Diazoacetonitrile (N₂CHCN): A Long Forgotten but Valuable Reagent for Organic Synthesis

Abstract

Diazoacetonitrile (N2CHCN) is a small reactive diazoalkane. It has been synthesized for the first time already in 1898 by Theodor Curtius, however, did not gain much recognition in organic synthesis until recently. Only in 2015, after introduction of in situ and flow protocols for the safe generation of diazoacetonitrile, it started gaining popularity. In this minireview, the synthetic properties and applications of this valuable reagent are discussed.

Exploiting Continuous Processing for Challenging Diazo Transfer and Telescoped Copper-Catalyzed Asymmetric Transformations

“…Having demonstrated efficient synthesis of α-diazoketones via the in situ generation and use of triflyl azide in flow, extension to a broader range of α-diazocarbonyl compounds was undertaken to expand the scope of this approach with a particular focus on nitrile derivatives which can be challenging to access in certain instances. Accordingly, Regitz-type diazo transfer employing our telescoped triflyl azide generation and diazo-transfer methodology proved successful when employing β-ketonitrile 37 as the substrate, affording the desired α-diazo-β-ketonitrile 38 in 85% yield (Scheme ); this outcome is comparable with the yields for α-diazo-β-ketonitriles under batch conditions reported by Charette, who had also utilized TfN 3 22 , and with the yields obtained when imidazole-1-sulfonyl azide hydrochloride was used. , It has also been demonstrated that acylation of diazoacetonitrile can afford α-diazo-β-ketonitriles; however, this reagent poses its own safety challenges . Interestingly, a debenzoylative diazo-transfer approach to 38 had proved unsuccessful, with the benzoylated starting material recovered essentially quantitatively.…”

“… 93 , 94 It has also been demonstrated that acylation of diazoacetonitrile can afford α-diazo-β-ketonitriles; 95 however, this reagent poses its own safety challenges. 96 Interestingly, a debenzoylative diazo-transfer approach to 38 had proved unsuccessful, with the benzoylated starting material recovered essentially quantitatively.…”

Fluorinated Pyrazoles: From Synthesis to Applications

“…A detailed study of the synthesis of difluoromethyl- and fluoromethyl-substituted pyrazoles using the deoxofluorination strategy was performed by Ma in 2019 . The authors first performed a cyclization of diazoacetonitrile ( 427 ) , with nitroalkenes ( 428 ) to afford cyano-substituted pyrazoles 429 (Scheme ). Reduction of the cyano group with ( i -Bu 2 AlH) 2 (DIBAL) gave aldehydes 430 .…”

From Rare Reagents to Rare Products: Regiospecific Silver‐Catalyzed [3+2] Cycloaddition of Aryl‐, Alkyl‐ and Aminosulfonyl Diazomethanes with Arenediazonium Tosylates

“…Diazo compounds are distinctly versatile reagents with multiple reactivity modes . However, some types of diazo reagents are either scarce (owing perhaps to the difficulties associated with their synthesis) or have not been investigated in a preparative chemistry context . The scarcity or absence of every such type of diazo reagent in the current arsenal of diazo reagents essentially deprives us of access to entire domains of the druglike chemical space .…”