Practical synthetic method for amino acids derived diazo-ketones – shelf-stable reagents for organic synthesis.

A novel approach for a safe generation of the diazomethane-contained organic solution has been proposed using a serial flow reactor. The productivity of the diazomethane generation has reached 0.45 mol/h. Several chiral diazoketones have been prepared in quantities up to 150 g through the reaction of diazomethane with mixed anhydrides, generated in situ by treatment of Boc-protected α-amino-acids with ethyl chloroformate. The synthesized diazoketones are crystalline sub-stances stable up to 110-142 °C and can easily be purified on silica gel and stored for a long term. The overall stability and availability on a large scale allow considering such diazoketones as promising bench-stable regents for the broad scope of applications. The quantum chemical studies show that the stability of diazoketones is probably connected with conjugation of the carbonyl group with diazo moiety. As an example of applicability: the reaction of diazoketones with concentrated HBr gives corresponding pure chiral α-bromoketones without additional purification was demonstrated.