New simple synthesis of ring-fused 4-alkyl-4H-3,1-benzothiazine-2-thiones: Direct formation from carbon disulfide and (E)-3-(2-aminoaryl)acrylates or (E)-3-(2-aminoaryl)acrylonitriles

Introduction

Molecules containing the 4H-3,1-benzothiazine moiety have received considerable interest from the chemical and medicinal community due to their promising biological activity [1-4] and the applications in recording and photographic materials [5-8]. A number of efficient approaches for their preparation have been reported in the literature [9-15]. 4-Alkyl-4H-3,1-benzothiazine-2-thiones are an important class of 4H-3,1-benzothiazine derivatives. Therefore, 4-alkyl-4H-3,1-benzothiazine-2-thione derivatives are also of potential biological importance. However, only a few practical routes for the synthesis of this class of 4-alkyl-4H-3,1-benzothiazine-2-thione derivatives have been reported [16,17]. Although Kobayashi and co-workers have reported the synthesis of 2-(2-thioxo-4H-3,1-benzothiazin-4-yl)acetic acid derivatives by the reaction of 3-(2-isothiocyanatophenyl)prop-2-enoates with sodium sulfide, this method suffers from the tedious synthesis of the substrates prepared in four steps from 2-iodoaniline [16]. Molina et al. also described the preparation of 4H-3,1-benzothiazine-2-thione derivatives by intramolecular heteroconjugate addition of carbodiimides or isothiocyanates bearing one o-substituted α,β-unsaturated carbonyl fragment promoted by the CS₂/TBAF system [17]. However, both the low yields (30–60%) of the products and the substrate limitations outweigh their advantages. As part of a continuing effort in our laboratory toward the development of novel natural-product-like compounds [18-22], we recently reported the practical synthesis of 2-mercapto-4-benzylidene-4H-benzo[d][1,3]thiazines starting from 2-alkynylbenzenamines with CS₂, and further transformations to highly functionalized 4-benzylidene-4H-benzo[d][1,3]thiazines (Scheme 1) [9].

Promoted by these results, we envisioned that (E)-3-(2-aminoaryl)acrylates or (E)-3-(2-aminoaryl)acrylonitriles could also be utilized as starting substrates for the synthesis of N-heterocycles. Therefore, we focused on the o-amino-α,β-unsaturated compound 1 (Scheme 2), which would be expected to construct 4-alkyl-4H-3,1-benzothiazine-2-thione derivatives through a one-pot base-promoted intermolecular addition/intramolecular Michael addition reaction.

Results and Discussion

In our initial study, we examined the tandem reaction with various bases and solvents to optimize the reaction conditions. (E)-Butyl 3-(2-aminophenyl)acrylate (1a) was chosen as a model substrate, and the results are summarized in Table 1. Among the bases screened, DABCO was found to be superior to the other organic or inorganic bases, although DBU, Et₃N, and KOH also provided good results (Table 1, entries 1–6). However, no product could be detected in the absence of base (Table 1, entry 7). When a catalytic amount of DABCO (20 mol %) was used, only a 69% yield of product 2a was obtained. Subsequently, the study results showed that the amount of CS₂ had a great effect on the reaction (Table 1, entry 1 versus entries 8–10). To reduce the amount of CS₂, we finally chose 4.0 equiv of CS₂. The results also suggested that the solvent was crucial for this transformation. Low-polar solvents such as toluene and CH₂Cl₂ inhibited the reaction (Table 1, entry 11 and entry 12). Among the polar solvents screened (Table 1, entries 13–16), DMSO was the best, affording the desired product in 88% yield (Table 1, entry 13). When the reaction was performed at 60 °C in a sealed tube, the yield of product 2a decreased to 65% after a similar reaction time (Table 1, entry 17).

