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Synlett
DOI: 10.1055/a-2463-4827
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Emerging Trends in Organic Chemistry: A Focus on India

A Resilient and Reusable Ion-Tagged Cu(II) Catalyst for the Microwave-Assisted Synthesis of 2-(N-Arylamino)benzothiazoles

Md Gulzar Ahmad
a   Department of Chemistry, School of Advanced Sciences, Vellore Institute of Technology, Vellore, 632014, India
,
M M Balamurali∗
b   Chemistry Division, School of Advanced Sciences, Vellore Institute of Technology, Chennai Campus, Chennai, 600127, India
,
Kaushik Chanda  ∗
c   Department of Chemistry, Rabindranath Tagore University, Hojai, 782435, India
› Author Affiliations

The authors wish to thank the management of the Vellore Institute of Technology (VIT) for providing seed money as a research grant.
› Further Information
 
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Abstract

A simple, quick, and cost-effective protocol is presented herein for the sustainable synthesis of 2-(N-arylamino)benzothiazoles from 2-haloanilines and arylisothiocyanates by using an ionic liquid supported heterogeneous Cu(II) catalyst derived from N-methylimidazole. Compared to the use of homogeneous catalysts and additives, which require long reaction times and high reaction temperatures, this methodology has a broad substrate scope and proceeds in short reaction times to afford compounds in excellent yields under microwave irradiation. In addition, the catalyst can be extracted easily and is recyclable up to five times with no significant loss in catalytic activity.


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Key words

2-aminobenzothiazoles - ionic liquids - microwave irradiation - Cu(II) catalysts - sustainable synthesis

2-Aminobenzothiazoles are an important class of heterocyclic scaffold with diverse applications in organic chemistry and the agrochemical and pharmaceutical industries.[1] [2] [3] [4] [5] [6] Compounds with this skeleton exhibit notable activities in pharmaceutics such as anticancer, antimicrobial, anti-infective, and antiviral agents, CNS depressants and HIV protease inhibitors, and they are useful reaction intermediates in organic transformations (Figure [1]).[7–16] Therefore, the development of synthetic routes to this moiety has attracted considerable attention.

Typically, 2-aminobenzothiazoles are synthesized through the Pd- or Cu-catalyzed cyclization of o-bromobenzothiourea.[17] [18] [19] However, the substrates are not easily accessible, requiring a further process for the synthesis of the required thioureas from the corresponding amines and isothiocyanates. Recently, there has been a lot of interest in the transition-metal-mediated synthesis of 2-substitutedbenzothiazoles from ortho-haloanilines and isothiocyanates as these approaches are efficient and inexpensive.[20–28] For example, Chen and co-workers developed a Cu-phenanthroline catalyst system for the synthesis of 2-(N-arylamino)benzothiazoles from 2-iodoanilines and aromatic isothiocyanates under argon atmosphere for 4 h.[20] Subsequently, the Mishra group reported the synthesis of a 2-aminobenzothiazole moiety by using copper iodide and glycosyl triazole ligand at a relatively higher temperature for 20 h.[24] Similarly, Ding et al. developed an FeCl3-phenanthroline catalyst system to synthesize 2-aminobenzothiazoles from o-halobenzeamines and aromatic isothiocyanates with the aid of a phase-transfer catalyst (Scheme [1]).[25] Although the reported transition-metal-catalyzed tandem reactions are very effective for generating 2-aminobenzothiazoles, these homogeneous catalysts are not recyclable and pose challenges with respect to separating them from the product. Moreover, the required high catalyst loading, use of additives, longer reaction time, and higher temperature show that a more sustainable synthetic route to 2-(N-substituted) aminobenzothiazole derivatives is needed.

Zoom Image
Figure 1 Structures of biologically active 2-aminobenzothiazoles
Zoom Image
Scheme 1 Various synthetic routes to 2-aminobenzothiazoles

In recent years, ionic liquid (IL) supported catalyst systems have emerged as exceptional heterogeneous catalysts for sustainable organic synthesis. Various low-molecular-weight ILs are employed in organic synthesis where they serve as supports, reagents, catalysts, and solvents.[29] [30] [31] [32] One advantage of using ion-tagged metal complexes is their facile extraction from the reaction medium upon the addition of a low-polarity solvent. Therefore, the recovered metal catalyst can be reutilized further without any significant decrease in its activity. Furthermore, the combination of microwave irradiation and IL-supported catalysts offers numerous advantages over classical heating systems in organic transformations, including simple, clean, efficient, inexpensive, and fast operation.[33–35]

Therefore, in line with our ongoing research interest in the synthesis of biologically active heterocyclic scaffolds via sustainable approaches,[36] [37] [38] [39] we herein report an efficient synthetic route to 2-(N-arylamino)benzothiazoles from 2-halobenzeneamines and isothiocyanates promoted by a recyclable ion-tagged copper(II) catalyst. In addition to being straightforward to implement, this technique enables short reaction times, works with a wide variety of substrates, and produces 2-aminobenzothiazoles in good to excellent yields.

