Ultrasonics Promoted Synthesis of 5-(Pyrazol-4-yl)-4,5-Dihydropyrazoles Derivatives

A series of new 1,3-diaryl-5-(1-phenyl-3-methyl-5-chloropyrazol-4-yl)-4,5-dihydropyrazole derivatives have been synthesized under sonication conditions in ethanol or methanol/glacial acetic acid mixture (5/1 ratio) with two equivalents of hydrazines and seven kinds of chalcone-like heteroanalogues obtained from 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde. The structures were established on the basis of NMR, IR, MS and element analysis. This method provides several advantages over current reaction methodologies, including a simple work-up procedure, shorter reaction times (2–20 min) and good yields (65%–80%).

The development of new, rapid and clean synthetic routes toward focused libraries of nitrogen-containing heterocycles is of great importance to both synthetic and medicinal chemists.They have been reported in literature procedures for the design and development of new heterocycles (pyrazole and pyrazoline derivatives) by means of multistep reactions [26][27][28], metal-catalyzed synthesis [29,30], domino reaction of 2-acylaziridines with the Huisgen zwitterions [31] and 1,3-dipolar cycloaddition reactions [32] to access important heterobiaryls.
The first synthesis of the pyrazoline framework by the reaction of an α,β-enone with a hydrazine derivative was published by Fischer and Knoevenagel [33].Then, the reaction of α,β-unsaturated aldehydes and ketones with hydrazine derivatives became one of the most popular methods for the synthesis of pyrazolines [34][35][36][37].
Cyclization of chalcones, leading to pyridine, pyrimidine and pyrazoline derivatives, has been a developing field within the realm of heterocyclic chemistry for the past several years, because of their ready accessibility and the broad spectrum of biological activity of the products [38][39][40][41][42][43][44].These observations led us to synthesize chalcones and its corresponding pyrazoline, exploring simple procedures.
Sonochemistry is attracting considerable research activity within the synthetic chemistry community, because it offers a new approach to the preparation of organic compounds.In the last two decades, sonochemical methods have become widely used in organic synthesis [45][46][47].Nowadays, the ultrasonic irradiation technique has been employed, not only to decrease reaction times, but also to improve yields in a large variety of polyfunctionalized heterocycles.Compared with traditional methods, this method is more convenient and easily controlled.A large number of organic reactions can be carried out in a higher yield shorter reaction time and milder conditions under ultrasound [48][49][50][51][52].

Apparatus and Analysis
Melting points were determined using a Thermo Scientific Fluke 51 II, model IA 9100 melting point apparatus and are reported uncorrected. 1 H NMR (400 MHz) and 13 C NMR (100 MHz) spectra were recorded at room temperature on a Bruker Ultra Shield 400 using tetramethylsilane (TMS) as the internal standard and deuterated chloroform (CDCl 3 ) as the solvent.EI-MS were run on a Shimadzu GC-MS 2010 spectrometer, which was operating at 70 eV.IR spectra were recorded as KBr pellets on a Shimadzu FTIR-8400 instrument.The ultrasonic irradiation was performed by using a Branson ultrasonic cleaner bath, model 1510, AC input 115 V, output 50 W, 1.9 liters with a mechanical timer (60 min with continuous hold) and heater switch, 47 KHz.High Resolution Mass Spectra (HRMS) were recorded in a Waters Micromass AutoSpec NT spectrometer (STIUJA).The elemental analyses have been obtained using a LECO CHNS-900 and Thermo Finnigan FlashEA1112 CHNS-O (STIUJA) elemental analyzers.The hydrazines and solvents used, such as, ethanol, dichloromethane, glacial acetic acid and ethyl acetate, were obtained from Merck Chemical Company.The chalcone-like heteroanalogues 1 were obtained according to the methodology described [39,53,54].

General Procedure for the Synthesis of 5-pyrazol-4,5-dihydropyrazoles Derivatives 3
A solution of equimolar amounts of chalcone-like heteroanalogues 1 (1 mmol) and hydrazine 2 (1 mmol), using as solvent ethanol or methanol/acetic acid mixture (5/1 ratio, 10 mL) in an Erlenmeyer, was placed in a water bath and sonicated at ambient conditions (35-40 °C), for an appropriate time (Table 2), until the reaction was completed (the reaction was monitored by TLC).The reaction mixture was then treated with cold ethanol and filtered to leave a solid product, which was crystallized from a hexane/ethanol mixture to yield pure product 3.All the products were characterized by their physical and spectral data (IR, MS, 1H NMR, 13 C NMR) and elemental analysis.

Results and Discussion
We continue our study to obtain functionalized heterocycles through the development of synthetic strategies.The starting compounds 1 were synthesized by Claisen-Schmidt condensation of 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde with acetophenones [53,54].As part of our ongoing research on the application of ultrasonic irradiation as a clean and useful technique in organic synthesis, we described in this work the synthesis of 5-(pyrazol-4-yl)-4,5-dihydropyrazole derivatives under ultrasound irradiation (Scheme 1).Scheme 1. Synthesis of 5-(pyrazol-4-yl)-4,5-dihydropyrazole derivatives.We preliminarily examined the cyclocondensation reaction of (E)-3-(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)-1-arylprop-2-en-1-one 1 with hydrazines in the presence of ethanol or methanol and acetic acid as the catalyst under sonication.To achieve suitable reaction conditions in terms of reaction time and catalysis at ambient conditions, we tested different proportions of a mixture of ethanol/methanol and acetic acid.The results are summarized in Table 1.b Isolated yields using ethanol as solvent.
To the best of our knowledge, this new procedure provides the first example of an efficient and ultrasound-promoted approach for the synthesis of 1,3-diaryl-5-(1-phenyl-3-methyl-5-chloro-pyrazol)-4,5-dihydropyrazoles.This method is the most simple and convenient and would be applicable for the synthesis of different types of nitrogen-containing heterocyclic compounds.The structures of all the synthesized compounds were established by their NMR, IR, MS and analysis elemental.

Table 1 .
Effect of reaction conditions.Green factors.