10.1002/chem.201801108
Chemistry - A European Journal
COMMUNICATION
desired C–O cyclization products of thiophene (2u−y, 2aa),
indole (2z), and dibenzofuran (2ac) derivatives were
successfully achieved under constant current electrolysis. It is
particularly noteworthy that this protocol tolerates pyridine
containing substrates (2ab and 2ad), which were not effectively
transformed under previous reported radical C–O cyclization
conditions.[5–6]
previous reported methods. In addition, we have demonstrated
the direct electrochemically C–O cyclization of drug molecule
telmisartan. We expect that this method can be used for the
synthesis of valuable biologically active molecules. Further
studies on electrochemically-based radical reactions are
ongoing in our laboratory.
In order to demonstrate the practicality of the
electrochemical C–O cyclization reaction in preparative organic
synthesis, a larger scale reaction was conducted. As depicted in
Scheme 3A, the reaction of 1a was conducted on 100 g (505
mmol) scale, and the desired product 2a was smoothly furnished
in 93% yield (92 g) after 55 h constant current electrolysis. It was
worth mentioning that all reaction steps were operated in air
atmosphere.[17]
Acknowledgements
We are grateful to the National Natural Science Foundation of
China (No. 21402036, 21472033, 21502038) and the
Fundamental Research Funds for the Central Universities for
financial support.
Keywords: electrochemistry • dehydrogenative • heterocycles•
cyclization • lactones
A. Larger scale reaction
O
O
[1]
Selected examples: a) N. Tibrewal, P. Pahari, G. Wang, M. K. Kharel, C.
Morris, T. Downey, Y. Hou, T. S. Bugni, J. Rohr, J. Am. Chem. Soc.
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Chem. 2015, 127, 7273.
OH C.C.E. j = 5.0 mA cm-2
O
LiClO4 (0.1 M)
CH3CN (5 L)
undivided cell
r.t., 55 h
air atmosphere
easy operation
mild conditions
[2]
For selected examples on the synthesis of biaryl lactones, see: a) W.
Zhang, B. I. Wilke, J. Zhan, K. Watanabe, C. N. Boddy, Y. J. Tang, J.
Am. Chem. Soc. 2007, 129, 9304; b) N. Thasana, R. Worayuthakarn, P.
Kradanrat, E. Hohn, L. Young, S. Ruchirawat, J. Org. Chem. 2007, 72,
9379; c) J. Luo, Y. Lu, S. Liu, J. Liu, G.-J. Deng, Adv. Synth. Catal.
2011, 353, 2604.
1a
(100 g, 505 mmol)
2a
(92 g, 93% yield)
B. Direct electrochemical C-O cyclization of telmisartan
[3]
[4]
a) S. Luo, F.-X. Luo, X.-S. Zhang, Z.-J. Shi, Angew. Chem. Int. Ed.
2013, 52, 10598; Angew. Chem. 2013,125, 10792; b) Y. Wang, J.-Y.
Gu, Z.-J. Shi, Org. Lett. 2017, 19, 1326.
Me
N
Me
N
N
N
C.C.E
For selected examples on transition metal-catalyzed C–H
functionalization/C–O oxidative cyclization, see: a) X. Wang, Y. Lu, H.-
X. Dai, J.-Q. Yu, J. Am. Chem. Soc. 2010, 132, 12203; b) B. Xiao, T.-J.
Gong, Z.-J. Liu, J.-H. Liu, D.-F. Luo, J. Xu, L. Liu, J. Am. Chem. Soc.
2011, 133, 9250; c) X.-F. Cheng, Y. Li, Y.-M. Su, F. Yin, J.-Y. Wang, J.
Sheng, H. U. Vora, X.-S. Wang, J.-Q. Yu, J. Am. Chem. Soc. 2013, 135,
1236; d) Y. Li, Y.-J. Ding, J.-Y. Wang, Y.-M. Su, X.-S. Wang, Org. Lett.
2013, 15, 2574.
64% yield
N
N
Me
Me
N
N
O
OH
Me
Me
O
O
3
4
telmisartan,
Scheme 3. Synthetic applicability. A. Larger scale reaction: 1a (100 g, 505
mmol), LiClO4 (53.2 g, 500 mmol), CH3CN (5 L), graphite anode (20 cm 15
[5]
a) J. Gallardo-Donaire, R. Martin, J. Am. Chem. Soc. 2013, 135, 9350;
b) Y. Wang, A. V. Gulevich, V. Gevorgyan, Chem.–Eur. J. 2013, 19,
15836.
cm) and graphite cathode (20 cm 15 cm), at a constant current of 1 A (janode
=
5.0 mA cm-2, effective electrode area was 200 cm2) for 55 h in an undivided
cell at room temperature. B. Direct electrochemical C–O cyclization of
telmisartan: 3 (0.2 mmol), LiClO4 (1.0 mmol), CH3CN/CHCl3 (4:1, 10 mL) as
the solvent, graphite anode and platinum cathode, at a constant current of 6
mA (janode= 4.0 mA cm-2) for 5 h in an undivided cell at room temperature.
[6]
[7]
[8]
[9]
J.-J. Dai, W.-T. Xu, Y.-D. Wu, W.-M. Zhang, Y. Gong, X.-P. He, X.-Q.
Zhang, H.-J. Xu, J. Org. Chem. 2015, 80, 911.
X. Wang, J. Gallardo-Donaire, R. Martin, Angew. Chem. Int. Ed. 2014,
53, 11084; Angew. Chem. 2014, 126, 11264.
a) N. P. Ramirez, I. Bosque, J. C. Gonzalez-Gomez, Org. Lett. 2015, 17,
4550.
For selected reviews on electro-organic synthesis, see: a) B. A.
Frontana-Uribe, R. D. Little, J. G. Ibanez, A. Palma, R. Vasquez-
Medrano, Green Chem. 2010, 12, 2099; b) R. Francke, R. D. Little,
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L. Wright, Chem. Soc. Rev. 2006, 35, 605; e) K. A. Ogawa, A. J.
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Also in connection to the synthetic utility, we next test the
direct electrochemical C–O cyclization of telmisartan 3, an
angiotensin II receptor antagonist used in the treatment of
hypertension (Scheme 3B). By applying the electrochemical C–
H
functionalization/C–O cyclization reaction, telmisartan
analogue 4 was isolated in 64% yield.[18]
In conclusion, an efficient electrochemical method for the C–
O cyclization of 2-(hetero)arylbenzoic acids is accomplished.
The reaction is operationally simple and scalable under ambient
conditions, presents a broad substrate scope. Importantly, a
range of valuable heterocycle-containing substrates are
obtained in good yields, thus highlighting the complementary to
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