Assessing the Limits of Sustainability for the Delépine Reaction

Herein,
we report our efforts to improve the sustainability of
the Delépine 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 Delépine 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.