Preparation of fluorinated phenoxathiin dioxide monoamine oxidase-A inhibitors: Intramolecular radical substitution at sulfur versus the Mauthner synthesis

Five unique fluorinated analogs, 8a-c and 15a,b, of the monoamine oxidase-A inhibitor 3-isopropoxyphenoxathiin 10,10-dioxide (II) were prepared via oxidation of the corresponding phenoxathiins 7 and 14. 3-Fluoro-7-isopropoxy- 7a, 2-fluuro-3-isopropoxy- 7b, and 2,7-difluoro-3-isopropoxyphenoxathiin (7c) were prepared by a modification of the Mauthner synthesis which involved cyclization of the corresponding 2-hydroxy-4-isopropoxythiophenols 4 with the appropriate 2-halonitrobenzenes 5 in the presence of potassium tert-butoxide. Preparation of 2,8-difluoro-3-isopropoxyphenoxathiin (14b) from 4b and 2,2,4-difluoronitrobenzene (5c) employing similar methods failed, leading instead to a novel macrocycle 9. Attempts to obtain 2-fluoro-7-isopropoxyphenoxathiin (14a) and the 2,8-difluoro analog 14b via trifluoroacetic acid deprotection of intermediate thio-protected 2-nitrophenyl 2-thiophenyl ethers 11a and c followed by cyclization of the resulting thiols were also unsuccessful. Deprotection of 11a with trifluoroacetic acid produced only complex product mixtures, while similar deprotection of Ile and treatment of the resulting crude product with potassium tert-butoxide in refluxing dimethylformamide produced the 2,7-difluorophenoxathiin analog 7c, a result consistent with a Smiles rearrangement of the intermediate thiol 12 prior to ring closure. The phenoxathiins 14 were ultimately prepared by a modification of a relatively unexploited phenoxathiin synthesis involving the intramolecular radical substitution at sulfur of 2-aminophenyl 2-thiophenyl ethers 13 containing para-methoxybenzyl and methoxymethylthio-protecting groups.