Synthesis of Multi-Substituted Benzo[b]thiophene-4-ol Derivatives Promoted by Organobase

doi:10.6023/cjoc202508019

Abstract

Multi-substituted benzo[b]thiophene skeleton is an important synthetic intermediate. A series of multi-substituted benzo[b]thiophene-4-ol derivatives were successfully constructed from 3-substituted 1-(thiophen-3-yl)prop-2-en-1-one and nitroso compound via organobase‑promoted cycloaddition reactions. Optimization experiments showed that the best expe- rimental conditions were as follows: using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (2.5 mmol) as base, 3-substituted 1-(thiophen-3-yl)prop-2-en-1-one (1.0 mmol) and nitroso compound (1.2 mmol) reacted in N,N-dimethylformamide (DMF) at room temperature for 8 h, affording multi-substituted benzo[b]thiophen-4-ol derivatives in 88% yield. The compositions and structures have been characterized by ¹H NMR, ¹³C NMR and HRMS (ESI). The mechanism for the reaction was proposed. The menthod has the characteristics of mild conditions and practical efficiency.

Key words: organobase-promoted, benzo[b]thiophene, synthesis

Cite this article

Chuanqing Ren, Xinxin Li, Jiawei Guo, Xiaohui Ji, Bo Liu. Synthesis of Multi-Substituted Benzo[b]thiophene-4-ol Derivatives Promoted by Organobase[J]. Chinese Journal of Organic Chemistry, 2026, 46(5): 2090-2095.

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Entry	Base (mmol)	Solvent	Temperature/℃	Time/h	Yield^b/%
1	K₂CO₃ (2.0)	DMF	r.t.	8	0
2	NaOH (2.0)	DMF	r.t.	8	21
3	DBU (2.0)	DMF	r.t.	8	78
4	DBU (2.1)	DMF	r.t.	8	80
5	DBU (2.2)	DMF	r.t.	8	81
6	DBU (2.5)	DMF	r.t.	8	84
7	DBU (3.0)	DMF	r.t.	8	82
8	N(C₂H₅)₃ (2.5)	DMF	r.t.	8	0
9	C₂H₅N[CH(CH₃)₂]₂ (2.5)	DMF	r.t.	8	0
10	C₅H₅N (2.5)	DMF	r.t.	8	56
11	DMAP (2.5)	DMF	r.t.	8	38
12	DBU (2.5)	CH₂Cl₂	r.t.	8	0
13	DBU (2.5)	DMSO	r.t.	8	79
14	DBU (2.5)	CH₃CH₂OH	r.t.	8	68
15	DBU (2.5)	DMF	r.t.	6	79
16	DBU (2.5)	DMF	r.t.	10	81
17	DBU (2.5)	DMF	40	8	82
18	DBU (2.5)	DMF	80	8	65

Entry	Base (mmol)	Solvent	Temperature/℃	Time/h	Yield^b/%
1	K₂CO₃ (2.0)	DMF	r.t.	8	0
2	NaOH (2.0)	DMF	r.t.	8	21
3	DBU (2.0)	DMF	r.t.	8	78
4	DBU (2.1)	DMF	r.t.	8	80
5	DBU (2.2)	DMF	r.t.	8	81
6	DBU (2.5)	DMF	r.t.	8	84
7	DBU (3.0)	DMF	r.t.	8	82
8	N(C₂H₅)₃ (2.5)	DMF	r.t.	8	0
9	C₂H₅N[CH(CH₃)₂]₂ (2.5)	DMF	r.t.	8	0
10	C₅H₅N (2.5)	DMF	r.t.	8	56
11	DMAP (2.5)	DMF	r.t.	8	38
12	DBU (2.5)	CH₂Cl₂	r.t.	8	0
13	DBU (2.5)	DMSO	r.t.	8	79
14	DBU (2.5)	CH₃CH₂OH	r.t.	8	68
15	DBU (2.5)	DMF	r.t.	6	79
16	DBU (2.5)	DMF	r.t.	10	81
17	DBU (2.5)	DMF	40	8	82
18	DBU (2.5)	DMF	80	8	65

Entry	Substrate	R¹	R²	R³	R⁴	Time/h	Product	Yield^b/%
1	1a	CN	Ph	CH₃CH₂	CH₃	8	2a	84
2	1b	CN	4-CH₃C₆H₄	CH₃CH₂	CH₃	8	2b	86
3	1c	CN	4-CH₃OC₆H₄	CH₃CH₂	CH₃	8	2c	87
4	1d	CN	4-CH₃CH₂OC₆H₄	CH₃CH₂	CH₃	8	2d	88
5	1e	CN	2-ClC₆H₄	CH₃CH₂	CH₃	10	2e	76
6	1f	CN	4-ClC₆H₄	CH₃CH₂	CH₃	10	2f	74
7	1g	CN	PhCH=CH	CH₃CH₂	CH₃	12	2g	72
8	1h	CN	3,4-O₂CH₂C₆H₃	CH₃CH₂	CH₃	10	2h	83
9	1i	CN	2-Thienyl	CH₃CH₂	CH₃	8.5	2i	71
10	1j	CN	2-Furyl	CH₃CH₂	CH₃	8.5	2j	73
11	1k	CN	t-Bu	CH₃CH₂	CH₃	10	2k	65
12	1l	COOC₂H₅	Ph	CH₃CH₂	CH₃	12	2l	81
13	1m	CN	Ph	CH₃	CH₃	8	2m	83
14	1n	CN	Ph	CH₃CH₂	CH₃CH₂	9	2n	80
15	1o	CN	4-CH₃OC₆H₄	CH₃CH₂	Ph	11	2o	68

Entry	Substrate	R¹	R²	R³	R⁴	Time/h	Product	Yield^b/%
1	1a	CN	Ph	CH₃CH₂	CH₃	8	2a	84
2	1b	CN	4-CH₃C₆H₄	CH₃CH₂	CH₃	8	2b	86
3	1c	CN	4-CH₃OC₆H₄	CH₃CH₂	CH₃	8	2c	87
4	1d	CN	4-CH₃CH₂OC₆H₄	CH₃CH₂	CH₃	8	2d	88
5	1e	CN	2-ClC₆H₄	CH₃CH₂	CH₃	10	2e	76
6	1f	CN	4-ClC₆H₄	CH₃CH₂	CH₃	10	2f	74
7	1g	CN	PhCH=CH	CH₃CH₂	CH₃	12	2g	72
8	1h	CN	3,4-O₂CH₂C₆H₃	CH₃CH₂	CH₃	10	2h	83
9	1i	CN	2-Thienyl	CH₃CH₂	CH₃	8.5	2i	71
10	1j	CN	2-Furyl	CH₃CH₂	CH₃	8.5	2j	73
11	1k	CN	t-Bu	CH₃CH₂	CH₃	10	2k	65
12	1l	COOC₂H₅	Ph	CH₃CH₂	CH₃	12	2l	81
13	1m	CN	Ph	CH₃	CH₃	8	2m	83
14	1n	CN	Ph	CH₃CH₂	CH₃CH₂	9	2n	80
15	1o	CN	4-CH₃OC₆H₄	CH₃CH₂	Ph	11	2o	68

有机碱驱动合成多取代苯并[b]噻吩-4-醇类化合物