Potassium carbonate-mediated tandem C–S and C–N coupling reaction for the synthesis of phenothiazines under transition-metal-free and ligand-free conditions

Abstract

An efficient potassium carbonate-mediated tandem C–S and C–N coupling reaction between N-(2-iodophenyl)acetamides and 2-halo-benzenethiols has been developed. This protocol affords a simple and efficient approach for the construction of phenothiazine derivatives without the need for addition of transition-metal catalyst or ligand for the first time. Furthermore, the reaction can be easily performed on a large scale.

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The phenothiazine backbone is widely present in various kinds of pharmaceuticals and biologically active molecules. Phenothiazine derivatives are well known for their antitubercular activity,¹ anticancer activity,² antioxidant potential,³ and many other biological activities (Scheme 1).⁴ Besides, these derivatives also play an important role in materials science due to their specialised optoelectrochemical and photophysical properties.⁵ For the above reasons, a novel and efficient method involving readily available materials for the preparation of substituted phenothiazines has always been a focus of organic chemists.

Scheme 1 Selected examples of pharmaceutically and biologically active phenothiazine derivatives.

The traditional synthesis method by heating the diphenylamines and sulfur is not appropriate for substituted phenothiazines because two regioisomers are obtained as a mixture.⁶ And Yale et al. first developed a four-step procedure to obtain substituted phenothiazines in 1954.^7a From then on many kinds of approaches for the regioselective synthesis of phenothiazine derivatives had been reported.⁷ The first one-step coupling reaction for the construction of phenothiazines was reported by Jørgensen et al. in 2008.^8a They used palladium as the catalyst and employed 1-bromo-2-iodobenzenes, primary amines and 2-bromo-benzenethiol as the reactants [Scheme 2, eqn (a)]. An efficient catalytic system for the formation of one C–S and two C–N bonds in a three-component reaction was developed. Later Ma et al. first realized the tandem coupling reaction leading to phenothiazines catalyzed by Copper in 2010 [Scheme 2, eqn (b)].^8b They employed readily-available starting materials to construct functionalized phenothiazines in the presence of CuI and L-proline. Then Zeng and co-workers^8c developed another CuI-catalyzed coupling reaction without ligand to obtain phenothiazine derivatives in 2012. More recently our group developed the first iron-catalyzed version to construct the functionalized phenothiazines^8d [Scheme 2, eqn (c)]. The protocol allowed for a reduction in the time required and the catalytic system was environmentally friendly, efficient and inexpensive.

Scheme 2 Strategies for the construction of functionalized phenothiazines.

Despite notable advance the transition-metal-catalyzed coupling reactions had, the transition metals are usually expensive and toxic to different extents. And the title products may contain trace transition metal impurity which easily affect the safety of pharmaceuticals. To meet the strict demand for the absence of any transition metals, developing a transition-metal-free protocol to construct important heterocycles is highly significant. During the past few decades, various remarkable progresses were made in transition-metal-free coupling reactions.⁹ Bolm et al. reported an intramolecular C–N coupling process of aromatic amines with aryl iodides in the absence of any transition metals in 2012.¹⁰ They fulfilled the N-arylation of N-[2-(2-iodophenoxy)-phenyl]acetamide catalyzed in the presence of N¹,N²-dimethylethane-1,2-diamine with K₂CO₃. And they concluded that the iodo-substituent was essential for the success of the cyclization. The reactions of aromatic amines with bromide substrates or chloride substrates are still challenge. Based on our previous work on C–S couplings and C–N couplings catalyzed by iron and iron–copper co-catalyst,^8d,11 we designed a transition-metal-free and ligand-free tandem intermolecular C–S coupling and intramolecular C–N coupling reactions to construct this important compounds [Scheme 2, eqn (d)]. Herein, we describe the development of this efficient and environment-benign catalytic system.

To our knowledge, N-(2-iodophenyl)acetamides with an electron-withdrawing group are more active to form a C–N bond with aryl halide, the more reactive N-(4-chloro-2-iodophenyl)acetamide (1a) and 2-bromo-benzenethiol (2a) were employed as the substrates to identify the optimum conditions for the reaction. We screened different bases and solvents (Table 1).

Table 1 Optimization of the reaction conditions^a

Entry	Base	Solvent	Yield^b (%)
a Reaction conditions: 2-bromo-benzenethiol (2a, 0.55 mmol), N-(4-chloro-2-iodophenyl)acetamide (1a, 0.5 mmol), base (2.0 mmol) were added to a solvent (3.0 mL), and the resulting mixture warmed at 135 °C for 48 h under N2.b Isolated yield based on 1a after silica gel chromatography.c K2CO3 (99.995%) from Alfa Asia.
1	KO^tBu	DMF	71
2	NaO^tBu	DMF	65
3	LiO^tBu	DMF	45
4	K2CO3	DMF	81
5	Cs2CO3	DMF	25
6	Li2CO3	DMF	0
7	KOH	DMF	0
8	NaOCH3	DMF	Trace
9	LiOCH3	DMF	Trace
10	KOAc	DMF	0
11	K2CO3	DMSO	47
12	K2CO3	Toluene	0
13	K2CO3	Xylene	0
14	K2CO3	NMP	Trace
15^c	K2CO3	DMF	79

