Hypervalent iodine as directing tool in iodine-retentive transformation of c-h bonds
- Autores: Yichen Wu
- Directores de la Tesis: Alexandr Shafir (dir. tes.)
- Lectura: En la Universitat Rovira i Virgili ( España ) en 2017
- Idioma: español
- Tribunal Calificador de la Tesis: Josep Bonjoch Sesé (presid.), Berit Olofsson (secret.), Kilian Muñiz Klein (voc.)
- Programa de doctorado: Programa de Doctorado en Ciencia y Tecnología Química por la Universidad Rovira i Virgili
- Materias:
- Enlaces
- Tesis en acceso abierto en: hdl.handle.net TDX
- Resumen
The chemistry of organic hypervalent iodine compounds has been a potent and versatile toolbox in organic synthesis. A variety of organic λ3-iodanes have been utilized as terminal 2-electron oxidants as well as oxidative functionalization partners in a wide range of processes. In virtually all cases, both classes of reactions involve the elimination (and loss) of an iodine-containing fragment. A less explored, but synthetically attractive possibility consists in incorporating both the organic group and the iodine atom into the final product. This approach presents additional synthetic opportunities by opening the door for downstream derivatization by transforming the C-I unit. In 2014, our group reported a direct metal-free α-arylation employing phenyliodine bis(trifluoroacetate) as as aryl transfer agent to construct α-aryl ketone cores with iodine retained ortho to the new C-C bond. The outcome was rationalized by invoking an intermediate iodonium O-enolate, which would undergo a [3,3] rearrangement to the final α-(2-iodophenyl)ketone.
Based on the group’s precedents, in chapter 2 we develop a method for direct metal-free oxidative coupling between commercially available iodoarenes and two families of activated ketones: 2-cyanoketones and cyclic β-diketones. The new approach eliminates the need for isolation and storage of the reactive trifluoroacetate-based λ3-iodane, thus amplifying the scope of the iodoarene coupling partners. Taking advantage of an efficient and rapid (reaction calorimetry profile) in situ conversion of ArI to a hypervalent species, the coupling between iodoarene and 2-cyanocyclohexanone to give 2-(2’-iodophenyl)-2-cyanocyclohexanone proceeded smoothly using Oxone® or mCPBA as oxidant. This protocol shows good functional group compatibility for iodoarenes cores, including those with an unstable hypervalent ArI(OCOCF3)2 form. Oxone was found to not only serve as oxidant, but also to favor the coupling through a pronounced sulfate-related acceleration. DFT calculations supported the proposed coupling via a [3,3] sigmatropic rearrangement, confirming a vanishingly small activation barriers for the so-called ¨iodonio-Claisen¨ process.
Further exploring the limits of the iodane-directed oxidative C-H functionalization, Chapter 3 describes the coupling between aryliodine diacetates, ArI(OAc)2 and unsaturated organosilanes. In particular, the use of trimethyl(benzyl)silane in the presence of a Lewis acid activated (BF3·Et2O, Tf2O) allowed for an unusual para-selective benzylation to give a family of iodinated diarylmethanes. A range of function groups was tolerated including a halide, an ester and azide. In the case where the para position on the iodoarene core is blocked, the coupling can be directed to the available meta position. Although the overall mechanism is not fully clear, the general Frediel-Crafts process is less likely by the result of competiting experiments. A diaryliodonium salt, which was initially assumed as the intermediate, was synthesized, however, was later proven not involved in the process. The Chapter also describes the ortho-coupling using homo-allenyl silane and a special class of benzothiophene-based allylsilane derivatives.
The last chapter describes a conceptually different approach for oxidative “iodoarylation” of imidazoles. The procedure is based on the discovery of a new family of diaryliodonium salts produced by the NH-imidazole with ArI(OAc)2, followed by the constitution of the synthetically challenging N-aryl-5-iodoimidazoles in the presence of copper catalyst. The C(5)-iodine moiety serves as placeholder for the subsequent introduction of a variety of substituents, acting as the handle for the synthesis of valuable 1,5-substituted imidazole cores. The method tolerates a variety of aryl fragments and is also applicable to substituted imidazoles. Experimental and DFT data suggest that the 1,5-selectivity is likely the result of an intramolecular copper-catalyzed iodine-to-nitrogen migration of the aryl fragments with a Zwitterionic iodonium ylide species (NMR, X-Ray) acting as the crucial intermediate.
In conclusion, the studies during this doctoral thesis establishes the regioselective iodane-directed oxidative C-H coupling as a potent tool for the synthesis of functionalized iodoarenes and iodo-heteroarenes. We envisage that by transforming the C-I unit, the methodology presented here will allow expedient access to synthetically challenging functionalized cores.
