
¨
L. Marzo, A. Das, R. Shaikh and B. Konig, Acc. Chem. Res., 2016,
49, 1566; (g) M. H. Shaw, J. Twilton and D. W. C. MacMillan, J. Org.
Chem., 2016, 81, 6898; (h) J. W. Tucker and C. R. J. Stephenson,
J. Org. Chem., 2012, 77, 1617; (i) K. L. Skubi, T. R. Blum and
T. P. Yoon, Chem. Rev., 2016, 116, 10035.
We are grateful for the financial support from the National
Natural Science Foundation of China (21662045) and the
Applied Basic Research Project of Yunnan (2016FB019) and
Innovative Research Team (in Science and Technology) in the
University of Yunnan Province (IRTSTYN 2014-11).
6 For recent selected examples for visible-light photoredox catalysts,
see: (a) H. Jiang, Y. Z. Cheng, R. Z. Wang, Y. Zhang and S. Y. Yu,
Chem. Commun., 2014, 50, 6164; (b) Y. S. Xu and W. D. Zhang,
ChemCatChem, 2013, 5, 2343; (c) G. B. Deng, Z. Q. Wang, J. D. Xia,
P. C. Qian, R. J. Song, M. Hu, L. B. Gong and J. H. Li, Angew. Chem.,
Int. Ed., 2013, 52, 1535; (d) J. D. Xia, G. B. Deng, M. B. Zhou, W. Liu,
P. Xie and J. H. Li, Synlett, 2012, 2707; (e) E. L. Tyson, Z. L. Niemeyer
and T. P. Yoon, J. Org. Chem., 2014, 79, 1427; ( f ) J. Xuan, Z. J. Feng,
S. W. Duan and W. J. Xiao, RSC Adv., 2012, 2, 4065; (g) J. Xuan,
X. D. Xia, T. T. Zeng, Z. J. Feng, J. R. Chen, L. Q. Lu and W. J. Xiao,
Angew. Chem., Int. Ed., 2014, 53, 5653; (h) J. Liu, Q. Liu, H. Yi, C. Qin,
R. P. Bai, X. T. Qi, Y. Lan and A. W. Lei, Angew. Chem., Int. Ed., 2014,
Notes and references
1 (a) Heterocyclic Scaffolds II: Reactions and Applications of Indoles,
ed. G. W. Gribble, Topics in Heterocyclic Chemistry, Springer,
Heidelberg, 2010, vol. 26; (b) S. Cacchi and G. Fabrizi, Chem. Rev.,
2011, 111, PR215; (c) H. T. Zhang, L. J. Gu, X. Z. Huang, R. Wang,
C. Jin and G. P. Li, Chin. Chem. Lett., 2016, 27, 256; (d) J. E. Saxton,
Nat. Prod. Rep., 1997, 14, 559; (e) D. F. Taber and P. K. Tirunahari,
Tetrahedron, 2011, 67, 7195; ( f ) A. J. Kochanowska-Karamyan and
M. T. Hamann, Chem. Rev., 2010, 110, 4489; (g) L. J. Gu, Y. S. Wang,
H. T. Zhang, H. J. Tang, G. P. Li and M. L. Yuan, ChemCatChem,
2016, 8, 2206.
2 For reviews on indole synthesis, see: (a) M. Shiri, Chem. Rev., 2012,
112, 3508; (b) G. R. Humphrey and J. T. Kuethe, Chem. Rev., 2006,
106, 2875; (c) G. W. Gribble, J. Chem. Soc., Perkin Trans. 1, 2000,
1045; (d) M. Inman and C. J. Moody, Chem. Sci., 2013, 4, 29; (e) T. L.
Guo, F. Huang, L. Yu and Z. K. Yu, Tetrahedron Lett., 2015, 56, 296.
3 For selected examples on indole synthesis, see: (a) G. Y. Zhang,
H. Yu, G. P. Qin and H. M. Huang, Chem. Commun., 2014, 50, 4331;
(b) M. Nakamura, L. I lies, S. Otsubo and E. Nakamura, Org. Lett.,
2006, 8, 2803; (c) S. Mu¨ller, M. J. Webber and B. List, J. Am. Chem.
