Arylpyran Pseudoacid Racemization: Rate Estimation and Structural Influences

Abstract: Arylpyran pseudoacids showed slow ring-opening to the oxocarboxylic acids, and fast ring-closure to the lactols (pseudoacids) in a process that amounts to racemization. Compounds studied were patterned on “Cooper’s Pseudoacid” [3-hydroxy-4,4-dimethylisobenzopyran-1-one, 1], to which modifications were introduced to influence racemization rates by steric compression. Pseudoacid 1 in d-DMSO had a barrier to racemization (ΔH) of +77.8(3) kJ/mol determined by dynamic nuclear magnetic resonance line-broadening measured from 25 °C to 100 °C, and coalescence of its diastereotopic gem-dimethyl signals at 78.5 °C. The solution half-life of 1 at room temperature is a few seconds. Introduction of various aryl 5-substituents lead to similar racemization barriers for the 5-fluoro-8-methyl derivative, and increasingly higher barriers for 5-methyl-8-methyl, 5-chloro-8-methyl, and 5-bromo-7-methyl derivatives. In 3-hydroxy-4,4,5,8-tetramethylisobenzopyran-1-one, the barrier was + 104(6) kJ/mol, and the solution enantiomer t at room temperature was of the order of hours. Chemical shift differences (Δν) between diastereotopic methyls of 8-methyl-5-substituted enantiomeric pseudoacids were observed in the order F < CH < Cl, and generally decrease with increasing temperatures. The pseudoaxial and pseudoequatorial dispositions of the gem-dimethyl groups show smaller torsional differences in the presence of adjacent aryl 5-substituents. The crystal structures of 5-fluoro, 5-chloro and 5-methyl derivatives of 3-hydroxy-4,4,8-trimethylisobenzopyran-1-ones and of 5-bromo-3-hydroxy-4,4,7-trimethylisobenzopyran-1-one are reported, along with several relevant secondary endocyclic pseudoamide derivatives. Electronic energy computations (B3LYP/6-31 + (G(d,p) level of theory) generally support the steric compression model. Equilibration between diastereomeric pseudoacids 3-hydroxy-4-ethyl-4-methylisobenzopyran-1-one and 3-hydroxy-4,5,8-trimethyl-4-phenylisobenzopyran-1-one were rapid with trans isomers decreasingly favored as temperature increases, and cis isomers less stable by + 4.8(2) kJ/mol and + 7.0(4) kJ/mol, respectively. The first-order rate of cis → trans conversion was measureable for 3-hydroxy-4,5,8-trimethyl-4-phenylisobenzopyran-1-one at 25 °C was found to be 0.00403/min, t = 2.87 h. Attempts to produce 5-isopropyl, 5-t-butyl and 4-phenyl-5-methyl pseudoacid derivatives were frustrated by aryl substituent rearrangement upon ring closure to the intermediate indanones. Structures of rearranged 3-hydroxy-4-methyl-4-(2′-chloro-5′-methylphenyl)isobenzopyran-1-one (pseudoacid) and N-benzyl-6-isopropyl-4,4,8-trimethylisobenzopyrimidin-1-one (pseudoamide) are reported. Graphic Abstract: Arylpyran pseudoacids undergo slow ring opening and fast ring closing in solution amounting to racemization, rates of which can be slowed considerably by steric compression between the 5-substituent and the adjacent gem-dimethyl groups.[Figure not available: see fulltext.]