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

Project Information

PHOTO-WALK

Grant agreement ID: 839980

DOI

10.3030/839980

Project closed

EC signature date 21 March 2019

Start date 3 February 2020

End date 5 May 2022

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 160 932,48

EU contribution

€ 160 932,48

Coordinated by

FUNDACIO INSTITUT CATALA D'INVESTIGACIO QUIMICA
Spain

Periodic Reporting for period 1 - PHOTO-WALK (Metal-catalyzed remote functionalization of aliphatic amines and amides triggered by photocatalytic sp3 C-H activation)

Reporting period: 2020-02-03 to 2022-02-02

Summary of the context and overall objectives of the project

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.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

PHOTO-WALK was aimed to the utilization of photo-driven processes for the mild and selective functionalization of unactivated sp3 CH bonds. The initial plan was the use of readily available aliphatic amine derivatives as substates for the activation and functionalization at a remote site, triggering carboxylation, arylation and alkylation processes by merging photocatalysis and Ni-catalyzed cross-coupling. Subsequently, based on the knowledge acquired during the study of this transformations, we realized that a similar approach could be used to trigger a more challenging and conceptually intriguing activation and manipulation of another strong sp3 bond, an aliphatic CO bond. Such high challenging, yet high rewarding strategy allowed the development of two methods targeting diols derivatives, as cheap, abundant, and synthetically important molecules.

The first project tackled the challenge of using metallaphotoredox catalysis for the activation of strong sp3 CO bonds within the structure of a cyclic acetal, allowing the mild and site-selective arylation and alkylation of 1,n-diols (n ≥ 4) derivatives. The results of this project have been collected in a scientific paper and submitted to a high-ranked journal, thus a publication will appear soon. In addition, they will be presented and shared at an international conference in June 2022 (BIENAL2022, Granada, Spain).

The second project targeted the use of mono-protected 1,2-diols as precursors for the synthesis of aliphatic ketones, exploiting a spin-center shift (SCS) mechanism, which is currently unknown for aliphatic, acyclic systems. In this case, a purely photocatalytic method, characterized by exceptionally simple reaction conditions, allows the synthesis of complex ketone structure starting from mono-protected 1,2-diols per se or, upon a cascade reaction, triggers the modular construction of the carbon skeleton in situ. This approach shows the great potential to be extended to metallaphotoredox catalysis, including a Ni-catalyzed cross-coupling step to further improve the generality and modularity of the method, disclosing an appealing tool for building up molecular complexity. The generality of this strategy and its extension to the metallaphotoredox catalysis is currently under study.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The results obtained working at the current projects and the imminent publications derived from them, represent an important advancement to contemporary synthetic chemistry, since they will provide the academic and industrial communities of new tools for the transformation of feedstocks and simple materials to more complex molecules. Besides the synthetic value of the methodologies developed, the conceptual contribution of the present work aided to unveil new strategies towards a more sustainable chemistry, which does not require pre-activation of substrates, the use of highly reactive reagents or harsh conditions. On a personal perspective, working at PHOTO-WALK, and the projects derived from it, allowed to acquire important expertise in the field of photocatalysis and to strengthen the understanding in organometallic chemistry. Both the fundamental knowledge and the practical aspects of working in these areas of cutting-edge research will be beneficial for boosting future career development, giving a more solid ground on which founding scientific proposals for starting an independent career.

General scheme of the PHOTO-WALK project