Preparation of Chalcones and Their Applications in Heterocycles Synthesis

: - Some new heterocyclic compounds containing, cyclohexenone, indazole, isoxazoline, pyrmidine and pyrazoline ring system were prepared from chalcones (1a,b). The starting chalcones (1a,b) were obtained by a base catalyzed condensation of appropriately substituted benzaldehydes and 2-acetylbenzofuran. The reaction of the prepared chalcones with ethylacetoacetate/hydrazine hydrate, hydroxylamine hydrochloride, urea, thiourea, hydrazine hydrate, phenyl hydrazine or hydrazide derivatives gave the mentioned heterocycles. All synthesized compounds have been characterized by physical and spectral methods


Introduction:-
Chalcones, one of the major classes of natural products and belongs to flavonoid family, have been reported to possess several biological activities [1,2].Chalcones are suitable for the synthesis of an important heterocycles like indazole, cyclohexenone, isoxazoline , pyrmidine and pyrazoline derivatives.Pyrazolines, for example, have attracted increasing attention due to their pharmaceutical applications such as: anti-bacterial [3], antifungal [4], enzymatic inhibitors [5] and the treatment of Parkinson's disease or head injuries [6].Pyrazolines also used in the synthesis of fluorescent dyes due to their optical properties [7], on the other hand isoxazoline known to display impressive therapeutic specifications in treatment of: bacterial infections in humans [8] and animals [9], immunological problems [10] and instance tumor growth [11] in addition to their use as insecticides, nematicides and molluscicides agents [12].Pyrimidine derivatives play an essential role in the medical field due to their antiinflammatory, anti-ulcerogenic [13], anti-AIDS [14], anti-depressant [15], HIF prolyl hydroxylase inhibition [16] activities.The importance of chalcones is their flexibility as synthons for the production of fused ring systems such 2H-indazoles via di-arylcyclohexenone derivatives as 12 -09 -1922 -971 -intermediates.Indazoles known to have medical uses in treating obesity and related diseases [17,18].Based on these considerations, we aimed to obtain the titled compounds.

Experimental:-
A-Materials: -All chemicals were supplied by Merck (Germany), Fluka (Germany) and Sigma Aldrich (UK) Chemicals Co. and used as received.

B-Instrumentation: -Melting points were determined in open capillary
tubes on an electro thermal digital melting point apparatus (USA) and were uncorrected.IR spectra were recorded on a SHIMADZU -FTIR-8400spectrophotometer in KBR discs. 1 H NMR spectra were measured with Bruker Ultra Shield AMX-300 MH2 Spectrometer (Germany) in DMSO and chemical shifts were recorded in a ppm relative to TMS as internal standard solvent.Elemental analyses were carried out using an EuroEA Elemental Analyzer at (The Central Service Laboratory-College of Education For Pure Sciences Ibn Al-Haitham).
Preparation of Chalcones and Their Applications in Heterocycles Synthesis …….Dheefaf F. Hassan

Synthesis procedures:-
All the prepared compounds were synthesized according to literature [19]

Preparation of cyclohexenone derivatives (2a,b):
A mixture of chalcones (1a,b) (0.01 mol) and ethyl acetoacetate (1.30 mL, 0.01mol) in absolute ethanol (10mL) containing aqueous potassium hydroxide solution (1 mL, 10%) was refluxed for 5h and then left overnight at room temperature.The solid formed was filtered off, air dried and recrystallized form absolute ethanol.The physical data of these compounds are listed in Table (1)

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A mixture of compounds (2a,b) (0.01 mol) and hydrazine hydrate 99% (5mL, 0.01 mol) in absolute ethanol (10 mL) containing glacial acetic acid (0.5 mL ) was refluxed for 2h.After cooling, the solid formed was filtered off, air dried and recrystallized form chloroform.The physical data of these compounds are listed in Table (1).

Preparation of 3-(benzofuran-2-yl)isoxazoline derivatives (4a,b):
To a mixture of chalcones (1a,b) (0.01 mol, 2.91 g) and hydroxyl amine hydrochloride (0.01 mol , 0.69 g) in absolute ethanol (30 mL), aqueous sodium hydroxide (10%, 6 mL) was added then the reaction mixture was heated under reflux for 8h and poured slowly into ice cold water and the product obtained was washed with water and recrystallized from absolute ethanol.The physical data of these compounds are listed in Table (1).

Preparation of pyrimidinone derivatives (5a,b):
To a solution of (0.01 mol, 2.91 g) of chalcones(1a,b) in absolute ethanol (10 mL), urea (0.01 mol, 0.6 g) of aqueous sodium hydroxide (10mL, 10 %) was added.The reaction mixture was heated under reflux for 5h and poured in ice-cold water.The product obtained was filtered washed with water and recrystallized from ethanol (95%).The physical data of these compounds are listed in Table (1).

Preparation of pyrimidinethion derivatives (6a,b):
To a solution of chalcones(1a,b) (0.01 mol) in absolute ethanol (10 mL), thiourea (0.01 mol, 0.6 g) and aqueous sodium hydroxide (10 mL, 20.0 mmol) were added.The reaction mixture was heated under reflux for 7h and poured into iced cold water the product obtained was filtered, washed with water and recrystallized from absolute ethanol.The physical data of these compounds are listed in Table (1).

