Synthesis of Functionalized 1,3‐Thiazine Libraries Combining Solid‐Phase Synthesis and Post‐Cleavage Modification Methods

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Abstract
The solid‐phase synthesis of diverse sets of 1,3‐thiazine‐5‐carboxylates on Wang resin is described. Acetoacetylation, followed by Knoevenagel condensation and an acid‐promoted ring‐closure reaction with thioureas furnished polymer‐bound 1,3‐thiazines. As an alternative to transesterification, a de‐novo synthesis of β‐keto esters, starting from polymer‐bound malonic acid through reaction with acyl imidazoles, was applied to increase the diversity. To reduce contamination, an on‐bead purification of resin‐bound 1,3‐thiazines that makes use of differences in the reactivity of ester bonds toward alkoxides is reported. A final four‐step post‐cleavage modification of thiazine‐5‐carboxylates, derived by TFA cleavage from the Wang linker, leads to esters or amides. Twenty 1,3‐thiazines were obtained in yields of up to 61 % over either 9 or 13 steps.