Unambiguous syntheses of four unreported monomethylated derivatives of 3-phenyldihydro-1,2,4-triazin-6(1H)-ones, namely, the 1-methyl (2), 2-methyl (3), 4-methyl (4) and the imidic O-methyl derivative (5), are described. Regioselectivity was achieved for the synthesis of (2) by addition of ethyl glycinate to the 1,3-dipolar nitrile imine derived from N- methylbenzohydrazonoyl bromide hydrobromide (8). The key step for the synthesis of (3) was addition of benzyl 3-methylcarbazate (14) to ethyl N-[ chloro (phenyl) methylene ] glycinate (15b). The 4-methyl compound (4) was prepared by cycloaddition of ethyl N-( thiobenzoyl ) sarcosinate (21) with hydrazine hydrate, and the O-methyl compound (5) was prepared by reaction of sodium methoxide with 6-chloro-3-phenyl-4,5-dihydro-1,2,4-triazine (23).
An unambiguous synthesis of the published structure for the natural product sinharine (1) showed that the assignment was incorrect. (E)-3-( Methylthio )-N-(2-phenylethyl) propenamide (4) was proposed as an alternative structure and this was confirmed by synthesis. Similarly the literature proposal for the structure of methylsinharine was reviewed and the natural product tentatively reassigned as (E)-N-methyl-3-( methylthio )-N-(2-phenylethyl) propenamide.
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