Z -Selective Synthesis of Trisubstituted Alkenes Bearing Allylic Tertiary Amines via Rhodium-Catalyzed Allylic Amination of 1,1-Disubstituted Fluoromethyl Trichloroacetimidates

High Resolution Image Download MS PowerPoint Slide Z -trisubstituted alkenes serve as key pharmaceutical building blocks and essential feedstocks for the selective synthesis and modification of drug molecules. Among these compounds, Z -trisubstituted alkenes that contain allylic tertiary amines are significant due to the increased solubility, lipophilicity, and metabolic stability provided by the tertiary amines. However, controlled synthesis of Z -trisubstituted alkenes with allylic tertiary amines has proven difficult, primarily due to thermodynamic challenges associated with the Z -isomer and the synthetic difficulties of accessing allylic tertiary amines. Here, we report a diene ligand-controlled rhodium-catalyzed amination of 1,1-disubstituted fluoromethyl allylic trichloroacetimidates with secondary aliphatic and aryl amines to afford the Z -trisubstituted alkenes bearing allylic tertiary amines in good yields (45–98% yields) and excellent selectivity ( E/Z > 1:20). A mechanistic investigation was conducted using both experimental and computational Density Functional Theory (DFT). DFT calculations showed a preference for bidentate coordination of the diene ligand to the rhodium, which is needed for the ionization of the 1,1-disubstituted fluoromethyl allylic trichloroacetimidate to generate anti - and syn -π-allyl-rhodium intermediates. The E - and Z -differentiation occurs prior to nucleophilic attack of the secondary amines onto the more reactive π-allyl intermediates. The syn π-allyl intermediates lead to the minor E -trisubstituted alkene product, whereas the more reactive anti intermediates give the major Z -product. DFT calculations showed that the rate of conversion between reactive anti and syn π -allyl intermediates via π–σ–π interconversion was faster than the rate of nucleophilic attack, establishing a Curtin–Hammett condition. The fluoromethyl substrate was essential for the linear regioselectivity, as it induced a crucial hydrogen bonding interaction between the 1,1-disubstituted fluoromethyl allylic trichloroacetimidate and the secondary amine nucleophile. Overall, we anticipate that this methodology will be broadly applicable to the development of medically relevant Z -alkenes bearing allylic tertiary amines. The mechanistic insights gained will also serve as a foundation for addressing the challenges involved in other classes of Z -configured alkenes.