Copper-catalysed one-pot synthesis of N-substituted benzo[d]isothiazol-3(2H)-ones via C-S/N-S bond formation

Abstract

One-pot synthesis of N-substituted benzo[d]isothiazol-3(2H)-ones has been described using copper-catalysis from N-substituted 2-halobenzamides and sulfur powder via C-S/N-S bond formation with high yield.

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N-Substituted benzo[d]isothiazol-3(2H)-ones and their analogues have attracted considerable interest in biological and chemical sciences due to their promising antibacterial and antifungal properties.^1,2 They have also been studied as potential antithrombotic agents,^3a antipsychotic agents^3c as well as models for the development of metallothionein inspired molecular pincers.^3g Furthermore, they are being investigated as potential inhibitors of phosphomannose^3h and NADPH-oxidase.^3h In addition, benzo[d]isothiazol-3(2H)-ones have been utilized for the development of glutamate receptor subtype-2.³ⁱ As a result, a number of routes leading to the target heterocycles have been reported,^3,4 but although they have been proven to be useful protocols, they generally require stoichiometric amount of the reagents and some of them involve highly toxic and corrosive agents such as chlorine gas.^4a Development of catalytic methods for the construction of the benzoisothiazol-3(2H)-one structural framework has thus been important in organic synthesis.

The recent advances in cross-coupling reactions using transition-metal-catalysis have led to the development of effective methods for the construction of carbon-heteroatom bonds.^5,6 Among them, copper-based catalytic systems are attractive because they are cheap, readily available and less toxic.^6–9 Herein, we wish to report a new one-pot synthesis of N-substituted benzo[d]isothiazol-3(2H)-ones from N-substituted 2-halobenzamides and sulfur powder using copper-catalyzed C-S cross-coupling reaction followed by N-S bond formation. The procedure is general and the target compounds could be obtained in high yield.

First, the optimization of the reaction conditions was performed with N-benzyl-2-iodobenzamide as a model substrate using different solvents, copper and sulfur sources at varied temperatures (Table 1). The reaction occurred to give the desired N-benzyl-benzo[d]isothiazol-3(2H)-one in 78% conversion when the substrate was stirred with 10 mol % copper source, 3 equiv. sulfur powder and 3 equiv. K₂CO₃ for 6 h at 75 °C in DMF under nitrogen. In a set of copper sources screened, CuCl, CuBr, CuI and Cu(OAc)₂·H₂O, CuCl gave the best result (entry 1). DMF was found to be the solvent of choice, whereas the reaction in DMSO gave the target product in 70% conversion. In contrast, the process in toluene showed no reaction. Sulfur powder was found to be the superior sulfur source compared to thiourea. Lowering of the reaction temperature (70 °C) or quantity of the catalyst (5 mol %) or sulfur source (2 equiv) or base (2 equiv) led to the formation of the target molecule in < 60% conversion. Control experiments confirmed that the desired heterocycle was not formed in the absence of the copper source.

Table 1 Optimization of reaction conditions

entry	catalyst	solvent	sulfur source	temp. (°C)	product (%)^a^b
a Determined by ^1H NMR spectroscopy. b N-Benzyl-2-iodobenzamide (0.5 mmol), copper source (10 mol %), sulfur source (1.5 mmol) and K2CO3 (1.5 mmol) were stirred at 75 °C for 6 h in DMF (1 mL) under N2. c Catalyst (5 mol %) used. n.d. = not detected.
1	CuCl	DMF	S powder	75	78
2	CuCl	DMSO	S powder	75	70
3	CuCl	toluene	S powder	75	n.d.
4	CuBr	DMF	S powder	75	70
5	CuI	DMF	S powder	75	65
6	Cu(OAc)2·H2O	DMF	S powder	75	45
7	CuCl	DMF	thiourea	75	51
8	CuCl	DMF	S powder	70	60
9	—	DMF	S powder	75	n.d.
10	CuCl	DMF	S powder	75	40^c

