Amines, ethers and small strained rings are ubiquitous structural motifs in biologically active compounds and consumer products. The motivation for this work was to develop operationally simple and efficient strategies for the formation C–N, C–O, and C–C bonds in structurally diverse molecules. Chapter 1 describes the development of two novel methods for the synthesis of primary aromatic and aliphatic amines via the electrophilic amination of the corresponding organometallic reagents. The key advance in these transformations is the application of sterically hindered NH-oxaziridines as chemoselective aminating reagents. The first method involves the transmetalation of aryl Grignard, organolithium, or organozinc reagents to the corresponding organocopper species and subsequent reaction with a di-tert-butyl NH-oxaziridine. The use of less basic organocopper reagents expands the substrate scope to incorporate electron-deficient and heterocyclic aryl rings as well as sensitive electrophilic functional groups in the desired primary amine products. The second method is an extension of the oxaziridine N-transfer chemistry that includes aliphatic organometallic reagents. The developed route is applied to sterically and electronically diverse primary, secondary, and tertiary alkyl Grignard and organozinc reagents to form the corresponding primary amines in good yields. Chapter 2 outlines the work conducted for the copper-catalyzed synthesis of sterically hindered ethers from -bromo carbonyl compounds. Coupling of an -bromocarboxamide or an -bromocarboxylic acid is successful with a wide variety of phenols in addition to primary, secondary, or tertiary alcohols under mild conditions. To showcase potential applications of the ether-forming method in medicinal chemistry, a mild route that improves upon literature precedent is designed and applied to the synthesis of a novel PAR-1 antagonist analogue. Chapter 3 describes advances made in the synthesis of spirocyclic NH-azetidine rings through a Ti(IV)-mediated Kulinkovich-type coupling of oxime ethers with primary alkyl Grignard reagents or terminal olefins. A significant development in this project is related to the purification and handling of the sensitive and basic NH-azetidine compounds. Oxime ether coupling with structurally and electronically diverse primary Grignard reagents evaluates the scope of NH-azetidine products while coupling with terminal olefins validates the proposed Kulinkovich-type reaction mechanism.
Finally, Chapter 4 outlines another project dedicated to the synthesis of small, strained rings. A combination of three synthetic steps is used for the formation of highly substituted cyclopropane rings. First, the formation of alpha,alpha-dichlorocyclobutanone rings proceeds via a [2+2] Staudinger ketene cycloaddition from cis- or terminal olefins. Next, a complete optimization study for the generation of alpha,alpha-dichlorocyclobutanols via 1,2-addition of organocerium reagents is described. Last, a base-mediated quasi-Favorskii reaction induces a ring-contraction of the alpha,alpha-dichlorocyclobutanol ring under mild reaction conditions to the corresponding highly substituted cyclopropane product. Overall, these five methods significantly contribute to advancements in the synthesis of compounds containing amine, ether or strained ring functional groups. In addition to studying innovative reactivity patterns, a wide variety of novel compounds with structurally and electronically diverse properties are characterized.