1,3-Benzoxathioles, synthesis

The asymmetric reduction of the benzoxathiin is very appealing because of its simplicity (Scheme 5.3). It was envisioned that intermediate 16 could be prepared from thiol-phenol 7 and bro moke tone 17. Scheme 5.8 summarized the synthesis for 16. The l,3-benzoxathiol-2-one 35 was prepared from 1,4-benzoquinone and thiourea following a literature procedure with minor modifications. Benzylation of 35 with benzyl bromide in the presence of KI gave benzyl ether 36 as a crystalline solid. It was observed that the benzylation gave better results when the reaction was run under anaerobic conditions. Hydrolysis of thiocarbonate 36 gave free thiophenol 7 which was used directly in the next reaction. 

SYNTHESIS To a well-stirred solution of 120 g thiourea in 800 mL 2N HCL, there was added a solution of 100 g benzoquinone in 500 mL acetic acid over the course of 15 min. Stirring was continued for an additional 0.5 h at room temperature, and then the reaction mixture was heated on the steam bath for 1 h. With cooling in ice water, a heavy crop of crystals separated. These were removed by filtration and air dried to provide 90.1 g of 5-hydroxy-l,3-benzoxathiol-2-one (2-mercaptohydro-quinone cyclic carbonate ester) with a melting point of 170.5-172.5 °C. 

SYNTHESIS To an ice cold and well stirred solution of 15 g vanillin and 20 g sodium thiocyanate in 150 mL acetic acid there was added, dropwise over the course of 15 min, a solution of 16 g elemental bromine in 40 mL acetic acid. This was followed by the addition of 30 mL of 5% HC1 and 300 mL EtOH, and stirring was continued for an additional 30 min. The mixture was heated to its boiling point, and filtered while hot. The mother liquor was diluted with an equal volume of H20, which initiated the crystallization of crude 5-form yl-7-methoxy-2-oxo-l,3-benzoxathiole as a flocculant yellow solid. On filtration and airdrying, this weighed 12.5 g. After recrystallization from EtOH, the product was white and had a mp of 164 °C sharp. 

Gross, H., and CostiseUa, B., a-Substituted phosphonates. Part 28. Synthesis of 2-phosphorylated 1,3-benzodioxoles, 1,3-benzoxathioles and 1,3-benzodithioles, Synthesis, 622, 1977. 

Beilstein Handbook Reference) BCG BRN 0372527 Bromcresol green EINECS 200-972-8 NSC 7817 Phenol, 4,4 - 1,1-dioxido-3H-2,1-benz-oxathiol-3-ylidene)bis(2,6-dibromo-3-methyl- Phenol, 4,4 -(3H-2,1-benzoxathiol-3-ylidene)bis(2,6-dibromo-3-methyl-, S,S-dioxide o-Toluenesulfonic acid, o-hydroxy-, gamma-sultone Tetrabromo-m-cresolphthalein sulibne. An acid indicator pH 3.8 (yellow)-5.4 (blue-green). Red-yellow crystals mp = 218.5° Xjn = 211, 278, 338,426 nm (e 54100. 8500, 7550, 17100 MeOH), 312, 394, 620 nm (s 13300, 8520, 40100 MeOH/KOH) insoluble in H2O, soluble in organic solvents. Lancaster Synthesis Co. Mallinckrodt Inc. Sigma-Aldrich Fine Chem. 

This method has been extensively exploited for the synthesis of a large group of 3H-2,1-benzoxathiole 1,1-dioxide derivatives known as sulphonephthaleins, many of which, such as phenol red, p-cresol red and bromothymol blue are well known acid-base indicators. There is excellent coverage of this subject in Breslow and Skolnik s monograph8 and equation 60 merely serves to illustrate two representative syntheses81,82. The sulphonephthaleins can also be prepared from 3ff-2,l-benzoxathiole-l-dioxide derivatives with reactive substituents (such as dichloro or carbonyl) at the 3-position (see Section III.D.3). 

Diethyl-1,3-benzoxathiole added to phenylmagnesium bromide in anhydrous toluene, vigorously stirred and refluxed ca. 8 hrs. product. Y 60%. F. e. s. S. Cabbiddu, Synthesis 1974 732. 

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