Development of novel synthetic methodologies in photocatalysis

The last decade has seen an impressive number of studies in the field of photocatalysis: the mild conditions used for the generation of radical intermediates and the possibility to couple it with other catalytic manifolds are among the reasons of such popularity. In this thesis, the use of some photocatalytic strategies in organic synthesis is presented. The development of a dual Ni-photoredox strategy for the asymmetric synthesis of N-benzylic heterocycles, interesting drug-like compounds, is described in Chapter 2: a privileged ligand system was found for inducing chirality, and the effect of different heterocycles (in particular bearing directing groups) was addressed. A different perspective is taken in Chapter 3: in this case the focus is not on the transformation, but on PXX (peri-xanthenoxanthene) as a new photocatalyst. Possessing a relatively high reduction potential in the excited state, PXX is capable of promoting a variety of reactions, from the addition of aryl radicals to radical traps, to the organocatalytic β-arylation of cyclic ketones, to Ni-catalysed carbon-heteroatom cross-couplings. The focus moves to organocatalysis in Chapter 4, in particular to the use of chiral iminium ions as photoredox-active species: paired with 4-alkyldihydropyridines as radical precursors, an asymmetric β-alkylation of enals is thus demonstrated. ii Chapter 5 takes back themes encountered in the previous chapters to briefly introduce some attempted but not successful transformations: an organocatalytic β-fluorination of aldehydes, and a cross-coupling strategy towards an API intermediate

Enantioselective synthesis of N-benzylic heterocycles: a nickel and photoredox dual catalysis approach

Reported herein is a dual nickel- and photoredox-catalyzed modular approach for the preparation of enantioenriched N-benzylic heterocycles. α-Heterocyclic carboxylic acids, easily obtainable from common commercial material, are reported as suitable substrates for a decarboxylative strategy in conjunction with a chiral pyridine–oxazoline (PyOx) ligand, providing quick access to enantioenriched drug-like products. The presence of a directing group on the heterocyclic moiety is shown to be beneficial, affording improved stereoselectivity in a number of cases

peri‐xanthenoxanthene (PXX): a versatile organic photocatalyst in organic synthesis

Recent years have witnessed a continuous development of photocatalysts to satisfy the growing demand of photophysical and redox properties in photoredox catalysis, with complex structures or alternative strategies devised to access highly reducing or oxidising systems. We report herein the use of peri‐xanthenoxanthene (PXX), a simple and inexpensive dye, as an efficient photocatalyst. Its highly reducing excited state allows activation of a wide range of substrates, thus triggering useful radical reactions. Benchmark transformations such as the addition of organic radicals, generated by photoreduction of organic halides, to radical traps are initially demonstrated. More complex dual catalytic manifolds are also shown to be accessible: the β‐arylation of cyclic ketones is successful when using a secondary amine as organocatalyst, while cross‐coupling reactions of aryl halides with amines and thiols are obtained when using a Ni co‐catalyst. Application to the efficient two‐step synthesis of the expensive fluoro‐tetrahydro‐1H‐pyrido[4,3‐b]indole, a crucial synthetic intermediate for the investigational drug setipiprant, has been also demonstrated

The Murai Reaction on Furfural Derivatives

Furfural and related compounds are industrially relevant-building blocks obtained from renewable resources; growing attention arose in recent years towards their utilisation as precursors for bulk and fine chemicals, being a “green” alternative to petroleum-based compounds. Several works reported the functionalisation of furfurals to obtain a wider range of chemicals, opening to new possibilities for synthesis and applications. C-H activation-based processes are the most attracting, for their atom economy and the possibility to employ non-activated substrates. In the case of furfural derivatives, the main results are in the field of arylation reactions. In this work, the directed hydroarylation of olefins (Murai reaction) on furfural derivatives has been investigated. A method for the formal insertion of olefins, especially vinylsilanes, into the C3-H bond of furfural has been developed. Different conditions and substrates have been tested, discovering that only a bidentate directing group is capable of providing good yields of the coupling products. As an added bonus, easy removal of the directing group is achieved during the work-up. These results represent one of the few examples of alkylation of furfurals through C-H activation reactions, and the only one occurring at the C3 position of the furan ring

C−H Activation Based Functionalization of Furfural Derivatives

International audienceFurfural and related compounds are building blocks of industrial interest, obtained from raw biomass. Their use as precursors of basic and fine chemicals has gained increasing attention as a green alternative to petroleum-derived compounds. Several works have reported the functionalization of furfurals to obtain a wider range of chemicals, opening up new synthetic possibilities and applications, ranging from biofuels to pharmaceuticals. Among these works, processes based on CÀ H activation are the most attractive ones for their atom economy and the possibility to use non-activated substrates. This minireview summarizes the reported methods of direct CÀ H functionalization of furfurals without prior modification of the redox state of the aldehyde function. In particular, the transition metal catalyzed functionalization of each bond of the heteroaromatic nucleus of these molecules is systematically discussed, as well as examples of CÀ H transformations of the aldehyde function

Direct Stereoselective Installation of Alkyl Fragments at the β‑Carbon of Enals via Excited Iminium Ion Catalysis

The direct introduction of sp³ carbon fragments at the β position of α,β-unsaturated aldehydes is greatly complicated by competing 1,2-addition manifolds. Previous catalytic enantioselective conjugate addition methods, based on the use of organometallic reagents or ground-state iminium ion activation, could not provide general and efficient solutions. We report herein that, by turning them into strong oxidants, visible light excitation of chiral iminium ions triggers a stereocontrolled radical pathway that exclusively affords highly enantioenriched β-substituted aldehydes bearing a variety of alkyl fragments