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 with anticancer and interferon-inducing properties. Synthetic routes to novel 5-aryl analogues of bropirimine have been developed and their potential molecular recognition properties analysed by molecular modelling methods. Sterically 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 converts the amphoteric pyrimidinones to their unreactive enolic forms. Palladium-mediated reductive dehalogenation of the pyrimidinone substrates effectively competes with cross-coupling. 2-Amino-5-halo-4-methoxy-6-phenylpyrimidines can be converted to a range of 5-aryl derivatives with the 5-iodopyrimidines being the most efficient substrates. Hydrolysis of the 2-amino-5-aryl-4-methoxy-6-phenylpyrimidines affords the required pyrimidin-4-ones in high yields. Semi-empirical quantum mechanical calculations show how the nature of the 5-substituent influences the equilibrium between the 1H- and 3H-tautomeric 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.
Hannah
D R
DR
Cancer Research Laboratories, School of Pharmaceutical Sciences, University of Nottingham, UK.
Sherer
E C
EC
Davies
R V
RV
Titman
R B
RB
Laughton
C A
CA
Stevens
M F
MF
D000276:Adjuvants, Immunologic / Q000737:chemistry* / Q000494:pharmacology*; D002384:Catalysis; D008958:Models, Molecular; D015394:Molecular Structure; D010165:Palladium / Q000737:chemistry*; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*; D013057:Spectrum Analysis; D013816:Thermodynamics
D000276:Adjuvants, Immunologic; D011743:Pyrimidines; D010165:Palladium