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The reaction was initially carried out in the system of 4.0 equiv. KO^tBu in DMF under N₂. To our delight, the corresponding product 3a was obtained in 71% yield (Table 1, entry 1). Then various bases were screened in DMF (Table 1, entries 1–10) and the results indicated K₂CO₃ was better than KO^tBu to mediate the reaction (Table 1, entry 1 and entry 4). NaO^tBu, LiO^tBu and Cs₂CO₃ can promote this reaction in lower yield than K₂CO₃ (Table 1, entries 2–5). Then DMSO, toluene, xylene and NMP were respectively employed as the solvents, the yields decreased to a different extent (Table 1, entries 11–14). Considering to that a trace amount of transition metals remaining in the base will fundamentally influence the exact reaction pathway in some cases,¹² high-purity K₂CO₃ (99.995%) from Alfa Asia was applied (Table 1, entry 15). We can also obtain the title product in 79% yield. And the main transition-metal impurities of reactants and K₂CO₃ had been also analyzed by ICP-MS.¹³ Finally, the optimal reaction condition was established and made up of 4.0 equiv. K₂CO₃ as the base and DMF as the solvent.

With the optimized conditions in hand, we investigated the substrate scope of coupling partners and the results were presented in Table 2. We primarily investigated the reactions of 2-bromo-benzenethiol (2a) with a series N-(2-iodophenyl)-acetamides (1a–e) bearing an electron-withdrawing group (Table 2, entries 1–5). N-(4-Chloro-2-iodophenyl)-acetamide (1a) and N-(4-bromo-2-iodophenyl)acetamide (1b) were transformed into the product 3a and 3b in 81% and 74% yield respectively (Table 2, entries 1 and 2). A low yield of ethyl 4-acetamido-3-iodobenzoate (1e) was found due to 1e bearing ester-group is easy to be hydrolyzed under the action of base (Table 2, entry 5). The title product (3e) and the hydrolyzed product (3ee) were respectively obtained in yields of 31% and 43%. Then 2-chloro-benzenethiol (2b) was employed, although the yield slightly decreased, all of the substrates could be transformed to the corresponding products (Table 2, entries 6–10). The influence of the substituent groups on 2-chloro-benzenethiol was also explored. When 2,5-dichlorobenzenethiol (2c) and 2,6-dichlorobenzenethiol (2d) were used, the yields increased compared with 2-chloro-benzenethiol (2b) (Table 2, entries 11–18). The results indicated that a chlorine on the 2-chlorobenzenethiol was beneficial to this coupling reaction. Finally, the reactions of N-(2-iodophenyl)acetamide (2e) with different 2-halo-benzenethiols were conducted. The corresponding products were obtained in moderate to low yields (Table 2, entries 19 and 20). The results confirmed that an electron-withdraw group is beneficial for the C–N coupling process.

Table 2 Substrate scope of reactions^a

a Reaction conditions: N-(4-chloro-2-iodophenyl)acetamide (1a, 0.5 mmol), 2-halo-benzenethiol (2a, 0.55 mmol), base (2.0 mmol) were added to a solvent (3.0 mL), and the resulting mixture warmed at 135 °C for 48 h under N₂.

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To highlight the synthetic unity of this protocol, a 10 mmol scale reaction was conducted. N-(4-Chloro-2-iodophenyl)acetamide (1a, 2.97 g) was selected as the substrate and the corresponding product 3-chloro-10H-phenothiazine (3a) was obtained in 78% yield (1.81 g) (Scheme 3).

Scheme 3 Large scale synthesis.

Although a detailed mechanism requires further investigation, several preliminary experiments were performed. When the reaction time was reduced to 10 h, the intermediate 4a was separated and 5a was detected by LC-MS. Then the intermediate 4a was employed instead of the reactants under the optimized condition and the product 3a was obtained in 83%. Based on these results, we proposed a plausible pathway for the reaction, which was shown in Scheme 4.

Scheme 4 Plausible pathway for the reaction.

When we performed the reaction under the optimum condition in the presence of 4.0 equiv. radical scavenger 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), the title compound was obtained in 21% because the reactant 2-bromo-benzenethiol (2a) was decomposed by TEMPO (Scheme 5). And the intermediate 4a was also employed under the optimum condition in the presence of 4.0 equiv. TEMPO, the product 3a was obtained in 79% yield. The results indicated the reaction might be completed without a radical pathway. To investigate whether a benzyne intermediate was formed during coupling progress, 3-bromo-benzenethiol was employed as the substrate instead of 2-bromo-benzenethio under the optimum condition (Scheme 5). And the corresponding product 3a was not observed.

Scheme 5 Investigations into the reaction mechanism.

In summary, a potassium carbonate-mediated tandem intermolecular C–S and intramolecular C–N coupling reaction was developed for the construction of pharmacological and clinical useful phenothiazine derivatives for the first time. This transition-metal-free and ligand-free protocol was economic efficiency and environment benign. The starting materials were readily available and the condition was simple. And the product could be obtained in good yield when large scale reaction was conducted.

Acknowledgements

We would like to gratefully acknowledge financial support from the A Project Funded by the Priority Academic Program for the Development of Jiangsu Higher Education Institutions, The Project of Scientific and Technologic Infrastructure of Suzhou (No. SZS201207) and the National Natural Science Foundation of China (No. 21072143).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra01295g

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