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

Abstract

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 Bocprotected α-amino acids with ethyl chloroformate. The synthesized diazoketones are crystalline substances 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 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 α-bromoketones without additional purification.

Nature-Inspired Tetrahydropentalene Building Blocks: Scalable Synthesis for Medicinal Chemistry Needs

“…Methyl ketone 9 was synthesized through the series of transformations included a catalytic hydrogenation step utilizing palladium on activated charcoal under ambient conditions and the subsequent acid-mediated deprotection with a combined near-quantitative yield. Taking advantage of our previously developed in-flow diazomethane generation method [11], the transformation of compound 7 was carried out with diazomethane in the presence of palladium(II) acetate to obtain spiro-cyclopropane derivative 10 with a yield of 95 %. It highlights this modern approach to the cyclopropanation of olefines and exhibits simplified and safer method for the synthesis of 10 compared to the previously described one [12].…”

Synthesis of Pyrazolesulfoximines Using α-Diazosulfoximines with Alkynes

“…On the other hand, sulfoximine containing diazo compounds are unknown. Furthermore, these present an unusual example of α-chiral diazo compounds, of which there are few examples . Notably, acyclic α-sulfoxide diazo compounds are intrinsically unstable, though cyclic derivatives have been isolated .…”

“…Furthermore, these present an unusual example of α-chiral diazo compounds, of which there are few examples. 17 Notably, acyclic α-sulfoxide diazo compounds are intrinsically unstable, though cyclic derivatives have been isolated. 18 Here we report the first synthesis of sulfoximine diazo compounds including an enantioenriched derivative.…”