partners with arylboronic acids. We report that this opens
an effective new avenue for modifications at C6 of purine
nucleosides.
Table 1. Yields of Coupling Products from Fluoropurines
entry
R
R′
Y
product (% yield)
Our first challenge was to identify a catalytic complex that
would insert readily into the purine C6-F bond. Several
methods involving different transition metal centers have
been described for activation of aromatic carbon-fluorine
bonds.7 Cross-couplings of phenylmagnesium halides and
fluorobenzenes have been performed at ambient temperature
with nitrogen-heterocyclic carbene ligands and nickel cata-
lysts.8
1
2
3
4
5
6
Mes
Mes
Mes
Mes
Tol
OMes
OMes
OMes
OMes
H
H
1a (84)
1b (82)
1c (84)
1d (73)
1e (60)
1f (67)
CH3
OCH3
F
CH3
F
Tol
H
We first tried Ni(COD)2 with addition of 1,3-bis(2,6-
diisopropylphenyl)imidazolin-2-ylidene (IPr) (Figure 1) for
It is noteworthy that poor results were obtained upon
replacement of Ni(COD)2 by Pd(PPh3)4 as the catalyst. With
Pd(PPh3)4, major formation of an oxygen-insertion9 com-
pound 2 (Figure 2) was observed.
Figure 1. Structure of the imidazolium-carbene ligand IPr.
attempted cross-coupling of 4-methoxyphenylboronic acid
and 6-fluoro-9-[2,3,5-tri-O-(2,4,6-trimethylbenzoyl)-â-D-ribo-
furanosyl]purine. At ambient temperature, none of the
coupling product was detected. However, we were delighted
to find that the desired 6-(4-methoxyphenyl)-9-[2,3,5-tri-O-
(2,4,6-trimethylbenzoyl)-â-D-ribofuranosyl]purine (1c) was
produced in high yield (84% isolated) in THF at 60 °C
(Scheme 1) (Table 1). Different boronic acids were employed
Figure 2. Structure of the oxygen-insertion compound 2.
We next focused our attention on cross-couplings of
6-alkylsulfanylpurine nucleoside derivatives, which are
readily accessible by SNAr displacements with 6-(imidazol-
1-yl)-,10 6-(1,2,4-triazol-4-yl)-,11 and 6-halopurine12 precur-
sors. They also are easily prepared by alkylation of thio-
inosine derivatives,12,13 which can be obtained by deoxy-
genative thiation of inosine or deaminative sulfhydrolysis
of 6-N-substituted adenosine intermediates.12 Cross-coupling
of Grignard reagents and 6-(methylsulfanyl)purine derivatives
with a nickel-phosphine complex had been reported.14
Scheme 1. Couplings with 6-Fluoropurine Nucleosides
Our first cross-coupling of 6-[(3-methylbutyl)sulfanyl]-9-
(2,3,5-tri-O-acetyl-â-D-ribofuranosyl)purine and 4-methoxy-
phenylboronic acid was incomplete after 8 h with Pd(OAc)2/
IPr/K2CO3/THF at 60 °C. However, when the solvent was
changed from THF to toluene and the temperature was
to evaluate the scope of this coupling reaction. Both electron-
rich and electron-poor arylboronic acids underwent coupling
in good yields with 6-fluoropurine nucleoside derivatives.
Application of this coupling protocol with a protected
6-fluoropurine 2′-deoxynucleoside also gave 6-arylpurine
products in good isolated yields (Table 1).
Scheme 2. Couplings with Sulfanylpurine Nucleosides
(7) (a) Braun, T.; Foxon, S. P.; Perutz, R. N.; Walton, P. H. Angew.
Chem., Int. Ed. 1999, 38, 3326-3329. (b) Mongin, F.; Mojovic, L.;
Guillamet, B.; Trecourt, F.; Queguiner, G. J. Org. Chem. 2002, 67, 8991-
8994. (c) Kim, Y. M.; Yu, S. J. Am. Chem. Soc. 2003, 125, 1696-1697.
(d) Widdowson, D. A.; Wilhelm, R. Chem. Commun. 2003, 578-579.
(8) Bohm, V. P. W.; Gstottmayr, C. W. K.; Weskamp, T.; Herrmann,
W. A. Angew. Chem., Int. Ed. 2001, 40, 3387-3389.
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Org. Lett., Vol. 7, No. 6, 2005