Amidines 4 -pyrimidinones

Literature reports on synthetic methods for the construction of the pyrimidinone core were very limited. Most of the synthetic strategies toward the densely functionalized core fell into two methodologies, which start from the same amidoxime 13 (Scheme 6.3). Route A is a three-step sequence that involves hydrogenation of 13 to prepare amidine 14. Claisen condensation of commercially available a-benzyloxy acetate and methyl tert-butyl oxalate provides the dihydroxyfumarate... 

Scheme 6.4 Condensation of dihydroxyfumarate derivatives with amidines to pyrimidinone...

Cyclobutane-fused pyrimidinones 39, precursors to quinone methide intermediates, have been prepared by reaction of amidines with the cyclopropane ester 38 <06EJOC2753>. 

Factors influencing the choice of synthetic routes to pyrimidines depend very much upon the substitution pattern of the desired product. For pyrimidines unsubstituted at the 4- and 6-positions, a two-component ring synthesis reaction involving a 1,3-dialdehyde and a urea or amidine derivative is the most straightforward route, but only if the dialdehyde is readily available. For example, synthesis of 2-chloro-5-(2-pyridyl)pyrimidine 989, an intermediate in the synthesis of a selective PDE-V inhibitor, was achieved in two steps in 40% overall yield by condensation of 2-(2-pyridyl)malondialdehyde 987 with methylurea, followed by demethylation/chlorination of the pyrimidinone 988 with a mixture of POCI3 and PCls <20070PD237>. 

In another cyclization procedure for the 1,5-benzodiazodne system, the nitriles (296) are converted to the aminodihydrodiazocines (297) (79CPB2589). Attack of nucleophiles on (297) occurs at the N-5—C-6 bond to give the 3,4,5,6-tetrahydrodiazodnes (298) with NaBH4 and the jS-aminoethylquinazolines (301) on hydrolysis. The diazocines (297) behave as typical amidines. Oxidation leads to the amidoximes (300) which on hydrolysis are converted to 2,1-benzisoxazoles (302), and reaction with diketene leads to the fused pyrimidinones (299 and l-methyl-3-one isomer) (79CPB2927). 

Cyclocondensation routes also provide access to pyrimidines. 2,3-Disubstituted pyrido[2,3-/i]-quinazolin-4(3//)-ones are obtained via cyclocondensation of 5-aminoquinoline-6-caiboxylic acid with acid chlorides <02SC235>. 5,6,8-Trialkyl-7-methoxy-2-aminoquinazolines are obtained from 1,3-dimethoxybenzenes via cyclocondensation of intermediate dihydrobenzenes with guanidine carbonate <02TL3295>. Diastereoselective intramolecular hetero Diels-Alder cyclization of a pyrazole carboxaldehyde condensed onto 1,3-dimethylbarbituric acid (101) gave polycyclic heterocycle 102 <02T531>. An efficient one-step synthesis of cyclobutene-annelated pyrimidinones 103 from methyl 2-chloro-2-cyclopropylideneacetate and amidines has been... 

Standard approach is the cyclocondensation of 1,3-diketones with N-C-N systems like amidines, ureas, thioureas and guanidines, which gives rise to 4,6- or 2,4,6-substituted pyrimidines 13, 2-pyrimidinones 14, 2-thiopyrimidinones 15, and 2-arninopyrimidines... 

Dihydro-4-pyrimidinones result from the cycloaddition of diphenylcyclo-propenones with guanidines and with amidines. A general route to the hitherto inaccessible 2-(pyrimidin-2 -yl)acetic acid (214) and its 4-substituted derivatives has been described/ the first stage of which involves self-condensation of malonamide to the dihydroxypyrimidine derivative (213). Heteroarylation and 2-hydroxymethylation of simple pyrimidines have been achieved in high yield. 

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