Synthesis of Difluoromethyl Substituted 1,2,4-Triazoline Compounds

doi:10.6023/cjoc202403020

Abstract

A 1,3-dipolar cycloaddition of difluoromethyl nitrile imines generated in situ from difluoroacetohydrazonoyl bromides with 3-iminooxindoles in the presence of base is described. Under mild reaction conditions, thirty-seven difluoro- methyl substituted spiro 1,2,4-triazoline oxindole compounds were successfully synthesized in up to 97% yield with excellent regioselectivity. This method provides a new method for the synthesis of difluoromethyl substituted 1,2,4-triazoline compounds, and further expands the application range of difluoromethyl nitrile imines in 1,3-dipolar cycloaddition reactions

Key words: 1,2,4-triazolines, difluoromethyl, difluoroacetohydrazonoyl bromides, 1,3-dipolar cycloaddition, synthesis

Cite this article

Ying Fan, Danfeng Huang, Hu Ma, Zuyu Bai, Ke-Hu Wang, Junjiao Wang, Yulai Hu. Synthesis of Difluoromethyl Substituted 1,2,4-Triazoline Compounds[J]. Chinese Journal of Organic Chemistry, 2024, 44(9): 2820-2831.

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Entry	n(1a)∶n(2a)∶n(base)	Base	Time/h	Temp/℃	Solvent	Isolated yield/%
1	1.2/1.0/1.2	K₂CO₃	9	35	CH₃CN	53
2	1.2/1.0/1.2	K₂CO₃	9	35	EtOH	85
3	1.2/1.0/1.2	K₂CO₃	9	35	1,4-Dioxane	90
4	1.2/1.0/1.2	K₂CO₃	9	35	THF	81
5	1.2/1.0/1.2	K₂CO₃	9	35	DCE	70
6	1.2/1.0/1.2	K₂CO₃	9	35	DCM	68
7	1.2/1.0/1.2	K₂CO₃	9	35	Toluene	69
8	1.3/1.0/1.3	K₂CO₃	9	35	1,4-Dioxane	95
9	1.5/1.0/1.5	K₂CO₃	9	35	1,4-Dioxane	89
10	1.1/1.0/1.1	K₂CO₃	9	35	1,4-Dioxane	68
11	1.3/1.0/1.3	Na₂CO₃	12	35	1,4-Dioxane	76
12	1.3/1.0/1.3	NaHCO₃	14	35	1,4-Dioxane	64
13	1.3/1.0/1.3	KOH	13	35	1,4-Dioxane	70
14	1.3/1.0/1.3	Et₃N	24	35	1,4-Dioxane	35
15	1.3/1.0/1.3	DBU	24	35	1,4-Dioxane	48
16	1.3/1.0/1.3	K₂CO₃	11	25	1,4-Dioxane	80
17	1.3/1.0/1.3	K₂CO₃	8	45	1,4-Dioxane	76

Entry	n(1a)∶n(2a)∶n(base)	Base	Time/h	Temp/℃	Solvent	Isolated yield/%
1	1.2/1.0/1.2	K₂CO₃	9	35	CH₃CN	53
2	1.2/1.0/1.2	K₂CO₃	9	35	EtOH	85
3	1.2/1.0/1.2	K₂CO₃	9	35	1,4-Dioxane	90
4	1.2/1.0/1.2	K₂CO₃	9	35	THF	81
5	1.2/1.0/1.2	K₂CO₃	9	35	DCE	70
6	1.2/1.0/1.2	K₂CO₃	9	35	DCM	68
7	1.2/1.0/1.2	K₂CO₃	9	35	Toluene	69
8	1.3/1.0/1.3	K₂CO₃	9	35	1,4-Dioxane	95
9	1.5/1.0/1.5	K₂CO₃	9	35	1,4-Dioxane	89
10	1.1/1.0/1.1	K₂CO₃	9	35	1,4-Dioxane	68
11	1.3/1.0/1.3	Na₂CO₃	12	35	1,4-Dioxane	76
12	1.3/1.0/1.3	NaHCO₃	14	35	1,4-Dioxane	64
13	1.3/1.0/1.3	KOH	13	35	1,4-Dioxane	70
14	1.3/1.0/1.3	Et₃N	24	35	1,4-Dioxane	35
15	1.3/1.0/1.3	DBU	24	35	1,4-Dioxane	48
16	1.3/1.0/1.3	K₂CO₃	11	25	1,4-Dioxane	80
17	1.3/1.0/1.3	K₂CO₃	8	45	1,4-Dioxane	76

二氟甲基取代的1,2,4-三氮唑啉化合物的合成