3-Benzoyl-2-hydroxy-3a-[(3-methylquinoxalin-2-yl)methyl]-1H-pyrrolo[2,1-c][1,4]benzothiazine-1,4(3aH)-dione

Abstract

The reaction of 3-benzoylpyrrolo[2,1-c][1,4]benzothiazine-1,2,4-trione with 2,3-dimethylquinoxaline afforded 3-benzoyl-2-hydroxy-3a-[(3-methylquinoxalin-2-yl)methyl]-1H-pyrrolo[2,1-c][1,4]benzothiazine-1,4(3aH)-dione in a moderate yield. The compound was fully characterized.

1. Introduction

3a-(Quinoxalin-2-ylmethyl)pyrrolo[2,1-c][1,4]benzothiazine A (Figure 1) core is a heterocyclic hybrid of two pharmacologically promising scaffolds, 1,4-thiazine [1] and quinoxaline [2]. For example, several heterocyclic compounds with a 1,4-thiazine core were reported to show good antibacterial [3,4,5] and antihypertensive [6,7,8] activities (Figure 1). In addition, several quinoxaline-based structures were used to develop antimicrobial [9] and cytotoxic [10] agents, inhibitors of platelet-derived growth factor receptor tyrosine kinase (PDGFR) [11], acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) [12] (Figure 1). Thus, structures with a 3a-(quinoxalin-2-ylmethyl)pyrrolo[2,1-c][1,4]benzothiazine A scaffold are attractive objects for medicinal and pharmaceutical studies.

Recently, 3-aroylpyrrolo[1,2-a]quinoxaline-1,2,4(5H)-triones 1 ([e]-fused 1H-pyrrole-2,3-diones (FPDs) [13,14,15] bearing a quinoxaline core) were reported to react with quinaldine 2 or 2-methylquinoxalines 3, 4 to afford corresponding 3a-(quinolin-2-ylmethyl)pyrrolo[1,2-a]quinoxalines 5 or 3a-(quinoxalin-2-ylmethyl)pyrrolo[1,2-a]quinoxalines 6, 7 under mild conditions (Scheme 1) [16]. Compounds 5–7 bear isosteric moieties of the pharmacologically attractive 3a-(quinoxalin-2-ylmethyl)pyrrolo[2,1-c][1,4]benzothiazine A (Scheme 1).

In order to achieve pharmacologically valuable 3a-(quinoxalin-2-ylmethyl)pyrrolo[2,1-c][1,4]benzothiazine A derivatives, we studied the reaction of an exemplar of a recently emerged class of FPDs bearing a 1,4-thiazine moiety (3-aroylpyrrolo[2,1-c][1,4]benzothiazine-1,2,4-triones (APBTTs) [17,18,19]), compound 8, with 2,3-dimethylquinoxaline 4 (Scheme 2).

2. Results and Discussion

APBTTs are known to be prone to react with mononucleophiles NuH at three various electrophilic centers (C¹, C^3a, and C⁴), resulting in three types of products 9–11 [18] (Scheme 3). The reaction direction is highly dependent on the structure of NuH [18]. Thus, a study on the reactions of APBTTs with various nucleophiles is of high theoretical and practical interest.

The title product 12 bearing a pursued 3a-(quinoxalin-2-ylmethyl)pyrrolo[2,1-c][1,4]benzothiazine A core was obtained in several steps (Scheme 4). Initially, benzoylpyruvic acid 13 was obtained via the Claisen condensation of acetophenone and diethyl oxalate in the presence of sodium methoxide [20]. Then, the reaction of compound 13, o-aminophenol, and dicyclohexylcarbodiimide (DCC) afforded 1,4-benzothiazinone 14 [21]. After that, acylation of compound 14 via oxalyl chloride resulted in APBTT 8 [17]. And finally, the reaction of APBTT 8 and 2,3-dimethylquinoxaline 4 afforded the title compound 12 in a moderate yield.

Obviously, the formation of compound 12 proceeded via a nucleophilic attack of the CH₂ group of the enamino–tautomer of 2,3-dimethylquinoxaline 4 on the C^3a electrophilic center of APBTT 8 (Scheme 4).

