Study On The Synthesis Of 3,4-Dihydropyrimidines And Its Derivatives

Although the acid-catalyzed one-pot condensation of aldehyde,β-ketoester,and urea to afford 3,4-dihydropyrimidinones(DHPMs),named as the Biginelli reaction from the name of its inventor,has been known for more than a century,the Biginelli-type 3,4-dihydropyrimidinones(DHPMs)were largely ignored in the early part of the 20th century. In the past decades,the scope of the original cyclocondensation reaction was gradually extended by variation of all three building blocks,allowing access to a large number of structurelly diversified multifunctionalized DHPMs.These nonplanar heterocyclic compounds have received considerable attention from the pharmaceutical industry because of their interesting multifaceted pharmacological profiles.In this thesis,the development of the Biginelli reaction.are reviewed and a seres of new methods for the synthesis of 3,4-dihydropyrimidines,N3-functionalized dihydropyrimidines, 5H-thiazolo[3,2-a]pyrimidines and dimethylated 3,4-dihydropyrimidin-thiones are described. These methods have the advantages of simple operation,high yield and high regioselectivity. More than,many reactions were carried out under environmently friendly conditions.The research results are summarized below:1.An efficient and environmentally friendly protocol for the synthesis of 3,4-dihydropyrimidones via the Biginelli-type condensation reaction using poly(ethylene glycol)bounded sulfonic acid as the catalyst under microwave has been developed.The funetionalized poly(ethylene glycol)acted simultaneously as catalyst and solvent in the condensation reaction.The work up was easily operated and the products were obtained in good to excellent yields and high purities.2.A new polymer supported sulfonic acid was prepared by the coupling reaction of crosslinked polystyrene-supported poly(ethylene glycol)with chlorosulfonic.This reagent was used to efficiently perform Biginelli reactions of aldehydes,β-ketoester compounds and urea or thiourea.This resulted in simple one-pot synthesis of the corresponding 3,4-dihydropyrimidinones.This reagent has advantages of simple operation,regeneration and reuse. 3.A simple and efficient method for the synthesis of N3-functionalized 3,4-dihydropyrimidinones by aza-Michael addition reactions of 3,4-dihydropyrimidinones toα,β-ethylenic compounds catalyzed by KF/Al₂O₃ is described.The advantages of this method are high regioselectivity,high purity,and the use of a cheaper,milder,and efficient catalyst for the hetero-Michael addition reaction.4.Poly(ethylene glycol)(PEG)is found to be an inexpensive,non-toxic,environmentally friendly reaction media for the Michael addition of 3,4-dihydropyrimidinones toα;β-ethylenic compounds to give N3-functionalized dihydropyrimidinones.Under the similar reaction conditions,2-amino-5-aryloxymethyl-1,3,4-thiadiazoles reacted with methyl acrylate to give unexpected products 5H,6H-[1,3,4]thiadiazolo[1,2-a]pyrimidine-7-ones through tandem Michael addition and intramolecular cyclization.5.5H-Thiazolo[3,2-a]pyrimidine can be efficiently prepared by the reaction of dihydropyrimidine-2-thione withα-bromoacetone,in water media.The easy and efficacy of this method provide an attractive route for the synthesis of 5H-thiazolo[3,2-a]pyrimidine derivatives.To the best of our knowledge,there has not been reported on the preparation of 5H-thiazolo[3,2-a]pyrimidine derivatives through reaction of dihydropyrimidine-thione withα-bromoacetone in aqueous media.6.An environmentally benign procedure for preparing dimethylated dihydropyrimidin-thiones has been developed by the reaction of dihydropyrimidin-thiones with dimethyl carbonate,a non-toxic and environmentally friendly reagent.The methylated of dihydropyrimidin-thiones is catalysted by MgO and TBAB under microwave.This protocol avoids the use of strong bases and highly toxic agents such as methyl halides or dimethyl sulfate.Additionally,the possible role of MgO/TBAB in the reaction is also presented.