Atropisomerization inN-aryl-2(1H)-pyrimidin-(thi)ones: A Ring-Opening/Rotation/Ring-Closure Process in Place of a Classical Rotation around the Pivot Bond

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 N-aryl-2(1H)-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(1H)-pyrimidinones 5a−5f and two 6-amino-5-cyano-4-p-tolyl-1-substituted-2(1H)-pyrimidinethiones 6a and 6b 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 6amino-5-cyano-1-o-tolyl-4-p-tolyl-2(1H)-pyrimidinone (5b) and 6-amino-5-cyano-1-(naphthalen-1-yl)-4-p-tolyl-2(1H)-pyrimidinone (5e) were found to be 120.4 and 125.1 kJ•mol −1 (n-BuOH, 117 °C), respectively, and those of the corresponding thiones were 116.8 and 109.6 kJ•mol −1 (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 o-tolyl versus 1-naphthyl in both series) was nicely reproduced by calculations when the rotation occurred via a ring-opened form in N-aryl-2(1H)-pyrimidinethiones.

Steric Scale of Common Substituents from Rotational Barriers ofN-(o-Substituted aryl)thiazoline-2-thione Atropisomers

“…It is also a major aspect to consider in medicinal chemistry to rationalize biological or enzymatic activities and in synthesis to explain reactivity and stereochemistry or to propose mechanisms . Furthermore, careful attention must be paid to steric parameters during investigations on nanomaterials and in dynamic stereochemistry …”

“…9 Furthermore, careful attention must be paid to steric parameters during investigations on nanomaterials 10 and in dynamic stereochemistry. 11 Therefore, ranking molecular fragments according to their apparent size represents a crucial point of interest. Measurements of steric bulk such as the Taft E s values were first derived from kinetic data 12 and considerable efforts were devoted to the separation of electronic from purely steric contributions in these models.…”

Solid Phase Deracemization of an Atropisomer

“…In addition, this compound racemizes swiftly in apolar solvents at elevated temperatures ( t 1/2 = 4 min in xylene at 50 °C), whereas racemization at room temperature in polar solvents is negligible. 11 Racemization takes place relatively easily since it proceeds via a reversible ring-opening and closing-mechanism, 12 rather than via rotation around the chiral axis. Fujita and co-workers already showed that total spontaneous resolution can be achieved for this compound.…”

Double Variational Binding—(SMILES) Conformational Analysis by Docking Mechanisms for Anti-HIV Pyrimidine Ligands

“…Therefore the concerned binding breaks go through a sort of SMILES transformations with a lower energy, following the principle of favoring the longest chain in molecular configuration. This is already a sort of structural variational principle in chemical bonding [ 108 ]; By the recent QSARINS-Chem model for QSAR studies recognizing the role of SMILES canonical rules in correctly assessing the query and parsing the structure-activity algorithm (for the LoSMoC and BraS conformations, for instance) [ 109 ]. …”

“…Therefore the concerned binding breaks go through a sort of SMILES transformations with a lower energy, following the principle of favoring the longest chain in molecular configuration. This is already a sort of structural variational principle in chemical bonding [ 108 ];…”