铜催化苯甲酰亚胺高烯丙酯的分子内胺化全氟烷基化反应

doi:10.6023/A19060220

摘要/Abstract

报道了铜催化苯甲酰亚胺高烯丙酯底物的分子内胺化全氟烷基化反应. 该反应以全氟碘代烷为全氟烷基化试剂, 醋酸铜为催化剂, 邻菲啰啉为配体, 在醋酸银存在下以中等的收率实现苯甲酰亚胺高烯丙酯底物末端双键的胺化全氟烷基化, 最终生成1,3-噁嗪类分子. 多种官能团取代的苯甲酰亚胺高烯丙酯和具有不同碳链长度的全氟碘代烷烃都能适用于该反应, 为多氟烷基取代的1,3-噁嗪类化合物的合成提供了一种简洁的方法. 多氟烷基取代的1,3-噁嗪类化合物还可在温和条件下高效转化为γ氨基醇衍生物. 初步的机理研究证明该反应经历了全氟烷基自由基对碳碳双键的亲电加成, 之后苯甲酰亚胺基团作为分子内亲核性胺源经历分子内亲核取代途径生成1,3-噁嗪骨架.

关键词: 苯甲酰亚胺高烯丙酯, 全氟碘代烷烃, 胺化全氟烷基化反应, 1,3-噁嗪, 铜催化

Azaheterocycles have been broadly applied in the development of therapeutic agents, agrochemicals and functional material molecules. Azaheterocycles equipped with perfluoroalkyl group usually manifest superior physical and biological properties than their parent molecules, such as showing improved metabolic stability and high lipophilicity. The synthesis of perfluoroalkyl modified azaheterocycles has attracted considerable research interest in recent years. The strategy of intramolecular aminoperfluoroalkylation of alkenes, which functionalize C=C bond with an external perfluoroalkyl group and an internal amine nucleophile in one pot, provides a streamlined synthesis of perfluoroalkyl substituted azaheterocycles. This strategy has been applied by Liu, Sodeoka and other research groups in the synthesis of perfluoroalkyl substituted aziridines, pyrrolidines, lactams and pyrazolines featuring the use of pendent amine, amide, hydrazone or urea group as internal amine source. We have previously developed a copper(I)-catalyzed intramolecular aminotrifluoromethylation reaction of O-homoallyl benzimidates with Togni reagent I for the synthesis of trifluoromethyl containing chiral 1,3-oxazines using a chiral BOX ligand. However, this method is limited to aminotrifluoromethylation reaction as other perfluoroalkyl substituted hypervalent iodine reagents are not easily accessible. Herein, we report our recent research results on the synthesis of perfluoroalkyl substituted 1,3-oxazines using commercial available perfluoroalkyl iodides as perfluoroalkyl source. This intramolecular aminoperfluoroalkylation reaction proceeds selectively in the presence of Cu(OAc)₂ catalyst, 1,10-phenanthroline ligand and AgOAc additive. A broad range of O-homoallyl benzimidates and perfluoroalkyl iodides are compatible with the reaction conditions, affording perfluoroalkyl substituted 1,3-oxazines in moderate to good yields. The 1,3-oxazine product can be prepared in gram scale and readily hydrolyzed under mild conditions to give perfluoroalkyl substituted 1,3-amino alcohols. Preliminary mechanism studies revealed that this intramolecular aminoperfluoroalkylation reaction initiated with the addition of a perfluoroalkyl radical to the terminal alkene, and the subsequent functionalization with the benzimidate motif via intramolecular substitution generated 1,3-oxazine products.

Key words: O-homoallyl benzimidates, aminoperfluoroalkylation, perfluoroalkyl iodides, 1,3-oxazines, copper catalysis

引用此文

张衡, 牟学清, 陈弓, 何刚. 铜催化苯甲酰亚胺高烯丙酯的分子内胺化全氟烷基化反应[J]. 化学学报, 2019, 77(9): 884-888.

Zhang, Heng, Mou, Xueqing, Chen, Gong, He, Gang. Copper-catalyzed Intramolecular Aminoperfluoroalkylation Reaction of O-Homoallyl Benzimidates[J]. Acta Chimica Sinica, 2019, 77(9): 884-888.

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图/表 6

图1. 分子内胺化多氟烷基化反应制备多氟烷基取代的氮杂环骨架

Figure 1. Perfluoroalkylative intramolecular difunctionalization of unactivated alkene

Entry	Catalyst	Additive	Solvent	Yield^a/% of 2
1^b	Cu(CH₃CN)₄PF₆	BOX ligand	DCE	NR
2	Cu(CH₃CN)₄PF₆	AgOAc	DCE	44
3	CuCl	AgOAc	DCE	54
4	CuBr	AgOAc	DCE	62
5	CuI	AgOAc	DCE	60
6	Cu(acac)₂	AgOAc	DCE	54
7	Cu(OTf)₂	AgOAc	DCE	45
8	Cu(OAc)₂	AgOAc	DCE	72 (64)^c
9	Cu(OAc)₂	AgOTFA	DCE	19
10	Cu(OAc)₂	AgOTf	DCE	47
11	Cu(OAc)₂	Ag₂CO₃	DCE	53
12	Cu(OAc)₂	Cs₂CO₃	DCE	20
13	Cu(OAc)₂	AgOAc	CH₃CN	67
14	Cu(OAc)₂	AgOAc	THF	52
15	Cu(OAc)₂	AgOAc	EtOAc	63
16	Cu(OAc)₂	—	DCE	NR
17		AgOAc	DCE	<5
18^d	Cu(OAc)₂	AgOAc	DCE	<5
19^e	Cu(OAc)₂	AgOAc	DCE	53

表1. 反应条件优化

Table 1. Reaction condition optimization

图2. 苯甲酰亚胺高烯丙酯类底物的适用范围

Figure 2. Scope of O-homoallyl benzimidate substrates All yields are based on isolated product on a 0.2 mmol scale

图3. 全氟碘代烷烃的适用范围

Figure 3. Scope of perfluoroalkyl iodides All yields are based on isolated product on a 0.2 mmol scale

图4. 克级反应和产物的进一步转化

Figure 4. Gram scale reaction and transformation of 1,3-oxazine

图5. 反应可能机理

Figure 5. Proposed mechanism a Yields are based on 1H NMR analysis of reaction mixture with 1,1,2,2-tetrachloroethane as internal standard on a 0.2 mmol scale

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