Nickel-catalyzed Chan–Lam coupling: an efficient route to N-arylated 2-aminobenzothiazoles under ambient conditions

Abstract

A nickel-catalyzed C–N coupling of 2-aminobenzothiazoles and aryl boronic acids under mild reaction conditions is disclosed. The reaction afforded N-arylated 2-aminobenzothiazoles in the presence of a Ni/4,4′-dOMebpy catalytic system under open-air conditions. The method encompasses a wide range of applicable substrates, including aryl boronic acids and 2-aminobenzothiazoles, affording the corresponding C–N coupled products in moderate to good yields in short reaction times.

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Introduction

The construction of C–N bonds is a highly active area of research as C–N bonds are omnipresent in biochemical structures and natural products.^1,2 Transition metal-catalyzed C–N bond-forming reactions have emerged as powerful tools, offering greater efficiency in synthesising aryl/heteroaryl compounds possessing nitrogenous functional groups.³ The conventional C–N bond formation through electrophile-nucleophile coupling is demonstrated by Ullmann–Goldberg reactions⁴ and Buchwald–Hartwig aminations.⁵ The Ullmann–Goldberg and Buchwald–Hartwig reactions refer to the Cu-mediated and Pd-catalyzed arylation of amines using aryl(pseudo)halides, respectively, to render arylamines.⁶ While extensive investigations have been made, Ullmann–Goldberg or Buchwald–Hartwig aminations pose certain limitations including the need of elevated temperatures, expensive Pd (pre)catalysts and strong bases to achieve optimal results.⁷ In 1998, Chan, Lam and Evans independently reported that copper salts facilitate the oxidative coupling of arylboronic acids with N- and O-nucleophiles to render C–X coupled products.⁸ The defining feature of this new Chan–Lam cross-coupling is the simple reaction conditions including inexpensive reagents, room temperature conditions, use of a weak base, and the “open-flask” chemistry.⁹

From the initial report of Raghuvanshi et al.,¹⁰ Ni-based catalysts emerged as a viable alternative to Cu-catalysed Chan–Lam reactions to achieve efficient C–N and C–S cross-couplings. Nickel, being a low-cost and earth-abundant metal with proven catalytic activity, has garnered significant attention in organic synthesis.¹¹ Although considerably less studied than Cu-catalysed Chan–Lam reactions, continual progress has also been made on the Ni-catalyzed version with respect to the use of novel Ni complexes, newer substrates and chemo-, regio- and enantioselective variants.¹²

Over the past years, Chan–Lam coupling has also found utility in the arylation of NH-heterocycles for synthesizing functionalized aryl heterocycles of interest.¹ Similar Ni-catalyzed transformations have been studied in recent years, where N-arylation of imidazoles,¹³ pyroglutamates,¹⁴ chemoselective N-arylation of 2-aminobenzimidazoles,¹⁵ etc. were successfully demonstrated (Scheme 1, paths a & b). To further expand the scope, we achieved the N-arylation of 2-aminobenzothiazole, a privileged class of fused heterocycles.

Scheme 1 Previous Ni-catalyzed strategies (a and b) and the present work (c) for the synthesis of functionalized heterocycles via Chan–Lam coupling.

2-Aminobenzothiazole constitutes a fused bicyclic framework with diverse medicinal and agrochemical applications.¹⁶ These scaffolds gained much attention because of their bioactivities including anti-inflammatory,¹⁷ antiviral,¹⁸ anticancer,¹⁹ antidiabetic,²⁰ antimalarial,²¹ antidepressant,²² and so on. Importantly, heterocyclic scaffolds hold a crucial role in drug design,²³ and there exist a series of N- and S- containing FDA-approved drugs so far.²⁴ Given the importance, numerous protocols towards the synthesis and functionalization of 2-aminobenzothiazoles are still in demand.

