An expedient synthesis of some new Pyrazole , Pyrazolone , Hydrazone and

Malonamic acid, Malonamic acid hydrazide and Malonamic acid amide was designed and synthesized from direct condensation of diethyl malonate with m-NO2 primary aromatic aniline which used as precursor for synthesis of various possible bio active molecules. We also designed and synthesized the novel non cyclic and heterocyclic compounds from malonamic acid hydrazide like hydrazone, thiosemicarbazide, pyrazole and pyrazolone were achieved by a single step condensation reaction in good to excellent yields. The simple starting materials, mild conditions, easy operation, high bioactivity of hydrazone, thiosemicarbazide, pyrazole and pyrazolone derivatives, this protocol has great potential in medicinal chemistry. All synthesized compounds evaluated for their antimicrobial activity and screening results are awaited. The structure elucidation of synthesized compounds was established on the basis of IR & NMR techniques ( 1 H-NMR) and elemental analysis.


Introduction:
Development of drug resistance in microorganism is a scuffle between science and nature.With an increase the antibiotic-resistant strain of microorganism increasing the public health problem [1] .Cyclic and noncyclic compounds containing the reactive methylene group provide magnificent intermediates in synthetic organic chemistry.These molecules have been found to be useful a precursor for various biological active agents.Using such type of compounds as starting material quiet a large number of heterocyclic and non-heterocyclic compounds can be prepared by condensing them with other substances.Heterocycles form by far the largest of classical divisions of organic chemistry.A broad spectrum of biological activity associated with heterocyclic compounds has attracted interest in drug discovery research.Various literature reported that, both synthetic as well as natural nitrogen containing heterocyclic molecules possesses a significant pharmaceutical importance, a large number have been made up to clinics for health care worldwide.Pyrazole and pyrazolone are classes of heterocycles which exhibits diverse chemical and biological properties [2][3][4][5][6][7][8][9][10][11][12][13][14][15] .Also the non-heterocyclic compounds like hydrazones and thiosemicarbazides have attracted researchers for their significant application in medicinal and agricultural chemistry [16][17][18][19][20][21][22][23][24][25][26][27] .

MATERIALS AND METHODS:
The purity of the synthesized compounds were checked on silica-gel-coated Al plates (Merck) various solvent systems using iodine vapors as detecting agent.Melting points were determined by the melting point determination apparatus in open capillary tubes and are uncorrected.On the basis of their Infra-red spectra (IR) using KBr discs, on a Perkin Elmer Spectrum RX1 infra-red spectrophotometer. 1 H NMR spectra were recorded in DMSO-d 6 on Bruker DRX-300 (300 MHz) and Jeol AL300 FT-NMR (300 MHz) systems; chemical shift (δ) is reported in ppm using TMS as an internal reference.Elemental analysis was performed on Elementor Vario EL III.All the compounds gave satisfactory microanalysis.All chemicals and reagents were obtained from CDH and Spectrochem Pvt. Ltd. (India) and were used without further purification.

General procedure for the preparation of compounds:
The title compounds were prepared in following steps: 1.

3-(3-nitrophenylamino)-3-oxopropanoic acid (I):
To the 3-nitro aniline (0.05 moles, 6.9 gm), diethyl malonate (0.05mol) was added and refluxed for 2 hr.It was then cooled and filtered.10 ml ethanol was added to the filtrate and the solution was concentrated on steam bath.Steam was blown into the mixture of above concentrated solution and 20 ml ethanol in the presence of 20% Na 2 CO 3 solution (10 ml).It was then cooled and filtered.
To the filtrate, conc.HCl was added.The cream colored solid thus separated was filtered, washed with water and recrystallized from absolute ethanol.

3-(3-nitrophenylamino)-3-oxopropanehydrazide (II):
To the 3-nitro aniline (0.05 moles, 6.9 gm), diethyl malonate (0.05mol) was added and refluxed for 2 hr.It was then cooled and filtered.10 ml ethanol was added to the filtrate and the solution was concentrated on the steam bath.After cooling it to the room temperature, 20 ml ethanol and hydrazine hydrate (0.05 mole, 99%) was added and refluxed for 45 mins on the steam bath.On cooling, white crystalline solid was separated; it was then filtered and recrystallized from absolute ethanol.

N 1 -(3-nitrophenyl)malonamide (III):
To the 3-nitro aniline (0.05 moles, 6.9 gm), diethyl malonate (0.05 mol) was added and refluxed for 2 hr.It was then cooled and filtered.10 ml ethanol was added to the filtrate and the solution was concentrated on the steam bath.After cooling, 10 ml ethanol and 10 ml of liquor ammonia (d= 0.88) was added to this concentrated solution, taken in a flask.The flask is tightly corked and shaken vigorously for 1 hr.leaving it overnight, pale yellow crystalline solid was separated; it was then filtered and recrystallized from absolute ethanol.

