Quaternary ammonium salt as alkylation agent in three-component reactions for the synthesis of benzothiazoles in water

Abstract

Substituted benzothiazoles are synthesized by metal-catalyst-free three-component reactions of o-iodoaniline, quaternary ammonium salt, and sulfur powder in water with moderate-to-excellent yields up to 95%.

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Multicomponent reactions (MCRs) have gained considerable and steadily increasing interest recently due to their convenience and atomic economy,¹ and they have served as a powerful tool in synthetic chemistry.²

Substituted benzothiazole cores are important biologically active motifs, which can usually be found in many natural products,³ drug molecules,⁴ and novel materials for sensors and indicators etc.⁵ Several synthetic approaches have been reported to obtain them. For example, one of the most general and flexible methods is the condensation reaction of 2-aminothiophenol with carboxylic acids or aldehydes, which may be limited by difficulties in obtaining the unstable 2-aminothiophenol substrate.⁶ Other methods comprising metal-catalyzed coupling reactions such as copper- or palladium-catalyzed intramolecular reactions starting from amines have then been developed.⁷ Recently, Itoh and Ma et al. reported a novel and practical synthetic method by using copper- or palladium-catalyzed cross-coupling reactions between 2-haloanilides and metal sulfides⁸ or 2-ethylhexyl-3-mercaptopropionate.⁹ Sun et al. also reported an efficient and convenient method for the formation of 2-substituted benzothiazoles via a copper-catalyzed condensation of 2-aminobenzenethiols with nitriles.¹⁰ In general, in most of these cases, metal catalysts were used and organic solvents were applied as reaction media.¹¹

Recently, we reported Cu-catalyzed three-component reactions involving 2-iodoaniline, aldehydes, and sulfur powder for the synthesis of substituted benzothiazoles in water.¹² To our surprise, during this work we found that substituted benzothiazoles could even be obtained in high yields without transition metal catalysts when quaternary ammonium salts were used instead of aldehydes. This reaction has the following advantages compared with the reported literature: (i) easy availability of substrates such as quaternary ammonium salt, o-iodoaniline, and sulfur powder; (ii) a metal-catalyst-free reaction avoids the introduction of heavy metal into the product as well as having a convenient work-up step; (iii) water was used as sole solvent instead of the normally used organic media; (iv) the reactions can be carried out in the air without requiring an inert atmosphere; (v) quaternary ammonium salts act as chemoselective alkylation agents as well as phase transfer reagents during the reaction.¹³

Initially, 2-iodoaniline, tetrabutylammonium bromide (TBAB) and elemental sulfur were tried as model substrates to optimize the reaction conditions. As shown in Table 1, bases seemed to be essential for the reactions, and control experiments confirmed that no product was detected without the addition of bases (Table 1, entry 1). The screening of different bases indicated KOH to be the correct one to give 93% yield, while the employment of organic bases and other inorganic bases such as triethylamine, pyridine, carbonate salts or NH₃·H₂O resulted in lower yields (Table 1, entries 2–8). Reaction temperature was another important factor affecting the results, as a temperature lower than 140 °C reduced the reaction rate (Table 1, entries 9–11). In addition, shorter reaction times had negative effects on the results, and 14 hours was chosen for further studies (Table 1, entries 12–14). The loading of tetrabutylammonium bromide and base was then investigated, and it was observed that decreasing the amount of the tetrabutylammonium bromide or base resulted in lower yields. Meanwhile, the amount of sulfur could be reduced to around 1.2 mmol with similar results (Table 1, entries 15–18). In summary, the optimal conditions for the synthesis of benzothiazoles in water consist of 2-iodoaniline (1.0 mmol), tetrabutylammonium bromide (1.0 mmol), sulfur powder (1.2 mmol) and KOH (2.0 mmol) at 140 °C for 14 h.

Table 1 Screening of reaction conditions for the three-component reactions^a

Entry	Base	Temp/°C	Time/h	Yield^b [%]
a Unless otherwise noted, the reactions were carried out with 2-iodoaniline (1.0 mmol), (n-Bu)4NBr (1.0 mmol), sulfur powder (3.0 mmol), and base (2.0 mmol) in water (10 mL) at 140 °C.b Isolated yields.c (n-Bu)4NBr (0.5 mmol) was used.d Sulfur powder (1.2 mmol) was added.e KOH (1.0 mmol) was added.f Sulfur powder (1.0 mmol) was added.
1	—	140	14	0
2	K2CO3	140	14	86
3	Cs2CO3	140	14	82
4	KOH	140	14	93
5	NaOH	140	14	90
6	NH3·H2O	140	14	5
7	Pyridine	140	14	8
8	Et3N	140	14	7
9	KOH	80	14	15
10	KOH	100	14	27
11	KOH	120	14	58
12	KOH	140	6	62
13	KOH	140	10	79
14	KOH	140	20	94
15	KOH	140	14	40^c
16	KOH	140	14	92^d
17	KOH	140	14	32^e
18	KOH	140	14	83^f

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Then, several commercially available quaternary ammonium salts were explored under the optimized reaction conditions. As shown in Table 2, most of the substrates provided moderate-to-excellent yields ranging from 74% to 93%. Anions of the quaternary ammonium salts showed few effects on the reaction. For example, when the cation is tetrabutylammonium, different anions, including I⁻, Br⁻, Cl⁻, F⁻, HSO4⁻, OH⁻ and CH₃COO⁻, gave similar results, around 90% yields (Table 2, entries 1–7). On the contrary, different cations exhibited significant effects on the results. Long-chain alkyl groups seemed to be beneficial to the reaction. Thus, tetrapropylammonium bromide, tetraheptylammonium bromide and tetraoctylammonium bromide gave 85%, 95% and 95% yields, respectively (Table 2, entries 8–10).

