Synthesis of Diastereomeric 2,6-bis{[3-(2-Hydroxy-5-substitutedbenzyl)octahydro-1H-benzimidazol-1-yl]methyl}-4-substituted Phenols (R = Me, OMe) by Mannich-Type Tandem Reactions

• Published in: MolBank 2024-09, Vol.2024 (3), p.M1876
• Main Authors: Quiroga, Diego, Ríos-Motta, Jaime, Rivera, Augusto
• Format: Article
• Language: English
• Subjects: cascade; Cascade chemical reactions; Catalysis; Chemical synthesis; cyclic aminal; diastereomeric Mannich bases; Dihydrofolate reductase; Ethanol; Imidazole; Kinases; Mixtures; NMR; Nuclear magnetic resonance; phenol; Phenols; poly-Mannich bases; Proteins; Reagents; Solvents; Substitutes; Temperature
• ISSN: 1422-8599; 1422-8599
• DOI: 10.3390/M1876

The synthesis and characterization of two novel diastereomeric Mannich bases was carried out from the reaction of the cyclic aminal (2R,7R,11S,16S)-1,8,10,17-tetraazapentacyclo[8.8.1.1.8,170.2,70.11,16]icosane 1 and p-cresol 2a and 4-methoxyphenol 2b in a water/dioxane mixture. The title compounds (4a–b) are interesting because bearing two 3-(2-hydroxy-5-substitutedbenzyl)octahydro-1H-benzimidazol-1-yl]methyl} substituents joined to an arenol ring. The formation of these new Mannich bases in the reaction mixture can be explained by aminomethylation of previously reported di-Mannich base 2,2′-((hexahydro-1H-benzo[d]imidazole-1,3(2H)-diyl)bis(methylene))bis(4-substituentphenol) 3a–b. NMR analysis demonstrated that compounds 4a–b were formed as diastereomeric mixtures. Subsequent experiments revealed that at longer reaction times, the percentage yield of these new products increased considerably (yield percentages up to 22–27%), suggesting a nucleophilic competition between the p-substituted phenols and Mannich bases of type 3 for aminal 1.