Synthesis of Some3-Chloro-2,3-dimethyl-1-phenylpyrazolidin-5-one (Chlorophenazone)Derivatives

(E)-3-Chloro-4-arylidene-2,3-dimethyl-1-phenylpyrazolidin-5-one 1(a-c) which were used as synthon for synthesis of all target compounds were prepared from the reaction of 3-chloro-2,3-dimethyl-1phenylpyrazolidin-5-one(Chlorophenazone)with aromatic aldehydes by 1,4-Michael addition . 4-Aryl-3-chloro-2,3-dimethyl-1-phenyl-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-6(5H)one2(a-c) and 6(5H)-thiones 2(d-f)were prepared in low yields(40-50%) by the reaction of 1 (a-c) with urea or thiourea respectively in refluxing ethanol. The refluxing of 1(a-c)with hydrazine hydrate in presence of pyridine afford 3-chloro-4-aryl-2,3-dimethyl-1-phenyl-1,2,3,5-tetrahydropyrazolo[3,4-c]pyrazole 3(a-c). Also, 2-benzyl-4-spiro-5-chloro-1,5dimethyl-2-phenylpyrazolidin-3-one (4) was obtained via epoxidation of 1(a) by hydrogen peroxide in presence of anhydrous sodium carbonate, the reaction of this spiro compound with hydrazine hydrate gave 3-chloro-2,3-dimethyl-1,4diphenyl-1,2,3,3a -tetrahydropyrazolo[3,4-c]pyrazole (5). Finally, the authentic samples of pyrazole (5) was prepared by the oxidation of 3(a) with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) . The structures of these compounds were confirmed by their physical properties in addition to the IR and UV Spectra.


Introduction
In the last decade an increasing attention has been focused on pyrazoline derivatives with its own moiety or fused with five or six membered azoheteocyclic rings (pyrazole or pyrimidine) [1][2]. One of the most important of 1,5-dimethyl-2-phenyl-1,2-dihydro-3Hpyrazol-3-one(phenazone) moiety was a classic NSAID [3]. A variety of methods have been reported for the preparation of this class of compounds after the pioneering work of Fischer and Knoevenagel in the 19th century, the refluxing of α,β-unsaturated aldehydes or ketones with phenylhydrazine in acetic acid became one of the most popular methods for the preparation of 2-pyrazolines. [4].The reaction of chalcones and phenylhydrazine hydrochloride in the presence of sodium hydroxide was carried out in the absolute ethanol at 70°C, but there was a disadvantage due to long reaction time (8 hours) [5]. In 2005, the synthesis of 3,5-diaryl-2-pyrazolines by refluxing of chlorochalcones with phenylhydrazine in acetic acid for (3hours) was reported [6][7]. Finally, chloroimidazole derivatives were important precursors for the preparation of calcium channel modulators and angiotensine receptor antagonists [8]. For this reason, efficient synthesis of these valuable and versatile intermediates was of interested as part of continuous program directed toward the studies with polyfunctionally substituted heterocyclic's [9][10], it was became of interest to investigate some important reactions of 3-chloro-2,3-dimethyl-1-phenylpyrazolidin-3-one(Chlorophenazone) and to synthesis a new class of compounds of general formula 1-5 that combined elements of both chlorophenazone and heterocyclices and might showed enhanced biological properties.

Experimental
All melting points were determined on a Gallen Kamp and Electro thermal 1A9300 Digital-Series (1998) apparatus and were uncorrected. The IR -spectra (νmax cm -1 KBr disc) were recorded on Perkin -Elmer 590B Spectrophotometer. V-On Shimadzu UV-160 spectrophotometer use EtOH as solvent.  Table (1).

Table (1): Physical and spectral data of compounds 1(a-c)
*All these compounds were white to pale orange in color.

2-Reaction of compound (4 )with hydrazine hydrate : [10]
To a mixture of (0.38gm,0.012 mole ) of compound (4)  was removed under pressure and the solid product was crystallized from acetic acid to give compound (5). This compound has the same melting points, mixed melting point and spectral data with that produced via method A.

Results and discussion
A convenient synthesis of target compounds were accomplished by the route outlined in Scheme (1).

(E)-3-Chloro-4-arylidene-2,3-dimethyl-1-phenylpyrazolidin-5-one 1(a-c)
The utility of Claisen-Schmidt condensation were demonstrated in the synthesis of these compounds by the reaction of 5-Chloro-1,5-dimethyl-2-phenyl pyrazolidin-3-one with the corresponding aromatic aldehydes in presence of KOH [10]. An examination of the reaction mixture by T.L.C. showed the presence of only one compound(E isomer) and no traces of a second isomer (Z isomer) was detected[E entgegen the two groups of higher priority (the aryl and exocyclic carbonyl) were on opposite side of the double bond] .The results were confirmed by IR and UV spectra of these products which showed the presence of conjugated carbonyl group at (1648-1667 cm -1 )with the exocyclic double bond(1595-1620 cm -1 ) ,
The IR spectra of compounds were reflected abroad band in the region(3422-3427 cm -1 )for NH vib., and strong band in the region (1676 cm -1 ) and(1741 cm -1 ) for C=O and C=S vibrations. The UV absorptions λ max(MeOH) were in the range(240-280nm) resemble to the published for similar compounds [10].
This pyrazoline ring in these compounds were assigned from their UV and IR spectra, which came in agreement with this moiety [10].

Method B; Oxidation by DDQ:
By the same manner the direct oxidation by DDQ gave compound (5), the structure of this compound was confirmed by the appearing of the C=N characteristic bands at (3332-3526 cm -1 ) in its IR absorption spectrum and this was in agreement with the literatures [9].
The formation of the same product from two different compounds indicated the correct assignment for these compounds. Scheme (3) 13-Saied,S.A.;"Syntheis of heterocyclic compounds from α -β unsaturated ketones; (2011);