Access to Benzo[a]carbazoles and Indeno[1,2-c]quinolines by a Gold(I)-Catalyzed Tunable Domino Cyclization of Difunctional 1,2-Diphenylethynes

Article abstract of DOI:10.1021/acs.orglett.7b01358

The cyclization order of the difunctional 1,2-diphenylethynes was precisely tuned under the catalysis of gold by changing the nitrogen substitution of the substrates, leading to the facile preparation of benzo[a]carbazole and indeno[1,2-c]quinoline derivatives. The mechanisms of these domino cyclizations were probed by control experiments, and an insight into the selectivity of the cyclization was gained by density functional theory (DFT) calculations. This research represents a unified and common method to access benzo[a]carbazoles and indeno[1,2-c]quinolines.

Full text of DOI:10.1021/acs.orglett.7b01358

Letter
pubs.acs.org/OrgLett
Access to Benzo[a]carbazoles and Indeno[1,2‑c]quinolines by a
Gold(I)-Catalyzed Tunable Domino Cyclization of Difunctional 1,2-
Diphenylethynes
Xiaoshi Peng,†,§ Lifeng Zhu,†,‡,§ Yuqian Hou,†,‡,§ Yadong Pang,†,‡,§ Yangming Li,†,‡,§ Jiayue Fu,†,‡,§
Lu Yang,†,‡,§ Bin Lin,*,†,§ Yongxiang Liu,*,†,‡,§ and Maosheng Cheng*,†,§
†Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education,
Shenyang 110016, P. R. China
‡Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, P. R. China
§Institute of Drug Research in Medicine Capital of China, Benxi, 117000, P. R. China
S
* Supporting Information
ABSTRACT: The cyclization order of the difunctional 1,2-
diphenylethynes was precisely tuned under the catalysis of
gold by changing the nitrogen substitution of the substrates,
leading to the facile preparation of benzo[a]carbazole and
indeno[1,2-c]quinoline derivatives. The mechanisms of these
domino cyclizations were probed by control experiments, and
an insight into the selectivity of the cyclization was gained by density functional theory (DFT) calculations. This research
represents a unified and common method to access benzo[a]carbazoles and indeno[1,2-c]quinolines.
enzo[a]carbazoles and indeno[1,2-c]quinolines represent
Btwo kinds of important heterocyclic skeletons for
discovering biologically active small molecules.1 A variety of
biological activities based on these scaffolds have been evaluated
such as anti-inflammatory,1a antifungal,1b antiproliferative,1c,d,f
antiosteoclastogenic,1e etc. Moreover, the benzo[a]carbazole
derivatives were also utilized in other fields such as dye-sensitized
solar cells (DSSC),2 light-emitting diodes (LEDs),3 and
fluorescent reagents.4 Benzo[a]carbazoles have been synthesized
extensively owing to the requirement of bioactive evaluation in
drug discovery and development and material science, which
sparked the development of a large number of synthetic
methodologies.2,5,6 The classic reactions such as thermal and
photochemical cyclizations,5c Fischer indolization,2,5a and
pericyclic reactions5b,d often suffered from harsh conditions
and long synthetic steps. Metal-catalyzed reactions have been
developed recently,6 such as functionalizations of indole
substrates,6a,b,e,f indole fomation/benzannulation,6c,d,g−i etc. In
contrast, there were few reports on the synthesis of indeno[1,2-
c]quinolines and the representative one was a multistep synthesis
starting from isatin and 4-methoxyphenylacetic acid.1c Tradi-
tionally, these two scaffolds were synthesized in distinctive
synthetic routes designed individually. In this study we
succeeded in constructing either a benzo[a]carbazole or
indeno[1,2-c]quinoline scaffold only by a single change of
substitution on the same substrate.
catalyzed pathway-controllable domino cyclizations,8 including
solvent-controlled cyclizations,8a angle strain-controlled cycliza-
tions,8b substitution-controlled cyclizations,8c and hydrogen
bond-controlled cyclizations.8d In this study, we observed an
interesting diverted domino cyclization of the difunctional 1,2-
diphenylethyne substrate with a sulfonamide and an electron-
rich enol ether on the aromatic rings. By tuning the electronic
nature of the amine, two distinguished nitrogen-containing
heterocycles benzo[a]carbazoles (Scheme 1, path a) and
indeno[1,2-c]quinolines (Scheme 1, path b) were synthesized
by changing the cyclization order of the difunctional groups.
