Three-component selective synthesis of phenothiazines and bis-phenothiazines under metal-free conditions

Abstract

An iodine-containing reagent promoted three-component method for the selective synthesis of phenothiazines and bis-phenothiazines has been developed. The present protocol starts from simple and easily available cyclohexanones, elemental sulfur, and inorganic ammonium salts, selectively producing phenothiazines and bis-phenothiazines in satisfactory yields under aerobic conditions. This method has the advantages of simple and readily available starting materials and metal-free conditions, affording a facile and practical approach for the preparation of phenothiazines and bis-phenothiazines.

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Phenothiazine derivatives have a broad spectrum of pharmacological activities and are widely applied in the pharmaceutical industry.^1,2 To date, more than 100 phenothiazine derivatives have been used as antipsychotic drugs in clinical settings. Moreover, phenothiazine derivatives have extensive application in the field of optoelectronic materials and dyes.^3,4 As special phenothiazine derivatives, bis-phenothiazines described as thia-bridged triarylamine heterohelicenes with an aryl ring and a nitrogen atom in common forced into a helical shaped structure by four long carbon–sulfur bonds have attracted increasing attention in recent years. Bis-phenothiazines have been applied as redox-driven molecular switches, organic dyes for dye-sensitized solar cells, and ultralong room-temperature phosphorescence (URTP) materials, due to their unique structural, unusual electronic, and photochemical properties (Fig. 1).⁵

Fig. 1 Some representative bis-phenothiazines.

On account of the significance of these compounds, a variety of methods for the synthesis of phenothiazines have been reported in the past decades.^6,7 With the rapid development of transition-metal catalysts, transition-metal-catalyzed coupling reactions have proved to be the most powerful tools for the preparation of phenothiazines.^8,9 However, metal contamination remains an important issue to be solved urgently, particularly in medicine and materials science. Although several metal-free approaches for the preparation of N-unsubstituted phenothiazines have been developed in recent years, the use of two kinds of ortho difunctionalized arenes as starting materials also limits their synthetic application.¹⁰ As for bis-phenothiazines, only a few methodologies have been developed due to their complex structure. And most of them require multi-step procedures or pre-functionalized complex substrates. For instance, in 2004 Okada et al. reported a four-step procedure for the preparation of bis-phenothiazines from 1,3-dichloro-2-nitrobenzenes and o-bromothiophenols (Scheme 1a).¹¹ In 2008, Menichetti and co-workers described a two-step synthesis of bis-phenothiazines from triphenylamines and phthalimidosulfenyl chloride by four consecutive electrophilic regioselective aromatic sulfur insertions (Scheme 1b).¹² In 2019, Viglianisi et al. developed a similar two-step approach for constructing bis-phenothiazines, which started from N-phenyl phenothiazines and phthalimidosulfenyl chloride.¹³ Despite their uses, the need for multiple steps or pre-functionalized precursors limits their synthetic application dramatically. Therefore, it is highly desirable to explore new approaches to synthesize phenothiazines and bis-phenothiazines from simple and easily available chemicals under metal-free conditions.

Scheme 1 General synthesis of bis-phenothiazines.

In recent years, elemental sulfur, as a cheap, easily available, nontoxic, stable, and easy to handle reagent, has been regarded as the best source of sulfur atoms in the formation of organosulfur compounds. It has shown great potential in C–S bond formation.¹⁴ A diverse range of methods for the preparation of sulfur-containing heterocycles have been developed using elemental sulfur as the sulfur source in the last few years.^15,16 Our group has been dedicated to the dehydroaromatization of cyclohexanones¹⁷ and construction of sulfur-containing heterocycles using elemental sulfur as the sulfur source in recent years.^18,19 As part of our sustained research in these fields, herein we describe an iodine-containing reagent promoted three-component selective synthesis of phenothiazines and bis-phenothiazines under aerobic conditions (Scheme 1c). The present protocol starts from cheap and easily available cyclohexanones, elemental sulfur, and inorganic ammonium salts, selectively producing phenothiazines and bis-phenothiazines in satisfactory yields under metal-free conditions.

