Dr. Ciro Romano

Prof. Rubén Martín

Metal-catalyzed remote functionalization of aliphatic amines and amides triggered by photocatalytic sp3 C-H activation

From 03/02/2020 to


PHOTO-WALK - GA 839980

Activation of traditionally inert bonds has attracted great attention in the last decades and impressive advancements have been achieved in the catalytic functionalization of C-H bonds. Although the great number of catalytic methodologies for the transformation at sp2 C-H sites, manipulation of the corresponding sp3 C-H bonds remains largely confined to activated allylic and benzylic positions or to sites within reach of an existing directing group. Transition metal-catalyzed olefin isomerization has provided an outstanding tool for remote functionalization of sp3 C-H bonds but it requires the use of prefunctionalized molecules, bearing a pi component or an alkyl bromide. On the other hand, photocatalysis has emerged as a novel strategy for sp3 C-H activation but it is limited to the functionalization at the alpha or delta positions with respect to a heteroatom. PHOTO-WALK will merge the photocatalytic activation of sp3 C-H bonds with a Ni-catalyzed chain-walking process, disclosing a completely novel triggering event for the remote functionalization of unactivated aliphatic amines and amides. The approach will overcome the limitations of current strategies for remote functionalization, allowing transformations at sp3 C-H sites unreachable by current photocatalytic methods and employing hydrocarbon feedstocks (aliphatic amines and amides) lacking of C=C or C-halide handles. Three functionalizations have been envisioned to increase molecular complexity by forging new C(sp2)–C(sp3) and C(sp3)–C(sp3) bonds: i) remote carboxylation, ii) remote arylation and iii) remote alkylation. PHOTO-WALK has the potential to be applied to the late-stage derivatization of pharmaceuticals, enabling the exploration of uncharted chemical spaces and offering the opportunity for structural diversification in drug discovery.

This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement 839980

Conformational Flexibility as a Tool for Enabling Site-Selective Functionalization of Unactivated sp3 C–O Bonds in Cyclic Acetals
Ciro Romano, Laura Talavera, Enrique Gómez-Bengoa, and Ruben Martin*
Journal of the American Chemical Society 2022, 144, 26, 11558–11563
DOI: 10.1021/jacs.2c04513