Synthesis of new 1,1’-di(4-nitro or 2-nitrophenyl)-5,5’-disubstituted-3,3’-bipyrazoles under microwave irradiation and classical heating conditions

Ten new 1,1’-di(4-nitro or 2-nitrophenyl)-5,5’-disubstituted-3,3’-bipyrazoles have been prepared in one step by N,N-arylation of 5,5’-disubstituted-3,3’-bipyrazoles with 4-fluoro and 2-fluoronitrobenzene. The reaction was carried out under microwave irradiation for 5 min and under classical heating conditions for one to two hours, affording high yields of diarylbipyrazole derivatives.


Introduction
Since Claisen's 1, 2 synthesis, many bipyrazole derivatives have been prepared for biological, medical and industrial purposes.They have been found to possess antiinflammatory, 2-4 cytoxic 2,5 and anti-microbial 4 properties.They are also useful as insecticides, 2,6 herbicides, 2,7 fungicides 2,8 and in the synthesis of heat resistant polymers. 9Other authors 10 reported bipyrazole derivatives as active components in capturing active oxygen and they are useful as agents for preventing or treating various diseases induced by active oxygen.Some bipyrazoles found application as agents for detecting singlet oxygen. 11The reaction of 3,3'dichloro-5,5'-bipyrazole with Ni(0)Lm, gives new poly(bipyrazoles) with high thermal stability. 12n this paper, we report two comparative approaches for the preparation of some new bipyrazole derivatives, by N,N-arylation reactions under microwave irradiation and classical heating conditions hoping to get improved catalytic and biologic activities.The compounds were obtained in excellent yields by a three-steps procedure.
Our strategy was to develop a simple and high yielding procedure, in few steps, to prepare the desired bipyrazolic compounds.The result of our investigation was given below (Scheme 1).The first step involves the synthesis of tetraketones 3a-e 13,14,15 by condensation of methyl ketones 1a-e with diethyl oxalate 2. The second step consists of the condensation of these compounds with hydrazine hydrate in refluxing ethanol yielding the corresponding bipyrazole derivatives 4a-e. 15,16These compounds have high melting points and low solubility properties in organic solvents.In the last step, the N,N-arylation of bipyrazoles 4a-e with 4fluoronitrobenzene and 2-fluoronitrobenzene under classical heating conditions using potassium tert-butoxide as a base and DMSO as a solvent at 70°C affords after 60 to 120 min novel 1,1'di(4-nitro or 2-nitrophenyl)-5,5'-disubstituted-3,3'-bipyrazoles 5, 6 (a-e) in good yields ( 62 -95 %).
The same reaction was then repeated using microwave irradiation, which has recently been used as an efficient technique to increase reaction rates.Thus, we have attempted to take advantage of it to decrease the reaction time of the previous N-arylation reaction, which was optimized with 4a bipyrazole in order to obtain the best yield and until complete consumption of the starting materials.The mixture of 5,5'-di(1-methylethyl)-3,3'-bipyrazole 4a, potassium tert-butoxide and 4-fluoronitrobenzene or 2-fluoronitrobenzene was introduced into a Pyrex tube, which was then placed under microwave irradiation (single-mode, Prolabo Maxidigest MX 350).However, under these reaction conditions compound 5a was isolated in poor yield and compound 6a was not obtained.In view of this poor reactivity, these reactions were performed with some drops of DMSO solvent.Indeed, the mixture of 5,5'-disubstituted-3,3'-bipyrazoles 4 (a-e), potassium tert-butoxide, 4-fluoronitrobenzene or 2-fluoronitrobenzene and some drops of DMSO solvent was introduced into a Pyrex tube which was then placed under microwave irradiation.Then the mixture was quenched with water.The precipitate was collected by filtration and was finally purified by column chromatography, if necessary, to afford regioselectively pure products 5, 6 (a-d) in good yields (83-98%).The disfavoured arylation of 4e to afford 5e and 6e may be attributable to the steric hindrance of the non-twisted aryl ring that prohibits access to the nitrogen atom next to the aromatic ring. 17This method appeared to be rapid and economical, with a wide range of applications.The reaction was found to proceed smoothly under microwave irradiation within 5 min whereas under classical heating conditions, 60-120 min were required (Table 1 The higher regioselectivity suggests stereoelectronic effects.In general, pyrazoles with more electron-deficient aromatic substituents gave higher regioselectivity.The spectral characteristics of new bipyrazoles are in good agreement with symmetrical 3,3'-regioisomers forms. 18n conclusion, we have developed an efficient access to new bidendate compounds.Essentially the N,N-arylation of some bipyrazole derivatives which have the nitro group, using two methods: microwave irradiation and classical heating conditions in DMSO.The present ARKAT work is an important addition to microwave-assisted synthetic methodologies.Further developments on this subject are currently in progress, particularly, the examination of molecular conformations of the new N-aryled bipyrazole derivatives.

Experimental Section
General Procedures.Melting points were determined in open glass capillaries using BUCHI 510 Melting Point apparatus and are uncorrected.The infrared (IR) spectra were recorded on PERKIN-ELMER 1310 infrared spectrophotometer using the KBr disk technique.NMR spectra ( 1 H, 13 C) were recorded on a BRUKER 300 NMR spectrometer (operating at 300 MHz for 1 H, 75 MHz for 13 C).Chemical shifts are listed in ppm and are reported relative to tetramethylsilane (TMS) as an internal standard.Splitting patterns were designed as follows: s: singlet; d: doublet; t: triplet; m: multiplet.Mass spectra were obtained an a VG7070E spectrometer.

Synthesis of 5,5'-disubstituted-3,3'-bipyrazole
To a solution of tetraketones 3c,d (8 mmol) in absolute ethanol was added the hydrazine hydrate (16 mmol) and the mixture was refluxed for one hour.The solvent was removed in vacuo at reduced pressure.The residue was washed with water (2x10 mL) and filtered to give the appropriate bipyrazoles 4c,d.