Abstract
The reaction of 5-halogenouracil and uridine derivatives 1 and 7 with active methylene compounds under basic conditions produced diverse and selective C-C bond formation products by virtue of the nature of the carbanions. Three different types of reactions such as the regioselective C-C bond formation at the 5- and 6-positions of uracil and uridine derivatives (products 2, 5, 8, 17, 20 and 21), and the formation of fused heterocycle derivatives 2,4-diazabicyclo[4.1.0]heptane (15) and 2,4-diazabicyclo-[4.1.0]nonane (16) via dual C-C bond formations at both the 5- and 6-positions were due to the different active methylene compounds used as reagents.
Highlights
IntroductionMany 5-substituted pyrimidine nucleoside derivatives and their base moieties possess antimicrobial, antifungus, antivirus and anticancer activities due mainly to antimetabolic effects (Table 1) [1,2,3,4,5,6]
We provide detailed results for the formation of the 5-substituted-uracil derivatives starting from the 5-halogenouracil derivatives using the carbanion generated from active methylene compounds and bases
Our initial studies focused on the formation of the 5-substituted uracils. 5-Bis(ethoxycarbonyl)methyl-1,3-dimethyluracil (2) was obtained by the reaction of 1,3-dimethyl-5-halogenouracils (1) and diethyl malonate (3.3 equiv.) together with sodium ethoxide (3.0 equiv., generated in situ from sodium metal and anhydrous EtOH) in anhydrous EtOH at rt in 60–67% isolated yields (Table 2)
Summary
Many 5-substituted pyrimidine nucleoside derivatives and their base moieties possess antimicrobial, antifungus, antivirus and anticancer activities due mainly to antimetabolic effects (Table 1) [1,2,3,4,5,6]. The Mannich reaction [15,16,17,18], hydroxymethylation [19,20], the Morita-Baylis-Hillman reaction [21,22] and Wittig reaction using 5-hydroxyuridine [23] are useful methods to synthesize chemically-modified uracil derivatives possessing a carbon functional group at the 5-position. Only few carbanion-mediated nucleophilic reactions of the 5-bromo-uracil derivatives have been reported. 5-bis(ethoxycarbonyl)methyl-substituted uridine derivative by the reaction of 5-bromo-5',N3dibenzoyl-2',3'-O-isopropylideneuridine and the carbanion generated from dimethylmalonate and 1,8diazabicyclo[5,4,0]undec-7-ene (DBU) [33]. We provide detailed results for the formation of the 5-substituted-uracil derivatives starting from the 5-halogenouracil derivatives using the carbanion generated from active methylene compounds and bases. The diversity of the reaction of the 5-bromouracil derivatives with carbanions exclusively based on the kind of active methylene compounds as carbanion sources
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