At the beginning of our proposed work, we aimed to synthesize the reusable IL-supported copper(II) catalyst from 1-methylimidazole as reported by us earlier.[37] Initially, 1-methylimidazole was treated with chloroacetic acid under microwave irradiation for 15 min at 80 °C, which led to exchange of anions with sodium tetrafluoroborate to afford the imidazolium-containing IL support. Subsequently, the synthesized ion-containing support was irradiated with microwaves for 20 min in the presence of copper acetate in H2O to generate the IL-tagged Cu catalyst 1 as a light-blue solid. From the structural point of view, the central Cu atom is in the +2 oxidation state, which is attached to two carboxyl group linkers, 1-(1-carboxymethyl)-3-methylimidazolium tetrafluoroborate ([carbmmim][BF4]). The catalyst was characterized by using 1H, 13C NMR, FT-IR, HRMS, and XPS analysis.

Table 1 Optimization of the Reaction Conditionsa

Entry

1 (mol%)

Base

Solvent

Temp (°C)

Time

Yield (%)b

 1

–

KOH

DMSO

90

12 h

NR

 2

10

KOH

DMSO

90

10 h

83

 3

10

–

DMSO

90

12 h

NR

 4

10

K2CO3

DMSO

90

10 h

80

 5

10

K2CO3

DMF

90

12 h

73

 6

10

K2CO3

toluene

90

12 h

65

 7

 5

K2CO3

DMSO

90

 9 h

81

 8

 5

K2CO3

DMSO

80 (MW)c

12 min

92

 9

 3

K2CO3

DMSO

80 (MW)c

20 min

85

10

 2

K2CO3

DMSO

80 (MW)c

20 min

76

11

 5

K2CO3

neat

80 (MW)c

20 min

NR

12

 5

K2CO3

H2O

80 (MW)c

20 min

traces

a Reaction conditions: 2-iodoaniline (1 mmol), phenylisothiocyanate (1 mmol), base (1.5 mmol), 90 °C.

b Isolated yield; NR: no reaction.

c MW: reaction performed under 280 W microwave irradiation.

To establish the optimum reaction conditions, 2-iodoaniline 2a and phenylisothiocyanate 3a were selected as model substrates and various reaction conditions were screened; the results are presented in Table [1]. Initially, the reaction was performed without any catalyst, which led to no product formation within 12 h (entry 1). Subsequently, with 10 mol% catalyst 1 and KOH as a base in DMSO solvent, 2-aminobenzothiazole 4a was afforded in 83% yield (entry 2). With the same catalyst loading, the role of the base was examined and it was found that although the reaction did not proceed without the base, using K2CO3 as a milder base resulted in a satisfactory yield of the product 4a (entries 3 and 4). The role of solvent in the reaction was examined and it was found that the use of DMF and toluene resulted in a lower yield of product 4a compared to the use of DMSO as a solvent (entries 5 and 6). Therefore, with the best base K2CO3 and solvent DMSO in hand, we performed the reaction with 5 mol% catalyst loading, which led to the formation of 2-aminobenzothiazole product 4a in 9 h with 81% yield (entry 7). The reaction was then performed under microwave irradiation, which afforded the best result; namely, 92% yield of product in 12 min (entry 8). However, when the catalyst loading was reduced to 3 and 2 mol% a significant decrease in the yield of product 4a was observed (entries 9 and 10). No product formation was observed when the reaction was conducted under neat conditions and only a trace amount of the desired product was formed when water was used as the solvent (entries 11 and 12). Finally, the optimized reaction conditions were established as 5 mol% catalyst 1 with K2CO3 as a base in DMSO solvent at 80 °C under microwave irradiation (entry 8).

The substrate scope of the reaction was investigated with a range of 2-haloanilines and phenylisothiocyanates with varying electronic properties under the optimized reaction conditions (Figure [2]). It was observed that electron-rich moieties on the phenylisothiocyanate ring afforded the desired product 4a–e in good yields. The reaction between 2-iodoaniline and benzylisothiocyanate formed the corresponding product 4f in poor yield; however, the presence of an electron-deficient group on the phenylisothiocyanate ring afforded the desired 2-aminobenzothiazole product 4g–i in excellent yields of up to 94%. We also explored the effect of substitution on the 2-haloaniline ring on the formation of 2-aminobenzothiazoles. It was found that electron-rich species on the 2-haloanilines resulted in better yield of the corresponding product than electron-deficient substituents (4j–q).