Results and discussion
The synthesis of chalcones and heterocyclic derivatives were performed as shown in schemes ( 1 -971 -chlorophenyl) prop-2-ene-1-one (1b), were synthesized via the Claisen-Schmidt reaction of 2-acetyl benzofuran with 4-hydroxybenzaldehyde and 4-chlorobenzaldehyde, respectively, in ethanol in the presence of aqueous sodium hydroxide at room temperature.The glow red and pale brown solids obtained were filtered, washed and recrystallized from chloroform, (65% and 78%), m.p = 105-107 0 C and 88-90 0 C, respectively.The structural assignments of the chalcones (1a,b) based on melting points and FTIR spectroscopy.The FTIR spectra of chalcones indicated the appearance of two peaks around 1655-1666 cm -1 and 1573-1612cm -1 due to C=O and C=C stretching vibrations, respectively.
The chalcones (1a,b) were allowed to react with ethyl acetoacetate (1:1) in the presence of an aqueous potassium hydroxide 10 % to give new cyclohexenone derivatives (2a,b) which were identified by their melting points, C.H.N analysis and FTIR spectroscopy.The FTIR spectral data of these compounds are shown in Table (2).The formation of cyclohexenones can be explained by based-catalyzed Michael addition conversion of the intermediates into cyclohexenones [20].2a,b) with hydrazine hydrate in the presence of glacial acetic acid afforded the corresponding indazoles.The reaction may have proceeded through condensation between C=O of cyclohexenone and NH 2 of hydrazine hydrate, followed by cyclization with the loss of an ethanol molecule [19].The new indazole derivatives (3a,b) were identified by their melting points, FTIR and 1 H NMR spectroscopy.The FTIR spectra of these compounds showed the disappearance of C=O and C-O-C absorption bands of esters and appearance of new absorption bands of NH and C=N group at 3228 cm -1 and 1610 cm -1 , respectively.Functional groups which are characteristic of these compounds are given in Table (2).The 1 H NMR spectrum of compound (3b) (in DMSO) shows the following signals: eight aromatic protons appeared in the region δ 7.20-8.73ppm, a singlet signal at δ 6.80 ppm for furan ring conjugate with benzene ring, a signal at δ 3.12 ppm that are attributed to cyclohexene protons and a singlet signal at δ 2.93 ppm which was assigned to NH proton.
Isoxazoline compounds (4a,b) were synthesized from the reaction of chalcones (1a,b) with hydroxylamine hydrochloride in alkaline medium.These compounds (4a,b) were identified by their melting points, FTIR and 1 H NMR spectroscopy.The FTIR spectra of isoxazoline (4a, b) showed the disappearance of two absorption bands of CH=CH and C=O groups of the starting materials with the appearance of new absorption bands for C=N group around 1630 cm -1 and C-O (cyclic ether) group around 1091 cm -1 .The FTIR spectral data for isoxazoline (4a, b) are listed in Table (2).
1 H NMR spectrum of compound (4b) , Figure (1), (in DMSO as a solvent), showed many signals of aromatic protons appeared in the region δ 7.04-7.88ppm and a signal in the region δ 6.68 ppm for furan ring conjugate with benzene ring.Furthermore, the triplet signal at δ 2.97 ppm and a doublet signal at δ 3.64 ppm due to one proton C-5 and two protons C-4 in the isoxazoline ring, respectively.In addition to a signal at δ 8.25 ppm which was assigned to the proton of OH.
The pyrimidinone derivatives (5a, b) were synthesized from the reaction of chalcones (1a,b) with urea in basic medium.The structures of

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the pyrimidinones (5a,b) are characterized by FTIR spectra which are showing the disappearance of two absorption bands and appearance of new absorption bands for NH and C=O groups around 3338cm -1 and 1665cm -1 , respectively.The other data of functional groups which are characteristic of these compounds are given in Table (2).
1 H NMR spectrum of pyrimidinone (6a), Figure (2), exhibited eight aromatic protons appeared at δ 7.11-7.88ppm, a singlet signal at δ 6.78 ppm for furan ring conjugate with benzene ring, a singlet doublet at δ 3.04 ppm for proton at C-5 of pyrimidinone ring, a singlet at δ 2.51ppm that could be attributed to one proton of NH group.In addition to a signal at 9.66 ppm which was assigned to the proton of OH.
Pyrimidinethion derivatives (6a,b) were synthesized from the reaction of chalcones (1a,b) with thiourea in basic medium.The structures of compounds (6a,b) are characterized by FTIR and 1 H NMR spectroscopy.The characteristic FTIR adsorption band of pyrimidinethion showed the disappearance of two absorption bands of the CH=CH and C=O groups in the chalcones and appearance of new absorption bands for NH and C=S groups around 3283cm -1 and 1280cm -1 , respectively.The FTIR spectral data of these compounds are shown in Table (2).
The structure of the pyrazoline derivatives (7-11a,b) were identified by their melting points, FTIR and 1 H NMR spectroscopy.The FTIR spectra of these compounds showed the disappearance of two absorption bands of the CH=CH and C=O groups in the chalcones (1a,b) and appearance of new absorption stretching bands of NH and C=N groups Table (2). 1 H NMR spectrum of compound (7b), (Figure 3), (in DMSO as a solvent), shows the following signals: a sharp singlet signal at δ 2.49 ppm due to a proton of the N-H group, sharp signals at δ 1.78 ppm could be attributed to two protons of CH 2 pyrazoline, signal in the region δ 7.35 ppm for furan ring conjugate with benzene ring and many signals (aromatic protons) appeared in the region δ 7.80-7.95ppm.