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(P,C) and (O,O) well-defined gold(III) complexes for the development of new gold(III) catalytic processes

Periodic Reporting for period 1 - Gold3Cat ((P,C) and (O,O) well-defined gold(III) complexes for the development of new gold(III) catalytic processes)

Reporting period: 2018-10-01 to 2020-09-30

Au(I) catalysis has progressed very rapidly over the last years. Comparatively, Au(III) catalysis is still underdeveloped due to the difficulty of accessing stable and catalytically active Au(III) complexes. Nevertheless, seldom examples of cross-coupling reactions proceeding via Au(I)/Au(III) redox catalytic cycles have been reported recently. Here, the Au(III) species are generated in situ in most cases using strong oxidants, which limits the scope and functional group compatibility.

The Gold3Cat project aimed at elaborating a library of well-defined Au(III) complexes and at developing a new facet of gold catalysis taking advantage of the rich and unique behaviour of these Au(III) complexes. The first step was the preparation of a range of stable and structurally diverse Au(III) complexes relevant to catalysis (including π-complexes), followed by the development of new and efficient Au(III)-catalyzed reactions.
Judicious ligand design has been demonstrated to promote oxidative addition of several C–X bonds to Au(I), a basic elementary step long considered inadequate to access Au(III) complexes. The access and study of new Au(III) complexes and their implication in catalytic cross-couplings has been widely studied during this fellowship.

A. Well-defined Au(III) complexes relevant to catalysis

At the beginning of this project, the hemilabile (P,N) MeDalphos ligand had been shown to trigger the oxidative addition of iodoarenes to gold. The first goal of the fellow was the thorough study of this oxidative addition process, demonstrating that gold displays a preference for electron-rich substrates (a reactivity trend opposite to that typically found with palladium) and to propose a rationale for it (Chem. Sci. 2019, 10, 7183).

The synthesis of the first Au(III) π-allyl complex and its bonding analysis was also achieved during this MSCA action, taking advantage of the stability imparted by a (P,C) chelate (ACIE, 2020, 59, 1511). Furthermore, the reactivity of these (P,C) Au(III) π-allyl complexes was studied, demonstrating that they readily react with β-diketo enolates. Mechanistic studies showed that Au(III) presents an unusual reactivity: the nucleophilic addition of enolates takes place through attack at the central carbon of the allyl group (unpublished results). However, the way of generating the Au(III) π-allyl complex is not optimal for using in catalysis and prompted us to explore the oxidative addition of allyl–X bonds to gold, and we found that it proceeds readily (unpublished results).

B. Application in catalysis

Having evidenced that the oxidative addition of C(sp2)–X bonds to Au(I) occurs readily with the (P,N)AuCl complex, we then demonstrated that the ensuing (P,N) Au(III) aryl complexes do engage in C–C and C–N catalytic cross-coupling. In particular, we applied the (P,N)AuCl complex to the catalytic modification of indoles. The (P,N)AuCl complex proved to be very efficient, general and robust for the regioselective C3 arylation of indoles (Chem. Sci. 2019, 10, 7183).

In addition, we reported that the (P,N)AuCl complex is fruitful to promote C–N catalytic cross-coupling. In particular, we described the efficient catalytic arylation of amines (Chem. Comm. 2020, 56, 94).

Besides arylations, we recently discovered Au(I)/Au(III) catalytic allylation reactions involving Au(III) π-allyl complexes (unpublished results).

An appealing feature of all these gold-catalyzed reactions lies in the mild conditions in which they operate, without any external oxidant. Furthermore, the transformations tolerate a broad variety of functional groups in the different coupling partners.

Dissemination of the results: Until now, the project has resulted in the publication of 3 papers in the best chemistry journals and the presentation of 1 oral communication at an international conference. We expect that at least 3 additional top level papers will come out.
Our thorough study of the oxidative addition of p-substituted iodoarenes to (P,N)AuCl has shown that, whatever the ligand, (P,P), (N,N) or (P,N), oxidative addition proceeds faster with electron–donating substituents, a reactivity trend opposite to that typically found with palladium. We have also demonstrated that gold is fruitful for the oxidative addition of allyl–X bonds, affording Au(III) π-allyl complexes, whose access by oxidative addition had not been described before. The only two Au(III) π-allyl complexes described to date have been prepared by Mg to Au(III) transmetallation. One of them was prepared during this fellowship using a (P,C) ligand. All these new Au(III) complexes were readily prepared and isolated and their structure was analyzed combining spectroscopic and crystallographic studies with detailed DFT calculations.

Furthermore, we have shown that the ensuing Au(III) complexes efficiently engage in C–C and C–N catalytic cross-coupling. Regarding C–C bond formation, we have obtained complete C3-regioselectivity in the arylation of indoles under very mild conditions. Thus, gold is very complementary to other transition metals, in particular palladium, which usually promote C2-arylation. The catalytic reactions tolerate a variety of functional groups at both the indole, N-nucleophile and electrophilic coupling partners. Moreover, we recently found the involvement of Au(III) π-allyl complexes in gold-catalyzed allylation reactions.

The stoichiometric reactivity of the (P,C) Au(III) π-allyl complexes with β-diketo enolates was also studied, showing that Au(III) presents a very specific reactivity with a reversible nucleophilic addition taking place through attack at the central carbon of the allyl group.

Impact for the fellow

The training on the design and handling of highly reactive organometallic species (synthesis, characterization by multi-nuclear NMR, X-ray diffraction), the study of their catalytic properties and the theoretical bonding/mechanistic analysis have widened the knowledge of the fellow in transition metal complexes and its application in catalysis. During this fellowship and combined with her previous high-level expertise in chemical biology, the fellow has gained an excellent background in diverse areas of chemistry (inorganic, organic, biological, organometallic and catalysis), broading her posibilities to develop widely diverse research projects and initiate her independent career.

Furthermore, the fellow has been involved in the tutoring of students and in the preparation of all manuscripts that arised from the project, together with the financial management of the fellowship, acquiring leadership and project management skills.

Impact in the scientific community and society

Direct beneficiaries of the results arised from this project are researchers in the fields of catalysis (Hashmi, Toste, Patil), organometallic chemistry (Nevado, Tilset) and biological chemistry (Spokoyny, Casini) across the globe. For example, (P,N) Au(III) complexes have already been applied for the modification of proteins (Spokoyny, JACS, 2018, 140, 7065) or for the construction of hybrid nanoclusters (Spokoyny, JACS, 2020, 142, 327). Besides the fundamental knowledge arising from the development of well-defined and stable Au(III) complexes, the efficient preparation of highly functionalized compounds by new catalytic reactions is definitely of high interest for a broad public audience and for pharmaceutical purposes.