(656f) Nearcritical Water for the Benign Removal of N-Boc Protecting Groups

The pharmaceutical and fine chemical industries rely heavily on protecting groups in the multi-step syntheses of reactive intermediates and products. One such protecting group is t-butoxycarbonyl (Boc), which is popular for reducing the reactivity of amine functionalities. Conventional methods for removal of the N-Boc protecting group involve the use of acids, introducing costly processing steps for the neutralization of excess acid and subsequent separation and disposal of the salt byproduct. We discuss the use of nearcritical water (200-300°C) for reversible in situ acid formation and its application to the removal of N-Boc protecting groups from substituted N-Boc anilines.

Water is the safest, cheapest, and most abundant solvent in the world. Utilizing this reversible in situ acid formation has a large potential for impact in industry by consolidating processing steps, reducing the energy input, replacing volatile organic compounds and eliminating waste. And although we often hear that ?oil and water don't mix,? at elevated temperatures water dissolves both salts and organics ? toluene and water are completely miscible at 305°C! Moreover, the dissociation constant of water increases exponentially in this temperature range, yielding free hydronium and hydroxyl ions that can catalyze reactions. Best of all, as the reaction mixture is cooled, product separation takes place and the ions benignly recombine with no waste products produced. The acidic cleavage of substituted N-Boc anilines in near critical water is kinetically examined to allow for elucidation of the rate expression, leading to direct application in commercial scale processing.