Development of Palladium and Hypervalent Iodine(III) Catalyzed Alkene Difunctionalization Reactions; Hydroamination, Carboamination, Aminofluorination & Diamination

Abstract

The investigation and development of synthetic methodologies for direct alkene difunctionalization is described. The utility of these processes is demonstrated by the synthesis of a number of functionalized nitrogen-containing heterocycles, including pyrrolidines and morpholines. As these are commonly-encountered motifs in a variety of medicinally active compounds, and useful synthetic molecules such as organocatalysts, ligands, or auxillaries, efficient and stereoselective methods for their preparation are of great interest to the synthetic community. This dissertation describes the use of palladium and hypervalent iodine-catalyzed reactions for the direct conversion of unactivated aminoalkenes into synthetically useful building blocks through the introduction of a C-N bond with simultaneous formation of either a second C-N bond, or a C-F, C-H or C-C bond, depending on the choice of reaction conditions. In Chapter 1, a palladium-catalyzed hydroamination reaction is used as the key step in the stereoselective synthesis of 2,5-disubstituted and 2,3,5-trisubstituted morpholines. Lewis acid-catalyzed ring opening of carbamate-protected aziridines with allyl alcohol was observed to consistently display selectivity for substitution at the more hindered position. Subsequent hydroamination of the resulting aminoalkenes gives 2,5-disubstituted and 2,3,5-trisubstituted morpholine products in high yields with excellent diastereoselectivities. The reaction was also amended to a one-pot sequence with comparable scope and efficiency to the two-step sequence. Chapter 2 outlines studies with palladium catalysts and a number of alkyl-, silyl- and aryl-substituted hypervalent iodine(III) reagents, which led to the successful development of an intramolecular aminoalkynylation reaction operating under a Pd(II)/(IV) catalytic cycle. Investigation of a number of reaction parameters revealed strong preferences for both linear alkynyl(aryl)iodine reagents with silyl substitution at the acetylenic carbon, in conjunction with use of diamine ligands bearing relatively wide bite angles, such as 4,5-diazafluoren-1-one. Finally, the intramolecular aminofluorination and diamination of para-toluoyl protected aminoalkenes is achieved using catalytic quantities of chiral and achiral iodine sources. N-fluoropyridinium salts were discovered to be effective promoters of the re-oxidation of iodine(I) to iodine(III) in situ. Both 3-amino- and 3-fluoro-piperidine products are accessed with moderate to excellent yields. Notably, only the endo-cyclized product was observed in reaction mixtures.