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. 2022 Feb 12;25(3):103906.
doi: 10.1016/j.isci.2022.103906. eCollection 2022 Mar 18.

Unlocking a self-catalytic cycle in a copper-catalyzed aerobic oxidative coupling/cyclization reaction

Jianming Liu  1 , Xiaopei Wang  1 , Zhiyue Wang  1 , Yan Yang  1 , Qinghu Tang  1 , Hongchi Liu  2 , Hanmin Huang  2
Affiliations

Unlocking a self-catalytic cycle in a copper-catalyzed aerobic oxidative coupling/cyclization reaction

Jianming Liu et al. iScience. .

Abstract

Presented here is a copper-catalyzed, aerobic oxidative C-H/C-H cyclization reaction, which occurs by cleaving the C-H and N-H bonds of 3-phenylindoles. A broad range of 3-phenylindoles can be well tolerated to produce the indole-containing polycyclic aromatic hydrocarbons (PAH) in good to excellent yields. An evaluation of the reaction mechanism is enabled by the isolation of the di- and tri-indole intermediates, highlighting the role of the substrate for this catalytic reaction. The results of these controlled experiments and kinetic studies provide solid experimental support for a self-catalysis reaction, which has rarely been observed in oxidative C-H activation reactions. Additional mechanistic studies indicate that the substrate for this reaction accelerates by the following mechanism: The substrate combines with the Cu catalyst to transform the less active di-indole intermediate into a tri-indole intermediate. This intermediate is quickly converted into the desired product along with regeneration of the substrate copper complex.

Keywords: Catalysis; Chemical engineering; Chemistry.

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Conflict of interest statement

The authors declare no competing interests.

Figures

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Graphical abstract
Figure 1
Figure 1
Self-catalysis involved Cu-Catalyzed oxidative coupling and cyclization of 3-arylindoles
Figure 2
Figure 2
The functionalization of the indole derivatives
Figure 3
Figure 3
The Kinetic Analysis of the Reaction of 1a (A) The 3D FTIR profile of the standard reaction. (B) Reaction profile of the standard reaction. 1a (1.0 mmol), Cu(OAc)2 (20 mol %), O2 (balloon), TFA (2.0 mL), 50 °C, 3 h.
Figure 4
Figure 4
Controlled experiments
Figure 5
Figure 5
Possible reaction pathways for the formation of 2a
Figure 6
Figure 6
The Reaction Profile of 3a and 4a (A) The standard spectrum of 2a, 3a and 4a. (B) The initial rate of intermediate 3a and 4a as determined by in situ IR. Reaction condition: 3a or 4a (0.30 mmol), Cu(OAc)2 (20 mol %), O2 (balloon), TFA (5.0 mL), 50 °C.
Figure 7
Figure 7
The Accelerated Role of Substrate 1g (A) The standard spectrum of 2a and 2g. (B) Kinetic plots of the reaction in 3a (0.30 mmol), Cu(OAc)2 (20 mol %), O2 and TFA (5.0 mL), the reaction in 3a (0.30 mmol), 4-methoxy-3-phenyl-1H-indole 1g (0.03 mmol), Cu(OAc)2 (20 mol %), O2 and TFA (5.0 mL) and the reaction in 3a (0.30 mmol), 4-methoxy-3-phenyl-1H-indole 1g (0.30 mmol), Cu(OAc)2 (20 mol %), O2 and TFA (5.0 mL)
Figure 8
Figure 8
Radical trapping and KIE experiments
Figure 9
Figure 9
Kinetic behavior of both 4a and Cu(OAc)2 (A) Plot of initial rates with Cu(OAc)2 showing zero-order dependence. Reaction condition: 4a (0.30 mmol), Cu(OAc)2 (2.5 mol%-25 mol %), O2 (balloon), TFA (5.0 mL), 50 °C. (B) Plot of initial rates with intermediate 4a showing first-order dependence. Reaction condition: 4a (0.05–0.50 mmol), Cu(OAc)2 (18 mg), O2 (balloon), TFA (5.0 mL), 50 °C.
Figure 10
Figure 10
Plausible reaction mechanism
Figure 11
Figure 11
Substrate Scope of 3-Arylindoles Reaction conditions: 1 (0.60 mmol), Cu(OAc)2 (20 mol %), O2 (balloon), TFA (2.0 mL), 50 °C, 8.0 h. Isolated yield.
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