DES-B-CAT · A Complementary Approach to Aromatic Synthesis by Diels-Alder Reactivity Followed by Desaturative Photoredox, Cobalt and HAT Triple Catalysis.

A Complementary Approach to Aromatic Synthesis by Diels-Alder Reactivity Followed by Desaturative Photoredox, Cobalt and HAT Triple Catalysis.

The main objective of this Marie Curie Fellowship was the development of new chemical reactions for the use of desaturative catalysis and boryl for the synthesis of aromatics with unusual substitution patterns that cannot be explored otherwise employing typical methods for aromatic functionalization. Particulalry, the overarching aim of the project was to demonstrate that photochemically-generated boryl radicals and Co-catalysis could be used as blueprint to by-pass the known issues of aromatic reactivity (SEAr) to access otherwise challenging substitution patterns of polysubstituted aromatics, with especial emphasis for streamlining the functionalization of drug-like molecules and agrochemicals. As a result of the project we have discovered new processes for aromatic functionalization employing conceptually novel approaches. This has enabled us to the use cobaloxime and photoredox catalysis towards the synthesis of aminated heterocycles via a desaturative approach. We eventually found out that the use of nucleophilic amines in presence of heteroatom-containing piperidones, pyrrolidines, tetrahydrofuranes, and tetrahydrothiophenes could be used to access C3 & C4 aminated heterocycles, which are otherwise difficult to make, via a Co-promoted desaturation approach under visible light. This provided a new solution to long-standing challenges in aromatic and cross-coupling chemistry. Detailed mechanistic studies enabled us to have strong evidence on the dual role of the cobaloxime catalyst both as HAT and SET to complete the desaturation step. Furthermore, during scope exploration, we demonstrated the compatibility of this chemistry with many building blocks of high relevance to both the pharmaceutical and agrochemical sectors. Subsequently, based on the knowledge that we acquired on amine-borane chemistry, we became interested in the possibility of using light for dearomatization of naphthalenes In this work, we reported the first umpolung approach of the Birch reaction. Mechanistically, the reaction is based on the increased basicity of excited arenes, promoting the break of aromaticity by protonation to form a transient carbocation, which is further trapped with a mild hydride donor (amine-borane). This is in sharp contrast to Birch-like reactivity, where a first SET is needed, enabling an exceptional functional group compatibility with no precedents in the literature. Additionally, we explored the reaction mechanism by making use of transient absorption spectroscopy (TAS), being able to detect the intermediate carbocation species, and testing the mechanistic proposal by DFT calculations. We have harnessed our knowledge on photoprotonation of aromatics for the development of a new method for the hydrogen isotope exchange (HIE) of aromatic C(sp2)ꟷH bonds using HFIP-d1 as the deuterium donor for the deuteration of pharmaceuticals with unusual site-selectivity that is orthogonal to thermal methods. Finally, we have also exploit the use of amine boranes for alkynylation reactions by using two different approaches. The first one pertains to the photogeneration of nucleophilic boryl radicals employing the cost-effective and highly stable Me3NꟷBH3 adduct. The key of the method consists of using photoexcited ketones (triplet diaryl ketones) to be used as HAT reagents, leading to a boryl radical that is highly reactive as halogen atom transfer (XAT) reagent in presence of alkyl iodides and bromides. The resulting C-centered radicals could be then trapped with SOMOphilic alkynylsulfones, making possible the metal-free Sonogashira-like reaction. The second approach is based on the use of a new boryl radical precursor described by the Leonori group (Me3NꟷBH2CO2H) to promote the formation of alkynyl-boranes by the addition of the nucleophilic boryl radical to the SOMOphilic alkynylsulfone.

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