This research was initiated by using 4-methylcyclohexanone (1a), elemental sulfur, and ammonium iodide as the reactants to probe the optimal reaction conditions (Table 1). Based on our previous studies,^19a this reaction was initially conducted with 0.2 equiv. of KI in chlorobenzene under an oxygen atmosphere at 150 °C. To our delight, product 2a was generated in 24% isolated yield and a trace amount of product 3a was also detected under these conditions (entry 1). Inspired by this, a number of ammonium salts were tested (entries 1–4). Among them, (NH₄)₃PO₄ showed the best efficiency to afford product 2a in 52% isolated yield (entry 4). Then various iodine-containing reagents were screened (entries 5–9). The highest yield of 2a was obtained when KIO₃ was used as the additive (entry 8). Encouragingly, the product 3a was obtained in 12% yield when 2.0 equiv. of DMSO were used as the co-oxidant (entry 10). Subsequently, a number of iodine-containing reagents were tested again (entries 11–14). The yield of 3a was enhanced to 20% isolated yield when NaI was used (entry 11). Then a few other solvents including PhMe, NMP, DMF, and ethyl acetate (EA) were screened (entries 15–18). Ethyl acetate (EA) proved to be the best solvent to provide product 3a in 26% yield (entry 18). The yield increased to 34% when the amount of NaI was increased to 0.3 equiv. (entry 19). It further increased to 55% isolated yield when 4.0 equiv. of elemental sulfur and 2.5 equiv. of NH₄I were used (entry 20). Regrettably, the yield of 3a could not be further improved either by increasing or decreasing the reaction temperature (entries 21 and 22).

Table 1 Optimization of reaction conditions^a

Entry	NH4X	Additive	Oxidant	Solvent	Yield^b (%)
					2a	3a
a Reaction conditions: 0.4 mmol of 1a for entries 1–9, 0.6 mmol of 1a for entries 10–22, S8 (0.1 mmol), NH4X (0.3 mmol), additive (0.04 mmol), DMSO (0.4 mmol), solvent (0.6 mL), 150 °C oil bath, under O2, sealed tube, 24 h. b Isolated yield. c NaI (0.06 mmol). d S8 (0.2 mmol), NH4I (0.5 mmol). e 140 °C. f 160 °C.
1	NH4I	KI	O2	PhCl	24	Trace
2	NH4OAc	KI	O2	PhCl	10	0
3	(NH4)2CO3	KI	O2	PhCl	45	0
4	(NH4)3PO4	KI	O2	PhCl	52	0
5	(NH4)3PO4	NaI	O2	PhCl	69	0
6	(NH4)3PO4	I2	O2	PhCl	47	0
7	(NH4)3PO4	IBr	O2	PhCl	56	0
8	(NH4)3PO4	KIO3	O2	PhCl	80	0
9	(NH4)3PO4	NaIO4	O2	PhCl	75	0
10	NH4I	KI	DMSO + O2	PhCl	8	12
11	NH4I	NaI	DMSO + O2	PhCl	10	20
12	NH4I	IBr	DMSO + O2	PhCl	12	8
13	NH4I	I2	DMSO + O2	PhCl	9	10
14	NH4I	KIO3	DMSO + O2	PhCl	16	11
15	NH4I	NaI	DMSO + O2	PhMe	11	14
16	NH4I	NaI	DMSO + O2	NMP	0	0
17	NH4I	NaI	DMSO + O2	DMF	0	0
18	NH4I	NaI	DMSO + O2	EA	13	26
19^c	NH4I	NaI	DMSO + O2	EA	11	34
20^c^,^d	NH4I	NaI	DMSO + O2	EA	8	55
21^c^,^d^,^e	NH4I	NaI	DMSO + O2	EA	7	50
22^c^,^d^,^f	NH4I	NaI	DMSO + O2	EA	9	48

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With the optimized conditions established, the scope and generality for phenothiazine formation were evaluated (Scheme 2). 4-Methylcyclohexanone offered product 2a in 80% isolated yield. However, cyclohexanone provided product 2b in 60% yield. Cyclohexanones with straight-chain alkyl or branched alkyl groups at the para-position reacted well to afford phenothiazine products in moderate to good yields (2c–2h). Cyclohexanones bearing a remote substituent at the C4 position also were able to give the corresponding products in moderate yields (2i and 2j). Regrettably, a trace amount of product 2k was generated when cyclohexanone with a strongly electron-donating group at the para-position was used as the substrate. However, the corresponding products were obtained in good yields when cyclohexanones with a strongly electron-withdrawing group were used (2l and 2m). In addition, 4-phenylcyclohexanone and 4-(4-chlorophenyl)cyclohexanone also reacted smoothly to provide target products 2n and 2o in acceptable yields. However, the desired product 2p was not detected when 4-(4-hydroxyphenyl)cyclohexanone was used. No significant steric hindrance effect was observed when 2-methylcyclohexanone was used as the substrate (2q).

