One-pot activation–alkynylation–cyclization synthesis of 1,5-diacyl-5-hydroxypyrazolines in a consecutive three-component fashion

Abstract

A consecutive three-component activation–alkynylation–cyclization reaction of (hetero)aryl glyoxylic acids, oxalyl chloride, arylacetylenes, and hydrazides efficiently forms 1,5-diacyl-5-hydroxypyrazolines in moderate to good yields. The structures were unambiguously corroborated by comprehensive NMR spectroscopy and X-ray structure analyses of selected derivatives.

Synthesis of Anti-Inflammatory Spirostene-Pyrazole Conjugates by a Consecutive Multicomponent Reaction of Diosgenin with Oxalyl Chloride, Arylalkynes and Hydrazines or Hydrazones

“…Alkyne-1,2-diones are of interest for the synthesis of a variety of functionalized and heterocyclic compounds because, as densely functional trielectrophiles (the alkyne, alkynone and dicarbonyl function), they can be easily and selectively transformed by a series of nucleophilic additions, annulations, condensations, and Diels–Alder reactions [ 37 , 38 , 39 , 40 , 41 , 42 , 43 ]. It is highly desirable to develop efficient reaction systems for the synthesis of functionalized pyrazoles from alkyne-1,2-diones and arylhydrazines with high efficiency and regioselectivity under mild reaction conditions.…”

“…It is highly desirable to develop efficient reaction systems for the synthesis of functionalized pyrazoles from alkyne-1,2-diones and arylhydrazines with high efficiency and regioselectivity under mild reaction conditions. Described atom- and step-economic synthesis of these heterocycles included the sequence of glyoxylation-alkynylation of aryl(hetaryl) substrates [ 38 , 44 ] or activation-alkynylation of (hetero)arylglyoxylic acids and the heterocyclization reaction of the resulting alkynyl diketones [ 39 , 40 ].…”

“…Based on the analysis of the spectral and analytical data of obtained pyrazoles 10 – 14 we can suggests that the heterocyclization reaction of alkyne-1,2-diones 4 – 8 started with the nucleophilic addition of phenylhydrazine at the carbonyl group conjugated with the triple bond to form the corresponding α,β-alkynyl phenylhydrazones, which then undergo intramolecular cyclization. Heterocyclization of (hetero)aryl alkyne-1,2-diones with N-acylhydrazines with the formation of pyrazole derivatives was performed in a medium of protic solvents—methanol or 2-methoxyethanol [ 38 , 40 ]. We also attempted to use ethanol at the stage of heterocyclization of spirostane alkyne-1,2-diones 4 – 8 with phenylhydrazine hydrochloride; however, their low solubility did not allow for achieving the formation of the target steroidal pyrazoles.…”

“…N-Acyl substituted hydrazones, as expected, showed a softer character of the nucleophilic center, which is expressed in their initial addition at the soft electrophilic center of the triple bond of alkynyl ketones with the formation of intermediate alken-hydrazide A and their subsequent intramolecular cyclization leading to 1-hydroxy-4,5-dihydro-1 H -pyrazoles [ 37 ]. The reactions of the in situ formed alkynyldiketones with N-acylhydrazides usually need an additional catalyst or high temperatures [ 40 ]. We found, that the consecutive four-component reaction of diosgenin 1 , oxalyl chloride, phenylacetylene 3a , and hydrazides of benzoic or 4-bromobenzoic acids 24a , b led to the formation of 3- O -(1-aroyl-5-hydroxy-3-phenyl-4,5-dihydro-1 H -pyrazoline)- spirostenes 25 or 26 isolated in the yield of 49 and 42%, respectively ( Scheme 6 ).…”

Heterocycles by Consecutive Multicomponent Syntheses via Catalytically Generated Alkynoyl Intermediates

“…Consequently, 1,5-diacyl-5-hydroxypyrazolines 11 are generated employing a consecutive sequence of activation of glyoxylic acids 9, alkynylation and cyclization with acylhydrazines 10. Görgen et al isolated 17 examples with 3 different points of variation in mostly good yields bearing different (hetero)aryl and alkyl substituents (Scheme 6) [47].…”