Deoxygenative Condensation Of 1,2-dicarbonyl Compounds With Modified Huisgen Zwitterions

The Huisgen zwitterions,a type of zwitterions generated in situ from phosphines and azodicarboxylates and is believed to be the key intermediate for classical Mitsunobu reaction,have attracted extensive attention from synthetic organic chemists due to their unique reactivity patterns.Over the past decade,a plethora of annulation reactions based on Huisgen zwitterions have been developed,which provide important synthetic approaches to various nitrogen heterocyclic compounds.In addition,the Huisgen zwitterions can also undergo deoxygenative condensations with electrophiles to afford nitrogen-containing chain structures.However,the azodicarboxylates used in these reactions,such as diethyl azodicarboxylate(DEAD)or diisopropyl azodicarboxylate(DIAD),are toxic and high-energy materials with explosive risk,potentially leading to environmental and safety issues.Moreover,the regioselectivity of these reactions is poor when structurally unsymmetrical azodicarboxylates are used.The arylazocarboxylates are a class of safe and reactive new azo compounds developed in recent years.The existed reports have unveiled that this class of compounds can function as an alternative to azodicarboxylates to participate in Mitsunobu reaction.However,the reactivity patterns of the Huisgen zwitterions derived from these compounds toward electrophiles have so far never been investigated.This thesis has systematically studied the deoxygenative condensation of the modified Huisgen zwitterions generated in situ from phosphine and arylazocarboxylate with 1,2-dicarbonyl compounds,leading to a highly efficient synthesis of N-aryl-N-acyl hydrazones.Notably,hydrazones are privileged structural motifs frequently present in a wide range of bioactive active molecules with significant pharmacological properties such as anti-depression,analgesia,anti-inflammatory,and anti-malarial properties.Results from the studies manifest that the reaction can afford the highest yield in CH₂Cl₂ at room temperature promoted by triphenylphosphine.Under the optimized reaction conditions,the deoxygenative condensation reaction exhibits a wide substrate scope.Several types of 1,2-dicarbonyl compounds including?-ketoesters,?-diketones,and isatin derivatives can participate in the reaction smoothly with different substituted arylazocarboxylates,furnishing the corresponding hydrazones in moderate to excellent yields.The structures of the hydrazones have been confirmed by a combination of ¹H and ¹³C NMR,high resolution mass spectrometry(HRMS),as well as single-crystal X-ray diffraction measurements.On the basis of ³¹P NMR tracking experiments,a reasonable mechanism is proposed:regioselective addition of triphenylphosphine to arylazocarboxylate generates the modified Huisgen zwitterion in situ,which undergoes nucleophilic addition to 1,2-dicarbonyl compound,followed by elimination of the triphenylphosphine oxide and nitrogen–nitrogen ester group migration to afford the final product.The study herein represents the first exploration of the reactivity patterns of the modified Huisgen zwitterions derived from arylazocarboxylates toward electrophiles,which expands the synthetic applications of the Huisgen zwitterions and affords a new highly efficient access to N-aryl-N-acyl hydrazones as well.