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Next, the scope of the procedure was investigated for the synthesis of a series of N-alkyl-benzo[d]isothiazol-3(2H)-ones (Table 2). 2-Iodobenzamides with N-butyl, N-cyclohexyl, N-isopropyl, N-(2-phenylethyl) and N-(3,4-dimethoxyphenethyl) substituents proceeded with 83–93% yield (entries 1–5). Similarly, 2-iodo-N-(2-(octyloxy)ethyl)benzamide and N,N′-(ethane-1,2-diyl)-bis(2-iodobenzamide) could be transformed into the corresponding N-alkyl-benzo[d]isothiazol-3(2H)-ones in 90% and 81% yield, respectively (entries 6 and 7). Furthermore, N-benzyl-2-iodobenzamides with 5-methoxy and 5-octyloxy substituents underwent reactions with 67% and 72% yield, respectively (entries 8 and 9), while the substrate with 5-nitro substituent on benzamide ring gave the target molecule in 85% yield (entry 10).

Table 2 Synthesis of N-alkylbenzo[d]isothiazol-3(2H)-ones

entry	product		time (h)	yield (%)^a^,^b
a N-Substituted 2-iodobenzamide (0.5 mmol), CuCl (10 mol %), sulfur powder (1.5 mmol) and K2CO3 (1.5 mmol) were stirred at 75 °C in DMF (1 mL) under N2. b Isolated yield. c CuCl (20 mol %), sulfur powder (3 mmol) and K2CO3 (3 mmol) were used.
1	R = n-butyl		9	93
2	R = cyclohexyl		8	95
3	R = isopropyl		8	90
4	R = 2-phenylethyl		8	87
5	R = 3,4-dimethoxy-phenethyl		8	83
6			10	90
7			12	81^c
8	R′ = OME	R = benzyl	16	67
9	R′ = OC8H17	R = benzyl	16	72
10	R′ = NO2	R = benzyl	8	85

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Furthermore, the synthesis of N-arylbenzo[d]isothiazol-3(2H)-ones was studied (Table 3). These reactions were found to be more effective using Cs₂CO₃ instead of K₂CO₃, leading to the target compounds in high yield. Thus, 2-iodobenzamides with N-phenyl, N-(2-methoxyphenyl), N-(2-methylphenyl), N-(4-chlorophenyl), N-(4-methoxyphenyl), N-(4-methylphenyl) and 4-((phenyldiazenyl)phenyl) substituents enabled the reactions to afford the corresponding N-arylbenzo[d]isothiazol-3(2H)-ones in 63–90% yield (entries 1–3, 5–7 and 9). Under these conditions, the substrates with N-(3-nitrophenyl) and N-(4-nitrophenyl) substituents were decomposed and the target compounds were not obtained (entries 4 and 8). However, 2-iodobenzamides with N-(2,4-dimethylphenyl), N-(2,6-dimethylphenyl) and N-(3,4-dimethylphenyl) substituents gave the target molecule in 86–92% yield (entries 10–12). Recrystallization of N-(4-methoxy)phenylbenzo-[d]isothiazol-3(2H)-one in CHCl₃ gave single crystals whose structure was determined using a X-ray analysis (Fig. 1).

Fig. 1 ORTEP diagram of N-(4-methoxyphenyl)benzo-[d]isothiazol-3(2H)-one. Thermal ellipsoids are drawn at a 40% probability level. Hydrogen atoms have been omitted for clarity.

Table 3 Synthesis of N-aryl benzo[d]isothiazol-3(2H)-ones

entry	product	time (h)	yield (%)^a^b
a N-Substituted 2-iodobenzamide (0.5 mmol), CuCl (10 mol %), sulfur powder (1.5 mmol) and Cs2CO3 (1.5 mmol) were stirred at 75 °C in DMF (1 mL) under N2. b Isolated yield. c CuCl (99.99%) was used. n.d. = not detected.
1		14	90, 91^c
2	R = OMe	10	84
3	R = Me	12	88
4		10	n.d.
5	R = Cl	18	85
6	R = OMe	10	89
7	R = Me	12	93
8	R = NO2	10	n.d.
9	R = N2Ph	21	63
10		14	92
11		14	91
12		14	86

