Supported synthesis and functionnalization of 2″-deoxyuridine by Suzuki-Miyaura cross-coupling

Article abstract of DOI:10.1080/15257770701534170

The synthesis and modification of 2′-deoxyuridine has been realized under Suzuki-Miyaura palladium-catalyzed cross-coupling conditions. Using Pd(PPh3)4 and Na2CO3, 5-iodo-2′-deoxyuridine bound to solid support is coupled with various boronic acids to give

Full text of DOI:10.1080/15257770701534170

Nucleosides, Nucleotides, and Nucleic Acids, 26:1395–1398, 2007
Copyright ꢀ Taylor & Francis Group, LLC
C
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770701534170
SUPPORTED SYNTHESIS AND FUNCTIONNALIZATION OF
2ꢀ-DEOXYURIDINE BY SUZUKI-MIYAURA CROSS-COUPLING
Sa¨ıd El Kazzouli, Sabine Berteina-Raboin, and Luigi A. Agrofoglio
2
Institut de Chimie Organique et Analytique, UMR CNRS 6005, Universite´ d’Orle´ans,
Orle´ans, France
The synthesis and modification of 2ꢁ-deoxyuridine has been realized under Suzuki-Miyaura
2
palladium-catalyzed cross-coupling conditions. Using Pd(PPh3)4 and Na2CO3, 5-iodo-2ꢁ-
deoxyuridine bound to solid support is coupled with various boronic acids to give 5-(hetero)aryl-
2ꢁ-deoxyuridine. Pd(PPh3)4 palladium catalyzed was found to be superior to Pd(OAc)2 and
(NHC)Pd(allyl)Cl for Suzuki-Miyaura palladium-catalyzed reactions.
Keywords Polystyrene; solid phase; Pd(0) cross-coupling; Suzuki-Miyaura; nucleosides
INTRODUCTION
The intense search for clinically useful nucleoside derivatives has re-
sulted in a wealth of new approaches for their synthesis from hundreds of
academic and pharmaceutical laboratories. One useful approach, recently
reviewed by our group, has involved the use of palladium-catalyzed insertion
and cross-coupling reactions (Heck, Stille, Sonogashira, Tsuji-Trost, etc.),
which have gained recognition due to their broad scope. Another approach
that has developed rapidly in recent years involves the synthesis of small or-
ganic molecule libraries by a parallel solid-phase strategy. Except for the very
well-known solid phase oligonucleotide synthesis, this powerful technology
has tardy been applied to mono nucleoside chemistry. Thus, as part of our
drug discovery program, we describe here the successful application and
optimization of palladium-assisted routes to pyrimidine nucleosides bound
to polystyrene resins. We have focused on the optimization of the Suzuki-
type reactions; the presented methods exhibit a significant improvement
and facilitate the synthetic procedure with respect to purification and yields
(determined after filtration over silica gel).
Address correspondence to Luigi A. Agrofoglio, Institut de Chimie Organique et Analytique, UMR
CNRS 6005, Universite´ d’Orle´ans, BP 6759, 45067 Orle´ans Cedex 2, France. E-mail: luigi.agrofoglio@
univ-orleans.fr
1395

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S. El Kazzouli et al.
SCHEME 1 General approach to C5-substituted carbanucleoside via solid-phase synthesis and Pd(o)
chemistry.
RESULTS AND DISCUSSION
Recently, we reported a new and useful approach for nucleoside synthe-
sis and modification by combination of solid-phase synthesis and palladium
mediated cross-coupling reaction.[1] As part of our continuing efforts to de-
velop this drug discovery program, we were interested herein in the use of
Suzuki-Miyaura[2] palladium cross-coupling reaction on 2ꢁ-deoxyuridine as
a route to new nucleoside (Scheme 1).
In our previous paper, we have reported the C-5-substitution on 5-iodo-
2ꢁ-deoxyuridine bound to polystyrene resin[3] using Heck, Stille and
Sonogashira palladium catalyzed reaction.[1] We described also that the
standard Suzuki-Miyaura cross coupling conditions gave the desired com-
pounds in very low conversion (<15%). For this reason, we decided to study
the scope and limitation of this reaction types using different experimental
conditions. We first prepared 5-iodo-2ꢁ-deoxyuridine bound to polystyrene
resin,[1] Scheme 2.
SCHEME 2 Conditions : i) B (1 equiv.), Me2C=C(NMe2)Cl (1.1 equiv.), CH2Cl2, 3 hours; then A
(1 equiv.), NEt3 (1.5 equiv.), pyridine (10 equiv.), DMAP (0.2 equiv.), CH2Cl2, 21 hours; ii) Ac2O,
pyridine, 4 hours; iii) TFA/CH2Cl2 (5/95), 15 hours; iv) NEt3 (1.1 equiv.), O-(1H-benzotriazol-1-yl)-
N,N,Nꢁ,Nꢁ-tetramethyl uronium tetrafluoroborate (1.1 equiv.), N-hydroxybenzotriazole (0.5 equiv.), diox-
ane, 5 hours, then resin C (0.25 equiv.), NEt3 (2.5 equiv.), DMAP (0.25 equiv.), dioxane, 60 hours;
v) Ac2O, pyridine, 18 hours; vi) I2/CAN, dioxane/CH3CN.