Soc., 2011, 133, 18534; (d) D. McAusland, S. Seo, D. G. Pintori,
J. Finlayson and M. F. Greaney, Org. Lett., 2011, 13, 3667; (e) D. Zhao,
Z. Shi and F. Glorius, Angew. Chem., Int. Ed., 2013, 52, 12426;
( f ) R. C. Larock, E. K. Yum and M. D. Refvik, J. Org. Chem., 1998,
63, 7652; (g) J. L. Rutherford, M. P. Rainka and S. L. Buchwald, J. Am.
Chem. Soc., 2002, 124, 15168; (h) Z. Z. Shi and F. Glorius, Angew.
Chem., Int. Ed., 2012, 51, 9220; (i) F. Huang, P. Wu, L. D. Wang,
J. P. Chen, C. L. Sun and Z. K. Yu, J. Org. Chem., 2014, 79, 10553;
( j) W. Q. Yu, Y. F. Du and K. Zhao, Org. Lett., 2009, 11, 2417;
¨
53, 502; (i) D. P. Hari and B. Konig, Chem. Commun., 2014, 50, 6688;
( j) A. K. Yadav, V. P. Srivastava and L. D. S. Yadav, New J. Chem.,
2013, 37, 4119; (k) T. B. Xiao, L. Y. Li, G. L. Lin, Q. L. Wang, P. Zhang,
Z. W. Mao and L. Zhou, Green Chem., 2014, 16, 2418; (l) L. Gu, C. Jin,
J. Liu, H. Zhang, M. Yuan and G. Li, Green Chem., 2016, 18, 1201;
(m) L. Gu, C. Jin and J. Liu, Green Chem., 2015, 17, 3733;
¨
(n) D. P. Hari, P. Schroll and B. Konig, J. Am. Chem. Soc., 2012,
134, 2958; (o) M. Majek and A. J. Wangelin, Angew. Chem., Int. Ed.,
2015, 54, 2270; (p) G. W. Wei, L. Q. Lu, Y. Wang, Y. N. Wang,
J. R. Chen and W. J. Xiao, Angew. Chem., Int. Ed., 2015, 54, 2265;
¨
(q) T. Hering, D. P. Hari and B. Konig, J. Org. Chem., 2012, 77, 10347;
(r) C. P. Johnston, R. T. Smith, S. Allmendinge and D. W. C.
MacMillan, Nature, 2016, 535, 322.
7 For recent selected examples, see: (a) J. Jin and D. W. C. MacMillan,
Nature, 2015, 525, 87; (b) J. A. Terrett, J. D. Cuthbertson, V. W.
Shurtleff and D. W. C. MacMillan, Nature, 2015, 524, 330; (c) X. Zhang
and D. W. C. MacMillan, J. Am. Chem. Soc., 2016, 138, 13862; (d) I. Ghosh
¨
and B. Konig, Angew. Chem., Int. Ed., 2016, 55, 7676; (e) A. Das, I. Ghosh
¨
and B. Konig, Chem. Commun., 2016, 52, 8695; ( f ) Z. Yuan, Q. Wang,
A. Zheng, K. Zhang, L. Lu, Z. Tang and W.-J. Xiao, Chem. Commun., 2016,
52, 5128; (g) B. Sahoo, M. N. Hopkinson and F. Glorius, Angew. Chem.,
Int. Ed., 2015, 54, 15545.
8 L. J. Gu, C. Jin, J. Y. Liu, H. Y. Ding and B. M. Fan, Chem. Commun.,
2014, 50, 4643.
9 F. Chen, F. Meng, Q. S. Han and B. Han, Org. Lett., 2016, 18, 3330.
(k) J. L. Chen, G. Y. Song, C. L. Pan and X. W. Li, Org. Lett., 2010, 10 J. Davies, T. D. Svejstrup, D. F. Reina, N. S. Sheikh and D. Leonori,
12, 5426; (l) M. P. Huestis, L. Chan, D. R. Stuart and K. Fagnou,
J. Am. Chem. Soc., 2016, 138, 8092.
Chem. Commun.
This journal is ©The Royal Society of Chemistry 2017