Three-Component Reaction of N-Acylalkylpyridinium Bromides, Conjugated Alkynyl Carbonyl Compounds and Alcohols for the Synthesis of 3-Alkyl Indolizines: Air as Oxidant

doi:10.6023/cjoc202510022

Abstract

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

Cite this article

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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Fig. & Tab. 8

Figure 1. Bioactive molecules containing the indolizine skeleton

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

Table 1. Optimization study

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).

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.

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).

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.

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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