Several Pd-catalyzed coupling reactions have been evaluated for the synthesis of 5-substituted uracils. A convenient reaction, further developed by us, is the Suzuki Pd(0)-catalyzed coupling between arylboronic acids and aryl bromides or iodides in weakly alkaline medium. However, all attempts to use 5-bromo- or 5-iodouracil as the aryl halide failed. On the other hand, couplings between 2,4-di-t-butoxy-5-bromopyrimidine and various arylboronic acids were successful. In cases when the arylboronic acids were not available, it was better to reverse the coupling functionalities and use 2,4-di-t-butoxy-5-pyrimidineboronic acid and arylbromides. A large number of 5-aryluracils were prepared in this way. They were obtained in almost quantitative yields by dealkylation of the 5-aryl-2,4-di-t-butoxypyrimidines. However, a great drawback of these procedures is the highly allergenic properties of 2,4-dichloro-5-bromopyrimidine, which is an intermediate in the synthesis of 2,4-di-t-butoxy-5-bromopyrimidine and 2,4-di-t-butoxy-5-pyrimidineboronic acid. In order to avoid this intermediate the coupling between 5-bromo-2,4-ditrimethylsilyloxypyrimidine and arylboronic acids were attempted but failed. Also attemptes to prepare 2,4-di-trimethylsilyloxy-5-pyrimidineboronic acid failed due to migration of a silyl group to the 5-position upon halogen-metal exchange. We therefore turned to the use of tin derivatives instead of boronic acids in the coupling reaction, which can be carried out under neutral conditions. Thus 5-(1-methyl-2-pyrrolyl)uracil, which could not be prepared from 2-bromo-1-methylpyrrole and 2,4-di-t-butoxy-5-pyrimidineboronic acid was obtained through the Pd(0)-catalyzed coupling of 1-methyl-2-trimethylstannylpyrrole and 2,4-di-t-butoxy-5-bromopyrimidine followed by dealkylation. However, the great advantage with the tin derivatives was that 5-bromo-2,4-ditrimethylsilyloxypyrimidine could be used in the coupling with aryltin derivatives giving 5-aryluracils in reasonable yields. We also tried to use unprotected 5-halouracils in the coupling reactions. We were unsuccessful with the 5-bromo derivative. However, with 5-iodouracil coupling was achieved in some cases.
