Synthesis of Some New Hydrazide-Hydrazone and Heterocyclic Compounds Thiophene, Imine, Coumarin and Pyrazole Derivatives

A series of new thiophene, imine, coumarin and pyrazole derivatives X4-X16 were synthesized from N-(1-(4-(benzylsulfonyl)phenyl)ethylidene)-2-cyanoacetohydrazide X3 as a starting material with different reagents (


Introduction
Hydrazones are considered organic compounds that contain two nucleophilic nitrogen atoms in addition to a double bond (C=N), which has the formula (R1HC=NNH2) 1 .Hydrazones are used in the synthesis of heterocyclic compounds due to their reactions with electrophiles and nucleophiles 2 .Hydrazones were formed by the reactions of an aldehyde or ketone with hydrazine or hydrazine derivatives 3 .Compounds containing the hydrazone group have different biological properties, which have entered into many studies because of their therapeutic value in the development of new agents such as anti-cancer 4 , anti-viral 5 and antiinflammatory 6 .Thiophene belongs to the class of five-heterocyclic compounds, the structure of thiophene is found in some natural products, and it is also found in many pharmacologically effective compounds, where thiophene is famous in therapeutic applied chemistry, such as antiinflammatory 7,8 , anti-tumour 9 , antihypertensive 10 and an inhibitor of corrosion of substances 11 .
Coumarins are simple and diverse structures of a basic family of natural products found in various microorganisms, where (benzopyrone) is the main structure the natural and synthetic coumarins 12 have received great attention from researchers due to their wide range of biological properties including anticancer activities 13 , anti-HIV 14 , anti-inflammatory 15,16 and anticoagulant 17,18 as well as many drugs have been marketed coumarin for the treatment of thrombosis 12 .Pyrazole is a five-membered heterocyclic ring consisting of three carbon atoms with two adjacent nitrogen atoms.Pyrazoles constitute an important class in organic construction, and the presence of the pyrazole nucleus in different structures leads to its use in various fields such as technology, medicine and agriculture 19  ( 1 H-NMR and 13 C-NMR) spectra were recorded using Bruker Bio Spin GmbH Spectrophotometer (400 MHz by using TMS as internal standard and using DMSO-d6 as a solvent) [(s) singlet, (d) doublet, (m) multiple].(FT-IR) spectra were measured using a Japanese-made device (Shimadzu FT-IR-ATR) in a region confined between 400-4000 cm -1 .TLC aluminum sheets silica gel 60 F254 was used to monitor the progress of all reactions and the homogeneity of the produced compound.As for the used mobile phase, it consisted of a mixture of ethyl acetate and n-hexane in a ratio of (5:5) ml.A mixture of hydrazide-hydrazone X3 (0.5 g, 1.4 mmol) with (1.4 mmol) of cyclic ketones (tetralone, cycloheptanone, cyclopentanone), (0.045gm,1.4mmol) of elemental sulfur and (0.056gm, 1.4mmol) of sodium hydroxide in 15ml absolute ethanol, the reaction mixture was refluxed for 6 hrs.(monitored by TLC), and then left to cool at room temperature.[29] The coumarin compounds are prepared in two methods:
The mixture is refluxed for 5hours (monitored by TLC), and after the end of reflux, the reaction mixture is left to cool at room temperature, filtered, dried and recrystallized with ethanol.

Results and discussion
The hydrazide-hydrazone X3 was reacted in this investigation in three paths ways to produce several compounds that are predicted to be just as effective biologically as the analogous compounds created in previously published literature 31 .Where the first path includes the synthesis of heterocyclic compounds (thiophene derivatives), the second path includes the synthesis of imine and coumarin derivatives, while the third path includes the synthesis of various heterocyclic compounds and pyrazole derivatives.The 4-(benzylthio)acetophenone X1a was prepared by reaction 4-flouro acetophenone with benzylthiol using KOH and absolute ethanol, then oxidation of compound X1a using H2O2 and acetic acid to give 4benzylsulfonylacetophenone X1b according to the method stated previously.As for 2cyanoacetohydrazide X2 was prepared by reaction of cyanoethylacetate with hydrazine hydrate according to the method listed previously 27 .The starting material hydrazide-hydrazone X3 was prepared from reaction 2-cyano acetohydrazide X2 with 4benzylsulfonyl acetophenone X1b in refluxing ethanol Scheme.1.The structure of the X3 was confirmed by physical and spectroscopic properties (FT-IR, 1 H-NMR and 13 C-NMR).The FT-IR spectrum showed the bands at 3029 cm -1 , 1664 cm -1 belonging to the (NH) and (C=N), respectively.In addition, the 1 H-NMR the spectrum of compound X3 showed (δ, ppm ): 11.25 [s, 1H, NH], 7.17-7.97[m,9H, Ar-H], 2.29 [s, 3H, CH3], the disappearance of NH2 bands in IR & 1 H-NMR spectrum are excellent evidence of the formation of the compound X3.While its 13

Scheme 1. Preparation of Hydrazide-Hydrazone X3
The thiophene derivatives X4-X6 were prepared from the reaction of the starting material hydrazidehydrazone X3 with cyclic ketones in the presence of elemental sulfur and using absolute ethanol as a solvent and sodium hydroxide as a base as shown in Scheme 2. The structure of the thiophene compound X5 was confirmed according to physical and spectroscopic methods (FT-IR, 1 H-NMR).The FT-IR spectrum showed the bands at 3063, 3032 cm -1 for (NH2).While the 1 H-NMR the spectrum of compound X5 showed signals at 1.58-3.37ppm [m, 10H, 5CH2-cycloheptane], 4.29 ppm [s, 2H, NH2], the appearance of NH2 bands and disappearance of nitrile band in IR spectrum and signals for protons NH2 and cyclic heptane in 1 H-NMR spectrum are strong evidence of the formation of the compound X5.

Scheme 2. Synthesis of Thiophene Derivatives X4-X6
Coumarin was prepared in two methods: the first method is the preparation of imine X7, X9 and coumarin X8, X10 compounds through two steps: the first is the preparation of imine compounds from the reaction of hydrazide-hydrazine X3 with 2hydroxynaphthaldehyde or 2-hydroxybenzaldehyde using absolute ethanol as a solvent and triethylamine as a base in the second step, the coumarin compounds are prepared through addition of HCl to imine compounds, Scheme.3.The structure of the imine compound X7 was confirmed according to physical and spectroscopic methods (FT-IR, 1 H-NMR, 13 C-NMR).The FT-IR spectrum showed the disappearance of nitrile bands.While the

Conclusion
This study used straightforward and basic working procedures, simple reaction conditions and inexpensive chemicals.Important compounds have been synthesized including hydrazide-hydrazone derivatives, thiophene, imine and Coumarin derivatives and some various compounds and pyrazole derivatives.It is believed to have biological value and medicinal applications depending on published literature.Therefore, this research focused on these derivatives.