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

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

In recent years, metal-catalyzed C–H and C–O functionalization, which is the use of these strong molecular bonds as functional groups, has provided new dogmas in retrosynthetic analysis, allowing to streamline synthetic sequences from simple precursors without the need for pre-activation at the targeted reaction site. Despite the spectacular advances realized in sp2 C–H and sp2 C–O functionalization, catalytic C–C bond-forming reactions via sp3 C–H and sp3 C-O activation in saturated hydrocarbon feedstocks still remain largely underdeveloped. This is due to the fact that i) sp3 C–H/C–O bonds lack proximal empty low energy or filled high-energy orbitals that interact with the d-orbitals of the transition metal (TM), ii) sp3 C–H bonds are less acidic than sp2 C–H bonds, iii) and the tridimensional structure of sp3 carbon centers hamper the approach of the TM. Additionally, site selectivity is not particularly straightforward due to the presence of multiple, yet similar sp3 C–H bonds in saturated hydrocarbons. Although chemists have navigated these issues by using directing groups, their installation and detachment can be rather problematic, so a better strategy is needed. PHOTO-WALK offers an opportunity to streamline the manipulation of readily accessible starting materials and contribute to the valorization of feedstocks. The typical mild reaction conditions ensured by the combination of light-driven processes with TM-catalysis offer the opportunity for diversification of advanced materials by rapidly and reliably generating structural diversity for lead generation in drug discovery, hence exploring currently inaccessible chemical spaces. PHOTO-WALK has studied the development of a new activation strategy based on merger of photocatalysis and nickel catalysis to control remote functionalization of unactivated aliphatic amines and amides, allowing traditionally unreachable sp3 CH sites to be targeted and functionalized by C-C bond-formation without the need for precursors possessing high energetic bonds, such as a pi-components or alkyl (pseudo)halides. The initial specific objectives being: 1. Remote photochemical carboxylation of aliphatic amines and amides with CO2. 2. Remote photochemical sp3 C–H arylation of aliphatic amines and amides with aryl halides. 3. Remote photochemical sp3 C–H alkylation of aliphatic amines and amides with alkyl halides. Due to the disclosure of an alpha sp3 C–H alkylation and arylation of amide derivatives using a metallaphotoredox approach at the very beginning of this project, it was envisioned the use of a closely related approach for the development of a different but equally impacting transformation. The efforts were directed towards the exploitation of a selective and mild photo-induced cleavage of sp3 CH bonds as an entry for the activation of another strong and traditionally inert bond, namely the sp3 C-O bond present in aliphatic alcohol derivatives. In particular, two challenging transformations have been targeted and achieved: 1. Site-selective mono-activation of sp3 C-O bonds of cyclic acetals for the synthesis of alcohol derivative arylated and alkylated at remote positions. 2. Use of mono-protected 1,2-diols as synthons for the synthesis of aliphatic ketones, exploiting a spin-center shift (SCS) mechanism for the concomitant cleavage of a sp3 CO bond and the formation of a C=O double bond.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз