Roger Bernard Titman

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.

Novel Preparation of 1-Aryl-3-(2-hydroxyphenyl)-2-pyrazolin-5-ones and their Conversion into 2-Aryl-4-methyl[1]benzopyrano[4,3-c]pyrazol-3(2H)-ones†

1-Aryl-3-(2-hydroxyphenyl)-2-pyrazolin-5-ones are prepared from 4-hydroxycoumarin and arylhydrazines and then cyclised with triethyl orthoacetate to give 2-aryl-4-methyl[1]benzopyrano[4,3-c]pyrazol-3(2H)-ones.

Use of highly stereospecific 1,3-dipolar cycloadditions of cyclic nitrones with acetylenes in the preparation of novel heterocyclic ring systems

Cyclic nitrones with substituents α to the nitrogen atom undergo 1,3-dipolar cycloadditions in a stereo- and regio-specific manner with acetylenes. The nitrone 3 reacts with methyl propiolate, methyl phenylpropiolate and methyl acetylpropiolate to give the corresponding pyrrolo[1,2-b]isoxazoles 5, 8 and 13 respectively. Compound 13 reacts with 4-chlorophenylhydrazine to afford the pyrazolo[4,3-a]pyrrolizine 15 by a novel rearrangement. The nitrone 18 undergoes a 1,3-dipolar cycloaddition with methyl propiolate in a stereo- and regio-specific manner to give the isoxazolo[2,3-a]pyridine 19. The nitrone 18, when reacted with methyl acetylpropiolate, gives a mixture of regioisomers in a ratio of 3∶2. The major regioisomer 21 reacts with 4-chlorophenylhydrazine to afford the novel pyrazolo[4,3-a]indolizine ring system 23. The bicyclic nitrone 26 reacts with methyl propiolate and methyl acetylpropiolate to give the cycloadducts 27 and 28 respectively; both these compounds contain the novel isoxazolo[3,2-i]indole ring system.