Selective Demethylation Reaction Under Microwave Irradiation And Its Application In Synthesis Of Scopoletin

Demethylation as one of the most important reactions is used extensively in drug synthesis and fine chemicals. The common way of protecting phenolic hydroxyl group is methylation or acetylation. However, each way has its advantages and disadvantages. Acylation and deacylation are easily with high yield. But methylation is facility and the product is stable, which is deprotected usually under special conditions in low selectivity. We hope to find an efficient technique for the selective demethylation with mild and rapid using aryl methyl ethers as substrate, and the application of the method to synthesize some biological active compoundes.Gerenally, demethylation reaction is usually performed with acids (including Lewis acids, i.e. AlCl₃ and BBr₃) or bases. However, these conditions are not compatible with compounds having acid- or base-sensitive functional groups. Up to now, there are few reports on the procedures for the chemo- and regioselective cleavage of aryl methyl ethers. Thus, it is necessary to develop a new and efficient procedure for selective cleavage of aryl methyl ethers in the presence of functional groups with cheap, commercial available reagents under essentially neutral conditions.First we investigated the demethylation reaction, used 6,7-dimethoxy-2H-1-Benzopyran-2-one as model compound. After a plenty of experimental researches, we finally find a satisfactory condition-demethylation being carried out under microwave irradiation (MWI) in N, N-dimethylformamide (DMF) with lithium chloride (LiCl) as promoter (LiCl-DMF-MWI system). In this condition, demethylation react rapidly and effectively with the chemo- and regioselectivity. And making use of the experimental methods, we analyse and investigate the usage amounts of solvent and salt ,and the effect to reaction by substituent and protect group; we also discuss the reacting selectivity of polymethoxyl phenols and the mechanism of the demethylation reaction; futher more, we do a comparison of reaction yield between microwave irradiation and traditional heating mode.In a word, this way makes a great progress, which can easily operated with cheap, commercial available reagents under essentially neutral conditions and less influence by acid or basic group, and the biggest advantage is that it offer pretty selectivity and high yield.The feasibility of the new way is also proved, In the technics improvement process of scopoletin, the selective demethylation reaction is performed in the lithium chloride-N, N-dimethylformamide (LiCl-DMF) system under microwave irradiation. Comparing with other methods, the synthetic route is able to shorten reaction time, improve the reaction yield and simplify operation after reaction completed. Undoubtedly, it is tendency that leads the synthesis of drugs to green chemistry considering the influence to environment. Quercetin is a kind of flavonoid, which is widely distributed in many dietary and medicinal plants including onion, tea, ginkgo biloba and others. It is a strongly natural antioxidant and such compound could play a key role in pharmacology, such as prevention of cardiovascular diseases, anticancer, neurodegenerative inhibition and so on. Therefore, quercetin attracts people attentions to do more researches on it.Quercetin structure has five phenolic hydroxyl groups, which in different positions are methylated can become other medicines with differently pharmacologically activities. It is well known that isorhamnetin is used in clinic to cure coronary artery diseases, rhamnetin is used as a fine anti-inflammatory, and these medicines are just such methylated products.The new way for synthesis of 3'-O-methylquercetin (isorhamnetin), 5-O-methylquercetin (azaleatin), 7-O-methylquercetin (rhamnetin) and intermediate compound 3, 3', 4', 5-tetra-O-benzylquercetin have been explored by the work on methylation of qucertin. In the synthesis processes of intermediate compound 3,3',4',5-tetra-O-benzylquercetin and 5-O-methylquercetin (azaleatin),we find metal complexes Copper(II) trifluoromethanesulfonate and reagent Toluene-4-sulfonyl azide with property of selective debenzylation ; making use of natrium biboricum let us have a chance to synthesize other methylation compounds. Adopting continuous reactions from protection reaction by natrium biboricum to methylation reaction, we successfully synthesize 7-O-methylquercetin (rhamnetin) by the only one step; Adopting three continuous steps reactions from ester exchange reaction, protection reaction by natrium biboricum to methylation reaction, we finally synthesize 3'-O-methylquercetin (isorhamnetin). The new method that include using natrium biboricum to protection reaction and many continuous steps reactions, can greatly shorten reaction time, decrease usage amounts of solvents, simplify operation after reaction completed and improve reaction yield.