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Figure 2 Substrate scope. Reaction conditions: 2-Haloaniline 2 (1 mmol), phenylisothiocyanate 3 (1 mmol), K2CO3, catalyst (5 mol%), MW, 80 °C, 12–15 min.

Upon completion of the reaction, the introduction of chilled ether into the reaction mixture precipitated the copper catalyst, which was then filtered to isolate the catalyst. Subsequently, upon evaporation of the solvent, the recycled catalyst could be used in the next cycle without requiring further purification. Notably, the recovered catalyst could be reused in five reaction cycles with no significant loss in activity (Figure [3]). The crude products were purified by washing with hexane/ethyl acetate solvent (8:2) and were characterized by 1H and 13C NMR and HRMS analysis.

Zoom Image
Figure 3 Recyclability of the Cu(II) catalyst for the synthesis of 2-(N-arylamino)benzothiazoles

We also conducted a split test to investigate the stability of the complex and to determine whether significant metal leaching occurred during the reaction. After 5 min reaction, the catalyst was removed from the reaction medium and the residual mixture was divided into two equal portions. With one part, the reaction was continued for a further 20 min without the addition of catalyst and the second portion was set aside. It was found that both parts contained almost the same amount of 2-aminobenzothiazole, suggesting that no metal leached during the reaction.

A plausible reaction mechanism for the sustainable synthesis of 2-(N-arylamino)benzothiazoles is presented in Scheme [2] in which the ionic liquid acts as a support. Once Cu(II) is loaded on the ionic liquid it serves as a heterogeneous catalyst. Initially, a nucleophilic substitution reaction between 2-iodoaniline 2a and phenylisothiocyanate 3a forms thiourea intermediate A, which, upon rearrangement, affords intermediate B. In the presence of the IL-supported copper catalyst, intermediate B forms a copper adduct C followed by the formation of intermediate D. Finally, the desired 2-aminobenzothiazole product 4a is obtained by cyclization of intermediate E and the catalyst is retrieved in its original form.

Zoom Image
Scheme 2 Plausible mechanism for the synthesis of 2-(N-arylamino)benzothiazoles by using IL-supported Cu(II) catalyst 1

To sum up, we have developed a sustainable synthetic protocol to afford 2-(N-arylamino) benzothiazoles from 2-haloanilines and arylisothiocyanates by using a recyclable IL-supported copper(II) catalyst under microwave irradiation.[40] This methodology offers a clean, inexpensive, and straightforward strategy and delivers a range of desired products in excellent yields. The reaction time was reduced greatly by microwave irradiation from hours to minutes in comparison to the use of classical heating systems. A key benefit of this methodology is the easy separation of the catalyst from the reaction medium by the addition of a less polar solvent upon completion of the reaction. The catalyst was recycled up to five times without a substantial decrease in the catalytic activity.


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Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

The authors thank the Chancellor and Vice Chancellor of the Vellore Institute of Technology (VIT) for providing the opportunity to carry out this study.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2463-4827.
  • Supporting Information

Corresponding Authors

Balamurali M M
Chemistry Division, School of Advanced Sciences, Vellore Institute of Technology
Chennai Campus, Chennai, 600127
India   

Kaushik Chanda
Department of Chemistry, Rabindranath Tagore University
Hojai, 782435
India   

Publication History

Received: 25 September 2024

Accepted after revision: 07 November 2024

Accepted Manuscript online:
07 November 2024

Article published online:
02 December 2024

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   Permissions and Reprints All articles of this category
Zoom Image
Figure 1 Structures of biologically active 2-aminobenzothiazoles
Zoom Image
Scheme 1 Various synthetic routes to 2-aminobenzothiazoles
Zoom Image
Figure 2 Substrate scope. Reaction conditions: 2-Haloaniline 2 (1 mmol), phenylisothiocyanate 3 (1 mmol), K2CO3, catalyst (5 mol%), MW, 80 °C, 12–15 min.
Zoom Image
Figure 3 Recyclability of the Cu(II) catalyst for the synthesis of 2-(N-arylamino)benzothiazoles
Zoom Image
Scheme 2 Plausible mechanism for the synthesis of 2-(N-arylamino)benzothiazoles by using IL-supported Cu(II) catalyst 1