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

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.