Fluoro, alkylsulfanyl, and alkylsulfonyl leaving groups in suzuki cross-coupling reactions of purine 2′-deoxynucleosides and nucleosides

Article abstract of DOI:10.1021/ol050063s

(Chemical Equation Presented) Protected 2′-deoxynucleoside and nucleoside derivatives of 6-fluoropurine, 6-(3-methylbutyl)sulfanylpurine, and 6-(3-methylbutyl)ylsulfonylpurine undergo nickel- or palladium-mediated C-C cross-coupling with arylboronic acids

Full text of DOI:10.1021/ol050063s

ORGANIC
LETTERS
2005
Vol. 7, No. 6
1149-1151
Fluoro, Alkylsulfanyl, and Alkylsulfonyl
Leaving Groups in Suzuki
Cross-Coupling Reactions of Purine
2′
-Deoxynucleosides and Nucleosides†
Jiangqiong Liu and Morris J. Robins*
Department of Chemistry and Biochemistry, Brigham Young UniVersity,
ProVo, Utah 84602-5700
morris_robins@byu.edu
Received January 12, 2005
ABSTRACT
Protected 2
undergo nickel- or palladium-mediated C
′
-deoxynucleoside and nucleoside derivatives of 6-fluoropurine, 6-(3-methylbutyl)sulfanylpurine, and 6-(3-methylbutyl)ylsulfonylpurine
C cross-coupling with arylboronic acids to give good yields of 6-arylpurine products.
−
Modified purines and purine nucleoside derivatives play a
major role in biochemistry and biology and as pharmaceutical
agents.1 Recently, 6-arylpurine ribonucleosides have been
shown to exhibit cytostatic activity.2 Classical methods for
synthesis of nucleoside biaryls via Suzuki-Miyaura proce-
dures have employed Pd- or Ni-mediated cross-couplings of
aryl halides or sulfonates with arylboronic acids.3 We recently
reported a heteroaromatic Finkelstein process for conversion
of 6-chloropurine 2′-deoxynucleoside and nucleoside deriva-
tives into the corresponding 6-iodopurine analogues and
noted the markedly increased reactivity of the iodo com-
pounds in certain classical organometallic cross-coupling
reactions.4 Aryl fluorides have rarely been used in such
processes because of their diminished reactivity.
In 1981, we reported efficient methodology for the
synthesis of 2-fluoropurine nucleosides by nonaqueous
diazotization fluoro-dediazoniation of the 2-amino group of
protected purine nucleosides.5 Secrist et al. have also applied
this protocol for the conversion of 6-amino- to 6-fluoropurine
nucleoside derivatives.6 We now report that this diazotative
fluoro-deamination of protected adenosine and 2′-deoxy-
adenosine analogues gives the 6-fluoropurine compounds in
good yields. We then began an investigation of the utility
of 6-fluoropurine nucleoside derivatives as cross-coupling
† Nucleic Acid Related Compounds. 125. Paper 124 is ref 9.
(1) (a) Brathe, A.; Gunderesen, L.-L.; Rise, F.; Eriksen A. B.; Vollsnes,
A. V.; Wang, L. Tetrahedron 1999, 55, 211-228. (b) Perez, O. D.; Chang
Y.-T.; Rosania, G.; Sutherlin, D.; Schultz, P. G. Chem. Biol. 2002, 9, 475-
483.
(2) (a) Hocek, M.; Holy, A.; Votruba, I.; Dvorakova, H. J. Med. Chem.
2000, 43, 1817-1825. (b) Hocek, M.; Holy, A.; Votruba, I.; Dvorakova,
H. Collect. Czech. Chem. Commun. 2000, 65, 1683-1697. (c) Hocek, M.;
Holy, A.; Votruba, I.; Dvorakova, H. Collect. Czech. Chem. Commun. 2001,
66, 483-499.
(3) Lakshman, M. K.; Thomson, P. F.; Nuqui, M. A.; Hilmer, J. H.;
Sevova, N.; Boggess, B. Org. Lett. 2002, 4, 1479-1482.
(4) Liu, J.; Janeba, Z.; Robins, M. J. Org. Lett. 2004, 6, 2917-2919.
(5) Robins, M. J.; Uznanski, B. Can. J. Chem. 1981, 59, 2608-2611.
(6) Secrist, J. A.; Bennett, L. L.; Allan, P. W.; Rose, L. M.; Chang, C.
H.; Montgomery, J. A. J. Med. Chem. 1986, 29, 2069-2074.
10.1021/ol050063s CCC: $30.25
© 2005 American Chemical Society
Published on Web 02/17/2005