With the preliminary optimized reaction conditions in hand, we next tested the generality of the (E)-3-(2-aminoaryl)acrylates (Table 2). As expected, a series of functional groups on the phenyl ring of the (E)-butyl 3-(2-aminoaryl)acrylates, such as methyl, chloro, fluoro, and nitro were compatible in this procedure, and the corresponding desired products 2b–2e were isolated in 36–86% yields. In general, substrates with electron-donating (methyl) and weakly or moderately electron-withdrawing groups (F, Cl) showed good results in the transformation. For instance, (E)-butyl 3-(2-amino-5-methylphenyl)acrylate (1b) reacted with CS₂ leading to the corresponding product 2b in 75% yield (Table 2, entry 2). A slightly higher yield was obtained when (E)-butyl 3-(2-amino-5-fluorophenyl)acrylate (1d) was used as a replacement in the above reaction (86% yield, Table 2, entry 4). It is worth noting that a substrate with strongly electron-withdrawing group (nitro) gave a low yield 36% of the product 2e. Further exploration indicated that various alkyl (methyl, ethyl, tert-butyl) 3-(2-aminophenyl)acrylates 1 were suitable reactants in the transformation, and the desired products 2f–2j were obtained in moderate to good yields (Table 2, entries 6–10). When (E)-ethyl 3-(2-aminophenyl)acrylate (1g) was employed in the reaction, the corresponding product 2g was isolated in 80% yield (Table 2, entry 7). We next examined the reaction of (E)-methyl 3-(2-aminophenyl)-2-methylacrylates 1k–1n with different substituents on the phenyl ring, and the desired products 2k–2n were isolated in 54–74% yield (Table 2, entries 11–14). Furthermore, the reaction conditions proved to be useful for (E)-3-(2-aminoaryl)acrylonitriles (1o–1r, Table 2, entries 15–18). For instance, (E)-3-(2-aminophenyl)acrylonitrile (1o) reacted with CS₂ affording the expected product 2o in excellent 90% yield (Table 2, entry 15). However, it was found that reactants 2-(2-aminobenzylidene)malononitrile (1s) and ethyl 3-(2-aminophenyl)-2-cyanoacrylate (1t) were not workable under the standard conditions (Table 2, entries 19 and 20).

The 2-(2-thioxo-2,4-dihydro-1H-benzo[d][1,3]thiazin-4-yl)acetate 2 could be further elaborated by alkylation with alkyl halide. For example, compound 2g reacted with iodomethane to afford the expected ethyl 2-(2-(methylthio)-4H-benzo[d][1,3]thiazin-4-yl)acetate (3) in 70% yield (Scheme 3).

Conclusion

In summary, we have successfully developed a new simple and efficient method to construct ring-fused 4-alkyl-4H-3,1-benzothiazine-2-thione derivatives. In the context of this method, carbon disulfide reacted with (E)-3-(2-aminoaryl)acrylates or (E)-3-(2-aminoaryl)acrylonitriles under metal-free conditions at room temperature. The newly developed method tolerates a wide range of substrates in moderate to excellent yields and provides promise for further alkylation or arylation. Moreover, this method is advantageous over previous ones [16,17] for the easy synthesis of reactants.

Experimental

General

All reactions were performed in test tubes in air. Flash column chromatography was performed with silica gel (200–300 mesh). Analytical thin-layer chromatography was performed on glass plates precoated with 0.25 mm 230–400 mesh silica gel impregnated with a fluorescent indicator (254 nm). Thin-layer chromatography plates were visualized by exposure to ultraviolet light. Organic solutions were concentrated on rotary evaporators at 25–35 °C. Commercial reagents and solvents were used as received. ¹H and ¹³C NMR spectra were recorded on a Bruker AV 400 at 400 MHz (¹H) and 100 MHz (¹³C) at ambient temperature. Chemical shifts are reported in parts per million (ppm) on the delta scale (δ) and referenced to tetramethylsilane (0 ppm). HRMS analyses were performed in ESI mode on a Bruker mass spectrometer.

General procedure for the synthesis of 2-(2-thioxo-2,4-dihydro-1H-benzo[d][1,3]thiazin-4-yl)acetate, 2: A mixture of 3-(2-aminoaryl)acrylate 1 (0.3 mmol), CS₂ (1.2 mmol, 4.0 equiv, 91.2 mg) and DABCO (0.3 mmol, 1.0 equiv, 33.6 mg) was stirred in DMSO (2 mL) at room temperature. After completion of the reaction as indicated by TLC (about 2 d), the reaction was quenched by water and extracted with ethyl acetate. The organic layers were dried with anhydrous MgSO₄, the solvent was evaporated under vacuum, and the residue was isolated by column chromatography with EtOAc/petroleum ether (1/5, v/v) as eluent to yield the desired products 2. For details, see Supporting Information File 1.