Atropisomerism in the 2-Arylimino-N-(2-hydroxyphenyl)thiazoline Series:  Influence of Hydrogen Bonding on the Racemization Process

Abstract

A series of original atropisomeric iminothiazolines 1 in which X ) OH or (and) Y ) OH were prepared from the corresponding methoxy precursors. The resolution of the atropisomeric enantiomers on chiral support is reported, and the barriers to enantiomerization are given. These barriers were determined either by off-line racemization studies or by treatment of the plateau-shape chromatogram during chromatography on chiral support. When X ) OH, the barriers are quite low due to the development of a hydrogen bond between the proton of the OH group and the nitrogen of the imino group. For these compounds, plateau shape chromatograms were obtained during HPLC on chiral support. DFT calculations confirmed the occurrence of hydrogen bonding all along the rotation process and produced calculated barriers in close agreement with the experimental data. Compound 1i (OH, OH) in which both X and Y are hydroxy groups was particularly easy to prepare by demethylation with BBr 3 of the dimethoxy precursor. Since the above-mentioned precursor is readily available from N,N′-bis(2-methoxyphenyl)thiourea and 1-chloropropan-2-one, 1i (OH, OH) is a good candidate for further functionalization. Atropisomerism in a 12-membered bridged bisether prepared from 1i (OH, OH) is reported as an illustrating example.

Determination of barriers to rotation of axially chiral 5‐methyl‐2‐(o‐aryl)imino‐3‐(o‐aryl)thiazolidine‐4‐ones

“…The energy barrier of compound 1 was also compared with those of 2-arylimino-N-(2-aryl)-thiazolines [15][16][17] (Fig. 5).…”

The solid-state continuum: a perspective on the interrelationships between different solid-state forms in drug substance and drug product

“…Both phenomena are very rare; in 2004, a survey of the Cambridge crystallographic data centre yielded four hits that qualified as atropisomers and ten hits that qualified as rotamers [33]. Despite the rareness of the forms, recent reviews can be found on both rotamers[34,35] and atropisomers [36–38]…”

Synthesis, chiral separation, and absolute configuration of bis‐(N‐aryl) atropisomeric triads: 1,2‐Bis‐[4‐methyl‐2‐(thi)oxo‐2,3‐dihydrothiazol‐3‐yl]‐benzene

“…Thanks to our longstanding interest in N-arylthiazolin-2-thione atropisomers, [5][6][7][8][9][10][11][12] it was clear that restricted rotation about the two N-aryl axes might lead to stable atropisomers and thus 1 would be a new example of ''atropisomeric molecular triad'' B-A-B, in which A is a 1,2-disubstituted benzene and B is a thiazoline-2-thione derivative. 13 In a study of atropisomeric molecular triad of the B-A-B type, several issues have to be addressed :…”