The synthesis of urea and thiourea analogs of the title aminothiochroman 6 is an area of current research for potential anticancer compounds of the heteroarotinoid class mimicking retinoids.The recently reported preparation of this late stage intermediate,however,suffers from a low overall yield of 5.3% from mesityl oxide that is limited by the nitration step and to a lesser degree upon the reduction employed in its preparation.Especially problematic was the 26% yield of the nitration step which introduced the nitrogen atom of the eventual amine moiety of the 6-aminothiochroman intermediate 6.The 40% yield in the reduction of the nitro group with Fe/HOAc offered cost advantages and a greater ease of workup over the previously employed TiCl3/HOAc method(50%)4 which justified the lesser yield.These combined poor yields necessitated increasing the scale of the previous steps which limited both the throughput for the preparation of in vivo testing quantities of a single compound and the potential to prepare multiple other urea and thiourea analogs from 6.The improved synthesis reported here is shorter and affords a higher overall yield of 6 that circumvents the nitration and the obligatory reduction by incorporating the nitrogen from the start of the synthesis.
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