Benzoxathiin Formation

Give a mechanistic explanation for the observation that heating of the sulfoxide 1 with 1.2 equivalents of PTSA in xylene for 50 minutes results in formation of the 3,1-benzoxathiin 2 (53%). 

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The key structural features of compound 1 are the chiral cis-diaryl benzox-athiin fused ring system, two phenols, and one phenol ether linkage with the pyrrolidinylethanol. Originally, SERM 1 was prepared by medicinal chemists from a key ketone intermediate 5 shown in Scheme 5.1. Compound 5 was prepared in four steps with rather low yield [4a], Among these steps, the high temperature de-methylation step and the use of extremely toxic MOM-C1 were not particularly suitable for scale-up. The ketone 5 was then brominated with PhMe3NBr3 (PTAB) and coupled with thiophenol 7 to produce adduct 8. The key step of the synthesis was the conversion of adduct 8 to cis-diaryl benzoxathiin 9 under the Kursanov-Parne reaction conditions (TFA/Et3SiH). This novel reaction allowed the formation... 

The cis-2,3-diaryl-2,3-dihydro-l,4-benzoxathiin is a very unique structural motif. Other than scattered reports in the literature on the formation of this scaffold, there was no effective asymmetric synthesis for it [6]. We explored two major synthetic approaches to realize the key chiral as-diaryl dihydrobenzoxathiin scaffold, as shown in Scheme 5.3. One was the quinone ketal route in which the quinone ketal 13 and the chiral mercaptol alcohol 14 were the key intermediates. The other approach was the stereo- and enantioselective reduction of the diaryl benzoxathiin 16. The key mercaptol alcohol 14 and the diaryl benzoxathiin 16 were both envisioned to be prepared from the key, common iodoketone intermediate 15. 

As already mentioned in CHEC-II(1996), 1,4-benzodioxins are often obtained from the corresponding dihydro compounds <1996CHEC-II(6)447>. Thus, elimination reactions of monoiodo and monobromo <2001HC0135> or dibromo benzodioxanes <2000EJM663> allow the formation of various 2-substituted-l,4-benzodioxins in good yields. 6-Methyl-l,4-benzoxathiin was prepared from the saturated derivatives by reaction with SOCI2, then quinoline <2003BML2083>. 

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>. 

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