钯催化的氯二氟乙基高价碘试剂对于乙酰苯胺C—H键的氯二氟乙基化反应研究

doi:10.6023/cjoc202203020

有机化学 ›› 2022, Vol. 42 ›› Issue (7): 2098-2105.DOI: 10.6023/cjoc202203020 上一篇下一篇

所属专题：有机氟化学虚拟合辑

研究论文

钯催化的氯二氟乙基高价碘试剂对于乙酰苯胺C—H键的氯二氟乙基化反应研究

曹成瑶^a, 牛亚茹^b, 蒋昀辰^a, 曲红梅^b, 陈超^a^,^c^,^*()

^a清华大学化学系生物有机磷化学与化学生物学教育部重点实验室北京 100084
^b天津大学化工学院制药工程系系统生物工程教育部重点实验室天津 300350
^c南开大学元素有机化学国家重点实验室天津 300071

收稿日期:2022-03-10 修回日期:2022-04-08 发布日期:2022-08-09
通讯作者: 陈超
基金资助:
国家重点研发项目(2016YFB0401400); 国家自然科学基金(22071129); 国家自然科学基金(21871158); 国家自然科学基金(21672120); 霍英东基金(151014)

Pd-Catalyzed Chlorodifluoroethylation Reaction of C—H Bond of Acetanilides with Chlorodifluoroethyl Iodonium Reagents

Chengyao Kimmy Cao^a, Yaru Niu^b, Yunchen Jiang^a, Hongmei Qu^b, Chao Chen^a^,^c()

^aKey Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084
^bKey Laboratory of Systems Bioengineering, Ministry of Education, Department of Pharmaceutical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300350
^cState Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071

Received:2022-03-10 Revised:2022-04-08 Published:2022-08-09
Contact: Chao Chen
Supported by:
National Key Research and Development Program of China(2016YFB0401400); National Natural Science Foundation of China(22071129); National Natural Science Foundation of China(21871158); the National Natural Science Foundation of China(21672120); Fok Ying Tong Education Foundation of China(151014)

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摘要/Abstract

二氟乙基化合物在生物医药和材料领域有着广泛的应用, 合成二氟乙基的化合物有着重要意义, 在此报道了一种钯催化的乙酰苯胺邻位氯二氟乙基化的反应, 该反应利用氯二氟乙基高价碘试剂(CDFI)作为CH₂CF₂Cl的来源. 进一步研究发现, 有机碱1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)加入到反应体系中, 可以通过消除反应制备乙酰苯胺邻位偕二氟乙烯基化产物.

关键词: C—H活化, 钯催化, 乙酰苯胺, 碘鎓盐, 氯二氟乙基化, 二氟乙烯基化

Difluoroethyl products have a wide range of applications in the fields of biomedicine and materials, and it is important to develop new method to synthesize difluoroethyl compounds. Herein, a palladium-catalyzed chlorodifluoroethylation was disclosed via ortho-C—H activation of acetanilide, using chlorodifluoroethyl(mesityl) hypervalent iodine reagent as the source of CH₂CF₂Cl. Moreover, adding organic base 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to the above system, the difluorovinylated acetanilide products were obtained via an elimination reaction.

Key words: C—H activation, palladium catalyzed, acetanilide, iodonium salts, chlorodifluoroethylation, difluorovinylation

引用此文

曹成瑶, 牛亚茹, 蒋昀辰, 曲红梅, 陈超. 钯催化的氯二氟乙基高价碘试剂对于乙酰苯胺C—H键的氯二氟乙基化反应研究[J]. 有机化学, 2022, 42(7): 2098-2105.

Chengyao Kimmy Cao, Yaru Niu, Yunchen Jiang, Hongmei Qu, Chao Chen. Pd-Catalyzed Chlorodifluoroethylation Reaction of C—H Bond of Acetanilides with Chlorodifluoroethyl Iodonium Reagents[J]. Chinese Journal of Organic Chemistry, 2022, 42(7): 2098-2105.

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图/表 6

Figure 1. Typical molecular uses CH2CF2/CH=CF2 group in drug design

Scheme 1. Synthetic entries to gem-difluorinated products

Entry	Catalyst	Solvent	Acid	NMR yield^b/%
1	Pd(OAc)₂	DCM	—	30
2	Pd(OAc)₂	DCM	AcOH	32
3	Pd(OAc)₂	DCM	TsOH	61
4	Pd(OAc)₂	DCM	BF₃•Et₂O	32
5	—	DCM	TFA	n.d.
6	PdCl₂	DCM	TFA	15
7	Pd₂(dba)₃	DCM	TFA	63
8	Cu(OTf)₂	DCM	TFA	n.d.
9	Pd(OAc)₂	DCM	TFA	93
10	Pd(OAc)₂	MeOH	TFA	n.d.
11	Pd(OAc)₂	THF	TFA	16
12	Pd(OAc)₂	Toluene	TFA	71
13	Pd(OAc)₂	DCM	TFA	99

Table 1. Optimization of palladium-catalyzed chlorodifluoroethylation reaction conditionsa

Table 2. Substrate scope of N-phenylacetamidesa

。

Table 3. Substrate scope for dehydrochlorination reaction

Scheme 2. A proposed mechanism of palladium-catalyzed chlorodifluoroethylation reaction

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钯催化的氯二氟乙基高价碘试剂对于乙酰苯胺C—H键的氯二氟乙基化反应研究

Pd-Catalyzed Chlorodifluoroethylation Reaction of C—H Bond of Acetanilides with Chlorodifluoroethyl Iodonium Reagents

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