Herein, we reported a concise pathway-controllable strategy to
the synthesis of structurally distinctive benzo[a]carbazoles and
indeno[1,2-c]quinoline scaffolds by employing the same
substrates with only a single change of substitution on the amine.
We first synthesized an alkyne substrate 1 with p-toluene-
sulfonamide and electron-rich alkene difunctional groups
installed on the aromatic rings. Then our research was
commenced by screening the optimal conditions. When the
substrate 1 was subjected to the commercially available gold
catalyst [bis(trifluoromethanesulfonyl)imidate] (triphenylpho-
sphine) gold(I) (Ph3PAuNTf2) (10 mol %) in toluene at 100 °C,
the benzo[a]carbazole 2 derived from the nucleophilic addition
of nitrogen in priority to the alkene was isolated with a yield of
33% (Scheme 1, path a). This promising result encouraged us to
screen the conditions systematically (see Table S1). Finally, the
optimal conditions were identified to include stirring the reaction
Gold-catalyzed pathway-controllable reactions have attracted
much attention for their potential in the rapid construction of
structurally diverse heterocyclic frameworks efficiently.7 Efforts
in our laboratory have been devoted to developing novel
methodologies in synthesizing heterocycles based on gold-
Received: May 5, 2017
© XXXX American Chemical Society
A
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Letter
surprisingly an indeno[1,2-c]quinoline product derived from
the addition of methoxyethelene to alkyne/cyclization and
bisbenzylic oxidation9 was isolated with a yield of 35% (Scheme
1, path b). This interesting result prompted us to prepare
indeno[1,2-c]quinolines. It was found that the E-geometry of
alkene had a profound influence on the improvement of yields
besides the substitution of amine. Thorough examination of
different parameters resulted in the optimal conditions as
follows: stirring the reaction in toluene at 50 °C under an
oxygen atmosphere overnight under the catalysis of 5 mol %
Ph3PAuNTf2 (see Table S2).
Scheme 1. Pathway-Controllable Synthesis of
Benzo[a]carbazoles and Indeno[1,2-c]quinolines
With the optimal conditions in hand, the scopes of the gold(I)-
catalyzed domino cyclization to benzo[a]carbazoles were
explored using the precursors with an E-geometrical alkene
prepared for the synthesis of indeno[1,2-c]quinolines. Most
examined substrates gave acceptable yields and clean reaction
profiles (Scheme 3, 4a−4r). The structures of the products were
determined by NMR spectroscopy and further confirmed by a
single crystal X-ray diffraction (Scheme 3, 4q).
in toluene at 100 °C for 2 h under the catalysis of 10 mol %
Ph3PAuCl/AgBF4.
Scheme 3. Substrate Scopes of Indeno[1,2-c]quinolines
Next, a systematic examination of the scopes of the domino
cyclization under the optimal conditions was conducted by
synthesizing a series of substrates with bisfunctional groups using
the general procedures. A variety of functional groups such as Cl,
F, Me, and OMe in both aryl rings of the substrates were well
tolerated, and acceptable yields were obtained from the
substrates with both electron-donating and -withdrawing
substitutions on the aryl rings (Scheme 2, 2a−2s). The
Scheme 2. Substrate Scopes of Benzo[a]carbazoles
To probe the detailed reaction mechanism, some control
experiments were performed as shown in Tables 1 and 2. When
substrate 1 was subjected to a gold(I) catalyst, an indole
intermediate 2′ resulting from the p-toluenesulfonamide attack
Table 1. Control Experiments for the Synthesis of
Benzo[a]carbazoles
replacement of the substitution on nitrogen by the 4-
nitrobenzenesulfonyl (Ns) group resulted in a lower yield
(Scheme 2, 2t). During exploring the substrate scopes of the
domino cyclization, we examined a readily available substrate 3
with a free amine substitution, the precursor of substrate 1. When
the substrate was subjected to the optimal conditions,
condition
catalyst
additive
solvent
t (°C)
yield (%)
c1
Ph3PAuCl
AgBF4
−
AgBF4
toluene
toluene
toluene
toluene
60
60
84
0
c1′
c2
−
Ph3PAuCl
100
100
95
0
c2′
−
−
B
DOI: 10.1021/acs.orglett.7b01358
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Letter
a
Table 2. Control Experiments for the Synthesis of Indeno[1,2-
Scheme 5. Free-Energy Profiles for Pathways a and b
c]quinolines
condition
catalyst
solvent
atmosphere t (°C) yield (%)
c3
Ph3PAuNTf2
toluene
toluene
toluene
toluene
N2
N2
O2
O2
50
50
50
50
98
0
c3′
c4
−
Ph3PAuNTf2
91
88
c4′
−
was isolated by lowering reaction temperature and decreasing the
reaction time, which could be transformed into the benzo[a]-
carbazole product 2 under the standard conditions (Table 1,
conditions c1 and c2). Control experiments showed that a
gold(I) catalyst was necessary for both cyclizations (Table 1,
conditions c1′ and c2′). The atmosphere was changed from
oxygen to nitrogen in the synthesis of benzo[a]carbazoles,
leading to the isolation of intermediate 4′. And the isolated
intermediate 4′ could be transformed into the final product 4
regardless of whether the gold(I) catalyst was present or not
(Table 2, conditions c4 and c4′). All these results indicated that
the oxidation happened after the cyclization and the gold(I)
catalyst was not crucial in the bisbenzylic oxidation.