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To reveal the reactivity of the other 2-halobenzamides, the reactions of 2-bromobenzamides were next studied (Table 4). These substrates underwent reactions at 100 °C to afford the target compounds in moderate to good yield (entries 1–7). Thus, N-butyl-2-bromobenzamide gave 60% yield, while the substrates with 5-nitro and 5-bromo substituents on the benzamide ring afforded the target molecules in 78% and 90% yield, respectively (entries 1–3). The substrate with a 5-methoxy substituent on the benzamide ring proceeded with a 45% yield (entry 4). Similarly, N-aryl-2-bromobenzamides containing N-(4-chlorophenyl) and N-(4-methylphenyl) substituents afforded the target compounds in moderate yield (entries 5 and 6), whereas N-(4-methylphenyl)-2-bromo-5-nitrobenzamide gave a 71% yield (entry 7).

Table 4 Synthesis of N-alkyl benzo[d]isothiazol-3(2H)-ones from N-substituted 2-bromobenzamides

entry	product		time (h)	yield (%)^a^b
a N-Substituted 2-bromobenzamide (0.5 mmol), CuCl (10 mol %), sulfur powder (1.5 mmol) and K2CO3 (1.5 mmol) were stirred at 100 °C in DMF (1 mL) under N2. b Isolated yield. c Cs2CO3 (1.5 mmol) was used.
1			9	60
2	R′ = NO2		10	78
3	R′ = Br		10	90
4	R′ = OMe		18	45
5^c	R′ = H	R = Cl	18	50
6^c	R′ = H	R = OMe	10	54
7^c	R′ = NO2	R = Me	10	71

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Finally, the reactions of the 2-chlorobenzamides were studied (Table 5).^6j These substrates enabled the reaction to proceed at 135 °C to give desired N-substituted benzo[d]isothiazol-3(2H)-ones in moderate yield (Table 5). For example, 2-chlorobenzamides with N-alkyl substituents, N-benzyl-2-chloro-5-nitrobenzamide and N-benzyl-2-chloro-5-bromobenzamide gave the target molecules in 35% and 21% yield, respectively (entries 1 and 2), whereas N-(4-methoxyphenyl)-2-chloro-5-nitrobenzamide and N-(4-methylphenyl)-2-chloro-5-nitrobenzamide reacted with 45% and 30% yields, respectively (entries 4 and 5). In contrast, the substrate with a 5-methoxy group on the benzamide ring showed no reaction and the formation of the target compound was not observed.

Table 5 Synthesis of N-alkyl benzo[d]isothiazol-3(2H)-ones from N-substituted 2-chlorobenzamides

entry	product		time (h)	yield (%)^a^,^b
a N-Substituted 2-chlorobenzamide (0.5 mmol, CuCl (10 mol %), sulfur powder (1.5 mmol) and K2CO3(1.5 mmol) were stirred at 135 °C in DMF (1 mL) under N2. b Isolated yield. c Cs2CO3 (1.5 mmol) used. d CuCl (10 mol % and 1,2- bis(diphenylphosphinoethane) (10 mol %) was used. n.d. = not detected.
1	R′ = NO2		28	35
2	R′ = Br		28	21
3	R′ = OMe		28	n.d.
4^c	R′ = NO2	R = Me	28	30
5^c	R′ = NO2	R = OMe	24	45,48^d

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Conclusions

In conclusion, copper-catalyzed one-pot synthesis of N-substituted benzo[d]isothiazol-3(2H)-ones has been described from N-substituted 2-halobenzamides and sulfur powder via C-S/N-S bond formation. Further study towards the elucidation of the mechanism is currently underway in our laboratory.

Acknowledgements

We thank Department of Science and Technology, New Delhi and Council of Scientific and Industrial Research, New Delhi for financial Support.

References

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Footnote

† Electronic Supplementary Information (ESI) available: experimental procedure, CCDC 876574 (N-(4-methoxyphenyl)benzo-[d]isothiazol-3(2H)-one) and NMR spectra (¹H and ¹³C). See DOI: 10.1039/c2ra20724a/

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