Diverse heterocyclic chemistry: Sulfoxides as oxidants, sulfoxides as sulfenylating agents and novel N,S-heterocycles from an arene reduction

Investigation of the Sulfoxide Electrophilic Sulfenylation (SES) reaction, an ring annulation and expansion protocol, has proven of the potential as an effective tool for preparation of large-ring N,S-hetrocycles. Covered in Part I (the central research plot) is the exploratory study of the applicability of the SES reaction to syntheses of molecules of biological potential, i.e., cyclic peptides featuring large-ring N,S-hetrocycles. Thus, a variety of structures, either acyclic or cyclic featuring benzothiochromanone, benzothiazine, and benzothiazepine derivatives, respectively, were designed and synthesized as the sulfoxide substrates. These sulfoxides displayed the Pummerer vs. SES dichotomy under the reaction conditions. Depending on substrate structures, reagents and conditions, one reaction might be favored over the other, and large-ring N,S-heterocycles formed in reactions where the SES reaction prevailed. Certain substrates underwent reaction cascades, orchestrated by the SES reaction, to afford unexpected final products.; Covered in Part II is the discovery and development of a novel 2-oxindole synthesis employing dimethyl sulfoxide (DMSO)/TFAA in THF solution. This reaction serves as a synthetic alternative for N,3-dialkylindoles to reactions requiring an intensely acidic aqueous environment (e.g ., DMSO/conc. HCl). Oxidation of N-unsubstituted indoles into 2-oxindoles is slow unless some acid (TFA) is added to the reaction medium. Mechanisms are proposed for the role of DMSO both as an indole activator (via trifluoroacetoxydimethylsulfonium trifluoroacetate) and as an oxidant. The role of acid in promoting oxidation of N-unsubstituted indoles is attributed to increased C-2 nucleophilicity of an intermediate protonated iminium species (3H-indolium ion) relative to its unprotonated counterpart.; An unprecedented cyclic amidine formation was observed from a stannous chloride (SnCl2) mediated nitroarene reduction. Further investigation with other nitroarenes unveiled the unprecedented formation of the novel cyclic N,O-acetals and the thiazepine derivatives. Mechanisms are proposed featuring the intramolecular trapping of hydroxylamines intermediates. It is followed, in the formation of thiazepine derivatives, by the cyclic nitrone-oxaziridine isomerization, the rearrangement of oxaziridines, and the in situ solvolysis of the resulting bicyclic lactams. These reactions involving stannous chloride as a reducing agent or Lewis acid, or both, may be useful for preparation of novel heterocycles not readily available otherwise. These make up Part III.