A facile and environmentally benign polyethylene glycol 600-mediated method for the synthesis of densely functionalized 2-aminothiophene derivatives under ultrasonication

Figures & data

Figure 1. Some typical biologically active compounds containing 2-aminothiophene scaffold.

Scheme 1. The Gewald reaction in PEG 600 medium under ultrasonic conditions at ambient temperature.

Table 1. Optimization of the Gewald three-component reaction under thermal and ultrasound conditions^a.

Entry	Conditions	Medium/(mL)	Temp. (°C)	Time (min)	Yield^b (%)
1	Thermal	PEG 400/2	90	40	85
2	Thermal	PEG 600/2	90	25	98
3	Thermal	PPG 1000/2	90	60	Nil^c
4	Thermal	PEG 600/1.5	90	35	96
5	Thermal	PEG 600/1	90	90	64
6	Thermal	PEG 600/2.5	90	25	98
7	Thermal	PEG 600/2	80	40	97
8	Thermal	PEG 600/2	70	55	95
9	Thermal	PEG 600/2	60	90	96
10	Thermal	PEG 600/2	100	25	97
11	US	PEG 400/2	Ambient	10	68
12	US	PEG 600/2	Ambient	10	98
13	US	PPG 1000/2	Ambient	10	Nil^c

^aReaction conditions: Cyclohexanone (1a, 1 mmol), malononitrile (2a, 1 mmol) and elemental sulfur (3, 1 mmol).

^bThe yields refer to the isolated product 4a.

^cThe Knoevenagel condensation product of 1a and 2a was isolated.

Table 2. Gewald reaction of various carbonyl compounds under the optimized conditions^a.

Entry	Product^b	Time (min)	Yield^c (%)	Mp (°C)
1		20	54	153
2		10	98	140
3		15	91	125
4		15	86	107
5		25	87	119
6		30	45	102
7		35	53	119
8		35	38	138
9		50	33	91
10		40	70	116
11		40	57	86
12		40	54	79
13		40	58	75
14		50	39	45
15		45	43	70
16		50	29	97

^aReaction conditions: Carbonyl compound (1, 1 mmol), activated nitrile (2, 1 mmol) and sulfur (3, 1 mmol) were sonicated in PEG 600 (2 mL).

^bAll products are known compounds and their structures were established from their spectral data and melting points as compared with authentic samples or literature values.

^cThe yields refer to the isolated products 4a–4q.

Scheme 2. Proposed mechanism for the three-component Gewald reaction in PEG 600 medium under ultrasonication.

Figure 2. Reusability of PEG 600 in the synthesis of 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (4b).

Table 3. Comparative synthesis of compound 4b using the reported methods versus the present method.

Entry	Catalyst	Solvent	Temp. (°C)/Cond.	Time (h)	Yield (%)	Reference
1	Nano-ZnO	Solvent-free	100	6	77	(32)
2	NaAlO2	EtOH	60	10	91	(45)
3	Bovine Albumin	DMF	50	4	99	(31)
4	(BmIm)OH	Solvent-free	60	2	88	(46)
5	Et3N	Water	rt	6	89	(47)
6	Et2NH	Water	US	0.08	96	(48)
7	NaOH	deep eutectic	60	4	88	(49)
8	Free	PEG 600	90	0.41	98	This work
9	Free	PEG 600	US	0.16	98	This work

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