Palladium-catalyzed direct 5-arylation of 1,3-dimethyluracil with aryl bromides: an electrophilic metalation–deprotonation with electrophilic arylpalladium intermediate

Modification of Purine and Pyrimidine Nucleosides by Direct C-H Bond Activation

“…Kim and coworkers reported the direct arylation of 1,3-dimetyluracil 65 with aryl bromides (including electron-deficient ones) in the presence of Pd(OAc) 2 , K 2 CO 3 and PivOH (130 °C/12 h/DMF to give predominantly C5 arylated products 66 in up to 79% yield. A small amount of 6-arylated isomers 67 were also observed [59]. However, application of this condition to 1-(tetrahydrofuran-2-yl)-3-benzyluracil 68 (a substrate having a glycosylic bond) resulted in severe decomposition.…”

Palladium‐Catalyzed Regioselective Cross‐Dehydrogenative Coupling of Benzofurans with Uracils at Room Temperature

“…[7] In 2011, Li and Zhang reported the palladium-catalyzed oxidative cross-coupling between pyridine N-oxides and indoles. [8] Hocek [9] and Kim [10] developed the direct C-H arylation of diprotected uracils with aryl halides under high temperatures (130-160°C). In 2014, Wnuk et al reported the palladium-catalyzed direct arylation of 5-halouracils with heteroarenes (Scheme 1).…”

Novel Approaches for the Synthesis of C-5 Modified Pyrimidine Nucleosides

“…7). 96 It's the typical selectivity problem observed during the C-H functionalization of uracil base.…”

“…Pd-catalyzed crosscoupling of 1,3-dimethyluracil 20 with arenes 28 in the presence of pivalic acid and silver acetate under the reflux condition gave 1,3-dimethyl-5-aryluracil 22 as the minor product and 1,3-dimethyl-6-aryluracil 23 as the major product (Scheme 12). 96 It is believed that reaction went through a concerted metalation-deprotonation (CMD) processes via Pd II (L)(OPiv) species by deprotonation of the more acid hydrogen at C6 of uracil ring, followed by another concert metalation-deprotonation to give the 6-arylated uracil product 23. Analogously, the C5-C5' and C5-C6' dimer or even C5-C5' and C6-C5' trimer could be synthesized under the similar condition.…”

“…The cleavage of the glycosidic bond was observed during the arylation, which is consistent with the literature report. 96 In the attempts to expand direct arylation to other pyrimidine systems, the 5-iodocytidine analogues were prepared by the modification of the existing procedure (Scheme 34). 148,149 Stirring of 112 with acetyl chloride in AcOH/CHCl 3 (1:1, v/v) at ambient temperature for 40 h gave 2',3',5'-tri-O-acetylcytidine in 96%, followed by iodination with I 2 /HIO 3 gave 113 in 63%.…”