The nucleophilic addition of TMSC(Li)N2 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)N2 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 Introduction Lithium trimethylsilyldiazomethane, [TMSC(Li)N2], eas- ily prepared from trimethylsilyldiazomethane and n-butyl- lithium, is a very useful [CNN] synthon for the prep- aration of azoles. The reaction of TMSC(Li)N2 with β- substituted α,β-unsaturated nitriles,  sulfones  or ke- tones usually proceeds by nucleophilic attack on the β- carbon followed by cyclization and elimination processes. Recently, as part of a project based on the study of the reactivity of organolithium-containing silicon reagents with uracil derivatives and pyrimidine nucleosides, we reported the first example of reactivity of TMSC(Li)N2 toward the 5,6-double bond of several 5-substituted uracil and uridine derivatives. This transformation, which provides a general method for the synthesis of annulated and fused 1H-pyr- azolo[4,3-d]pyrimidindiones I (Figure 1), proceeds through a selective addition of TMSC(Li)N2 at the C-6 position of the uracil ring. Nucleophiles invariably react at the C-6 po- sition of uracil and C-5 substituted uracil derivatives giving rise to a 5,6-dihydrouracil intermediate from which the re- spective product is formed. Reactions of nucleophiles at the C-6 position of uracil derivatives are of biological signifi- cance since they represent significant steps in the biosynthe- sis of DNA in both bacteria and animals. In particular, the thymidylate synthase-catalysed conversion of 2-deoxyurid- ine monophosphate (dUMP) to 2-deoxythymidine mono- phosphate (dTMP), which requires the nucleophilic attack [a] Dipartimento Agrochimico Agrobiologico, Universita` della Tuscia, Via San Camillo de Lellis, 01100 Viterbo, Italy E-mail: firstname.lastname@example.org [b] Dipartimento di Chimica, Universita` “La Sapienza”, Ple. Aldo Moro 5, I-00185, Roma, Italy [c] Dipartimento di Scienze e Tecnologie Chimiche, Universita` di Tor vergata, Via della Ricerca Scientifica, I-00133 Roma, Italy [d] Dipartimento Farmaco Chimico Tecnologico, Universita` degli Studi di Siena, Via Banchi di sotto 55, I-53100 Siena, Italy 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)N2 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.
|Data di pubblicazione:||1999|
|Titolo:||Umpolung of reactivity of lithium trimethylsilyldiazomethane at the C-5 position of 6-substituted uracil derivatives|
|Rivista:||EUROPEAN JOURNAL OF ORGANIC CHEMISTRY|
|Digital Object Identifier (DOI):||http://dx.doi.org/1434193X/99/1111|
|Appare nelle tipologie:||2.1 Articolo su rivista |
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