Institute of Pharmaceutical Chemistry, University of Szeged, Eötvös u. 6, H-6720 Szeged, Hungary.
Department of Organic Chemistry, Eötvös Loránd University, P.O. Box 32, H-1518 Budapest, Hungary.
Int J Mol Sci. 2022 Oct 15;23(20):12329. doi: 10.3390/ijms232012329.
6-Hydroxyquinoline and 3-hydroxyisoquinoline as -containing naphthol analogues were tested in modified Mannich reactions (Mr's). In the case of 6-hydroxyquinoline, the outcomes of the attempted Mannich reactions were strongly influenced by the amine components. Aminoalkylation of this substrate with reagents 1-naphthaldehyde and -benzylmethylamine led to the isolation of a diol regarded as a stabilised water adduct of an -quinone methide (-QM), of which formation can be ascribed to the presence of a hydroxide ion in a relatively higher concentration generated by the bulky and basic amine component with decreased nucleophilicity. The classical Mannich base was isolated as a single product when the amine component was replaced for morpholine, featuring nucleophilicity rather than basic character under the applied reaction conditions. Starting from the isomer substrate 3-hydroxyisoquinoline, independently on the nucleophile (methanol or morpholine) besides the formation of the classical Mannich base, the nucleophilic attack at position one of the heterocyclic substrate was also observed. The DFT analysis of the acceptor molecular orbitals of the potential electrophilic components and the thermodynamics of the assumed-possible transformations demonstrated that this regioselective addition is a feasible process on the investigated heterocyclic skeleton. DFT modelling studies also suggest that besides the steric bulk, the orbital-controlled electronic properties of the aryl group, originating from the aldehyde components, have a strong influence on the ratios and the NMR-monitored interconversions of the C-1-substituted 3-hydroxyisoquinolines and the classical Mannich bases formed in multistep reaction sequences. On the basis of the DFT analysis of the thermodynamics of alternative pathways, a reaction mechanism was proposed for the rationalization of these characteristic substrate-controlled interconversions.
6-羟基喹啉和 3-羟基异喹啉作为含萘酚类似物在改良的曼尼希反应（Mr's）中进行了测试。在 6-羟基喹啉的情况下，尝试的曼尼希反应的结果受到胺成分的强烈影响。用试剂 1-萘醛和 -苄基甲胺对该底物进行氨基烷基化，导致分离出二醇，被认为是 -醌甲叉（-QM）的稳定水加合物，其形成可以归因于在相对较高浓度下存在的氢氧离子通过体积大和碱性的胺成分生成，该胺成分的亲核性降低。当胺成分被吗啉取代时，经典的曼尼希碱作为单一产物被分离出来，在应用的反应条件下具有亲核性而不是碱性。从异构体底物 3-羟基异喹啉开始，除了形成经典的曼尼希碱之外，亲核试剂（甲醇或吗啉）在杂环底物的一个位置的亲核攻击也被观察到。对潜在亲电成分的受体分子轨道的 DFT 分析以及假设可能转化的热力学表明，这种区域选择性加成是在所研究的杂环骨架上可行的过程。DFT 建模研究还表明，除了空间位阻外，来自醛成分的芳基的轨道控制电子性质对 C-1 取代的 3-羟基异喹啉的比例和 NMR 监测的互变异构以及多步反应序列中形成的经典曼尼希碱的互变异构具有强烈影响。基于对替代途径热力学的 DFT 分析，提出了一个反应机制，用于合理化这些特征的底物控制的互变异构。
