Atropisomerization in <i>N</i>‑aryl-2(1<i>H</i>)‑pyrimidin-(thi)ones:
A Ring-Opening/Rotation/Ring-Closure
Process in Place of a Classical Rotation around the Pivot Bond
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Abstract
Uncatalyzed racemization processes
in atropisomeric diphenyl-like
frameworks are classically described as the result of the rotation
around the pivotal single bond linking two planar frameworks. Severe
constraints leading to more or less distorted transition states account
for the experimental barrier to atropenantiomerization. In 1988, one
of us hypothesized that, in <i>N</i>-aryl-2(1<i>H</i>)-pyrimidin-(thi)ones, a ring-opening/ring-closure process was contributing
to the observed racemization process accounting for the lower barriers
in the sulfur analogues than in oxygen analogues. Now, a series of
six novel 6-amino-5-cyano-1,4-disubstituted-2(1<i>H</i>)-pyrimidinones <b>5a</b>–<b>5f</b> and two 6-amino-5-cyano-4-<i>p</i>-tolyl-1-substituted-2(1<i>H</i>)-pyrimidinethiones <b>6a</b> and <b>6b</b> were synthesized and characterized
through spectroscopic and X-ray diffraction studies. Semipreparative
HPLC chiral separation was achieved, and enantiomerization barriers
were obtained by thermal racemization. The rotational barriers of
6-amino-5-cyano-1-<i>o</i>-tolyl-4-<i>p</i>-tolyl-2(1<i>H</i>)-pyrimidinone (<b>5b</b>) and 6-amino-5-cyano-1-(naphthalen-1-yl)-4-<i>p</i>-tolyl-2(1<i>H</i>)-pyrimidinone (<b>5e</b>) were found to be 120.4 and 125.1 kJ·mol<sup>–1</sup> (<i>n</i>-BuOH, 117 °C), respectively, and those
of the corresponding thiones were 116.8 and 109.6 kJ·mol<sup>–1</sup> (EtOH, 78 °C), respectively. DFT calculations
of the rotational barriers clearly ruled out the classical rotation
around the pivotal bond with distorted transition states in the case
of the sulfur derivatives. Instead, the ranking of the experimental
barriers (sulfur versus oxygen, and <i>o</i>-tolyl versus
1-naphthyl in both series) was nicely reproduced by calculations when
the rotation occurred via a ring-opened form in <i>N</i>-aryl-2(1<i>H</i>)-pyrimidinethiones