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Dinuclear Gold Catalysis: A New Platform for Cross-Coupling Reactions

Periodic Reporting for period 1 - TWINGOLD (Dinuclear Gold Catalysis: A New Platform for Cross-Coupling Reactions)

Reporting period: 2019-01-03 to 2021-01-02

At the early stage of this action, preliminary investigations were carried out using several dinuclear Au(I) complexes as catalysts to promote the coupling of alkyl iodides with aryl boronic acids. After a closely related paper based on the same concept was published, the project was changed to study the Rh(III)-catalyzed direct alkynylation of unactivated alkenes. At the end of this action, an unprecedented alkene C-H alkynylation was realized under mild reaction conditions and a broad range of alkene substrate scope was investigated. This protocol offers a convenient access to 1,4-enynes (skipped enynes), which are versatile synthetic intermediates with two different handles that allow further transformations.

The first goal of the project focused on the development and study dinuclear gold(I) complexes as promising catalysts for the facile functionalization of organohalides and subsequent efficient cross-coupling reactions. This gold catalysis project aimed at broadening the current applications of gold catalysis, exploring and identifying reliable dinuclear gold(I) catalysts in C-C forming reactions.
The new approach on Rh-catalyzed direct alkynylation of unactivated alkenes aims to simplify the synthesis of 1,4-enynes (skipped enynes), which are versatile synthetic intermediates with two different handles for further transformations. Previous methods to synthesize 1,4-enynes require prefunctionalized alkenes bearing leaving groups at their allylic position, such as halides, phosphonates, acetates, ethers, sulfones and carbonates. The installation of these functional groups requires additional synthetic steps and narrows the transformation scope. Therefore, from the viewpoint of atom- and step-economy, the direct C-H modification of simple alkenes would be highly desirable. As a continuous interest in Prof. Echavarren’s group for the development of efficient alkynylation reactions, this project aims at broadening the current application of Rh-catalyzed allylic C-H functionalization, using more efficient, mild and greener methods.

The investigation in this work will significantly promote the field of direct alkene functionalization by exploring novel alkynylation reaction and the related mechanistic elements behind them, making target synthetic protocols shorter, enabling the use of more diverse raw materials and, thus, ensuring a more sustainable and inclusive economy in EU. A quick access to 1,4-enynes could benefit other related fields, as these are important intermediates in the synthesis of natural products, pharma compounds and related products.
In addition, the project has enabled the Experienced Researcher to develop a full range of scientific and transferable skills following a personalized Career Development Plan to become an established researcher (R3).

This Rh-catalyzed project aims at broadening the current applications of rhodium catalysis, exploring and identifying reliable Rh-based catalyst systems in C-C forming reactions. On this purpose, the following specific objectives have been identified:
(i) Test the feasibility of Rh-catalyzed allylic C-H alkynylation of simple alkenes under various conditions as well as using different alkynyl sources, which could provide access to valuable 1,4-enynes in a more straightforward and convenient way.
(ii) Investigate and optimize suitable reaction conditions for the allylic alkynylation and test the diversity of alkenes species, which would make the transformation applicable for a broad substrate scope.
(iii) Investigate and elucidate detailed reaction mechanisms of the newly developed Rh-catalyzed process.
During this project, we have found that the direct allylic C-H alkynylation of simple alkenes could be accomplished by using rhodium catalysis. This type of transformation has not been reported yet and represents a novel development of the Cp*Rh(III)-catalyzed allylic functionalization reactions. This alkynylation protocol could operate under mild conditions (40 oC or room temperature) and is applicable to a broad range of alkene substrate scope. The observed excellent selectivity and functional group tolerance would make this protocol a reliable avenue to the synthetically important 1,4-enynes.
Allylic C-H functionalization has currently obtained an increasing attention among organic chemists as it provides numerous efficient methods for the construction of C-C bonds. Very recently, rhodium catalysis has been reported to have excellent reactivity in allylic C-H transformations, such as intermolecular amination and oxygenation of simple alkenes. Despite these advances, the direct allylic C-H alkynylation of unactivated alkenes has not been reported. In this project, we developed an efficient method for the construction of 1,4-enynes via unprecedented allylic C-H alkynylation. Compared with previously methods to access 1,4-enynes (Pd-catalyzed mainly), our protocol obviates the need for leaving groups at the allylic position, which represent a more atom-economic and sustainable process.
The project results on Rh-catalyzed allylic C-H alkynylation may open new avenues in synthetic chemistry, enhancing the recognition of the researcher and the research group at ICIQ as leading experts in the catalysis field in EU.
Further exploitation of the results could lead to cost-effective and environment-benign industrial applications, which will generate new competitive processes being developed in the EU.