Methyl (1aRS,7aSR)-7-formyl-1a-phenyl-1,1a-dihydroazirino[2,3-b]benzo[e][1,4]thiazine-7a(7H)-carboxylate

Abstract

The first representative of the aziridine-fused benzo[e][1,4]thiazine series was synthesized from methyl 2-bromo-2-phenyl-2H-azirine-2-carboxylate and benzo[d]thiazole in 74% yield. The reaction proceeds via the S_N2′-S_N2′-cascade to form the azirinylthiazolium salt followed by a water-induced thiazole ring expansion. The structure of the title compound was established based on ¹H, ¹³C, 2D NMR spectroscopy and high-resolution mass spectrometry, and unambiguously confirmed by X-ray diffraction analysis.

1. Introduction

Heterocyclic compounds containing a benzo[1,4]thiazine moiety have emerged as attractive building blocks in medicinal chemistry. The benzo[1,4]thiazine skeleton alongside its 2,3-hydrogenated and S-oxidized analogues is found in compounds exhibiting anticancer [1], antimicrobial [2], antifungal [3], antiviral [4], antihypertensive [5], anti-inflammatory [6], cardiovascular [7], anti-rheumatic [8], anti-allergic [9], and other biological activities [10,11]. Several synthetic strategies have been developed for the construction of the benzo[1,4]thiazine skeleton, the most common of which rely on cyclocondensation of o-aminothiophenols and related substrates with electrophiles [12]. There is much less information on the synthesis of these heterocycles via cyclization of substituted anilines [13,14], ring contraction of benzothiazocines [15], and ring expansion of benzo[d]thiazoles and benzo[d]thiazolines. In particular, using the latter approach, 3-alkylidene-substituted benzo[1,4]thiazines were prepared via intramolecular oxidative five-membered ring expansion in benzothiazolines [16]. Adib et al. reported intermolecular ring expansion of benzothiazoles using diaroylacetylenes and Meldrum’s acid [17].

Herein, we describe the first synthesis of an aziridine-fused benzo[1,4]thiazine by intermolecular ring expansion of benzo[d]thiazole under the action of methyl 2-bromo-3-phenyl-2H-azirine-2-carboxylate (1) operating as a transannulation agent. Annulation reactions involving mono- and disubstituted azirines are well known and have been widely used in the synthesis of various pyrrolo-fused systems [18,19]. Trisubstituted azirines, in contrast, are inactive in annulation reactions and can react only in four ways: ring opening, ring expansion, addition to the C=N bond, and substitution reaction [20]. The synthesis reported herein represents the first example of a transannulation reaction involving a trisubstituted azirine and provides access to a previously unknown class of azirino-fused benzo[1,4]thiazines.

2. Results and Discussion

Bromoazirine 1 required for the present study was prepared according to the published procedure [21]. We found that azirine 1 reacts with benzothiazole in acetonitrile at room temperature and is completely consumed within 10 h, yielding a mixture of several difficult to separate products. However, the addition of water dramatically improves the selectivity. When a 3:2 acetonitrile–water mixture was used as the solvent, only one product, aziridinobenzothiazine 2, was observed. The compound was isolated by column chromatography, and subsequent recrystallization from a diethyl ether–hexane mixture provided analytically pure compound 2 (Scheme 1).

The structure and stereochemistry of product 2 were confirmed by single-crystal X-ray diffraction analysis (Figure 1). A crystal suitable for X-ray crystallography was obtained by slow crystallization from a diethyl ether–hexane–dichloromethane mixture as a clear colourless prism. The crystal structure of compound 2 belongs to the monoclinic system, space group P2₁/n. According to crystallographic data, the nitrogen atom bearing the formyl group has a hybridization close to sp², as a result of which all four carbon atoms bound to it lie in the same plane.

A plausible mechanism for the formation of azirinobenzothiazine 2 is depicted in Scheme 2. The reaction begins with nucleophilic substitution of bromine by benzothiazolium substituent to form salt 3. This exchange proceeds in two stages via an S_N2′-S_N2′ cascade mechanism and is similar to the known reaction of azirine 1 with pyridines leading to pyridinium salts [22]. Subsequent nucleophilic addition of water to intermediate 3 occurs with elimination of HBr. Opening of the thiazolium ring, most likely promoted by another water molecule, yields thiophenol 4, which undergoes intramolecular HBr-catalyzed cyclization to give the final product 2.

