Atropisomerism in Amidinoquinoxaline <i>N-</i>Oxides: Effect of the Ring Size and Substituents on the
Enantiomerization
Barriers
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Abstract
The atropisomerism of novel 2,3-dihydro-1<i>H</i>-pyrimido[1,2-<i>a</i>]quinoxaline 6-oxides <b>1</b> bearing dissymmetric
(<i>ortho</i>-substituted) 5-aryl residues and the homologous
1,2-dihydroimidazo[1,2-<i>a</i>]quinoxaline 5-oxides <b>2</b> was investigated. The existence of a chiral axis was demonstrated
for compound <b>1a</b> by X-ray diffraction and by DFT calculations
of the ground state geometry. The resolution of the atropisomeric
enantiomers on chiral stationary phases is reported. The barriers
to enantiomerization were determined by off-line racemization studies
and/or by treatment of the plateau-shaped chromatograms during chromatography
on chiral support. A clear ring size effect was evidenced. In all
cases, six-membered amidine derivatives <b>1</b> showed higher
barriers than the corresponding lower homologues <b>2</b>, which
also display lower sensitivity to the substituent size. Transition
states for the interconversion of the atropisomers were located using
DFT calculations, and involved the interaction of the <i>ortho</i> substituent with the formally sp<sup>2</sup> nitrogen in the amidine
moiety. In contrast, in the most favored enantiomerization transition
state of the 2-nitro derivative the <i>ortho</i> substituent
is close to the <i>N</i>-oxide group