Thermal Stability and Utility of Dienes as Protecting Groups for Acrylamides

Acrylamides are privileged electrophiles used in targeted covalent therapies, often installed at the end of a synthetic sequence due to their reactive nature. Herein, we report several diene-acrylamide adducts with a range of thermal stabilities toward retro-Diels-Alder deprotection of the acrylamide, enabling this masked functionality to be introduced early in a synthetic route and deprotected in a specific temperature range. Through kinetic studies, we identify solvent and structural trends that impact the stability of trimethylsilyl cyclopentadiene (TMS-CP) acrylamide adducts. TMS-CP protected acrylamides were installed on several amine-containing drugs, whose acrylamides were thermally unveiled (T = 160 degrees C, time <= 1 h) in moderate to high yields. We also showcase the potential utility of this protection strategy by improving the yield of a base-promoted SNAr reaction when the acrylamide is masked.

Automated summary

In this study, a masking strategy using acrylamides is reported, allowing the introduction of masked functionality early in a synthetic route and specific thermal deprotection. The stability of acrylamide adducts is influenced by solvent and structural factors, as determined through kinetic studies. This protection strategy improves the yield of base-promoted reactions.