Practical Synthetic Method for Amino Acid-Derived Diazoketones Shelf-Stable Reagents for Organic Synthesis

A novel approach for safe generation of diazomethane-contained organic solution was proposed using a serial flow reactor. The productivity of diazomethane generation 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 the treatment of Boc-protected alpha-amino acids with ethyl chloroformate. The synthesized diazoketones are crystalline substances stable up to 110-142 degrees 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 reagents for a broad scope of applications. The quantum chemical studies show that the stability of diazoketones is connected with conjugation of the carbonyl group with the diazo moiety. As an example of applicability, the reaction of diazoketones with concentrated HBr gives the corresponding pure chiral alpha-bromoketones without additional purification.