钯催化吡咯环内共轭双键的Heck反应

doi:10.6023/A20110520

摘要/Abstract

基于迁移插入策略, 研究了钯催化吡咯环内共轭双键的分子内Heck反应. 在温和的反应条件下, 以良好至优异的收率合成了一系列含有二氢吡咯及2-吲哚酮结构的螺杂环化合物. 同时, 以八氢联萘酚衍生的亚磷酰胺为手性配体, 初步探索该对映选择性反应, 获得中等水平的对映体过量值.

关键词: 钯, Heck反应, 吡咯, 吲哚酮, 对映选择性

3,2’-Spiropyrrolidine-2-oxindole scaffold is found as a key unit in a number of pharmaceutical candidates and nature products. It is highly desirable to develop efficient synthetic strategies to access such a structural scaffold. Recently, dearomatization reactions have received considerable attention as an efficient and straightforward synthetic method to convert readily available aromatic compounds to three-dimensional organic molecules. Amongst them, the transition-metal-catalyzed dearomative functionalization of endocyclic C=C bonds of aromatic compounds initiated by dearomative migratory insertion has been extensively established. A number of dearomative Heck reactions, reductive Heck reactions, and domino Heck-anionic capture sequences have been developed. Nevertheless, the present studies are mainly focused on the dearomatization reactions of indoles and furans. In contrast, there are rare examples reported for the dearomatization of pyrroles. In this communication, we report a palladium-catalyzed intramolecular Heck reaction of the endocyclic conjugated C=C bonds of C2-tethered pyrroles through an initial migratory insertion to formal conjugate diene and subsequent hydride elimination. A range of 3,2’-spiropyrrolidine-2-oxindole derivatives are obtained in good to excellent yields, showing broad substrate scope. In addition, a preliminary study of enantioselective reaction implies that the target product could be obtained in moderateee under the help of a H₈-BINOL-based chiral phosphoramidite ligand. A general procedure for this dearomative Heck reaction is depicted as the follows: to a dried Schlenk tube were added pyrrole substrate 1 (0.20 mmol), Pd(dba)₂ catalyst (5.8 mg, 0.010 mmol), and PPh₃ ligand (5.2 mg, 0.020 mmol) under N₂ atmosphere. 2.0 mL of MeCN solvent and 83 µL of Et ₃N were then introduced through a syringe and the Schlenk tube was sealed using a Teflon cap. The resulting reaction mixture was stirred at 100 ℃ for 16 h. After the reaction was completed (monitored by TCL), the mixture was concentrated under vacuum and the residue was purified by flash column chromatography on silica gel to afford the product 2.

Key words: palladium, Heck reaction, pyrrole, oxindole, enantioselectivity

引用此文

周波, 梁仁校, 曹中艳, 周平海, 贾义霞. 钯催化吡咯环内共轭双键的Heck反应[J]. 化学学报, 2021, 79(2): 176-179.

Bo Zhou, Renxiao Liang, Zhongyan Cao, Pinghai Zhou, Yixia Jia. Palladium-Catalyzed Heck Reaction of Endocyclic Conjugated C=C Bonds of Pyrroles[J]. Acta Chimica Sinica, 2021, 79(2): 176-179.

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图/表 6

图1. 含3,2’-螺环吡咯啉-2-吲哚酮结构的代表性活性分子

Figure 1. Representative bioactive molecules containing 3,2’-spiropyrrolidine-2-oxindole scaffold

图2. 钯催化的吡咯环内共轭双键的Heck反应

Figure 2. Palladium-catalyzed Heck reaction of the endocyclic conjugated C=C bonds of pyrroles

Entry	Solvent	Ligand	Base	Yield/%
1	DMF	PPh₃	K₂CO₃	63
2	toluene	PPh₃	K₂CO₃	88
3	THF	PPh₃	K₂CO₃	90
4	MeCN	PPh₃	K₂CO₃	92
5	CHCl₃	PPh₃	K₂CO₃	n.r.
6	MeCN	PCy_3·HBF₄	K₂CO₃	90
7	MeCN	P(O ⁿ Bu)₃	K₂CO₃	89
8 ^b	MeCN	dppe	K₂CO₃	17
9 ^b	MeCN	BINAP	K₂CO₃	20
10	MeCN	PPh₃	Na₂CO₃	93
11	MeCN	PPh₃	Cs₂CO₃	85
12	MeCN	PPh₃	KF	80
13	MeCN	PPh₃	K₃PO₄	93
14	MeCN	PPh₃	CH₃CO₂Na	92
15	MeCN	PPh₃	DBU	76
16	MeCN	PPh₃	Et₃N	97
17 ^c	MeCN	PPh₃	Et₃N	95
18 ^d	MeCN	PPh₃	Et₃N	51

表1. 吡咯环内共轭双键的Heck反应条件优化a

Table 1. Opimization of the Heck reaction of pyrroles

表2. 底物考察a

Table 2. Substrate scope

图3. 钯催化吡咯环内共轭双键的不对称Heck反应

Figure 3. Pd-catalyzed asymmetric Heck reaction of Pyrroles

图4. 可能的反应机理

Figure 4. Proposed reaction mechanism

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