Electrophilic Hydrazination of Cyclopropanols Using Azodicarboxylates via Copper(II) Catalysis: An Umpolung Strategy to Access β-Hydrazino Ketone Motifs

Abstract

The scope of an umpolung approach to expand synthetic access to bifunctional γ-keto hydrazine intermediates via electrophilic amination of β-homoenolates derived from cyclopropanol precursors that took advantage of azodicarboxylates or azodicarboxamides as electron-deficient nitrogen sources was examined. This new synthetic procedure avails commercially available or readily accessible starting materials along with a ligand-free Cu(II) salt as an inexpensive catalyst. Using this operationally simple reaction, which proceeds under mild conditions (open-flask and ambient temperature) and is suitable for multigram scale, preparative applications were established with a range of aryl-and alkyl-substituted cyclopropanols and azodicarboxylate/ azodicarboxamide substrates (26 examples, 74−95% yields). Further, the obtained products have been shown to provide convenient synthetic access to γ-hydroxy hydrazide, γ-amino hydrazide, and heterocyclic derivatives.

Developing a transition-metal-free green protocol for the electrophilic hydrazination of silyl enol ethers using diazo electrophiles with EtOH–H2O as a safe solvent

“…Hydrazine derivatives are among the most valuable functionalities in organic chemistry and can undergo synthetic transformations to derive diverse building blocks that include α-amino ketones, 1,2-amino alcohols, α-amino acids and their derivatives, and heterocyclic compounds. [1][2][3] Compounds that incorporate the N-N group are ubiquitously present in biologically active substances and marketed pharmaceutical drugs, especially as part of heteroaromatic rings that include pyrazole, pyridazine, oxadiazole, and thiadiazole heterocycles. [4][5][6] β-Ketohydrazide derivatives have been found to be useful as pharmaceutically active substances, and their representative examples are presented in Fig.…”

“…These limiting factors inspired us to examine the scope of developing an environmentally-sustainable protocol, adhering to the key green chemistry principles of waste prevention, the use of less hazardous synthesis conditions, the implementation of a safer solvent and the improvement in energy efficiency. As part of our recent interest in hydrazine-containing ketone derivatives, 3 we report herein the electrophilic hydrazination of difluoroenoxy silanes and desfluoro enoxy silanes with azo esters or azo amides as electrophilic substrates using a benign protocol that (a) eliminates the requirement of a metal catalyst and HF as a reagent ( preventing the use of hazardous chemicals and eliminating the consequent waste), (b) takes advantage of a combination of EtOH-H 2 O as an environmentally safe reaction medium (replacing chlorinated and ether solvents), (c) can be conducted under open air conditions, thereby eliminating the requirement of an inert gas atmosphere, (d) is compatible with room temperature (RT) conditions in contrast to the reported sub-ambient temperature conditions at the expense of energy waste, and (e) is amenable to solvent-free conditions. [15][16][17][18][19] In recent years, ethanol has attracted significant interest both as a green industrial solvent and as a bio-fuel because of the sustainable nature of its production from biomass feedstocks including sugarcane and corn.…”

Promoting Catalytic C-Selective Sulfonylation of Cyclopropanols against Conventional O-Sulfonylation Using Readily Available Sulfonyl Chlorides

“…We have previously demonstrated an efficient nucleophilic addition of copper homoenolates derived from cyclopropanols and a Cu(OAc) 2 catalyst to diazo electrophiles. 20 This literature precedent inspired the replacement of the silver salt with Cu(OAc) The Journal of Organic Chemistry impact the C−S coupling with reduced yields of the product of 25−32% (entries 13−15). The addition of the inorganic base Na 2 CO 3 also resulted in a decrease in the yield to 46% (Table 1, entry 16).…”

Iodine-Mediated α-C–H Amination of Carbonyl Compounds via Nitrogen-Directed Oxidative Umpolung

“…Direct sp 3 C–H amination has been utilized extensively in organic synthesis for the construction of nitrogen-containing frameworks from readily accessible alkane substrates without prefunctionalization . The umpolung strategy is a powerful tool to realize such amination reactions, and significant achievements have been made in the use of transition-metal catalysts . However, such transformations with no use of transition metals have been less investigated .…”