As part of our continuing interests in low-cost transition metal catalysed cross-couplings and heterocycle synthesis,²⁵ we envisioned the potential applicability of Ni-catalyzed Chan–Lam coupling in the N-arylation of 2-aminobenzothiazoles. Herein, we present a facile synthesis of N-arylated 2-aminobenzothiazole derivatives via Chan–Lam coupling of 2-aminobenzothiazoles and phenyl boronic acids under Ni catalysis. The optimal reaction employed Ni/4,4′-dOMebpy catalytic system in the presence of Na₂CO₃ as the base in acetonitrile at 50 °C for 1–3 h reaction time (Scheme 1, path c). This reaction could be effectively carried out under air without the need for any external oxidant.

Results and discussion

In the initial studies, 2-aminobenzothiazole 1a and phenyl boronic acid 2a were chosen as model substrates for the reaction. Based on the previously known Ni-based catalytic systems in Chan–Lam coupling,⁹ we have identified NiCl₂·6H₂O (20 mol%) as the catalyst along with 2,2′-bipyridine (20 mol%) as the ligand in the presence of Na₂CO₃ (2 equiv.) as the base in acetonitrile for the coupling reaction between 1a and 2a. The reaction mixture was stirred in an open vessel at 60 °C for 8 h. Under this condition, the reaction afforded the desired C–N coupled product N-phenylbenzo[d]thiazol-2-amine 3a in 55% yield. The structure of the column-purified product was confirmed by HRMS and NMR analyses. From the GC-MS analysis, the reaction mixture showed phenol and biphenyl as the byproducts derived from phenyl boronic acid upon oxidation and reductive homocoupling, respectively. This accounted for the reduction in the conversion of 1a in the reaction.

An extensive optimization study was performed to arrive at the best reaction condition for this transformation, minimizing the possible byproducts. Changing the Ni source from NiCl₂·6H₂O to other nickel salts did not improve the reaction yields (Table 1, entries 1–5). Additionally, the necessity of nickel catalyst was verified experimentally, and the expected product did not form in the absence of NiCl₂·6H₂O (Table 1, entry 6). While screening ligands, bipyridine ligands L1–L4 proved effective, consistent with the literature-known Ni-catalyzed Chan–Lam coupling reactions⁹ (Table 1, entries 7–9). Among these, 4,4′-dimethoxy-2,2′-bipyridine L4 provided the highest yield of 71%, making it a promising candidate (Table 1, entry 9). Bidentate N-donor ligands like 1,10-phenanthroline and diamines resulted in lower yields (Table 1, entries 10,11). The O-donor ligands such as 1,1′-bi-2-naphthol and trans-1,2-cyclohexanediol, and a ligand-free reaction afforded only traces of the product (SI, Table 3.2).

Table 1 Optimization studies for the Ni-catalysed C–N coupling of 2-aminobenzothiazole 1a and phenyl boronic acid 2a^a

Entry	Ni catalyst	Ligand	Base	Solvent	Yield (%)^b
a Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), Nickel salt (20 mol%), ligand (20 mol%), base (2 equiv.), solvent (2 mL), 8 h, 60 °C.b Isolated yield.
1	NiCl2·6H2O	L1	Na2CO3	CH3CN	55
2	Ni(OAc)2·4H2O	L1	Na2CO3	CH3CN	39
3	Ni(NO3)2·6H2O	L1	Na2CO3	CH3CN	49
4	NiBr2	L1	Na2CO3	CH3CN	34
5	Ni(acac)2	L1	Na2CO3	CH3CN	33
6	—	L1	Na2CO3	CH3CN	nr
7	NiCl2·6H2O	L2	Na2CO3	CH3CN	65
8	NiCl2·6H2O	L3	Na2CO3	CH3CN	57
9	NiCl2·6H2O	L4	Na2CO3	CH3CN	71
10	NiCl2·6H2O	L5	Na2CO3	CH3CN	43
11	NiCl2·6H2O	L6	Na2CO3	CH3CN	43
12	NiCl2·6H2O	—	Na2CO3	CH3CN	traces
13	NiCl2·6H2O	L4	K2CO3	CH3CN	66
14	NiCl2·6H2O	L4	NaOH	CH3CN	41
15	NiCl2·6H2O	L4	Et3N	CH3CN	47
16	NiCl2·6H2O	L4	—	CH3CN	48
17	NiCl2·6H2O	L4	Na2CO3	DMSO	34
18	NiCl2·6H2O	L4	Na2CO3	DMF	46
19	NiCl2·6H2O	L4	Na2CO3	DCE	57
20	NiCl2·6H2O	L4	Na2CO3	EtOH	38

