Assessing the Limits of Sustainability for the Delepine Reaction

Herein, we report our efforts to improve the sustainability of the Delepine reaction for the formation of primary amines from activated alkyl halides. A number of alternative greener, more sustainable solvents to the traditionally employed chloroform were identified, and the use of dimethyl carbonate (DMC) as a solvent was exemplified in the synthesis of a number of pharmaceutically relevant building blocks including the 40 mmol scale synthesis of N-Boc-3-pyrroline. Green chemistry metrics were calculated to identify areas of the Delepine reaction that could potentially be improved upon. Poor atom economy (A.E.) was identified as a key shortcoming of this methodology, although our efforts to improve A.E. and reduce waste were unfortunately unsuccessful. A preliminary thermal safety evaluation was conducted using differential scanning calorimetry due to stability concerns raised over the nature of the products; none of the products were considered to have shock-sensitive or explosive propagating properties. The limits of potential sustainability improvements that could be achieved are critically discussed including the inherent issues with this methodology such as the release of formaldehyde, generation of carcinogenic bis(chloromethyl)ether, and poor atom economy.