Syntheses and Reactions of 4′-[(ω-Bromoalkyl)oxy]-and 4′,4′′′-(Polymethylenedoxy)-bis Substituted Chalcones

Base catalyzed condensation of 4-hydroxyacetophenone (1) with several aldehydes resulted 4′-hydroxychalcones (2a-c). Reaction of α,ω -dibromoalkanes (3, n=2, 4 & 6) with (2a-c) in equimolar ratio resulted a mixture of 4′-[(ω-bromoalkyl)oxy]- substituted chalcones (4a-i) and 4′,4′′′-(polymethylenedioxy)-bis substituted chalcones (5a-i) separated by ethanol as soluble (4a-i) and insoluble (5a-i) products. Compounds (5a-i) were also synthesized by another route. Compound 1 on treatment with 3 in molar ratio 2:1 resulted 4′,4′′′-(polymethylenedioxy)-diacetophenone (4#a-c) which on base catalyzed condensation gave compounds (5a-i). Reaction of 4d with substituted phenols and thiophenols gave corresponding phenoxy and thiophenoxy substituted chalcones (6a-f) where as compounds 5a, 5b, 5d, 5h and 5e on treatment with hydrazine hydrate furnished corresponding bis-2-pyrazolines (7a-e). The structures of all synthesized compounds were confirmed on the basis of analytical and spectral data.


Introduction
Chalcones are natural or synthetic compounds bearing the 1,3-diphenylpropenone framework. Depending on the substitution pattern on the two aromatic rings, a wide range of pharmacological activities have been identified for various chalcones. These include among others, cytotoxic, antitumor, antiviral and antiprotozoal activities 1,2 . More recently, there has been strong interest in the potential antimalarial 3 activity of chalcones and bis-chalcones. The antimalarial activity of chalcones was first noted when lipochalcone-A, a natural product isolated from Chinese liquorice roots, was reported to exhibit potent in vivo and in vitro antimalarial activity 4 . Subsequently, a synthetic analogue, 2,4-dimethoxy-4′-butoxychalcone was reported to have outstanding antimalarial activity 5 . Variously substituted pyrazolines and their derivatives are important biological agents and a significant amount of research activity has been directed towards this class [6][7][8][9][10] . Prompted by the varied biological activities of the chalcones, bis-chalcones and pyrazolines and in continuation to our work on 4′-alkoxy substituted chalcones 11 and other substituted analogues [12][13][14][15] for biological evaluation and synthesis of variously sized heterocycles it was contemplated in this present work to synthesize variously substituted 4′-[(ω-bromoalkyl)oxy]chalcones, 4′,4′″-polymethylenedioxybischalcones and 4′,4′″-polymethylenedioxy-bis-2-pyrazolines.

Experimental
All melting points were determined in open capillaries in liquid paraffin bath and are uncorrected. The IR spectra were recorded on Perkin-Elmer-783 spectrophotometer ‫ט(‬ max in cm -1 ) using KBr pellets. 1 H NMR spectra were recorded on a Bruker DRX-300 MHz spectrophotometer (δ, ppm) using CDCl 3 / DMSO-d 6 as a solvent and TMS as internal standard. The purity of the compounds was checked by TLC on silica gel coated glass plates. The elemental analyses were performed on Carlo-Erba-1108 analyzer and were within ±0.5% of the calculated values. Syntheses of 4′-hydroxychalcones and α,ω-dibromoalkanes (Br-(CH 2 ) n -Br: n= 2,4 & 6) were carried out by literature methods 16 .

General procedure for the preparation of 4′-[(ω-bromoalkyl) oxy]-substituted chalcones (4a-i) and 4′,4′″-(polymethylenedioxy)-bis substituted chalcones (5a-i)
An appropriate 4′-hydroxy chalcone 2 (0.01 mol) and α,ω-dibromoalkane 3 (0.01 mol) (n = 2, 4 or 6) in dry acetone (100 mL) and anhydrous potassium carbonate (0.02 mol) were refluxed (10-15 h). The completion of the reaction was judged by negative test with alcoholic ferric chloride. After completion of the reaction, acetone was distilled off and the residue in the flask was treated with ice cold water and stirred well. Separated solid was filtered and washed with 5% NaOH solution and finally with water (3 x 30 mL). The solid was dried, dissolved in boiling ethanol and filtered hot. Some solid remains insoluble which was washed again with hot ethanol. The filtrate after concentration afforded a solid which on crystallization from proper solvent gave compounds (4a-i). Whereas ethanol insoluble solid resulted bis chalcones (5a-i) General procedure for the preparation of 4',4'''-(polymethlenedioxy) diacetophenones (4 # a-c) 4-Hydroxyacetophenone (1) and α,ω-dibromoalkane (3 n= 2, 4 or 6) in the molar ratio 2:1 in acetone (100 mL) and anhydrous K 2 CO 3 (0.025 mol) were refluxed (10 to 15 h). The completion of the reaction was judged by the negative alcoholic ferric chloride test. On completion of the reaction, acetone was distilled off and the residue was treated with cold water (3 x 30 mL). The solid obtained on recrystallization from ethanol afforded the compounds 4 # a-c. Using this procedure following compounds were prepared.

General procedure for the preparation of 4′,4′′′-(polymethylenedioxy) bis substituted chalcones (5a-i) from compounds 4 # a-c
Diacetophenone 4 # (0.01 mol) and appropriate substituted aromatic aldehyde (0.025 mol) were dissolved in ethanol (100 mL). To this solution NaOH (20 mL, 15%) was added and the mixture was stirred constantly at room temperature (5 h), when a semi solid mass separated. It was acidified with dilute HCl and separated solid was filtered, washed with water (2 x 30 mL), dried and recrystallized from proper solvent to afford analytical samples of (5a-i) in 60 to 80% yield and were fully characterized by m.p., m.m.p., co-TLC and super imposable IR spectra with authentic samples prepared by another route.

General procedure for the preparation of 3,3′-[poly methylene bis (oxy-ophenylene)] bis[5-(p-substituted phenyl)-2-pyrazolines] (7a-e)
To a solution of bis chalcone 5 (0.01 mol) in DMF (40 mL), hydrazine hydrate (0.2 mol, 95%) was added drop wise. The reaction mixture was heated under reflux for 8-10 h. The contents were poured into ice water with stirring. The resulting solid product was filtered, washed with water and dried. Further purification was done by crystallization using suitable solvents.

Results and Discussion
The synthesis of chalcones was effected via carbon-carbon bond formation using a Claisen-Schmidt condensation reaction. p-Hydroxyacetophenone (1) was condensed with appropriate aromatic aldehydes in equimolar ratio in presence of base at room temperature. The formation of chalcones (α,β-unsaturated ketones) 2, was adjudged by the appearance of the carbonyl stretch at 1650-1670 cm -1 and disappearance of carbonyl stretch at 1683.8 cm -1 of p-hydroxyacetophenone. The trans alkene (E-form) nature of these chalcones was judged by 1 H NMR spectroscopy.
Finally compounds (5a, 5b, 5d, 5h and 5i) were treated with hydrazine hydrate in presence of DMF afforded the corresponding bis-2-pyrazolines (7a-e). The analytical and spectral data of synthesized compounds were in conformity with the proposed structure (Scheme 1).

Conclusion
A convenient synthetic methodology for a new class of chalcones, bis chalcones and bispyrazolines was described. It can be concluded that this class of compounds certainly holds great promise towards the pursuit for further synthetic and biological evaluation.