Thermal Stability and Utility of Dienes as Protecting Groups for Acrylamides

Annie R Hooper; Alexander S Burns

doi:10.1021/acsmedchemlett.2c00075

Thermal Stability and Utility of Dienes as Protecting Groups for Acrylamides

ACS Med Chem Lett. 2022 Apr 14;13(5):833-840. doi: 10.1021/acsmedchemlett.2c00075. eCollection 2022 May 12.

Authors

Annie R Hooper¹, Alexander S Burns²

Affiliations

¹ Rodger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, Illinois 61801, United States.
² Discovery Chemistry, Janssen Research & Development L.L.C., San Diego, California 92121, United States.

Abstract

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 °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 S_NAr reaction when the acrylamide is masked.