Rhodium(II)-catalyzed Ring-opening of Cyclopropenes for Dearomative Cyclopropanations, and Synthesis of Pro-Nematicides with Imidazothiazole Core

The use of transition metals for the dearomative functionalization of planar aromatic systems has been applied in the synthesis of complex 3D structures that find application throughout the pharmaceutical and agrochemical industry. Several reports from the Lautens group have demonstrated this concept, with a focus on the palladium- and nickel-catalyzed dearomative difunctionalization of indoles.Chapter 1 describes the rhodium(II)-catalyzed dearomative cyclopropanation of benzofurans, indoles and styrene derivatives from the ring-opening of cyclopropenes. Using cyclopropenes as the carbene precursor leads to the formation of a donor vinyl carbene, which can be difficult to synthesize by other methods. This approach offers a complementary one to the classic methods of cyclopropane synthesis, that are typically not amenable to the synthesis of vinyl cyclopropanes. The method described requires mild conditions, and the catalyst loading was further lowered on scale-up without any effect on yield or stereoselectivity. In Chapter 2, the ring-opening of cyclopropenes for the dearomative cyclopropanation of naphthols using rhodium(II) and acid catalysis is described. In contrast to the reactivity of naphthols previously reported, this methodology allows for functionalization at the 3- and 4-positions of naphthols instead of the 1-position. The various sites of reactivity in the vinyl cyclopropane products could be uniquely exploited with several transformations, forming new carbon-carbon or carbon-heteroatom bonds. Substrate modification can allow for the formation of the [4+1]-cycloaddition product between the in-situ generated rhodium carbene and ortho-quinone methide intermediates. Experimental evidence for the proposed mechanism is described. Chapter 3 describes the synthesis of imidazothiazole compounds for control of plant parasitic nematodes, an ongoing collaboration with the Roy group at the University of Toronto. The synthesis of a putative bioactive metabolite and various derivatives was conducted, and the compounds were tested against the free-living nematode Caenorhabditis elegans by the Roy group. Many analogues in the unsaturated imidazothiazole series were synthesized and tested against the plant parasitic nematode Meloidogyne incognita by the Roy group, with some derivatives showing excellent activity and selectivity towards the target organism. The lead and parent compounds in the series were synthesized on larger scale for rat oral toxicity assays.

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