Based on precedent studies8a,10 and the control experiments, a
plausible mechanism for the domino cyclization was proposed as
depicted in Scheme 4. For the sulphonamide substrate 1,
activation of alkyne by cationic gold(I) species promoted the first
cyclization to afford indole intermediate R-1-2. Coordination of
electron-rich enol ether with a gold(I) catalyst initiated the
second cyclization to produce the benzo[a]carbazole 2 after
protodeauration (Scheme 5, pathway a). Alternatively, for the
amine substrate 3, electron-rich enol ether instead of an amino
group would attack the activated alkyne to give the indene
intermediate R-3-2 after isomerization. Activation of the alkene
induced the nucleophilic addition of an amine to the oxonium
ion via intermediate R-3-3 to provide aromatic product R-3-4
followed by the release of a methanol, which was transformed
into the final product 4′ after protodeauration (Scheme 4,
pathway b). We rationalized that the choice of the two different
pathways was attributed to the opposite polarization of the C−C
a
Pathway a was depicted in green and pathway b was depicted in
black, corresponding to those in Scheme 4.
triple bond resulted from the substitution on the amino group. In
the case of the free amino group more electron density is donated
toward the distal sp carbon atom of the tripe bond, resulting in
the preferable coordination of this carbon with the gold(I)
catalyst, which oriented the direction of the nucleophilic addition
by enol ether to generate the indeno[1,2-c]quinoline. In contrast,
the polarization of the C−C triple bond resulting from the
sulfonamide is exactly the opposite, leading to a totally opposite
nucleophilic addition by sulfonamide to afford benzo[a]-
carbazole as the product.
Scheme 4. Proposed Mechanism for the Substitution-Controlled Domino Cyclizations of Substrates 1 and 3
C
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In order to gain an insight into the selectivity of the cyclization,
a systematic computational study assisted by DFT calculation-
s11a,b was performed upon the proposed mechanism of the
cyclizations. As shown in Scheme 5, it was possible for compound
1 (in which R was Ts) or compound 3 (in which R was H) to go
through either pathway a or b to yield a carbazole or quinoline
product. The free energy profiles of both pathways were
calculated by the M11 method11c in toluene, and the results
are shown as follows. The first reaction where intermediate R-1-1
was converted to R-1-2 in pathway a and intermediate R-3-1 was
converted to R-3-2 in pathway b was where the two pathways
diverged from the same starting point; therefore, it controlled the
fate of the pathways. The free energies of the transition states
were calculated to be 9.7 kcal/mol for pathway a and 11.3 kcal/
mol for pathway b where R was Ts. It showed that pathway a was
the more favorable one to follow compared to pathway b,
eventually resulting in carbazole products. When R was
hydrogen, the free energies of the transition states were
calculated to be 13.7 kcal/mol for pathway a and 7.9 kcal/mol
for pathway b, suggesting that in this case pathway b was the
more favorable one to go through therefore eventually resulting
in quinoline products. Such computational results were
consistent with the experimental observations that carbazole
products were obtained where R was Ts and quinoline products
were obtained where R was H, shedding light on the mechanism
of the reactions which were differentiated by a single substitution
on the amino group.
financial support from Natural Science Foundation of China
(Grant No. 21406143).
