Microwave-assisted synthesis of curcumin analogs

Curcumin, a 1,7-diaryl-1,6-heptadiene-3,5-dinone, has attracted considerable attention worldwide owing to its outstanding biological properties. Microwave-assisted expeditious synthesis of numerous cyclic analogs of curcumin under solvent-free and environmentally-benign conditions in moderate to excellent yields is reported here.


Introduction
Curcumin (1) is a phytochemical obtained from Curcuma longa, commonly known as turmeric, a spice widely used in South-East Asia.It has attracted a lot of attention due to its promising biological properties to treat cancer, 1 Alzheimer's disease, 2 HIV, 3,4 chronic inflammations, 2 oxidative stress, 5 and cystic fibrosis. 6Curcumin underwent clinical trial for cancer owing to its prominent activity as an antitumor and chemopreventive agent. 7However, this trial ceased due to poor bioavailability of the molecule. 8,9Clinical trials are ongoing to test the efficacy of curcumin against Alzheimer's disease 10 and cystic fibrosis. 11[14][15][16][17]  Unlike 2,4-pentadione, 2-acetylcycloalkanones not only have a more nucleophilic and more crowded active methine, but are also very prone to ring cleavage under aqueous basic conditions. 21A procedure reported for condensation of aromatic aldehydes on cyclic β-diketones involved the use of 1 molar equivalent of boron oxide in presence of catalytic amounts of morpholine and acetic acid under solvent-free heating conditions. 20The complexation with boron oxide also protects the 2-acetylcycloalkanones from potential ring cleavage reaction. 20The reported yields under these conditions are moderate to good; however, the work-up conditions pose difficulties in purification of compounds.
We herein report a modification of this procedure with significant improvement in yields, reaction time and purity of isolated products.

Results and Discussion
Numerous microwave-assisted aldol condensations have been reported [22][23][24] but the use of microwave energy in carrying out boron-assisted regioselective aldol condensation was not found in literature.3][24][25] Since the reported procedure for synthesis of carbocyclic analogs of curcumin involved heating conditions, it appeared logical to attempt their synthesis under microwave irradiation conditions.Moderate to excellent yields of the desired compounds were obtained when the reaction mixture was irradiated for 1 minute by ARKAT microwaves.It should be noted that the reactions were carried out in a conventional microwave oven at highest power where the control of the reaction course is not ideal; however we found these reactions to be qualitatively (based on tlc intensities) reproducible.
A modified work-up procedure made the isolation and purification of compounds simpler.As indicated in the experimental section, the yields of the compounds made under this investigation under microwave-assisted conditions are consistently higher than those reported under conventional conditions.Although the work-up conditions are generally product specific, the work-up of relatively non-polar compounds was straightforward.Digestion in methanol produced reasonably pure product in powder form.Polar products (2d, 2f, 3d and 3f) containing a hydroxyl group had appreciable solubility in methanol and were purified by column chromatography.
The compounds were characterized by spectroscopic means and by comparison to reported data wherever possible. 20NMR spectra revealed that the compounds exist in enol form in solution.The H-bonded hydroxyl proton of the enol form expected in highly desheilded region (>δ 13) was not always seen; the active methine (-COCHCO-) of the diketo tautomer was never observed.When subjected to HR-MS, all compounds concurred very well with calculated values.The biological activity of these compounds will be published subsequently.

Conclusions
In conclusion, an efficient, expeditious and simple procedure for the synthesis of carbocyclic curcumin analogues has been developed.It furnishes the desired compound with greater purity and moderate to excellent yields.

Experimental Section
General Procedures.All chemicals and reagents were obtained from Aldrich Chemical Co.Column chromatography purifications were undertaken using silica gel (230-400 mesh) obtained from Silicycle. 1 H NMR and 13 C NMR were recorded on Bruker AV300 NMR spectrometer.EI-MS and HR-MS spectra were obtained on CEC 21-110B Sector instrument.Melting points were recorded on an electro-thermal apparatus and are uncorrected.UV-Vis and IR spectra were recorded on LKB Biochrom Ultraspec Plus 4054 and Nicolet Avatar 330FT-IR spectrophotometers respectively.A domestic 1.2 cu.ft.microwave oven equipped with a turntable manufactured by Kenmore with 4kV DC operating voltage was used for the microwaveassisted reactions.The highest power (900 W) and operating frequency (2450 MHz) were employed.General synthesis of carbocyclic curcumin analogs 2a-h and 3a-g.The cycloalkanone (10 mmol) was mixed with the boron oxide (10 mmol) in a 50 mL Erlenmeyer flask.The appropriate aromatic aldehyde (20 mmol), acetic acid (50 mg), and morpholine (50 mg) were then added.The reaction was irradiated with the microwave at high power for 1 minute.The flask was cooled for 2 minutes and then methanol (30 mL) was added.This mixture was then sonicated until a fine powder was obtained.The product so obtained was filtered and washed with cold methanol.Compounds 2d, 2f, 3d and 3f did not respond favourably to methanol treatment and consequently they were purified by silica gel column chromatography using dichloromethane-methanol as gradient solvent for elution.