Benzoxathiins

Benzoxathiin formed a stable addition product with bromine (54JA1068). 

We have developed the efficient synthesis of the SERM drug candidate 1 and successfully demonstrated the process on a multiple kilogram scale to support the drug development program. A novel sulfoxide-directed borane reduction of vinyl sulfoxides was discovered. The mechanistic details of this novel reaction were explored and a plausible mechanism proposed. The sequence of asymmetric oxidation of vinyl sulfoxides followed by stereospecific borane reduction to make chiral dihydro-1,4-benzoxathiins was applied to the asymmetric synthesis of a number of other dihydro-1,4-benzoxathiins including the sweetening agent 67. 

Many oxidizing agents have been used to afford almost all the possible oxide derivatives of 1,4-dithiin, 1,4-benzoxathiin, 1,4-benzodithiin, thianthrene, and phenoxathiin <1984CHEC(3)943, 1996CHEC-II(6)447>. 

Benzoxathiins 265 can be prepared by rearrangement of the 8-(2-bromoethoxy)-2,3-dihydro-2//-l-benzothio-pyran 264 in DMF at 80°C (Equation 41) <2003MI187>. 

Benzoxathiins, considered as 4-thiaflavans, have shown antimicrobial <2004MI317> and antioxidant activity and seem to operate by both the flavonoid-like and the tocopherol-like mechanisms <2001CC551, 20050BC3066>. 

Derivatives of 2,3-dihydro-l,4-oxathiin and 1,4-benzoxathiins have been patented as agrochemicals. An important development in fungicidal research has been the discovery of so-called systemic fungicides. Unlike surface fungicides which may require repeated... 

Heating solutions of 5-aryloxy-l,2,3-thiadiazoles 82 (X = O) in DMF at 100 °C in the presence of excess sodium hydride afforded 1,4-benzoxathiins 84 (X = O). The transformation was proposed to proceed via initial cleavage of the thiadiazole ring with subsequent N2 elimination to give the intermediate 83. Subsequent intramolecular rearrangement of intermediates gave the 1,4-benzoxathiins 84 (X = O) <02H483>. 

The cycloaddition reaction of o-thioquinones with acyclic 1,3-dienes is a finely tuned process that can involve either reagent behaving as the diene component. It has now been established that formation of a 2-spiro-linked thiopyran by a [2-1-4] reaction is kinetically controlled and that the [4-1-2] alternative leads to the thermodynamic product, a 1,4-benzoxathiin (Scheme 31). Cyclic dienes yield only the oxathiin <03T5523>. Incorporation of the thionocarbonyl diene unit into fiiran and pyran rings and reaction with carbohydrate glycols leads to tricyclic oxathianes, desulfurisation of which yields 2-deoxydisaccharides <03T4249>. 

Triflic anhydride effects the cyclisation of methylthioethyl phenyl ethers to the sulfonium salt, demethylation of which affords the 2,3-dihydro-1,4-benzoxathiin (Scheme 34). The... 

As for 1,4-benzodithiin, it reacts smoothly with various electrophiles to give 2-substituted derivatives in a range of reactions. Studies have also been done of 1,4-benzoxathiin, and its chemical properties are found to fall between those of 1,4-benzodioxin and 1,4-benzodithiin . 

Dihydro-1,4-benzodithiins and 2,3-dihydro-1,4-benzoxathiins react with sodium methoxide in dimethylacetamide to give 1,3-benzodithioles (104) and 2-(vinylthio)phenols (105), respectively <89CL2111>. 

The method using Amberlyst 15 can also be applied to the 2,3-dihydro-1,4-benzoxathiin and 2,3-dihydro-1,4-benzodithiin series <93JCS(P1)1359>. 

In the 1,4-benzoxathiin series, neither dehydration of the hydroxy compound (207) nor elimination of ethanol from (208) gives a very satisfactory yield of (6), and once again the best yield (76%) is obtained by pyrolysis of the 2-acetoxy derivative (209). 3-Methyl-1,4-benzoxathiin is obtained by an analogous route <66HC(2l-2)852>. 

Benzoxathiin and benzodithiin derivatives can also be derived as rearrangement products of other heterocyclic rings. Thus, nonstereospecific ring expansion reactions of 1,3-benzoxathiole sulfoxides (210) and 1,3-benzodithiole sulfoxides (211) with acetic anhydride or /j-toluenesulfonic acid afford the corresponding 1,4-benzoxathiins or 1,4-benzodithiins (212) and (213) in satisfactory yields... 

In the 2,3-dihydro-1,4-benzoxathiin series, the 2,2-(2,6-dimethoxyphenoxy)ethylamino methyl-... 

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