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Subsequently, a range of bases, including inorganic and organic bases, were screened (SI, Table 3.3). Na₂CO₃ proved to be the optimal base, yielding 71% of the product, whereas other inorganic bases cannot improve the yields (Table 1, entries 13,14). Further exploration of organic bases revealed that bases like DABCO and Et₃N rendered 57% and 47% of the product, respectively, while DBU only provided traces of the product in this reaction (SI, Table 3.3). Under base-free conditions, the formation of 3a was lowered to 48% yield (Table 1, entry 16).

Analysis of the most widely used polar aprotic solvents revealed that CH₃CN is the most suitable solvent that rendered maximum yield, while DMSO, DMF and DCE gave moderate yields of the product (SI, Table 3.4). Other screened polar protic solvents lead to lower conversion of starting materials, accompanied with inferior yields (SI, Table 3.4). Encouragingly, the reaction proceeded smoothly with similar yields at a reduced temperature of 50 °C (Table 2, entry 3). A reaction at room temperature and at 70 °C didn't improve the reaction yields (Table 2, entry 2; SI, Table 3.5). Then, the reaction time was varied at the optimal temperature of 50 °C.

Table 2 Optimization of reaction conditions^a

Entry	NiCl2·6H2O (x mol%)	L4 (y mol%)	Temperature (^°C)	Time (h)	Yield (%)^b
a Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), NiCl2·6H2O (x mol%), L4 (y mol%), Na2CO3 (2 equiv.), CH3CN (2 mL).b Isolated yield.c Under O2 atmosphere.d Under N2 atmosphere.e 1 equiv. of Na2CO3 was used.f 1.5 equiv. of 2a was used.
1	20	20	60	8	71
2	20	20	70	8	56
3	20	20	50	8	72
4	20	20	50	12	66
5	20	20	50	4	75
6	20	20	50	1	72
7	10	10	50	1	72
8	5	5	50	1	65
9	10	10	50	1	52^c
10	10	10	50	1	traces^d
11	10	10	50	1	74^e
12	10	10	50	1	60^f

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It is noteworthy that the reaction offered comparable yields even at a shortened period of 4 h and 1 h, suggesting faster reaction rates (Table 2, entries 5,6). Upon altering the catalyst loadings, we found that 10 mol% of NiCl₂·6H₂O and L4 was sufficient for the formation of 3a in good yields (Table 2, entry 7). Further attempts to reduce the catalyst loading to 5 mol% resulted in lowered yield of 65% (Table 2, entry 8). Also, varying the catalyst-to-ligand ratio from 1 : 1 to 1 : 2 or 2 : 1 proved unfavourable (SI, Table 3.6).

Moreover, we identified that 1 equivalent of base was adequate for the reaction (Table 2, entry 11). A reaction was carried out under pure O₂ atmosphere, however no improvement in yield was obtained (Table 2, entry 9). Likewise, the reaction under N₂ afforded only traces of the product indicating the role of an oxidative atmosphere in this transformation (Table 2, entry 10). Decreasing the equivalents of boronic acid 2a to 1.5 equivalents lowered the yield to 60%, implying the need of 2 equivalents of 2a to effect better conversion (Table 2, entry 12). We chose the reaction conditions shown in entry 11 (Table 2) as the optimal conditions for the Ni-catalyzed N-arylation of 2-aminobenzothiazoles 1.

With the optimized conditions in hand, the generality of the developed method was studied. The scope of differently substituted aryl boronic acids in the C–N coupling of 1a were studied (Scheme 2).

Scheme 2 Substrate scope of phenyl boronic acids.

