Sulfoxides as an intramolecular sulfenylating agent for indoles and diverse applications of the sulfide-sulfoxide redox cycle in organic chemistry

This dissertation involves study of various aspects of sulfoxide chemistry. Specifically designed t-butyl and propanenitrile sulfoxides tethered to indole-2-carboxamide were used as a source of intramolecular sulfenylating agents to synthesize novel indolo[3,2-b]-1-5-benzothiazepinones which are structurally analogous to the other biologically active benzothiazepinones. This study reveals that the intramolecular cyclization of sulfoxide follows an electrophilic sulfenylation (Sulfoxide Electrophilic Sulfenylation, SES) reaction pathway. Evidence of the absence of sulfenic acid as a transient reactive intermediate in such intramolecular cyclization is also provided. In another study, sulfoxide was used as a “protecting group” of thioether to synthesize 8-membered, indole substituted, thiazocine-2-acetic acid derivative via Ring Closing Metathesis (RCM). Protection (oxidation) of inert (to RCM) sulfide to sulfoxide followed by RCM produced cyclized product in good yields. Deprotection (reduction) of sulfoxide was achieved using Lawessons Reagent (L.R.). Application of the sulfide-sulfoxide redox cycle to solve the existing difficulties in using RCM methodology to thioethers is illustrated. A new design of a “molecular brake”, based on the sulfide-sulfoxide redox cycle is described. N-Ar rotation in simple isoindolines is controlled by the oxidation state of the proximate sulfur atom. Sulfide [S(II)] shows “free” [brake OFF] N-Ar rotation whereas sulfoxide displayed hindered [brake ON] N-Ar rotation. The semi-empirical molecular orbital (PM3) calculations revealed concerted pyramidalization of amidic nitrogen with N-Ar rotation

Simple Thiazocine-2-acetic Acid Derivatives via Ring-Closing Metathesis

A new protocol for synthesis of 2-heterocylylacetic acid derivatives involving conjugate addition of allyl mercaptan to an acrylate containing a tethered olefinic site followed by RCM (ring-closing metathesis) is described. In this series, sulfanyl derivatives were unreactive, while sulfoxide and sulfone analogues provided the corresponding thiazocines in fair to excellent yields. Use of the sulfoxide oxidation state as a protecting group for sulfides inert to RCM is demonstrated also. Thus, oxidation of sulfide 9 [N-allyl-N-[2-(allylthio)-4-(1H-indol-1-yl)-4-oxobutyl] -4-methylbenze-nesulfonamide] followed by cyclization yielded the corresponding thiazocine sulfoxide 12. Deprotection (deoxygenation) of 12 was accomplished using Lawesson\u27s reagent, producing 1-[[4-[4-(methylphenyl)sulfonyll-3,4,5,8-tetrahydro-2H-1,4-thiazocin-2-yl] acetyl]-1H-indole (21) in 67% unoptimized yield

A redox-mediated molecular brake: Dynamic NMR study of 2-[2-(methylthio)phenyl]isoindolin-1-one and S-oxidized counterparts

A redox-mediated molecular brake based on the sulfide-sulfoxide redox cycle is illustrated by modulation of the rotation rate of an N-Ar shaft by varying the oxidation state of sulfur in 2-[2-(sulfur-substituted)phenyl]-isoindolin-1-ones. N-Ar rotational barriers in methylsulfinyl (2) and methylsulfonyl (3) derivatives (13.6 kcal mol -1) are ∼5 kcal mol-1 higher than sulfide 1. Rate reduction for N-Ar rotation is ∼104 s-1 (280 K) upon oxidation. Correlated N-pyramidalization/N-Ar rotation reduces the effectiveness of the brake by decreasing the energy barrier to N-Ar bond rotation

Intramolecular sulfoxide electrophilic sulfenylation in 2- and 3-indoleanilides

When N-[2-(alkylsulfinyl)phenyl]-1H-indole-2-carboxamides with varying degrees of indolic and amidic N-alkylation are heated in an inert solvent or treated with trifluoroacetic anhydride; only compounds in which the amidic nitrogen is methylated cyclize to indolo[3,2-b]-1,5-benzothiazepinones (9, 10). Successful cyclization is attributed to the ability of N-Me amides to readily adopt a conformation conducive to cyclization, which other derivatives are unable to achieve. The analogous 3-indoleanilide, N,N-dimethyl N-[2-(ethylsulfinyl)phenyl]-1H-indole-3-carboxamide (17a), undergoes SES/rearrangement to produce 10 upon heating in p-xylene. An intermediate 3H-indolinium spirocyclic species is proposed to account for this result. © 2007 Elsevier Ltd. All rights reserved

Conformational Equilibria of Ethanolamine and Its Hydrochloride in Solution

The conformational preferences of ethanolamine and its hydrochloride in solution were estimated by comparing experimental NMR vicinal proton−proton coupling constants to semiemprical coupling constants for each staggered rotamer, derived by the Haasnoot−Altona method. Strong gauche preferences are observed for both ethanolamine and its hydrochloride over a wide range of solvent polarities. Concentration was not observed to significantly affect the position of the conformer equilibria

A Domino Approach of Heck Coupling for the Synthesis of β-Trifluoromethylstyrenes

A domino approach of Heck coupling was used to synthesize β-trifluoromethylstyrene derivatives from iodoarenes and 1-iodo-3,3,3-trifluoropropane in moderate to good yields. This method avoids the use of low-boiling, gaseous reagents such as 3,3,3-trifluoropropene, and additives and phosphines in the catalytic system