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.
by TBAF. -The presented method may be useful for the synthesis of fluorescent 5-heteroaryl substituted nucleosides. However, the reaction is limited to electron-rich arenes and heteroarenes and fails for arenes bearing electron withdrawing groups. The fact that N3-substituted nucleobases like (IVb) do not participate in the coupling reaction suggests that an enolizable structure facilitates the intramolecular process of hydrogen abstraction. -(LIANG, Y.; GLOUDEMAN, J.; WNUK*, S. F.; J. Org. Chem. 79 (2014) 9, 4094-4103, http://dx.
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