Part 1. Skeletal editing of N-heterocycles: single N-atom insertion and N2-to-S swap Part 2. P(III)-mediated transformations of 1,2- dicarbonyl compounds: relayed heteroatom group transfer and geminal fluorocyclization

Abstract

Part 1. Skeletal editing of N-heterocycles: single N-atom insertion and N2-to-S swap Skeletal editing has recently emerged rapidly as a new stream of synthetic chemistry. In particular, the late-stage diversification of biologically active N-heterocycles, such as indole, has been at the center of vibrant research. Encouraged by these trends, we discovered a new single nitrogen atom insertion strategy through NO- translocation and deoxygenative rearrangement to afford regiochemically orthogonal 1,4-diazines. In contrast to well-developed single atom modification of indoles utilizing activated C2–C3 bond with nitrene reagents, our single nitrogen atom insertion breaks the nearly inert C3–C4 bond and provides quinoxalines, underexplored pharmacophores, that are inaccessible through previous works. This remarkable reactivity could be applied to various bio-relevant indoles and isotope labelling chemistry. The combined experimental and computational studies revealed the unprecedented mechanism for this unique selectivity pattern. As another skeletal editing strategy, we developed an N2-to-S swap transformation of phthalazine derivatives. By expanding our group’s diastereoselective cis-thiirane synthesis to cyclic analogues, the sequential N-oxidation and sulfuration of 1,4-diarylphthalazines affords benzo[c]thiophenes, realizing a previously unseen N2-to-S swap. Subsequently, our unique process was applied to other 1,2-diazines, but these efforts were unfruitful. In addition, the alteration of the incorporating atom was attempted by utilizing oxophilic ylides analogous to the successful sulfurating reagents. Unfortunately, although some desired reactivity was observed in the cases of iminoiodinane, the instability of the product made it difficult to render into a useful synthetic method. Part 2. P(III)-mediated transformations of 1,2-dicarbonyl compounds: relayed heteroatom group transfer and geminal fluorocyclization Dioxaphospholenes, also known as the Kukhtin-Ramirez adducts, from the reaction of 1,2-dicarbonyl compounds and trivalent phosphorus reagents have received significant attention over the recent decade due to their unique carbene-like reactivities. While continuing our interest in this chemistry, an unexpected structural reorganization was discovered. In this dissertation, a newly discovered relayed heteroatom group transfer process between bisthioesters and triaminophosphines is described. Through the oxygen/nitrogen exchange between the two simple starting materials in addition to the 1,2-sulfur migration of a putative carbene intermediate, an organized relocation of the O/S/N groups proceeded to give a variety of α,α-disulfenylamides with excellent efficiency under ambient conditions. The experimental and computational mechanistic studies revealed the sequence of the relayed group shifts via an α,α-disulfenyl phosphonium enolate intermediate as well as the dual role of triaminophosphine as both an oxygen acceptor and a nitrogen donor. As an expansion of our research utilizing dioxaphospholenes, geminal fluorocyclization of 1,2-diketones with an internal nucleophile was developed. Among various 1,2-diketones, aryl-aryl 1,2-diketones with o-methoxy groups were found as proper substrates. Some efforts to increase the reaction efficiency with an external nucleophile were unsuccessful. Nevertheless, the application of other internal nucleophiles was enabled, such as an ester group.