Regioselective Synthesis of Hydrazines and Heterocycles by Catalytic and Electrochemical N–N Bond Formation

Abstract

Two new synthetic methods for preparing NN bond-containing heterocycles have been presented: one, by copper-catalyzed oxidative NN bond formation and two, by electrochemical reduction of N-nitroso compounds and subsequent ring-closing. The first method is copper(I)- and copper(II)-mediated pyrazole synthesis through a catalytic oxidative NN bond formation between an imidate and amine under air. Arylimidate esters prepared from -amino acrylonitrile undergo intramolecular oxidative NN bond formation in the presence of a 1 : 1 combination of copper acetate and copper iodide in DMSO at 60 °C, with concomitant aromatization in the presence of molecular oxygen, providing 3-ethoxy-1-arylpyrazoles. The second method is a novel and general electroreductive synthesis, producing substituted hydrazines, pyrazoles, and pyrazolines regioselectively from N-nitroso compounds. Nitrosylation of corresponding aniline derivatives affords the desired N-nitrosamines in high yields using standard methodology. Electrochemical reduction of N-nitrosamines in an undivided cell leads to the respective hydrazines, followed by intramolecular ring closure to give either pyrazolidinones of pyrazolines in one-pot. Inexpensive and non-toxic stainless steel and zinc electrodes were used as the cathode and anode, respectively. Different combinations of other standard electrode systems do not improve the results, producing the N-nitroso bond cleavage product, sometimes exclusively. Furthermore, the use of lithium bromide as the electrolyte and mildly basic pyridine improves the selectivity of the reaction. Various aryl functional groups with different electronic effects, as well as heteroaryl and alkyl groups, are well tolerated under the reaction conditions. Moreover, electrochemical oxidation of pyrazolidinones to the corresponding pyrazoles was also investigated. Electrochemical reduction of N-nitroso compounds is under-reported in the literature and mostly require a divided cell and/or toxic electrodes. This work fills this void and provides a valuable new strategy for the synthesis of hydrazines and heterocycles – structurally vital building blocks for agricultural and pharmaceutical intermediates under very mild reaction conditions using a simple, scalable set-up.