Exciting Iron Catalysis: A route towards sustainable cross-couplings Enabled by Light

Project Information

ExCEL

Grant agreement ID: 101116163

DOI

10.3030/101116163

EC signature date 13 September 2023

Start date 1 January 2024

End date 31 December 2028

Funded under

• European Research Council (ERC)

Total cost

€ 1 499 995,00

EU contribution

€ 1 499 995,00

Coordinated by

UNIVERSIDAD DE MURCIA
Spain

Periodic Reporting for period 1 - ExCEL (Exciting Iron Catalysis: A route towards sustainable cross-couplings Enabled by Light)

Reporting period: 2024-01-01 to 2026-06-30

Summary of the context and overall objectives of the project

The use of transition-metal catalysis has become an indispensable asset for organic synthesis, particularly for the assembly of C–C bonds. This synthetic tool enables the construction of desired molecular scaffolds thanks to the ability of catalysts to link together (cross-coupling) complex structural motifs, which is pivotal for the manufacture of many high-value chemicals that sustain our daily lives. The field of cross-coupling is largely dominated by catalysts based on precious metals, with palladium arguably being the most relevant metal for this task. Yet, in view of the rapid increase of the price of palladium and its progressive depletion, it is crucial to invent alternative and more sustainable systems based on Earth-abundant metals to ensure the viability in the long term of these strategic processes that provide us with materials, agrochemicals or medicines. Iron is considered the ideal candidate because it is endless, inexpensive and largely biocompatible. However, despite its early discovery, iron-catalyzed cross-couplings have been underutilized owing to their narrower scope and the need for strong organometallic reductants or harsh conditions, which hampers their applicability in complex targets and densely-functionalized substrates.

This proposal introduces a fundamentally new approach to overcome the issues that restrain the development of iron-catalyzed cross-couplings, exploiting the innate ability of iron complexes to harvest light and repurposing it to “activate” catalysis. Capitalizing on novel modes of reactivity accessed upon visible-light irradiation, this research programme offers a strategy to access key catalytically active iron species under mild conditions without the use of strong organometallic reductants, enabling unprecedented transformations with extended scope. Overall, ExCEL aims to introduce a new paradigm to upgrade the potential of iron catalysis in organic synthesis, and will pave the way for the discovery of exciting new synthetic transformations.

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

During the first period of ExCEL, we developed the use of simple oxalate salts as photo-activable, 2-electron reductants for iron catalysis. This strategy was inspired by the classic photochemistry of Fe(III) oxalates (ferrioxalate) which, despite of being known for 130 years and being routinely used in actinometry, had no precedents in synthetic applications. Light irradiation of Fe(III) oxalate catalysts provides access to ligand-to-metal charge-transfer (LMCT) excited states, which ultimately result on the generation of highly active reduced Fe species which hitherto unexplored reactivity. Initial work was focused on demonstrating: (i) the catalytic activity of ferrioxalate under light irradiation; (ii) the highly reductive character of low-valent Fe species generated under these conditions; (iii) the broad compatibility with functional groups, which set this strategy apart from previous approaches based on Grignard reagents.

Since the photocatalytic performance of ferrioxalate towards organic molecules was unprecedented, exploratory work has been carried out to provide feasibility to this strategy and identify the most promising catalytic transformations with applicability in organic synthesis. We succeeded at developing a range of transformations of synthetic interest, including:
• Dehalogenation of aryl chlorides with reduction potentials close to – 3 V vs SCE, including a scope of pharmaceuticals to showcase the broad functional group tolerance under these conditions.
• The reductive Heck-type coupling between aryl halides and inactivated alkenes, using H2O as terminal hydrogen source.
• An unprecedented strategy for the direct assembly of indanones from ortho-bromoaryl nitriles and alkenes, allowing to access this important motif from commercially available building blocks via double C–C bond formation in one step.
• Hydrocarboxylation of inactivated alkenes, using oxalate as CO2 source.
• The reductive cross-coupling of electron-deficient alkenes. This synthetic method without precedents in transition-metal catalysis allows to couple a range of enones with other alkenes in intermolecular fashion, opening up new retrosynthetic disconnections.
• Intermolecular cross-coupling between ketones and alkenes: a new approach for Csp3–Csp3 formation

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 work done during the first stage of ExCEL has resulted in the discovery and development of “ferrioxalate photocatalysis”, a new concept in transition metal catalysis with broad applications in synthetic organic chemistry. This system allows to carry out challenging transformations under mild conditions and broad functional group tolerance, while using sustainable and Earth-abundant catalysts. This new activation mode to access reduced metal species via LMCT excitation, unprecedented within the arena of transition-metal catalysis, has remained a pure photophysical aspect and has never been used for synthetic purposes. Differently from metallaphotoredox approaches, this blueprint is based on the ability of iron species to perform as standalone photocatalysts, without the need for additional photoredox catalysts or photosensitizers. The results obtained so far represent an important advance in the field of iron catalysis, as it provides access to reactivities and tolerance to functional groups which was inaccessible to previous systems. Moreover, the synthetic applications unveiled by ferrioxalate photocatalysis transcend the field of iron catalysis, because they also enable completely new synthetic transformations which are unprecedented within the arena of transition-metal catalysis. The multitasking ability of these iron enables transformations hitherto inaccessible to previous strategies based iron catalysis or LMCT reactivity, representing a privileged new system to discover unprecedented transformations for sustainable organic synthesis.