Copper-Catalyzed Synthesis Of Bicyclic Pyrimidinones

Nitrogen-containing compounds are abundant in nature, and nitrogen heterocyclic ring exists widely in some bioactive products and medicinal compounds. The bicyclic pyrimidinones and their derivatives, nitrogen-containing six-member ring structures usually existing in HIV-1 integrase inhibitors, have very important physiological functions. However, the traditional synthesis of bicyclic pyrimidinones was limited by the complicated procedures and harsh reaction conditions.In recent years, copper-catalyzed Ullmann coupling reactions have attracted much attention, as the copper-catalysts are cheaper, low toxic, easy to prepare and relatively stable in air. Several useful domino processes have been developed to construct nitrogen heterocyclic ring based on copper-catalyzed Ullmann-type C-N coupling reactions such as N-arylation or N-vinylation. Mild conditions, simple and quick Ullmann coupling reactions can be achieved by the optimization of copper-catalysts, bases, ligand and additives to synthesize abundant bioactive and medicinal compounds. Herein, on the basis of reported copper-catalyzed Ullmann coupling reactions, we established a catalyst system to synthesize the bicyclic pyrimidinones.The method uses readily available 2-bromocyclo-1-enecarboxylic acids, amidines or guanidines as the starting materials, CuI as catalyst, Cs2CO3 as base, DMF as solvent, then one-pot cascade couplings provide the corresponding bicyclic pyrimidinones without addition of any ligand or additive under very mild conditions (room temperature to 50 oC). The target products were obtained in good yields (60~84 %) in a short time. Cyclopropanecarboxamidine and isonicotinamidine exhibited higher reactivity than other amidines. Guanidines also provided the corresponding bicyclic pyrimidinones in moderate to good yields when temperature was raised to 40 or 50 oC. For the 2-bromocyclo-1-enecarboxylic acids containing six, seven and eight-membered rings, their reactive activity did not show evident difference. The coupling reactions of the 2-bromocyclo-1-enecarboxylic acids with amidines or guanidines provide the opportunity for construction of the complex molecules, therefore, the method is of a lot of practical applications in synthetic chemistry, medical science and biology.This method has several advantages as follows: (1) Simple conditions and procedures; (2) Using the cheap and lowly toxic copper salt as the catalyst; (3) Without addition of any ligand or additive; (4) Under very mild conditions (room temperature to 50 oC); (5) Quick reaction (2h or more).