Synthesis of 3,5-Diaryl-1,2,4-oxadiazole by One-Pot Homocoupling Reaction

doi:10.6023/cjoc202401030

Abstract

3,5-Diaryl-1,2,4-oxadiazoles were synthesized by homocoupling of chloroarylaldoxime from arylaldoxime and N-chlorosuccinimide (NCS) in the presence of Cs₂CO₃ in one pot. The method is suitable for thiophene-3-carbaldehyde, isonicotinaldehyde and arylaldehyde without active substituent with a yield from 19% to 78%. However, it was not suitable for aliphatic aldehydes, other heteroaromatic aldehydes and benzaldehydes carrying active groups (hydroxyl, amino and carboxylic acid). Compared to reported methods, this method uses only aromatic aldoxime as a single substrate. The process is simple, convenient, and green, making it a reliable way to synthesize 3,5-(homo-substituted)-1,2,4-oxadiazoles.

Key words: 1,2,4-oxadiazole, homocoupling reaction, aldehydes, chlorobenzaldoxime, cyclic addition

Cite this article

Mengjin Liu, Yan Xiao, Kai Zhou, Zicheng Li, Wencai Huang. Synthesis of 3,5-Diaryl-1,2,4-oxadiazole by One-Pot Homocoupling Reaction[J]. Chinese Journal of Organic Chemistry, 2024, 44(7): 2251-2256.

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Entry	Solvent	Base	Yield^a/%
1	DMF	NaOH	22
2	DMF	NaHCO₃	25
3	DMF	Na₂CO₃	27
4	DMF	Cs₂CO₃	39
5	DMF	Ammonia	Trace
6	DMF	DBU	10
7	DMF	t-BuOK	29
8	DMF	Et₃N	31
9	DMF	n-Propylamine	Trace
10	DMF	N-Ethylpiperidine	33
11	DMF	KOH	20
13	DMF	Cs₂CO₃(2.5^b)	44
14	DMF	Cs₂CO₃(3.5^b)	55
15	DMF	Cs₂CO₃(4.5^b)	49

Entry	Solvent	Base	Yield^a/%
1	DMF	NaOH	22
2	DMF	NaHCO₃	25
3	DMF	Na₂CO₃	27
4	DMF	Cs₂CO₃	39
5	DMF	Ammonia	Trace
6	DMF	DBU	10
7	DMF	t-BuOK	29
8	DMF	Et₃N	31
9	DMF	n-Propylamine	Trace
10	DMF	N-Ethylpiperidine	33
11	DMF	KOH	20
13	DMF	Cs₂CO₃(2.5^b)	44
14	DMF	Cs₂CO₃(3.5^b)	55
15	DMF	Cs₂CO₃(4.5^b)	49

Entry	Temp./℃	Time/h	Catalyst (0.05 equiv.)	Yield^a/%
1	15	8	—	49
2	35	8	—	56
3	45	8	—	65
4	65	8	—	57
5	95	8	—	33
6	45	10	—	65
7	45	8	Pd(OAc)₂	18
8	45	8	CuCl	67
9	45	8	FeCl₃	50
10	45	8	PdCl₂	30
11	45	8	ZnCl₂	43

Entry	Temp./℃	Time/h	Catalyst (0.05 equiv.)	Yield^a/%
1	15	8	—	49
2	35	8	—	56
3	45	8	—	65
4	65	8	—	57
5	95	8	—	33
6	45	10	—	65
7	45	8	Pd(OAc)₂	18
8	45	8	CuCl	67
9	45	8	FeCl₃	50
10	45	8	PdCl₂	30
11	45	8	ZnCl₂	43

Entry	R	Yield^a/%
1	Phenyl (1a)	65
2	4-Tolyl (1b)	37
3	4-Methoxyphenyl (1c)	50
4	3-Methoxyphenyl (1d)	54
5	4-Nitrophenyl (1e)	78
6	4-Chlorophenyl (1f)	72
7	3-Chlorophenyl (1g)	70
8	3-Bromophenyl (1h)	69
9	2-Methylphenyl (1i)	41
10	4-Trifluoromethylphenyl (1j)	35
11	1-Naphthyl (1k)	52
12	2-Naphthyl (1l)	61
13	2-Chloropyridin-4-yl (1m)	43
14	3-Thiophenyl (1n)	19

一锅法自偶联反应合成3,5-二苯基-1,2,4-噁二唑