The development of radical-based remote C(sp3)-H functionalizations of redox-active alcohol derivatives, oxidative cycloaddition and rearrangement transformations under visible light photocatalysis constitute the basis of this thesis.
The first chapter describes the exploration of several strategies to effect the β- and γ-C(sp3)-H functionalization of alcohols under reductive conditions through the 1,5-hydrogen atom transfer of reactive radical intermediates. Two types of N-phthalimidoyl precursors were synthesized and used under metal and photoredox catalysis to effect a formal γ-C(sp3)-H functionalization. The fragmentation of primary N-phthalimidoyl oxalates could be smoothly realized under photoredox catalysis. However, the generated alkoxycarbonyl radicals did not allow for a distal functionalization and instead could only be trapped by direct addition to electron-poor alkenes. More potent 1-alkoxy vinyl radical intermediates proved to be too unstable and no control of the fragmentation could be achieved. Two approaches were designed to pursue the β-C(sp3)-H functionalization of redox-active alcohols. An iron-catalyzed C-H azidation of N-acyloxy imidates was discovered and optimized to enable, after simple hydrolysis, the synthesis of valuable β-azido alcohols. N-phthalimidoyl carbonates were also investigated to this end, however the exceptional hydrogen abstracting properties of these electrophilic (alkoxycarbonyl)oxyl radicals could not be tempered and only decomposition to the parent alcohol was detected.
The study of two photoredox catalyzed oxidative transformations is discussed in the second chapter. Building on the propensity of indoles to produce radical cation intermediates under photoinduced single electron oxidation, an innovative oxidative ring-expansion of 1-(indol-2-yl)cyclobutan-1-ols was developed. Under mild aerobic visible-light conditions, a series of 2,3,4,9-tetrahydro-1H-carbazol-1-ones were accessed with complete regioselectivity in the presence of a catalytic amount of mesityl acridinium salt. Gratifyingly, this reaction could be extended to benzo[b]thiophenes analogues. The synthetic potential of this transformation was demonstrated by achieving a total synthesis of (±)-uleine, using our methodology to furnish one of the key fragment. A series of experiments were performed to gain insights in the mechanism of this transformation. A complex cascade reaction was suggested, involving two successive oxidative 1,2-alkyl shifts and initiated by the formation of a radical cation. Next were started synthetic studies toward the total synthesis of (±)-decursivine, a moschamine-related indole alkaloid, with the aim of developing an intramolecular oxidative [3+2]-cycloaddition under photoredox catalysis. Several precursors were synthesized and attempted under a large variety of reaction conditions to effect the cycloaddition, unfortunately without success. At best, the dimerization of a transient phenolic radical was observed. Efforts to promote an intramolecular reaction remained unsuccessful.