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

increased to 90 °C, the coupling reaction was complete in 8
h. Electron-rich and electron-poor arylboronic acids were also
well tolerated with the alkylsulfanylpurine substrates (Scheme
2; Table 2).
Scheme 3. Coupling with a Sulfonylpurine Nucleoside
Table 2. Yields of Coupling Products from Sulfanylpurines
entry
R
Y
product (% yield)
1
2
3
Tol
Ac
Tol
CH3
OCH3
F
3a (69)
3b (78)
3c (71)
as substrates for Suzuki and Stille couplings,15 but we did
not find prior examples of Suzuki couplings with sulfones.
In summary, we have developed nickel- and palladium-
based systems with imidazolium-carbene ligands that catalyze
efficient Suzuki cross-couplings of arylboronic acids and
6-fluoro-, 6-[(3-methylbutyl)sulfanyl]-, and 6-[(3-methyl-
butyl)sulfonyl]purine nucleoside derivatives to give the
corresponding 6-arylpurine products. These reactions enlarge
the scope of our complementary Suzuki couplings of
arylboronic acids and 6-(azolyl)purine derivatives and expand
possibilities for new medicinal applications.
The oxidation state of the sulfur substituent at C6 was
then briefly probed. Oxidation of 6-benzylsulfanylpurine
nucleoside derivatives with Oxone in buffered brine had
given 6-benzylsulfonyl compounds in high yields.10 Oxida-
tion of a protected 6-(isopentylsulfanyl)purine nucleoside
gave 6-[(3-methylbutyl)sulfonyl]-9-[2,3,5-tri-O-(2,4,6-tri-
methylbenzoyl)-â-D-ribofuranosyl]purine (4). The sulfone 4
and 4-methoxyphenylboronic acid underwent coupling at 60
°C in 8 h [Pd(OAc)2/IPr/K3PO4/THF] to give 1c (81%,
isolated yield) (Scheme 3).
Acknowledgment. We gratefully acknowledge pharma-
ceutical company gift funds in support of this research
(M.J.R.) and the award of a Roland K. Robins Graduate
Research Fellowship (J.L.) by Brigham Young University.
This coupling with the sulfone 4 occurred more readily
(60 °C, THF) than with the corresponding thioether (90 °C,
toluene). It was known that arylsulfonyl chlorides function
(9) Liu, J.; Robins, M. J. Org. Lett. 2004, 6, 3421-3423.
(10) Lin, X.; Robins, M. J. Org. Lett. 2000, 2, 3497-3499.
(11) (a) Samano, V.; Miles, R. W.; Robins, M. J. J. Am. Chem. Soc.
1994, 116, 9331-9332. (b) Miles, R. W.; Samano, V.; Robins, M. J. J.
Am. Chem. Soc. 1995, 117, 5951-5957.
Supporting Information Available: Experimental pro-
cedures, characterization data, and 1H and 13C NMR spectra
for new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(12) Srivastava, P. C.; Robins, R. K.; Meyer, R. B., Jr. In Chemistry of
Nucleosides and Nucleotides; Townsend, L. B., Ed.; Plenum: New York,
1988; Vol. 1, pp 113-281.
OL050063S
(13) (a) Lin, T.-S.; Cheng, J.-C.; Ishiguro, K.; Sartorelli, A. C. J. Med.
Chem. 1985, 28, 1481-1485. (b) Gupte, A.; Buolamwini, J. K. Bioorg.
Med. Chem. Lett. 2004, 14, 2257-2260.
(15) (a) Dubbaka, S. R.; Vogel, P. J. Am. Chem. Soc. 2003, 125, 15292-
15293. (b) Dubbaka, S. R.; Vogel, P. Org. Lett. 2004, 6, 95-98.
(14) Sugimura, H.; Takei, H. Bull. Chem. Soc. Jpn. 1985, 58, 664-666.
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