Efficient Syntheses of Some Versatile 3,5-Bifunctional Pyrazole Building Blocks

Abstract

A series of convenient synthetic procedures are reported for pyrazole derivatives with carbonyl or ester groups in the 3-and 5-positions and variable substitution pattern at C4 and at the functional side arms. All compounds have been characterized by 1 H and 13 C NMR spectroscopy, elemental analyses, and mass spectrometry. In addition, the structures of several pyrazole derivatives have been determined by single crystal X-ray diffraction, which provides insight into the effect of functional side arms on the hydrogenbonded supramolecular motifs of NH-pyrazoles.Pyrazoles are considered as extremely versatile building blocks in organic chemistry. 1 They constitute key fragments in active pharmaceutical and agrochemical ingredients, which have found widespread use as ligands for transition-metal complexes. 2,3 Decoration of the pyrazole core often requires the attachment of functional substituents at the 3-and 5-positions of the heterocycle, which can then be further manipulated. Recent examples of valuable 3,5-difunctionalized pyrazoles comprise aminopyrazole derivatives as nonpeptidic templates capable of recognizing β-sheet structures, 4 and compartmental pyrazole/ imine ligand scaffolds that form binuclear Pd and Ni complexes for catalytic olefin polymerization. 5The most common methods for the preparation of pyrazoles are the reaction of hydrazines with β-dicarbonyl compounds, and 1,3-dipolar cycloadditions of diazo compounds onto triple bonds. 6 The former process, usually considered to be the best and most versatile method, involves the double condensation of 1,3-diketones with hydrazine or its derivates. While this works well for simple pyrazoles bearing various alkyl or aryl substituents in the 3-and 5-positions, however, most electrophilic functional groups such as aldehydes, nitriles, esters, and alkyl halides do not survive such transformation. On the other hand, there is a paucity of 3,5-bifunctional pyrazole compounds that would allow facile subsequent derivatization. These should be amenable via high-yielding and straightforward syntheses, which is particularly true for N-unsubstituted pyrazoles. 7,8 Established pyrazole building blocks include dialdehyde A 9 and diacid dichloride B 10 as well as diester C 11 (Figure1), all of which have proven useful for the preparation of, for example, macrocycles and multidentate ligand scaffolds incorporating one or more pyrazole moieties. 3In order to broaden the scope of these systems, we set out to develop efficient syntheses for a variety of new 1H-pyrazole derivatives related to A-C with carbonyl or ester groups in the 3-and 5-positions, but with different substitution pattern both at the pyrazole-C4 position and the side arm carbonyl functions. For the synthetic approaches it was aimed to avoid toxic hydrazine or its derivatives. Finally, it was deemed interesting to study the solid-state structures of such pyrazole synthons that are decorated with functional groups, since the presence of multiple Hbonding donor and acceptor sites may give rise to complex ag...