Benzyl methyl morpholinium hydroxide (BMMorph)OH: a new basic ionic liquid for N-alkylation of bioactive N-heterocycles

Abstract

We report benzyl methyl morpholinium hydroxide ([BMMorph]OH) as a novel, stable basic ionic liquid that exhibits dual functionality as both an efficient reaction medium and a strong base for the N-alkylation of bioactive N-heterocycles. [BMMorph]OH was synthesized through a simple two-step process: quaternization of 4-methylmorpholine with benzyl bromide, followed by anion exchange with potassium hydroxide. Comprehensive characterization by TGA, IR, and NMR confirmed good thermal stability (up to ∼150 °C) and broad solubility in common polar solvents. Under optimized neat conditions (100 °C, 0.4 mol% [BMMorph]OH), diverse heterocycles—including purines (adenine, theophylline), pyrimidines (uracil, thymine), and azoles (imidazoles, benzimidazoles)—were efficiently alkylated with carbon electrophiles such as alkyl halides, epoxides, and Michael acceptors, affording good to excellent isolated yields. Comparative studies demonstrated that [BMMorph]OH outperformed conventional hydroxide ionic liquids (e.g., imidazolium and quaternary ammonium hydroxides). Notably, adenine alkylation showed exceptional regioselectivity, favoring the N9 isomer over N7, attributed to hydrogen-bonding interactions with the morpholinium oxygen. The ionic liquid was recyclable for at least five cycles, with only gradual activity loss due to atmospheric CO₂ absorption. Beyond its catalytic efficiency, [BMMorph]OH offers a sustainable alternative for nucleobase alkylation in carboacyclic nucleoside synthesis, reducing reliance on toxic solvents such as DMF and DMSO. These findings establish [BMMorph]OH as a promising, reusable basic ionic liquid for green C–N bond formation in heterocyclic chemistry.