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 6 -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 1/2 at room temperature was of the order of hours. Chemical shift differences (Δν Me ) between diastereotopic methyls of 8-methyl-5-substituted enantiomeric pseudoacids were observed in the order F < CH 3 < 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 1/2 = 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.

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芳基吡喃假酸外消旋化：速率估计和结构影响

摘要 芳基吡喃假酸在相当于外消旋化的过程中对氧代羧酸显示出缓慢的开环和对内酯（假酸）的快速闭环。所研究的化合物在“Cooper's Pseudoacid”[3-羟基-4,4-二甲基异苯并吡喃-1-one, 1 ] 上形成图案，通过空间压缩对其进行修饰以影响外消旋化速率。d 6 -DMSO 中的假酸 1 对外消旋化的屏障 (ΔH ‡ ) 为 +77.8(3) kJ/mol，通过在 25 °C 至 100 °C 下测得的动态核磁共振谱线展宽及其非对映宝石的聚结确定-二甲基信号在 78.5 °C。1 在室温下的溶液半衰期是几秒钟。各种芳基 5-取代基的引入导致 5-氟-8-甲基衍生物类似的外消旋化障碍，5-甲基-8-甲基、5-氯-8-甲基和5-溴-7-甲基衍生物的壁垒越来越高。在 3-羟基-4,4,5,8-四甲基异苯并吡喃-1-one 中，屏障为 + 104(6) kJ/mol，室温下的溶液对映异构体 t 1/2 为数小时。观察到 8-甲基-5-取代的对映体假酸的非对映异构甲基之间的化学位移差异 (Δν Me ) 的顺序为 F < CH 3 < Cl，并且通常随着温度的升高而降低。在相邻芳基 5-取代基的存在下，gem-二甲基基团的拟轴和拟赤道排列显示出较小的扭转差异。3-羟基-4,4,8-三甲基异苯并吡喃-1-酮和5-溴-3-羟基-4,4,7-三甲基异苯并吡喃-的5-氟、5-氯和5-甲基衍生物的晶体结构1-1报道，以及几种相关的二级环内假酰胺衍生物。电子能量计算 (B3LYP/6-31 + (G(d,p) 理论水平) 通常支持空间压缩模型。非对映体假酸 3-羟基-4-乙基-4-甲基异苯并吡喃-1-one 和 3- 之间的平衡羟基-4,5,8-三甲基-4-苯基异苯并吡喃-1-one 反应迅速，随着温度升高，反式异构体逐渐减少，顺式异构体稳定性下降 + 4.8(2) kJ/mol 和 + 7.0(4) kJ/ mol，分别为 3-hydroxy-4,5,8-trimethyl-4-phenylisobenzopyran-1-one 在 25 °C 下可测量的顺式 → 反式转化的一级速率为 0.00403/min，t 1 /2 = 2.87 h. 尝试生产 5-异丙基，5-叔丁基和4-苯基-5-甲基假酸衍生物因芳基取代基重排而受阻，环闭合为中间体茚满酮。重排的 3-hydroxy-4-methyl-4-(2'-chloro-5'-methylphenyl)isobenzopyran-1-one (pseudoacid) 和 N-benzyl-6-isopropyl-4,4,8-trimethylisobenzopyrimidin-1 的结构-一（假酰胺）被报道。图形摘要 芳基吡喃假酸在溶液中经历缓慢开环和快速闭环，相当于外消旋化，其速率可以通过 5-取代基和相邻的 gem-二甲基基团之间的空间压缩而显着减慢。