Study of gold-catalyzed hydroarylations in unconventional media

The following manuscript collect the scientific effort of the last three years of research that the author spent in the laboratory of Prof. Andrea Biffis. The general topic is related to cationic Au-catalysis and, in particular, how cationic gold complexes can be involved in the electrophilic activation of unsaturated substrate to fabricate new C-C bonds. After an introductory chapter on the general aspects of gold-chemistry and an overview on alkyne hydrofunctionalization reactions (Chapter 1), we report a new methodology for the direct synthesis of coumarins by hydroarylation of the analogous aryl-alkynoates (Chapter 2.1). The element of novelty is about the use of ionic liquids (ILs) as reaction media, which led to enhanced catalytic activity and a significant reduction in the amount of gold complex required (0.01-0.5mol%). In the following section (Chapter 2.2), the same reaction was tackled by an intermolecular approach, hence starting from alkynoate derivatives and phenols as coupling reagents. Building on the previous MSc theses of Dr. Sara Bonfante and Pietro Bax in our group, we carried out a systematic investigation to identify suitable conditions to favor the desired transformation over competing side reactions, with selectivity emerging as the main challenge. Ultimately, we developed an efficient protocol to obtain coumarin derivatives from both simple propiolates and more elaborate alkynoates, while also demonstrating the recyclability of the system. Nonetheless, certain limitations remain: deactivated aromatic rings and monosubstituted phenols often display poor reactivity or lead to competing pathways, reducing overall efficiency. Motivated by these observations, we were interested in evaluating the effect of more polarizing Au(III)-complexes for the activation of electron-poor rings (Chapter 3). The project was developed in collaboration to the group of Dr. Didier Bourissou, which in 2018 reported well-defined cyclometalated gold(III) complexes bearing a phosphino-naphthyl backbone capable of promoting hydroarylation of alkynes with activated arenes. The complexes were recorded to be unactive contextually to the direct activation of aryl-propiolates with activated phenols. Nevertheless, we conducted complementary studies to understand the behavior of (P,C)Au2+ complexes in ionic liquids, addressing in detail the role of the counter-anion and of the acidic additive to enhance the reactivity and/or specific selectivity Although these complexes were inactive for the direct activation of aryl propiolates with activated phenols, we performed complementary studies to probe the behavior of (P,C)Au(III) complexes in ionic liquids, paying particular attention to the influence of the counterion and acidic additives on reactivity and selectivity. Stoichiometric test put under evidence the reasons why only the intramolecular version of the reaction is effective in yielding the desired product. Finally, Chapter 4 presents a novel Au-catalyzed methodology for the direct amidation of heteroaromatic substrates. We demonstrate that organic isocyanates can act as electrophilic partners in a hydroarylation-type process. In analogy to the corresponding alkyne reactions, we carried out a mechanistic study to confirm the outer-sphere pathway, supported by Hammett analysis of substituted aryl isocyanates and kinetic isotope effect measurements with deuterated nucleophiles. Furthermore, we isolated and characterized a family of Au(I)–(isocyanate) adducts, which displayed distinct NMR signatures upon metal coordination. The addition of N-methylpyrrole enabled the formation of a new π-complex that, in the presence of isocyanates, delivered the amidation products, confirming its role as a key resting state in the catalytic cycle.