The reaction accommodated a range of phenyl boronic acids with electron-rich or electron-deficient substituents in the para-, meta- and ortho-positions. It was noted that with halogenated (fluoro, chloro) phenyl boronic acids, para- and meta-substituted substrates underwent successful coupling in shorter time with an improved yield when compared to ortho-substituted derivatives (3b–3g). Also, a further increase in reaction time to 8 h didn't improve the yield in ortho-derivatives (3f, 3g).

While 4-tolyl boronic acid afforded the corresponding product 3h in good yield of 70%, the expected product was not formed with 2-tolyl boronic acid, possibly due to the steric effect of the ortho-methyl group. 4-Ethyl and 4-methoxy phenyl boronic acids gave the reaction in moderate yields (3j, 3k). Electron-withdrawing groups (–NO₂, –CF₃, –C(O)CH₃) on 2 reduced the reaction rate in comparison to electron-rich derivatives, and afforded moderate yields of desired products (3l, 3m, 3n, 3o, 47–61%).

The scope of electronically diverse 2-aminobenzothiazoles was also studied (Scheme 3). Relatively, 2-aminobenzothiazoles 1 with electron-rich substituents viz. methyl and methoxy at the 6th position showed quick reactivity with good yields of 76% and 78%, respectively. However, the presence of methyl group at the 4th position of 2-aminobenzothiazole seriously hampered the reactivity, providing only traces of product 3q (confirmed by GCMS analysis). 2-Aminobenzothiazoles with electron-withdrawing groups (–NO₂, –CO₂Et) reacted smoothly to give 3t and 3u, but required an extended reaction time of 3 h for acceptable yields. 2-Amino-6-bromobenzothiazole can be converted into the corresponding coupled product 3s in 58% yield in 1 h. To our delight, 2-aminothiazole reacted well under the optimized conditions and the expected product 3v was formed in 50% yield.

Scheme 3 Substrate scope of 2-aminobenzothiazoles.

Based on the analysis of previously reported Chan–Lam couplings and experimental observations,^9,26 we proposed a plausible mechanism for the aforementioned reaction, and is presented in Scheme 4.

Scheme 4 Mechanism proposed for the Ni-catalyzed Chan–Lam coupling of 2-aminobenzothiazole 1a with phenyl boronic acid 2a.

The reaction was proposed to proceed in a catalytic cycle involving a sequence of ligand displacement, transmetalation, and reductive elimination. Initially, the coordination of amine 1a with Ni(II) complex A results in the formation of Ni(II) complex B upon ligand displacement. Here, this ligand exchange occurs in the presence of a base that enhances the formation of B. The complex B participates in transmetalation with phenylboronic acid 2a to form Ni(II) complex C. Then, the reductive elimination of C produced the desired product 3a and Ni (0) species D. Finally, the complex D is re-oxidized to Ni(II) complex A in the presence of O₂ present in air. The aerobic regeneration of the catalyst is validated by a control experiment under nitrogen atmosphere providing only trace amounts of product.

Conclusions

In summary, we have put forward an efficient and facile Ni-catalyzed Chan–Lam coupling of 2-aminobenzothiazoles and phenyl boronic acids to form the C–N coupled products in a shorter reaction time. This presents a novel entry to the heterocyclic amine substrates explored so far under Ni-catalyzed Chan–Lam protocols. The reaction afforded moderate to good yields of diverse N-arylated 2-aminobenzothiazoles, tolerating a range of functional groups. This ‘open-flask’ chemistry featuring mild and easy-to-handle reaction conditions proved a very attractive tool for the direct synthesis of N-arylated 2-aminobenzothiazoles.

Conflicts of interest

“There are no conflicts to declare”.

Data availability

The data supporting this article have been included as part of the supplementary information (SI). Supplementary information: experimental procedures and spectral data (¹H and ¹³C NMR) of all compounds. See DOI: https://doi.org/10.1039/d5ra06530e.

Acknowledgements

RMP thanks the Council of Scientific and Industrial Research (CSIR-New Delhi) and PSD thanks the University Grants Commission (UGC, New Delhi) for the award of research grants.

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