REFERENCES
■
(1) (a) Beight, D. W.; Kinnick, M. D.; Lin, H.; Morin, J. M.; Richett, M.
E.; Sall, D. J.; Sayer, J. S. U. S. Patent WO 2002050034, Chem. Abstr.
2002, 137, 47114. (b) Segall, A. I.; Vitale, M. F.; Perez, V. L.; Pizzorno,
M. T. J. Pharm. Biomed. Anal. 2003, 31, 1021. (c) Tseng, C. H.; Chen, Y.
L.; Chung, K. Y.; Cheng, C. M.; Wang, C. H.; Tzeng, C. C. Bioorg. Med.
Chem. 2009, 17, 7465. (d) Tseng, C. H.; Tzeng, C. C.; Yang, C. L.; Lu, P.
J.; Chen, H. L.; Li, H. Y.; Chuang, Y. C.; Yang, C. N.; Chen, Y. L. J. Med.
Chem. 2010, 53, 6164. (e) Tseng, C. H.; Lin, R. W.; Chen, Y. L.; Wang,
G. J.; Ho, M. L.; Tzeng, C. C. J. Med. Chem. 2011, 54, 3103. (f) Tseng, C.
H.; Tzeng, C. C.; Chiu, C. C.; Yang, C. L.; Lu, P. J.; Chou, C. K.; Liu, C.
Y.; Chen, Y. L. MedChemComm 2014, 5, 937.
(2) Paramasivam, M.; Chitumalla, R. K.; Singh, S. P.; Islam, A.; Han, L.;
Rao, V. J.; Bhanuprakash, K. J. Phys. Chem. C 2015, 119, 17053.
(3) Chen, J. P.; Tanabe, H.; Li, X. C.; Thoms, T.; Okamura, Y.; Ueno,
K. Synth. Met. 2003, 132, 173.
(4) You, J.; Zhao, W.; Liu, L.; Zhao, X.; Suo, Y.; Wang, H.; Li, Y.; Ding,
C. Talanta 2007, 72, 914.
(5) (a) Dufour, F.; Kirsch, G. Synlett 2006, 7, 1021. (b) Tao, Y.; Zhang,
F.; Tang, C. Y.; Wu, X. Y.; Sha, F. Asian J. Org. Chem. 2014, 3, 1292.
(c) Yang, J.; Zhang, Q.; Zhang, W.; Yu, W. RSC Adv. 2014, 4, 13704.
(d) Wu, L.; Huang, H.; Dang, P.; Liang, Y.; Pi, S. RSC Adv. 2015, 5,
64354.
(6) (a) Tsuchimoto, T.; Matsubayashi, H.; Kaneko, M.; Nagase, Y.;
Miyamura, T.; Shirakawa, E. J. Am. Chem. Soc. 2008, 130, 15823. (b) Shi,
Z.; Ding, S.; Cui, Y.; Jiao, N. Angew. Chem., Int. Ed. 2009, 48, 7895.
(c) Chen, C. C.; Chin, L. Y.; Yang, S. C.; Wu, M. J. Org. Lett. 2010, 12,
5652. (d) Hirano, K.; Inaba, Y.; Watanabe, T.; Oishi, S.; Fujii, N.; Ohno,
H. Adv. Synth. Catal. 2010, 352, 368. (e) Kianmehr, E.; Ghanbari, M.
Eur. J. Org. Chem. 2012, 2012, 256. (f) Xie, R.; Ling, Y.; Fu, H. Chem.
Commun. 2012, 48, 12210. (g) Xia, X. F.; Wang, N.; Zhang, L. L.; Song,
X. R.; Liu, X. Y.; Liang, Y. M. J. Org. Chem. 2012, 77, 9163. (h) Jash, M.;
Das, B.; Chowdhury, C. J. Org. Chem. 2016, 81, 10987. (i) Li, N.; Lian,
X.; Li, Y.; Wang, T.; Han, Z.; Zhang, L.; Gong, L. Z. Org. Lett. 2016, 18,
4178.
(7) (a) Krafft, M. E.; Vidhani, D. V.; Cran, J. W.; Manoharan, M. Chem.