Table 2 Synthesis of substituted benzothiazoles by using different quaternary ammonium salts^a

Entry	PTC	Products	Yield^b [%]
a Reaction conditions: 2-iodoaniline (1.0 mmol), quaternary ammonium salt (1.0 mmol), sulfur powder (1.2 mmol), KOH (2.0 mmol), and H2O (10 mL), 140 °C, 14 h.b Isolated yields.
1	(CH3CH2CH2CH2)4NI		89
2	(CH3CH2CH2CH2)4NBr		93
3	(CH3CH2CH2CH2)4NCl		92
4	(CH3CH2CH2CH2)4NF		91
5	(CH3CH2CH2CH2)4NHSO4		90
6	(CH3CH2CH2CH2)4N(OCOCH3)		80
7	(CH3CH2CH2CH2)4NOH		87
8	(CH3CH2CH2)4NBr		85
9	[CH3(CH2)6]4NBr		95
10	[CH3(CH2)7]4NBr		95
11			74
			18
12			80
			—
13			78
			17

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More importantly, these reactions seemed to be highly chemoselective when the quaternary ammonium salts consisted of different alkyl groups. For example, when dodecyltrimethylammonium bromide, benzyltrimethylammonium bromide or benzyltributylammonium bromide were reacted with 2-iodoaniline, the corresponding major products were 2-undecylbenzothiazole and 2-phenylbenzothiazole, respectively (Table 2, entries 11–13), which indicated that quaternary ammonium salts would act as potential alkylation reagents, and long-chain or benzyl alkyl groups seemed to be beneficial to the reactions.

In an endeavor to expand the scope of this methodology, a series of substituted 2-halogenated anilines were also examined in the presence of straight-chain quaternary ammonium salts (TBAB) and benzyltrimethylammonium bromide. As shown in Table 3, most 2-iodoanilines, especially those bearing electron-donating substituents, provided good-to-excellent yields. The highest yield, 94%, was obtained in the case of 2-iodo-4-methylbenzenamine, while 81% yield was obtained in the case of 5-fluoro-2-iodoaniline when TBAB was used (entries 1 and 6). As expected, in the case when benzyltrimethylammonium bromide was used as PTC as well as alkylation reagent, lower yields were obtained due to the competition reaction between different alkyl groups (entries 9–11). Furthermore, 2-bromoaniline gave a lower yield of product, at 65%, compared with the iodo analogs (entry 8).

Table 3 Synthesis of substituted benzothiazoles by using different 2-iodoanilines and quaternary ammonium salts^a

Entry	PTC	Iodoaniline	Products	Yield^b [%]
a Reaction conditions: o-iodoaniline (1.0 mmol), PTC (1.0 mmol), sulfur powder (1.2 mmol), KOH(2.0 mmol), and H2O (10 mL), 140 °C, 14 h.b Isolated yields.
1	[CH3(CH2)3]4NBr			94
2				92
3				82
4				86
5				83
6				81
7				82
8				65
9				84
				Trace
10				70
				Trace
11				62
				Trace

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Next, the reaction pathway was studied in the synthesis of benzothiazoles from 2-iodoaniline, quaternary ammonium salt, and sulfur powder. According to Scheme 1, disulfide ether could be obtained in high yield from quaternary ammonium salt and sulfur powder. Meanwhile, no reaction was observed in the case of iodoaniline with sulfur or PTC, indicating the difference between this reaction and our former work, in which disulfide ether was obtained from iodoaniline with sulfur in the presence of a copper catalyst.¹²

Scheme 1 Investigation of the reaction pathway.

Further, disulfide ether was isolated and reacted with iodoaniline as shown in Scheme 2. As with our former work, the product could be obtained in high yield in the presence of elemental sulfur, which indicated that an excess amount of sulfur was necessary in the reaction. Furthermore, 2-(benzylthio)benzenamine was detected during the reaction, which would be a possible intermediate. Actually, the isolated 2-(benzylthio)benzenamine could be smoothly transformed to the final product under the reaction conditions.

Scheme 2 Control experiments.

Based on our work as well as the literature, a plausible reaction pathway was proposed as shown in Scheme 3. Benzyltrimethylammonium bromide was first reacted with sulfur powder to generate dibenzyl disulphide I, which would be reacted with iodoaniline to give 2-(benzylthio)benzenamine II. Then, the target product was obtained after the intramolecular cyclization reaction of II.¹⁴

Scheme 3 Possible reaction pathway for the three-component synthesis of substituted benzothiazoles

In summary, we have developed an efficient and environmentally friendly method for the preparation of substituted benzothiazoles by three-component reactions of o-iodoaniline, quaternary ammonium salt, and sulfur powder in a simple one-pot procedure in water. This method avoids the use of transition metal catalysts, and water was used as solvent. Quaternary ammonium salt acts as a phase transfer reagent as well as an alkylation reagent. The application of this method is still in progress in this lab.

Acknowledgements

We are grateful to the Natural Science Foundation of China (nos 21072132, 21272161, 21372163) and the Ministry of Education (no. 20120181110050) for financial support. We also acknowledge the Key Laboratory of Green Chemistry and Technology of Ministry of Education for HRMS analysis.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra04145c

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