The structure of compound 12 was confirmed using single-crystal X-ray analysis (CCDC 2307237, Figure 2, Figure 3 and Figure 4), IR, and NMR spectra.

3. Materials and Methods

3.1. General Information

¹H and ¹³C NMR spectra (Supplementary Materials) were acquired using a Bruker Avance III 400 HD spectrometer (Bruker BioSpin AG, Faellanden, Switzerland) (at 400 and 100 MHz, respectively) in DMSO-d₆ using the solvent residual signal (in ¹H NMR, 2.50; in ¹³C NMR, 39.52) as an internal standard. The IR spectrum was recorded using a Perkin–Elmer Spectrum Two spectrometer (PerkinElmer Inc., Waltham, MA, USA) from a mull in mineral oil. Melting points were measured using a Mettler Toledo MP70 apparatus (Mettler-Toledo (MTADA), Schwerzenbach, Switzerland). Elemental analysis was conducted on a Vario MICRO Cube analyzer (Elementar Analysensysteme GmbH, Langenselbold, Germany). The single-crystal X-ray analysis of compound 12 was performed on an Xcalibur Ruby diffractometer (Agilent Technologies) (Oxfordshire, UK). The empirical absorption correction was introduced using a multi-scan method using the SCALE3 ABSPACK algorithm [22]. Using OLEX2 [23], the structures were solved with the SHELXS [24] program and refined using the full-matrix least-squares minimization in the anisotropic approximation for all non-hydrogen atoms with the SHELXL [25] program. Hydrogen atoms were positioned geometrically and refined using a riding model. All procedures with compound 8 were performed in oven-dried glassware. Benzene for procedures with compound 8 was distilled over Na before the use.

3.2. 3-Benzoyl-2-hydroxy-3a-[(3-methylquinoxalin-2-yl)methyl]-1H-pyrrolo[2,1-c][1,4]-benzothiazine-1,4-(3aH)-dione 12

A mixture of 50.0 mg (149 µmol) of APBTT 8 and 23.5 mg (149 µmol) of 2,3-dimethylquinaxaline 4 in 2 mL of anhydrous benzene was stirred in a screw-capped vial at 85 °C for 2 h (until a yellow transparent solution was formed instead of a dark violet suspension characteristic of APBTT 8). Then, the reaction mixture was cooled to room temperature. About 1 mL of the solvent was evaporated. The formed precipitate was filtered off. Then, it was stirred in 1 mL of benzene at 85 °C for 5 min. Then, the formed precipitate was filtered off to yield the title compound 12. Yield: 48 mg (65%); white powder; mp 161–163 °C (decomp.). ¹H NMR (DMSO-d₆, 400 MHz): δ = 11.88 (br. s, 1H), 8.08 (m, 1H), 7.91–7.84 (m, 2H), 7.74 (m, 4H), 7.57 (m, 2H), 7.50–7.41 (m, 3H), 7.34 (m, 1H), 4.12 (m, 1H), 3.24 (m, 1H), 2.66 (s, 3H) ppm. ¹³C NMR (DMSO-d₆, 100 MHz): δ = 192.2 (C⁴), 191.2 (COPh), 163.8 (C¹), 153.5 (C²), 152.2 (C^2′=N), 151.5 (C^3′=N), 139.7, 139.5, 137.6, 132.8, 129.6, 129.4, 129.1 (2C), 128.9, 128.3, 128.1 (2C), 128.1, 127.9, 126.6, 126.5, 123.3, 123.2, 111.6 (C³), 70.9 (C^3a), 31.9 (CH₂), 22.2 (CH₃) ppm. IR (mineral oil): 3060, 1723, 1694, 1645 cm⁻¹. Anal. Calcd. (%) for C₂₈H₁₉N₃O₄S: C 68.14; H 3.88; N 8.51. Found: C 68.10; H 3.96; and N 8.59. The crystal structure of compound 12 was deposited at the Cambridge Crystallographic Data Centre with the deposition number CCDC 2307237.