Commun. 2011, 47, 6707. (b) Wang, T.; Shi, S.; Vilhelmsen, M. H.;
Zhang, T.; Rudolph, M.; Rominger, F.; Hashmi, A. S. K. Chem. - Eur. J.
2013, 19, 12512. (c) Undeela, S.; Thadkapally, S.; Nanubolu, J. B.;
Singarapu, K. K.; Menon, R. S. Chem. Commun. 2015, 51, 13748.
(d) Thummanapelli, S. K.; Hosseyni, S.; Su, Y.; Akhmedov, N. G.; Shi, X.
Chem. Commun. 2016, 52, 7687. (e) Ding, D.; Mou, T.; Feng, M.; Jiang,
X. J. Am. Chem. Soc. 2016, 138, 5218. (f) Medran, N. S.; Villalba, M.;
Mata, E. G.; Testero, S. A. Eur. J. Org. Chem. 2016, 2016, 3757.
(g) Wang, Z.; Ying, A.; Fan, Z.; Hervieu, C.; Zhang, L. ACS Catal. 2017,
7, 3676.
(8) (a) Liu, Y.; Guo, J.; Liu, Y.; Wang, X.; Wang, Y.; Jia, X.; Wei, G.;
Chen, L.; Xiao, J.; Cheng, M. Chem. Commun. 2014, 50, 6243. (b) Jin, S.;
Jiang, C.; Peng, X.; Shan, C.; Cui, S.; Niu, Y.; Liu, Y.; Lan, Y.; Liu, Y.;
Cheng, M. Org. Lett. 2016, 18, 680. (c) Liu, Y.; Jin, S.; Wang, Y.; Cui, S.;
Peng, X.; Niu, Y.; Du, C.; Cheng, M. Chem. Commun. 2016, 52, 6233.
(d) Jiang, C.; Xiong, Z.; Jin, S.; Gao, P.; Tang, Y.; Wang, Y.; Du, C.;
Wang, X.; Liu, Y.; Lin, B.; Liu, Y.; Cheng, M. Chem. Commun. 2016, 52,
11516.
In conclusion, benzo[a]carbazoles and indeno[1,2-c]-
quinolines have been synthesized simultaneously for the first
time via a gold(I)-catalyzed pathway-tunable domino cyclization
of difunctional 1,2-diphenylethyne substrates by changing the
substitutions of amino groups. The substrate scopes of the
cyclization were examined by a variety of synthetic substrates.
A plausible mechanism for the diverted domino cyclization
was proposed based on a series of control experiments, which
was further supported by DFT calculations.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b01358.
Experimental procedures, X-ray crystal structure analyses,
compound characterization data, and computational
details (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: randybinlin@gmail.com.
*E-mail: yongxiang.liu@syphu.edu.cn.
*E-mail: mscheng@syphu.edu.cn.
(9) (a) Shing, T. K. M.; Yeung, Y. Y.; Su, P. L. Org. Lett. 2006, 8, 3149.
(b) Wang, H.; Wang, Z.; Huang, H.; Tan, J.; Xu, K. Org. Lett. 2016, 18,
5680.
ORCID
Yongxiang Liu: 0000-0003-0364-0137
Notes
(10) (a) Grise, C. M.; Barriault, L. Org. Lett. 2006, 8, 5905. (b) Hashmi,
A. S. K.; Wolfle, M. Tetrahedron 2009, 65, 9021. (c) Hashmi, A. S. K.;
̈
Yang, W.; Rominger, F. Angew. Chem., Int. Ed. 2011, 50, 5762. (d) Graf,
K.; Hindenberg, P. D.; Tokimizu, Y.; Naoe, S.; Rudolph, M.; Rominger,
F.; Ohno, H.; Hashmi, A. S. K. ChemCatChem 2014, 6, 199.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(11) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (b) Lee, C.; Yang,
W.; Parr, R. G. Phys. Rev. B: Condens. Matter Mater. Phys. 1988, 37, 785.
(c) Peverati, R.; Truhlar, D. G. J. Phys. Chem. Lett. 2011, 2, 2810.
We thank the program for innovative research team of the
Ministry of Education and the program for Liaoning innovative
research team in university. B.L. would like to acknowledge the
D
DOI: 10.1021/acs.orglett.7b01358
Org. Lett. XXXX, XXX, XXX−XXX