Result and Discussion:
To gain access to a good amount of novel malanomic acid (I), hydrazide (II) and amide (III) by direct condensation of commercially available diethyl malonate and 3-nitroaniline in absence of acid or base catalyst.Diethyl malonate and 3-nitro aniline was refluxed in equimolar proportion.It was then cooled and concentrated at room temperature.N-(3-nitro) phenyl malonamic acid(I), N-(3-nitro) phenyl malonamic acid hydrazide (II) and N-(3-nitro) phenyl malonamide (III) were obtained by treating the above concentrated liquid with hydrazine hydrate (99%) and ammonia (d=0.88)respectively.The chemical reaction proceeds as described in Scheme 1.Our next concern was directed towards the reaction of a compound (II).Further, the hydrazide (II) when refluxed with 3,4-dimethoxy benzaldehyde and p-fluoro phenyl isothiocyanate in the presence of ethanol (absolute) furnished hydrazone (IV) and thiosemicarbazide (V) respectively.Pyrazole (VI) and pyrazolin-5-one (VII) is obtained in good yield by condensation of compound (II) with 2,3-diketo-3-(4-nitro phenyl azo)pentane and ethyl-2,3-dioxobutyrate-2-(4-chloro phenyl azo) hydrazone in absolute ethanol with catalytic amount of glacial acetic acid (GAA).Reaction summary is illustrated in Scheme 2. The structures of these compounds were confirmed by analytical and (IR & 1 H NMR) spectral data.The structure of (I) was confirmed by IR spectra which showed the presence of characteristic absorption bands corresponding to (-CONH-) group at 1594 cm -1 , (OH) group at 2729 cm -1 , (NH) group at 3355 cm -1 . 1 H NMR showed a signal corresponding to CONH group as a singlet at 8.61ppm, signal corresponding to COOH group as a singlet at 10.66 ppm.The structure of compound (II) was confirmed by IR spectra which showed the presence of characteristic absorption bands corresponding to (-CONH-) group at 1595 cm -1 , (-N-N-) group at 1511 cm -1 , (NH) group at 3478 cm -1 .showing singlet signal at 1.04 ppm of one methyl group proton and singlet at 2.24 ppm of CH proton of pyrazolne ring.All synthesized compounds evaluated for their antimicrobial activity and screening results are awaited

Conclusion:
In our effort to develop novel, versatile and efficient method for the synthesis of bioactive malonamic acid, acid hydrazide, acid amide, hydrazone, thiosemicarbazide, pyrazole and pyrazolone, we herein report efficient synthesis of these candidates from easily commercially available reactive methylene compounds of malonamic acid hydrazide series.Furthermore literature revealed that introduction of methylene (-CH 2 -) group was found to be promising in improving biological profile of compounds.All synthesized compounds evaluated for their antimicrobial activity and results awaited.To the best of our knowledge, the reactions occurred very fast under mild conditions using reasonable reagents and solvents and products yields are also remarkable.
1H NMR showed a signal corresponding to CONH group as a singlet at 5.79 ppm, signal corresponding to (NH) group as a singlet at 4.30, signal corresponding to CONH-Ar group as a singlet at 9.21ppm.The structure of compound (III) give characteristic peaks of various group (CONH) at 1592 cm -1 , (CONH 2 str.) 1689 cm -1 , (N-H str.) 3445 cm -1 ; 1 H NMR showed a signal corresponding to NH 2 at 5.79 ppm and for CONH group singlet at 8.64 ppm.Compound (IV) was established by their IR spectra showing stretching of various groups at (C=O) 1725, (NH) 3445, (C=N & C=C) 1660, (OCH 3 ) 2819 cm -1 .1HNMR spectra showing the appearance of two methoxy (OCH 3 ) group proton at 3.57-3.79ppm.The IR spectra of compound (V) displayed new band streching of (C=S) group at 1050 cm -1 and (C-F) group at 1012 cm -1 .Compounds (VI) and (VII) were established by their IR and 1 H NMR spectra both compounds displayed particular new stretching of azo (-N=N-) group at 1519-1485 cm -1 and compound give one new band stretching of (C-Cl) group at 810 cm -1 .The proton spectra of compound (VI) showing the two methyl group proton which present on pyrazole ring displayed singlet signal at 2.79-2.70ppm while compound (VII)