Scheme 2 The substrate scope for phenothiazine formation.

Next, the substrate scope for the synthesis of bis-phenothiazines was investigated (Scheme 3). The product 3a was acquired in 55% isolated yield under standard conditions. It's worth noting that the structure of product 3a was further confirmed by single-crystal X-ray diffraction.²⁰ Cyclohexanones bearing straight-chain alkyl or branched alkyl groups at the para position reacted smoothly to afford bis-phenothiazine products in moderate yields (3b–3e). However, the product was obtained in lower yield when cyclohexanone with a phenyl group at the para position was used as the substrate (3f). Unfortunately, the corresponding products were generated in trace amounts when cyclohexanones with a strongly electron-donating group or strongly electron-withdrawing group at the para position were used as the substrates (3g and 3h).

Scheme 3 The substrate scope for bis-phenothiazine formation. ^a 160 °C.

To demonstrate the synthetic applicability of this three-component reaction, the large-scale and derivatization reaction carried out (Scheme 4). The product 3d was obtained in 48% yield when the reaction was scaled up to 1.0 mmol. It should be noted that product 3d could be applied as a redox-triggered chiroptical switch.^5a,e Furthermore, product 3d could be oxidized into the derivative 4a in 98% isolated yield when it was treated with 3-chloroperoxybenzoic acid (m-CPBA). The derivative 4a could be applied as an ultralong room-temperature phosphorescence (URTP) material.^5c

Scheme 4 The large-scale and derivatization reaction.

To investigate the mechanism, some control experiments were carried out (Scheme 5). The phenothiazine product 2a was obtained in 80% isolated yield under the optimized conditions. The yield of 2a did not decrease significantly when 2,6-di-tert-butyl-4-methylphenol (BHT) or 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) was added to this reaction (Scheme 5a). Moreover, radical scavengers BHT and TEMPO also could not impede the formation of product 3a (Scheme 5b). These results indicate that this reaction probably does not involve a radical process. In addition, product 3a could not be generated when phenothiazine 2a was treated with 4-methylcyclohexanone 1a and elemental sulfur under the optimized conditions, indicating that product 3a was not transformed from phenothiazine 2a (Scheme 5c).

Scheme 5 Control experiments.

Based on the above-mentioned experimental results and related literature,^16d,19a,21 a plausible mechanism is proposed (Scheme 6). Condensation of ammonium salts with three equiv. of 4-methylcyclohexanone (1a) provides intermediate A, which attacks elemental sulfur via the Willgerodt–Kindler procedure to afford intermediate B. Intermediate C is formed from intermediate B by the release of sulfur (S_n−1) and a proton. Subsequently, intermediate C is oxidized into intermediate D in the presence of elemental iodine from NaI, which is further converted into intermediate Evia intramolecular addition. Deprotonation of intermediate E produces intermediate F, which is further translated into intermediate Gvia the second thionation process. Finally, oxidative dehydrogenation of intermediate G affords product 3a with the aid of a NaI/DMSO/O₂ system. Moreover, product 2a is formed via a similar pathway.

Scheme 6 Possible mechanism.

Conclusions

In conclusion, we have disclosed an iodine-containing reagent promoted three-component method for the selective synthesis of phenothiazines and bis-phenothiazines. The present protocol starts from cheap and easily available cyclohexanones, elemental sulfur, and inorganic ammonium salts, selectively producing phenothiazines and bis-phenothiazines in satisfactory yields under aerobic conditions. In this work, multiple C–N bonds and C–S bonds were constructed in one pot under metal-free conditions. This method has the advantages of simple and readily available starting materials and metal-free conditions, affording a facile and practical approach for the preparation of phenothiazines and bis-phenothiazines.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

Financial support was provided by the National Natural Science Foundation of China (No. 22201240, 22271244 and 21871226), the Hunan Provincial Natural Science Foundation of China (No. 2020JJ5531), and the Open Research Fund of School of Chemistry and Chemical Engineering, Henan Normal University (2022C02). The Undergraduate Investigated Study and Innovated Experiment Plan from the Ministry of Education of China and the Science and Technology Innovation Program of Hunan Province (2020RC1009) are gratefully acknowledged.

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20. The CCDC number of 3a: 2112855.†.
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Footnotes

† Electronic supplementary information (ESI) available. CCDC 2112855. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d3ob00055a

‡ These authors contributed equally to this work.

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