A Modified Synthesis of 3-Methyl-Flavones Under Microwave Conditions

Abstract

3-Methyl flavones are important members of the flavonoid family which are widely found in nature and are well known for their biological activities. A new, efficient method has been developed for their synthesis using 2-hydroxydibenzoylmethane and iodomethane with potassium carbonate under microwave irradiation for 30 seconds followed by a reaction with phosphorus pentoxide. This protocol offers advantages such as avoiding hazardous chemicals and organic solvents, shorter reaction times, and higher yields than traditional methods.

Introduction: Flavonoids are polyphenolic compounds found in many plants. Most flavonoids have been reported to react selectively with free radicals and exhibit anti-inflammatory activity^1-7. Flavanols and their derivatives have received special attention from chemists because they prevent various degenerative diseases, such as cardiovascular and cancer^8-9. These are also found to possess various pharmacological activities like antidiabetic, hepatoprotective, antidiabetic^10-15, etc. Due to their pharmacological importance, much emphasis has been placed on the synthesis of 3-methyl flavones. One widely used method was the Allan-Robinson method¹⁶. This method involves heating 2-hydroxy ω-methoxy acetophenones with aromatic acid anhydrides in the presence of the potassium salt of the acids. The improved synthetic method involves a novel demethylation process of the 3-methoxy group without the need of hydrogen peroxide. By utilizing a combination of mild demethylation conditions and a catalyst, the 3-methoxy group can be selectively removed, leading to the synthesis of 3-methylflavones with enhanced purity and yield. This novel approach eliminates the challenges posed by the insolubility of 2′-hydroxy chalcones and the use of hazardous substances, thereby aligning with green chemistry principles and the growing demand for sustainable synthetic pathways. These reactions are carried out through grinding and microwave techniques which are successfully employed in several organic transformations^17-26. It is well established that the energy produced on the surface of the friction of the molecules caused by grinding and microwave provides the activation energy for the reaction²⁷. Moreover, this technique can be employed on an industrial scale very easily, by using an electric food mixer with stainless steel rotors, or by using a ball mill. Therefore, it was thought worthwhile, to synthesize substituted flavonols, through the grinding and microwave technique.

Methods: Melting points were determined in an open capillary tube. TLC is used to monitor the reactions. A mortar and pestle made of porcelain was used to carry out the reaction. ¹H NMR, ¹³CNMR, and mass spectra were used to characterize the synthesized compound. The IR spectra were recorded on a Perkin Elmer spectrum BX series FT-IR spectrophotometer with KBr pellets. ¹H NMR spectra were recorded on Bruker Avance 400 MHz instrument using TMS as the internal standard. All the chemicals were obtained commercially and used without further purification.

Results The reaction of 2-hydroxydibenzoylmethane with iodomethane and potassium carbonate through grinding followed by microwave irradiation to afford 3-methyl flavones was taken as a model reaction. The compound was extracted by acidifying the reaction mixture in cool, concentrated hydrochloric acid. The reaction of 2-hydroxydibenzoylmethane with iodomethane and potassium carbonate through grinding followed by microwave irradiation to afford 3-methyl flavones was taken as a model reaction. The compound was extracted by acidifying the reaction mixture in cool, concentrated hydrochloric acid.

Conclusions:  The protocol for synthesizing 3-methyl flavone using potassium carbonate via oxidative cyclization of 2-hydroxydibenzoylmethane is highly efficient and eco-friendly as it avoids toxic organic solvents. This is the clean, mild, high-yield, and expeditious method that also avoids the formation of any by-products.