2ꢁ-Deoxyuridine
1397
TABLE 1 Optimization of Suzuki-Miyaura cross-coupling reactions
Entry
1
Condition
Conversion (%)
RB(OH)2 (4 equiv.), K2CO3 (9 equiv.), Pd(OAc)2 (0.1 equiv.),
dioxane/H2O, 80◦C
RB(OH)2 (8 equiv.), K2CO3 (9 equiv.), Pd(OAc)2 (0.1 equiv.),
<15
<20
<10
100
2
3
4
dioxane/H2O, 80◦C
RB(OH)2 (4 equiv.), NaOtBu (0.1 equiv.), Cs2CO3 (1.5 equiv.),
(NHC)Pd(allyl)Cl (0.1 equiv.), 80◦C
RB(OH)2 (4 equiv.), Na2CO3 (9 equiv.), Pd(PPh3)4 (0.1 equiv.),
DME/H2O, 80◦C
We set out to investigate the feasibility of Suzuki-Miyaura cross coupling
on 5-iodo-2ꢁ-deoxyuridine bound to polystyrene resin 2 using the Pd(OAc)2
(0.1 equiv.), K2CO3 (9 equiv.) and a excess of 4-methoxyphenylboronic acid
(4–8 equiv.), unfortunately, the desired product 3 was obtained with low con-
version (<20%). We observed a mixture of 1 and a large amount of starting
2ꢁ-deoxyuridine. We then turned our attention to apply the very well-known
Nolan Palladium-catalyzed conditions.[5] Thus, using (NHC)Pd(allyl)Cl
(0.1 equiv.), Cs2CO3 (1.5 equiv.), NaOtBu (0.1 equiv.) and 4 equivalents
of 4-methoxyphenylboronic acid at 80◦C, we obtained less than 10% conver-
sion. Finally, we founded that the optimum conditions using Pd(PPh3)4 as
catalyst. When the reaction conducted with 4-methoxyphenylboronic acid
(4 equiv.), Na2CO3 (9 equiv.) and Pd(PPh3)4 (0.1 equiv.) in a mixture of
DME/H2O at 80◦C, occurred, the compound 3 were quantitatively con-
verted (Scheme 2, Table 1).
Encouraged by these promising results, we prepared various 5-
(hetero)arylated derivatives under the optimized Suzuki-Miyaura cross cou-
pling conditions (Scheme 3). All desired products were obtained in 27–35%
of yields (after five steps). It’s noteworthy that all the conversion rates of
SCHEME 3 Optimized Suzuki-Miyaura cross-coupling conditions.

1398
S. El Kazzouli et al.
TABLE 2 Suzuki-Miyaura cross-coupling
Entry
1
R
Product
Conversion (%)a
100
Yield (%)b
27
3
2
3
4
5
100
100
35
30
4
6
100
32
aConversions were calculated from 1H MNR of crude product after cleavage.
b Yields (after 5 steps).
these reactions were totals, thus, the reported yields are those calculated af-
ter a simple washing of crude product with acetone (Table 2). Typically, the
resin-bounded (170 mg, 0.08 mmol) was suspended in clean DME (2 mL)
containing 330 µL of H2O. Na2CO3 (9 equiv.) and Pd(PPh3)4 (0.1 equiv.)
were successively added prior to the addition of 4 equiv. of the boronic acid
derivatives. The suspension was strirred at 80◦C and then cooled to room
temperature and filered through a fritted glass funnel. Standard cleavage
of the resin followed by flash column chromatography of the crude resin
afforded desired nucleosides.
In summary we have for a first time found the optimum conditions for a
new Suzuki-Miyaura palladium-catalyzed reaction on 5-iodo-2ꢁ-deoxyuridine
bound to solid support using Pd(PPh3)4, Na2CO3 and various boronic acids.
Under these conditions, various compounds were prepared with good yield
and excellent purity.
REFERENCES
1. Aucagne, V.; Berteina-Raboin, S.; Guenot, P.; Agrofoglio, L.A. J. Comb. Chem. 2004, 6, 717.
2. For recent article on Suzuki-Miyaura see: a) Agrofoglio, L.A.; Gillaizeau, I.; Saito, Y. Chem. Rev. 2003,
103, 1875; b) Western, E.C.; Daft, J.R.; Johnson, E.M., II; Gannett, P.M.; Shaughnessy, K.H. J. Org.
Chem. 2003, 68, 6767.
3. For article on aminomethylated resin see: a) El Kazzouli, S.; Berteina-Raboin, S.; Mouaddib, A.;
Guillaumet, G. Tetrahedron Lett. 2003, 44, 6265; b) El Kazzouli, S.; Berthault, A.; Berteina-Raboin,
S.; Mouaddib, A.; Guillaumet, G. Lett. Org. Chem. 2005, 2, 184.
4. Viciu, M.S.; Germaneau, R.F.; Navarro-Fernandez, O.; Stevens, E.D.; Nolan, S.P. Organometallics 2002,
21, 5470.
5. a) Glaser, C. Ber. 1869, 2, 422; b) Glaser, C. Ann. 1870, 137, 154; c) Eglington, G. Chem. Ind. 1956,
737.