Structural studies on bioactive compounds. Part 29: Palladium catalysed arylations and alkynylations of sterically hindered immunomodulatory 2-amino-5-halo-4,6-(disubstituted)pyrimidines

The immunological agent bropirimine 5 is a tetra-substituted pyrimidine wit h anticancer and interferon-inducing properties. Synthetic routes to novel 5-aryl analogues of bropirimine have been developed and their potential mol ecular recognition properties analysed by molecular modelling methods. Ster ically challenged 2-amino-5-halo-6-phenylpyrimidin-4-ones (halo = Br or I) are poor substrates for palladium catalysed Suzuki cross-coupling reactions with benzeneboronic acid because the basic conditions of the reaction conv erts the amphoteric pyrimidinones to their unreactive enolic forms. Palladi um-mediated reductive dehalogenation of the pyrimidinone substrates effecti vely competes with cross-coupling. 2-Amino-5-halo-4-methoxy-6-phenylpyrimid ines can be converted to a range of 5-aryl derivatives with the 5-iodopyrim idines being the most efficient substrates. Hydrolysis of the 2-amino-5-ary l-4-methoxy-6-phenylpyrimidines affords the required pyrimidin-4-ones in hi gh yields. Semi-empirical quantum mechanical calculations show how the natu re of the 5-substituent influences the equilibrium between the 1H- and 3H-t automeric forms, and the rotational freedom about the bond connecting the 6 -phenyl group and the pyrimidine ring. Both of these factors may influence the biological properties of these compounds. (C) 2000 Elsevier Science Ltd . All rights reserved.