Palladium-catalyzed direct arylation of 5-halouracils and 5-halouracil nucleosides with arenes and heteroarenes promoted by TBAF.
The 1-N-benzyl-5-iodo(or bromo)uracil undergoes Pd-catalyzed [Pd2(dba)3] direct arylation with benzene and other simple arenes in the presence of TBAF in DMF without the necessity of adding any ligands or additives to give 5-arylated uracil analogues. The TBAF-promoted coupling also occurs efficiently with electron rich heteroarenes at 100 °C (1 h) even with only small excess of heteroarenes. The protocol avoids usage of the arylboronic acid or stannane precursors for the synthesis of 5-(2-furyl, or 2-thienyl, or 2-pyrrolyl)uracil nucleosides, which are used as important RNA and DNA fluorescent probes. The fact that 1-N-benzyl-3-N-methyl-5-iodouracil did not undergo the TBAF-promoted couplings with arenes or heteroarenes suggests that the C4-alkoxide (enol form of uracil) facilitates coupling by participation in the intramolecular processes of hydrogen abstraction from arenes. TBAF-promoted arylation was extended into the other enolizable heterocyclic systems such as 3-bromo-2-pyridone. The π-excessive heteroarenes also coupled with 5-halouracils in the presence of Pd(OAc)2/Cs2CO3/PivOH combination in DMF (100 °C, 2 h) to yield 5-arylated uracils.
Department of Chemistry and Biochemistry, Florida International University , Miami, Florida 33199, United States.
Yong
Y
Liang
Jennifer
J
Gloudeman
Stanislaw F
SF
Wnuk
D001555:Benzene Derivatives / Q000138:chemical synthesis / Q000737:chemistry*; D002384:Catalysis; D015394:Molecular Structure; D009705:Nucleosides / Q000737:chemistry*; D010165:Palladium / Q000737:chemistry*; D000644:Quaternary Ammonium Compounds / Q000737:chemistry*; D014498:Uracil / Q000031:analogs & derivatives / Q000737:chemistry*
D001555:Benzene Derivatives; D009705:Nucleosides; D000644:Quaternary Ammonium Compounds; D014498:Uracil; D010165:Palladium; C009405:tetrabutylammonium