Mitsunobu cyclodehydration of N-pivaloyl-2-aminophenethyl alcohol for asymmetric synthesis of trans-2,3-disubstituted indolines

(+)‐Sparteine‐Mediated Substitution of o‐Benzyl‐N‐pivaloylaniline with Ketones

“…Recently, we reported that 2‐(2‐aminophenyl)ethanol could serve as the substrate in the asymmetric synthesis of trans ‐2,3‐disubstituted indolines through an intramolecular nucleophilic substitution reaction 2c,2d. An extension of this approach to the asymmetric synthesis of 2,2,3‐trisubstituted indolines was examined by using 2‐(2‐aminophenyl)ethanols 3 , 5 , and 8 under acidic conditions (see Scheme ).…”

“…For example, racemic dilithioaniline 1 was thermodynamically resolved by employing (–)‐sparteine to afford highly diastereoenriched organolithium intermediate ( S )‐ 1 /(–)‐sparteine and by allowing the reaction mixture to reach thermodynamic equilibrium before the addition of an electrophile (see Figure 1). The subsequent invertive substitution with alkyl halides, α,β‐unsaturated esters, and aldehydes afforded diverse 2‐alkyl‐substituted aniline derivatives with high enantioselectivity, the products of which were further used for the asymmetric syntheses of highly functionalized benzazepine,2a tetrahydroquinoline,2b and indoline2c,2d derivatives. To expand the scope and utility of this sparteine‐mediated lithiation–substitution method, we, herein, report the (+)‐sparteine‐mediated DTR of 1 to afford the ( R )‐ 1 /(+)‐sparteine intermediate and the subsequent addition of ketone electrophiles such as α‐keto esters and α,β‐unsaturated ketones to afford highly enantioenriched tertiary alcohols and conjugate addition products.…”

Chemistry of α-Oxoesters: A Powerful Tool for the Synthesis of Heterocycles

“…The overall yield for two steps is 67% (Scheme 69). 129 By treatment of lithiated N-BOC-3,4-difluoroaniline with ethyl bromopyruvate, unexpected ethyl 4,5-difluoroindole-3carboxylate 247 was obtained in 26% yield. Reaction was carried out by in situ generation of lithiated N-BOC-3,4difluoroaniline from reaction of N-BOC-3,4-difluoroaniline 246 with t-BuLi in anhydrous THF at −78 °C, then by addition of ethyl bromopyruvate and stirring at 0 °C for 2 h, which afforded intermediate 247 via alkylation of lithiated C2 with ketone group of pyruvate.…”

“…One example of 3-phenylindolines, ethyl 3-phenyl- N -pivaloylindoline-2-carboxylate 245 , was synthesized by Mitsunobu cyclodehydration reaction of ethyl 3-(2-aminophenyl)-2-hydroxy-3-phenylpropanoate 244 with PBu 3 (2.5 equiv) and DEAD (2.5 equiv) in CH 3 CN at room temperature during 6 h. 244 was prepared from reaction of o -benzyl- N -pivaloylaniline 243 with ethyl glyoxalate (2.5 equiv) mediated by (−)-sparteine (2.2 equiv) and n -BuLi (2.2 equiv) in MTBE at −78 °C for 20 min. The overall yield for two steps is 67% (Scheme ) …”