A convenient synthesis of 2H-furo[3,2-b][1,4]benzothiazin-2-one: a novel triheterocyclic ring system

Anton V. Dolzhenko¹*, Wai-Keung Chui², Paul W. S. Heng²

¹Perm State Pharmaceutical Academy, Perm, Russian Federation;

²Pharmacy Department, National University of Singapore, Singapore.

avdolzh@hotmail.com

Abstract: 3-Methyl-2H-furo[3,2-b][1,4]benzothiazin-2-one (10) has been prepared from o-aminothiophenol (1) by condensation with citraconic anhydride followed by intramolecular cyclization and oxidation of the resulting 2-(3,4-dihydro-2H-1,4-benzothiazin-2-yl)propanoic acid (5) with thionyl chloride.

Keywords: 2H-furo[3,2-b][1,4]benzothiazin-2-one, o-aminothiophenol, citraconic anhydride, thionyl chloride, cyclization, oxidation.

1. Introduction

(3-Oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)acetic acid (2) is known to be a product of the reaction between o-aminothiophenol (1) and maleic anhydride [1] (Scheme 1).

The reaction of the acid 2 with thionyl chloride has been reported to afford the acid chloride 3 [2] or lactone 4 [3] (Scheme 2). However structure of 3 was confirmed only by further chemical conversion to amides [2] that cannot exclude the structure of 3,3a-dihydro-2H-furo[3,2-b][1,4]benzothiazin-2-one (4). In turn the structure of 4 was established based on the signal of the carbonyl group of the lactone 4 in IR-spectra and the reactions of the product with anilines [3]. System of 2H-furo[3,2-b][1,4]benzothiazine has not been reported in the literature.

2. Results and discussion

Herein we report a convenient synthesis of 3-methyl-2H-furo[3,2-b][1,4]benzothiazin-2-one (10) from o-aminothiophenol (1). The key step of the preparation of 10 was the formation of 2-(3,4-dihydro-2H-1,4-benzothiazin-2-yl)propanoic acid (5) by the treatment of 1 with methylmaleic (citraconic) anhydride (Scheme 3). This reaction afforded a mixture of regioisomeric acids 5 (major) and 6 (minor). Fractional crystallizations of the mixture provided the pure acid 5.

Refluxing of compound 5 with thionyl chloride in toluene led to the formation of 3-methyl-2H-furo[3,2-b][1,4]benzothiazin-2-one (10) in good yield. The proposed mechanism of the formation of 10 is depicted in Scheme 4. The intramolecular cyclization of the acid 5 afforded lactone 7, which was oxidized to 10. It was assumed that the initial step of oxidation of the lactone 7 was the enolization to 8, followed by addition of thionyl chloride to produce 9. 3-Methyl-2H-furo[3,2-b][1,4]benzothiazin-2-one (10) might have arisen from 9 by a concerted elimination of HCl and sulfur monoxide.

3. Conclusion

The condensation of o-aminothiophenol (1) with citraconic anhydride followed by intramolecular cyclization and oxidation of the resulting acid 5 was shown to be a simple and convenient synthesis of the 2H-furo[3,2-b][1,4]benzothiazine system that afforded good yield.

4. Experimental

2-(3,4-Dihydro-2H-1,4-benzothiazin-2-yl)propanoic acid (5). To a solution of citraconic anhydride (1.12 g; 0.01 mole) in diethyl ether (20 ml) a solution of o-aminothiophenol (1.25 g; 0.01 mole) in diethyl ether (10 ml) was added. The reaction mixture was stirred at room temperature for 2 h. The precipitation was filtered to afford after fractional crystallization from ethanol pure 5.

Yield 1.71 g (72 %).

Mp: 251-252 ºC (white crystals)

MS: [M+1]⁺ 238.0.

IR (KBr, n, cm^-1): 3316 (COOH), 3198 (NH), 1689 (COOH), 1662 (C=O).

¹H NMR (300.13 MHz, DMSO-d₆, d, ppm): 1.16 (3H, d, J=7.2 Hz, Me), 2.80 (1H, p, J=7.2 Hz, CH(Me)COOH), 3.77 (1H, d, J=8.6 Hz, С²H), 6.98 (1H, dd, J=8.3 Hz, 1.5 Hz, C^(D)H), 6.99 (1H, td, J=6.8 Hz, 1.5 Hz, C^(B)H), 7.20 (1H, td, J=7.5 Hz, 1.5 Hz, C^(C)H), 7.34 (1H, dd, J = 7.9 Hz, 1.5 Hz, C^(A)H), 10.66 (1H, s, NH), 12.52 (1H, broad s, COOH).

3-Methyl-2H-furo[3,2-b][1,4]benzothiazin-2-one (10). A mixure of 2-(3,4-Dihydro-2H-1,4-benzothiazin-2-yl)propanoic acid (5, 2.37 g, 0.01 mole) and thionyl chloride (8 ml) in toluene (50 ml) was heated under reflux for 4 h. The solvent and excess of thionyl chloride were removed under reduced pressure and resulting solid crystallized from acetone to yield 10.

Yield 1.95 g (90 %).

Mp: 199-200 ºC (yellow crystals).

MS: [M+1]⁺ 218.1.

IR (KBr, n, cm^-1): 1762 (C=O), 1652, 698 (C=C), 1603 (C=N), 1437, 1383 (CH₃), 1288, 1227 (C-O-C).

¹H NMR (300.13 MHz, DMSO-d₆, d, ppm): 1.96 (3H, s, Me), 7.45 (1H, td, J=7.2 Hz, 1.9 Hz, C^(B)H), 7.51 (1H, td, J=7.5 Hz, 1.9 Hz, C^(C)H), 7.66 (1H, dd, J= 7.5 Hz, 1.9 Hz, C^(D)H), 7.73 (1H, dd, J= 7.5 Hz, 1.9 Hz, C^(A)H).

¹³C NMR (75.47 MHz, DMSO-d₆, d, ppm): 9.1 (Me), 117.6 (C^(D)), 119.8 (C⁹), 125.7 (C^(B)), 128.0 (C^(C)H), 128.3 (C^(A)), 131.9 (C³), 133.6 (C⁴), 137.9 (C¹¹), 153.8 (C¹³), 165.8 (C=O).

Acknowledgments

A. V. Dolzhenko thanks Russian Ministry of Education for the fellowship.

5. References

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2. C. O. Okafor and M. U. Akpuaka, J. Chem. Soc., Perkin Trans. 1, 1993, 159.

3. C. V. R. Sastry, K. S. Rao, and M. L. Jain, Indian J. Chem., 1991, 30B, 535.