Umpolung of reactivity of lithium trimethylsilyldiazomethane at the C-5 position of 6-substituted uracil derivatives

The nucleophilic addition of TMSC(Li)N-2 at the low reactive C-5 position of the uracil ring of C-6 substituted uracil derivatives is reported. The ratio of C-5 versus C-6 nucleophilic addition of TMSC(Li)N-2 dramatically depends on the stereoelectronic properties of the C-6 substituent. In particular, substituents characterized both by sterically bulky and/or electron-withdrawing (EWG) effects appear to direct the nucleophile mainly (methyl, chloromethyl or halogen) or completely (isopropyl) toward the C-5 position. The fine-tuned substituent selectivity found in the nucleophilic addition of TMSC(Li)N-2 to C-6 substituted uracils plays a leading role in the synthesis of new trimethylsilyl-1H-{[4,3-d]pyrimidin-5,7-dione derivatives, which can in turn be easily modified through known silicon chemistry.}