Building Up Molecular Complexity with Homologation Chemistry: New Rearrangements, Reaction Mechanisms and Tandem Transformations

Since their introduction in the early 1960s, carbenoids have attracted interest within the synthetic community for their unique potential to permit the insertion of a (per se reactive) CH2X fragment into a recipient carbon skeleton and trigger, by means of the intrinsic element of latent reactivity X, cascades of molecular events which enable the assembly of challenging scaffolds in a single synthetic operation. The variety of carbenoid structures reported to date, generated by accurately selecting the metal source and the precursors featuring the X group, gives access to a wide spectrum of reagents displaying radically different reactivities. Altogether, carbenoids of electrophilic and/or nucleophilic nature have given rise to unique chemical transformations. This elegant attractiveness is however restricted by their high instability, which has limited their employment in organic synthesis for years. Nevertheless, the development of more stable reagents and more finely elaborated protocols has been making feasible new functionalizations previously considered impossible. Within this doctoral thesis, we disclose the use of lithium carbenoids for assembling novel functionalized moieties. We demonstrated the versatility of the addition of a methylene fragment featuring a precise degree of functionalization to heterocumulene-type electrophiles, as a straightforward route for the preparation of α-substituted amides, amidines and sulfinamides. Carbenoids-mediated manipulation of carbonyl and carboxyl compounds enabled us to increase the molecular complexity on simple scaffolds, establishing new strategies for accessing poly-halogenated derivatives or for purely homologating the original array. Rare heterocyclic structures have been prepared via one-pot homologative processes involving new mechanisms, tautomerisms, trappings of electrophiles and rearrangements. Additionally, the constitutive capability of the silicon atom to generate hypercoordinated species, was used to realize the controlled C2-derivatization of activated aromatic N-heterocycles. This homologative transformation – depictable as a sila-variant of Matteson 1,2-shifts – furnished functionalized 2-benzyl pyridines through the generation and rearrangement of multiple penta- and hexa-valent silicon ate complexes Finally, we have summarized and explained the versatility and uses of bromochloromethane, bromofluoromethane, bromotrichloromethane, dibromodichloromethane and tribromochloromethane in organic synthesis