Reductive Ring Opening of 3 , 5-Bis ( 2-arylethenyl ) isoxazoles with Molybdenum Hexacarbonyl : A Novel Route to Symmetrical and Unsymmetrical Curcumin Derivatives

Curcumin derivatives were successfully synthesized from 3,5-dimethylisoxazole by lateral metalation and condensation with various aromatic aldehydes sequentially at C5and C3-methyl groups. After dehydration, further transformation of isoxazole ring to b-diketone moiety was accomplished by reductive ring opening using molybdenum hexacarbonyl [Mo(CO)6] and subsequent simple acidic hydrolysis. key words : Curcumin derivatives, Reductive ring opening, Molybdenum hexacarbonyl, Lateral metalation


INTRODUCTION
C u r c u m i n , 1 , 7 -b i s ( 4 -h y d r o x y -3methoxyphenyl)-1,6-heptadien-3,5-dione, is a bioactive compound isolated from Curcuma longa rhizomes.Curcumin has been reported to possess antioxidant, anti-inflammatory, antitmicrobial and anticarcinogenic activities. 1 Various curcumin derivatives have been synthesized for testing their biological activities.Synthetic symmetrical curcumin derivatives reported in literature [2][3][4][5] were obtained from Pabons procedure. 6Unsymmetrical curcumin derivatives, on the other hand, were synthesized by solid-phase synthetic strategy. 7Both syntheses proceeded through acetylacetone-boric anhydride complex which methyl terminals of this complex were allowed to undergo aldol condensation.

Experimental Section general
Melting points were determined by usinga Sanyo Gallenkamp melting point apparatus and are uncorrected.IR spectra were taken with a Perkin Elmer Spectrum One FT-IR Spectrometer. 1 H and 13 C NMR spectra were recorded using a VARIAN MERCURY plus (400 MHz FT NMR).
n -BuLi and s-BuLi were prepared and their concentration were determined following the standard procedure. 8,9eparation of 3,5-dimethylisoxazole (5) 10 A solution of hydroxylamine hydrochloride (8.34 g, 0.12 mole) in water (10 ml) was added a solution of 2,4-pentanedione (6) (10.2 g, 0.1 mole) in ethanol (10 ml).The mixture was heated under reflux temperature for 3 hours, then allowed to cool to room temperature and poured into cold water (60 ml).The resulting mixture was extracted with ether (3x40 ml).The combined organic layer was dried (Na 2 SO 4 ) and evaporated to dryness under reduced pressure.The brown oily residue was purified by distilling under reduce pressure to give 3,5-dimethylisoxazole (

general procedure for preparation of 5-(2-aryl-2hydroxyethyl)-3-methylisoxazoles 4a-c
To a stirred solution of 3,5-dimethylisoxazole (5) (2.91 g, 30.0 mmol) in dry THF (60 ml) was added n-BuLi (1.0 M in hexane; 30 ml, 30.0 mmol) dropwise under N 2 at -78 °C and the mixture was stirred for an additional1 hour.A solution of aromatic aldehyde (30.0 mmol) in THF (6 ml) was then added.The resulting mixture was allowed to warm up to room temperature and treated with water.The phases were separated and the aqueous layer was extracted with ethyl acetate (3x120 ml).The combined organic layer was dried (Na 2 SO 4 ) and concentrated under reduce pressure.Purification of the residue using column chromatography on silica gel with a gradient of 10-50% ethyl acetate in hexane as eluent gave 5-(2-aryl-2-hydroxyethyl)-3-methylisoxazoles 4a-c (70-84%) as yellow oils or as white crystalline solids.

Scheme 4:
N O Ar
The weak N-O bond of isoxazole ring is easily cleaved into b-aminoenone by either catalytic hydrogenolysis with platinum or palladium and Raney nickel under normal pressure and temperature 16,17 or by treatment with transition metal carbonyls such as molybdenum hexacarbonyl [Mo(CO) 6 ]. 18 To avoid catalytic hydrogenation at the two styryl groups, 3,5-bisstyrylisoxazoles 2a-f were treated with molybdenum hexacarbonyl in moist acetonitrile at reflux temperature.This treatment successfully provided the corresponding 1,7-diaryl-5-amino-1,4,6-heptatrien-3-ones 8a-f in moderate yields ( Scheme 5).
b -Aminoenones are easily transformed into b-hydroxyenones by simple acidic hydrolysis. 19,20n our final step, hydrolysis of b-aminoenones 8a-f was carried out by treatment with hydrochloric acid in ethanol at pH 4-5.The corresponding curcumin derivatives, in their enol forms 1a-f were obtained in satisfied yields (Scheme 6).

CONCLUSIONS
The present six steps procedure provides a novel alternative route to symmetrical and unsymmetrical curcumin derivatives.Good to moderate yields of expected products were obtained from each step.