Microwave To Promote Cross-coupling Reactions And Synthesis Of Quinazoline Ketones And Application

The use of microwave heating as a tool for organic synthesis has been a very promising area and microwave-promoted reactions have witnessed many recent research activities during the past decades. The advantages of the microwave method over conventional techniques include the significantly shortened reaction time, more eco-friendly and, in certain cases, higher purity of final products than conventional reactions. Even some reactions that don't occur under traditional conditions can proceed smoothly under microwave heating condition. In this dissertation we wish to report our recent investigations on the synthesis of diaryl ethers, diaryl sulfides, heteroaryl ethers and heteroaryl sulfides, quinazolines, and aromatic sulphones. Also we have achieved the synthesis of the anti-cancer drug ZD1839 based on the construction of the key quinazolin-4(3H)-one intermediate under microwave irradiation.In chapter 2 of this dissertation, we describe the synthesis of diaryl ethers, diaryl sulfides, heteroaryl ethers and heteroaryl sulfides. Initially, we used the model reaction of phenol with 4-fluorobenzonitrile to explore the optimized condition by varying solvents, bases and ratio of reactants. It was found that K₂CO₃ as the base and DMSO as the solvent, the reactants ratio was 1:1.2 and microwave heating 5-10 minutes was enough. Under these conditions several activated halobenzenes underwent smooth coupling with phenols which bearing a wide range of functional groups, even with strong electron withdrawn groups, to provide good yields of the ether products. But in the case of aryl halides without electron withdrawn group the reaction didn't occur, if any. In this chapter, we also studied the coupling of thiophenol with electron-deficient aryl halides through S_nAr reaction. The scope of the protocol can be expanded to the reaction of a pool of six-membered heterocycles bearing a hydroxyl group as well as 2-pyrimidinethiol with mildly activated aryl halides, providing heteroaryl ethers and sulfides, respectively.In chapter 3 of this dissertation, we study the synthesis for the quinazoline derivativesunder microwave irradiation. After screening solvents, ligands and ratio of reactants, we found the optimized reaction condition for this reaction using acid as the catalyst and DMSO as the solvent. Under these conditions, both anthranilamide and anthranilic acid can couple with amids giving the corresponding 2-yl-quinazoline-4(3H)-one in good yields. Furthermore, we found that anthranilamide can couple with ketones under microwave irradiation giving 2,2-diyl-2,3-dihydroquinazolin-4(1H)-one and with carbamide affording quinazoline-2,4(1H, 3H)-dione.In chapter 4 of this dissertation, we study the synthesis of new anti-cancer drug ZD1839. Firstly, we started our work from the building of side chain using the reported method but the yield was unacceptable. We then optimized the reaction condition and gained the side chain in good yields. Using isovanillin as the staring material, we completed the synthesis of the target molecule ZD1839 over 12 steps. In the synthesis of quinazoline-4-one, we used MWI method to shorten the reaction time and raise the yield.In chapter 5 of this dissertation, the cross-coupling reaction between aryl activated aryl halides and sodium sulfinate under MWI was investigated. Initially, we used the model reaction of sodium benzosulfinate with 4-fluorobenzonitrile to explore the optimized condition by varying solvents, ligands and ratio of reactants. It was found that DMSO as the solvent, with reactants ratio being 1:2 satisfactory yields of the sulfone compounds could be achived. Under these conditions, sodium benzosulfinate coupled with several electron-deficient aryl halides through S_NAr reaction. We also explored the coupling of sodium methylsulfinate with electron-deficient aryl halides and moderate to high yields were obtained.