3. Materials and Methods

3.1. General Instrumentation

The melting point was determined on a Stuart SMP30 melting-point apparatus. NMR spectra were recorded on a Bruker Avance 400 spectrometer (Karlsruhe, Germany) in DMSO-d₆. ¹H and ¹³C{1H} NMR spectra were calibrated according to the residual signal of DMSO-d₆ (δ = 2.50 ppm) and the carbon atom signal of DMSO-d₆ (δ = 39.5 ppm), respectively. High-resolution mass spectra were recorded with a Bruker maXis HRMS-QTOF (Bremen, Germany), via electrospray ionization. Thin-layer chromatography (TLC) was conducted on aluminum sheets precoated with SiO₂ ALUGRAM SIL G/UV254 (Düren, Germany). Column chromatography was performed on silica gel 60 M (0.04–0.063 mm). Commercially available benzo[d]thiazole was used without further purification. All solvents were distilled and dried prior to use. Single crystals of compound 2 were grown by slow evaporation of its solution in diethyl ether–hexane–dichloromethane mixture. Crystallographic data were collected on a SuperNova, single source at offset/far, HyPix3000 diffractometer (Rigaku, Wroclaw, Poland) using graphite monochromatic Cu–Kα radiation (λ = 1.54184 A). The crystal was kept at 99.9(2) K during data collection. Using the Olex2 version 1.5 (International Union of Crystallography, Chester, England) [23], the structure was solved with the ShelXT (International Union of Crystallography, Chester, England) [24] structure solution programme using the intrinsic phasing method and refined with the ShelXL [25] refinement package using least squares minimization. CCDC 2503941 contains crystallographic data for compound 2. The data can be obtained free of charge from the Cambridge Crystallographic Data Centre via https://www.ccdc.cam.ac.uk/structures (accessed on 19 November 2025).

3.2. Methyl (1aRS,7aSR)-7-formyl-1a-phenyl-1,1a-dihydroazirino[2,3-b]benzo[e][1,4]thiazine-7a(7H)-carboxylate (2)

To a solution of bromoazirine 1 (127 mg, 0.5 mmol) in an MeCN-H₂O (3:2, 2.5 mL) mixture, benzo[d]thiazole (135 mg, 1 mmol, 2 equiv) was added, and the resulting mixture was stirred at room temperature for 4.5 h. The product was extracted with ethyl acetate (2 × 5 mL), and the organic layer was dried over Na₂SO₄. Evaporation of the solvent followed by column chromatography (eluent hexane–ethyl acetate, from 5:1 to 1:1) and recrystallization from the diethyl ether–hexane mixture gave compound 2 (120 mg, 74%) as a colourless solid.

Mp = 157–158 °C. ¹H NMR (400 MHz, DMSO-d₆), δ, ppm: 8.86 (s, HCO, 1H), 7.64–7.62 (m, H_arom._, 1H), 7.54–7.52 (m, H_arom._, 1H), 7.43–7.40 (m, H_arom._{, kl}1H), 7.34–7.29 (m, H_arom., 6H), 4.74 (s, NH, 1H), 3.31 (s, OCH₃, 3H). ¹³C{¹H} NMR (100 MHz, DMSO-d₆), δ, ppm: 165.7 (C), 162.6 (CH), 137.2 (C), 135.2 (C), 128.4 (CH), 128.2 (CH), 127.9 (CH), 127.7 (CH), 127.0 (CH), 126.4 (CH), 126.3 (C), 122.1 (CH), 57.1 (C), 55.5 (C), 52.9 (CH₃).

HRMS (ESI/Q-TOF) m/z: [M + H]⁺ Calcd for C₁₇H₁₅N₂O₃S⁺ 327.0798; Found 327.0807.

4. Conclusions

The first representative of aziridine-fused benzo[e][1,4]thiazine series was synthesized from methyl 2-phenyl-2-bromo-2H-azirine-2-carboxylate and benzothiazole in 74% yield. The reaction proceeded via an S_N2′-S_N2′-cascade sequence to form the intermediate azirinylbenzothiazolium salt, followed by water-induced thiazole ring expansion. The structure of the product was established using ¹H, ¹³C, [¹H, ¹³C]-HSQC, [¹H, ¹³C]-HMBC NMR spectroscopy, HRMS, and confirmed by X-ray diffraction analysis.