Photosensitizer-Free Visible-Light-Promoted Trifluoromethylation of Imidazo[1,2-a]pyridines

doi:10.6023/cjoc202103004

Chinese Journal of Organic Chemistry ›› 2021, Vol. 41 ›› Issue (7): 2684-2692.DOI: 10.6023/cjoc202103004 Previous Articles Next Articles

Special Issue: 有机光催化虚拟合辑

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无光敏剂参与的可见光诱导咪唑并[1,2-a]吡啶的三氟甲基化反应

姚瑞超^a, 陈文博^a^,^*(), 沈其龙^b^,^c^,^*()

a 上海电力大学上海市电力材料防护与新材料重点实验室上海 200090
b 中国科学院上海有机化学研究所分子合成卓越中心中国科学院有机氟化学重点实验室上海 200032
c 中国科学院大学北京 100049

收稿日期:2021-03-02 修回日期:2021-03-25 发布日期:2021-04-12
通讯作者: 陈文博, 沈其龙
基金资助:
国家自然科学基金(21625206); 中国科学院战略性先导科技专项(B类)(XDB20000000); 上海市自然科学基金(20ZR1471600); 上海市科学技术委员会(19DZ2271100)

Photosensitizer-Free Visible-Light-Promoted Trifluoromethylation of Imidazo[1,2-a]pyridines

Ruichao Yao^a, Wenbo Chen^a(), Qilong Shen^b^,^c()

a Shanghai Key Laboratory of Materials Protection and Advanced Materials in Electric Power, Shanghai University of Electric Power, Shanghai 200090
b CAS Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032
c University of Chinese Academy of Sciences, Beijing 100049

Received:2021-03-02 Revised:2021-03-25 Published:2021-04-12
Contact: Wenbo Chen, Qilong Shen
Supported by:
National Natural Science Foundation of China(21625206); Strategic Priority Research Program of the Chinese Academy of Sciences(XDB20000000); Natural Science Foundation of Shanghai(20ZR1471600); Science and Technology Commission of Shanghai Municipality(19DZ2271100)

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Abstract

A photosensitizer-free visible-light-promoted method for direct trifluoromethylation of imidazo[1,2-a]pyridine derivatives using an electrophilic trifluoromethylating reagent based on sulfonium ylide skeleton was described. The reaction occurred in broad substrate scope under mild conditions and tolerant various functional groups. Initial mechanistic experiments including reactions in the presence of radical scavengers and UV absorption spectroscopic studies were conducted. Inhibition by the radical scavengers were observed. In addition, an extra-absorption peak between 500~510 nm in UV-Vis absorption spectrum was observed. These observations led us to propose a working mechanism. Finally, application of the current method for the preparation of trifluoromethylated derivative of gastroproctive drug zolimidine was demonstrated.

Key words: trifluoromethyl, visible light, photosensitizer free, imidazo[1,2-a]pyridine

Cite this article

Ruichao Yao, Wenbo Chen, Qilong Shen. Photosensitizer-Free Visible-Light-Promoted Trifluoromethylation of Imidazo[1,2-a]pyridines[J]. Chinese Journal of Organic Chemistry, 2021, 41(7): 2684-2692.

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Fig. & Tab. 7

Figure 1. Drug molecules with an imidazo[1,2-a]pyridine core

Scheme 1. Approaches for the preparation of trifluoromethylated imidazo[1,2-a]pyridine derivatives

Entry	Solvent	Time/h	Yield/%
1	DMSO	24	68^b
2	DMSO	24	82 (70^c)
3	DMF	24	61
4	DMAc	24	75
5	CH₃CN	24	44
6	CH₃OH	24	61
7	CH₂Cl₂	24	59
8	THF	24	17
9	Toluene	24	13
10	DMSO	18	79
11	DMSO	12	64
12	DMSO	4	26
13^d	DMSO	24	72
14^e	DMSO	24	―

Table 1. Optimization of the conditions for visible-light- promoted trifluoromethylation of 2-phenyl imidazo[1,2-a]pyri- dine with reagent 1

Table 2. Scope for visible-light-promoted trifluoromethylation of 2-phenyl imidazo[1,2-a]pyridine with reagent about the mechanism of the reaction, we conducted a few experiments to probe whether a free radical is involved in the reaction. First, we conducted four parallel experiments in the presence of 2.0 equiv. of different radical scavengers. As shown in Scheme 2, reaction using 2,2,6,6-tetra- methylpiperidinooxy (TEMPO) as the radical inhibitor was completely shut down and the reaction in the air gave much lower yield, while the reaction with 2,6-di-tert-butyl- 4-methylphenol (BHT) was not affected at all. From these1

Scheme 2. Visible-light-promoted trifluoromethylation of 2- phenyl imidazo[1,2-a]pyridine with reagent 1 in the presence of radical inhibitors

Figure 2. UV-Vis absorption spectra of 2-phenyl imidazo[1,2- a]pyridine, reagent 1 and 1∶1 adduct of two compounds in DMSO

Scheme 3. Proposed mechanism for visible-light-promoted trifluoromethylation of 2-phenyl imidazo[1,2-a]pyridine with reagent 1

References 20

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无光敏剂参与的可见光诱导咪唑并[1,2-a]吡啶的三氟甲基化反应

Photosensitizer-Free Visible-Light-Promoted Trifluoromethylation of Imidazo[1,2-a]pyridines

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