溴化N-酰烷基吡啶、共轭炔羰基化物与醇的三组分反应合成3-烷基中氮茚: 空气作为氧化剂

doi:10.6023/cjoc202510022

摘要/Abstract

报道了一种无金属参与, 由溴化N-酰烷基吡啶、共轭炔羰基化物和醇三组分高效构建3-烷基中氮茚骨架的方法. 该反应以1,2-二氯乙烷为溶剂, 二异丙基乙基胺为碱, 经历酮促进的吡啶叶立德的形成、(3+2)环加成和醇参与的氧化过程, 生成3-烷基中氮茚衍生物, 产率为41%~68%. 该策略展现出良好的底物适用性与官能团兼容性. 此外, 所得3-烷基中氮茚骨架可进一步进行多种衍生化反应, 如酰胺化、还原、水解和酯交换等.

关键词: 三组分反应, 吡啶叶立德, 环加成, 碳碳键断裂, 3-烷基中氮茚

A metal-free approach for the efficient construction of 3-alkylindolizine frameworks via a three-component reaction involving N-acylalkylpyridinium bromides, conjugated alkynyl carbonyl compounds, and alcohols is reported. Using 1,2-dichloroethane as the solvent and N,N-diisopropylethylamine as the base, the reaction proceeds via ketone-promoted formation of pyridinium ylide, followed by (3+2) cycloaddition and an alcohol-participated oxidation process, affording 3-alkyl indolizine derivatives with yields ranging from 41% to 68%. This strategy demonstrates broad substrate scope and good functional group tolerance. Furthermore, the resulting 3-alkylindolizine skeletons can be readily functionalized through various transformations including amidation, reduction, hydrolysis, and transesterification.

Key words: three-component reaction, pyridinium ylide, cycloaddition, C—C bond cleavage, 3-alkylindolizine

引用此文

贾天猛, 孙帅, 孙伟, 苏毅进. 溴化N-酰烷基吡啶、共轭炔羰基化物与醇的三组分反应合成3-烷基中氮茚: 空气作为氧化剂[J]. 有机化学, 2026, 46(6): 2387-2398.

Tianmeng Jia, Shuai Sun, Wei Sun, Yijin Su. Three-Component Reaction of N-Acylalkylpyridinium Bromides, Conjugated Alkynyl Carbonyl Compounds and Alcohols for the Synthesis of 3-Alkyl Indolizines: Air as Oxidant[J]. Chinese Journal of Organic Chemistry, 2026, 46(6): 2387-2398.

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图/表 8

图1. 含有中氮茚骨架的生物活性分子

Figure 1. Bioactive molecules containing the indolizine skeleton

图式1. 中氮茚骨架的合成途径

Scheme 1. Synthesis pathway of the indolizine scaffold

Entry	Base	Solvent	T/℃	Atmosphere	Yield^b/%
1	None	Dioxane	55	N₂	5
2	DBU	Dioxane	55	N₂	37
3	NEt₃	Dioxane	55	N₂	42
4	Pyridine	Dioxane	55	N₂	44
5	i-Pr₂NEt	Dioxane	55	N₂	56
6	i-Pr₂NEt	Dioxane	55	Air	49
7	i-Pr₂NEt	Toluene	55	N₂	48
8	i-Pr₂NEt	CH₃CN	55	N₂	56
9	i-Pr₂NEt	THF	55	N₂	52
10	i-Pr₂NEt	DCE	55	N₂	63
11	i-Pr₂NEt	DCE	r.t.	N₂	56
12	i-Pr₂NEt	DCE	40	N₂	68
13	i-Pr₂NEt	DCE	80	N₂	44
14	i-Pr₂NEt	DCE	100	N₂	45
15^c	i-Pr₂NEt	DCE	40	N₂	53

表1. 优化实验

Table 1. Optimization study

图式2. 溴化N-酰烷基吡啶的底物范围

Scheme 2. Substrate scope of pyridinium salt Reaction conditions: pyridinium salts (0.30 mmol), methyl propiolate (54 μL, 0.60 mmol), 1,1,1,3,3,3-hexafluoro-2-propanol (95 μL, 0.90 mmol), i-Pr2NEt (79 μL, 0.45 mmol), DCE (2.0 mL).

图式3. 溴化N-酰烷基吡啶的底物范围

Scheme 3. Substrate scope of pyridinium salt Reaction conditions: pyridinium salts (0.30 mmol), methyl propiolate (54 μL, 0.60 mmol), 1,1,1,3,3,3-hexafluoro-2-propanol (95 μL, 0.90 mmol), iPr2NEt (79 μL, 0.45 mmol), DCE (2.0 mL). For synthesis of 4jaa, air was used as atmosphere instead of N2 gas.

图式4. 共轭炔羰基化物的底物范围

Scheme 4. Substrate scope of alkyne Reaction conditions: pyridinium salts (87 mg, 0.30 mmol), alkne (0.60 mmol), 1,1,1,3,3,3-hexafluoro-2-propanol (95 μL, 0.90 mmol), iPr2NEt (79 μL, 0.45 mmol), DCE (2.0 mL).

图式5. 醇的底物范围

Scheme 5. Substrate scope of alcohol Reaction conditions: pyridinium salts (87 mg, 0.30 mmol), methyl propiolate (54 μL, 0.60 mmol), alcohol (0.90 mmol), iPr2NEt (79 μL 0.45 mmol), DCE (2.0 mL). For synthesis of 4aah, 2,5-dihydroxy-1,4-benzoquinone (0.90 mmol) was used as additive.

图式6. 中氮茚产物的转化与衍生

Scheme 6. Conversion and derivatization of indolizine products Reaction conditions: (i) 4aaa (138 mg, 0.3 mmol), BnNH2 (80 mg, 0.75 mmol), NEt3 (37 mg, 0.36 mmol), DCM (6 mL), r.t., 12 h; (ii) 4aaa (138 mg, 0.3 mmol), NaBH4 (23 mg, 0.6 mmol), MeOH (6 mL), 0 ℃, 2 h; (iii) 4aaa (138 mg, 0.3 mmol), NaOH (0.9 mL, 1 mol/L, 0.90 mmol), THF (6 mL), H2O (2 mL); (iv) 4aaa (138 mg, 0.3 mmol), NEt3 (92 mg, 0.9 mmol), MeOH (6 mL), r.t. 12 h.

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