New, efficient approach for the ligand-free Suzuki-Miyaura reaction of 5-iodo-2′-deoxyuridine in water

Article abstract of DOI:10.1055/s-0032-1317847

A series of 5-aryl-2′-deoxyuridines was prepared, using ligandless Suzuki-Miyaura cross-coupling reactions in neat water, starting from 5-iodo-2′-deoxyuridine as totally deprotected starting material. This ligand-free process gave good to high isolated yi

Full text of DOI:10.1055/s-0032-1317847

330▌
SHORT PAPER
short paper
New, Efficient Approach for the Ligand-Free Suzuki–Miyaura Reaction of
5-Iodo-2′-deoxyuridine in Water
Ligand-Free Suzuki–Miyaura Reaction of 5-Iodo-2′-deoxyuridine
Guillaume Sartori, Gwénaëlle Hervé, Gérald Enderlin, Christophe Len*
Transformations Intégrées de la Matière Renouvelable, UTC-ESCOM, Centre de recherche Royallieu, BP 20529, 60205 Compiègne, France
Fax +33(3)44971591; E-mail: christophe.len@utc.fr
Received: 14.10.2012; Accepted after revision: 19.11.2012
in organic solvents, starting from protected 5-halouridines
Abstract: A series of 5-aryl-2′-deoxyuridines was prepared, using
and 2′-deoxyuridine, respectively.9,12,14,19–29 In regard to
ligandless Suzuki–Miyaura cross-coupling reactions in neat water,
the development of green chemistry, academic and indus-
starting from 5-iodo-2′-deoxyuridine as totally deprotected starting
trial research has permitted the establishment of a catalyt-
ic Suzuki–Miyaura protocol based on atom economy, less
hazardous chemical syntheses, and safer solvents and aux-
iliaries. In this respect, the Suzuki–Miyaura reaction has
been developed with or without ligand in safe, economical
and environmentally benign aqueous media such as a co-
solvent mixture in water30,31 or neat water.32 Recently,
aqueous-phase Suzuki–Miyaura reactions of unprotected
5-halo-2′-deoxyuridines with boronic acids have been de-
veloped either in water/various organic cosolvent
mixtures3,5–8,11,13–16,33–40 or, to a lesser extent, in sole wa-
ter.2,41,42 In order to prepare 5-aryl-2′-deoxynucleoside de-
rivatives, our group developed an efficient, sustainable
protocol starting from the corresponding iodo analogue in
neat water in the presence of a low loading of catalyst
[Na2PdCl4 (0.1 mol%) and sodium triphenylphosphine tri-
sulfonate (TPPTS, 0.25 mol%)].41 It is notable that this
strategy permitted the target nucleoside analogues to be
obtained without any protection/deprotection steps. In or-
der to have a ‘greener’ protocol, atom-economy should be
examined and unnecessary derivatization (use of blocking
groups, protection/deprotection, temporary modification
of physical/chemical processes) should be minimized or
avoided if possible because each step requires additional
reagents and can generate waste. Here, we report on an ef-
ficient extension of this work in order to establish whether
the presence of the ligand influences the reaction results.
material. This ligand-free process gave good to high isolated yields
within short reaction times and with low loadings of palladium.
Key words: Suzuki–Miyaura reaction, ligandless, nucleosides,
green chemistry
Nucleoside analogues have attracted much attention due
to their potential biological activities as antiviral and anti-
tumoral agents and their use as building blocks for oligo-
nucleotides with promising therapeutic and diagnostic
applications. C-Aryl-substituted nucleosides are an im-
portant class of nucleoside analogues which have received
considerable attention in recent years (e.g., compound 1,1a
d4T analogue 21b,c and benzo[c]furan derivative 3;1d–k Fig-
ure 1). Very recently, compounds with a C-aryl group in
the aglycone part have been used as a biosensor for the de-
tection of uridine-related protein targets,2 and as fluores-
cent probes for the study of electron transfer in DNA.3–16
O
O
NH
NH
O
N
O
O
HO
N
O
HO
HO
OH
1
2
For this purpose, 5-iodo-2′-deoxyuridine (4) and phenyl-
boronic acid were engaged in Suzuki–Miyaura cross-
coupling reactions with different amounts of palladium
(0.01–0.5 mol%) either in the presence or absence of
TPPTS (2.5 equiv/Pd) at 100 °C (Table 1). In the present-
ed work, the reaction time was determined by monitoring
the reaction until full conversion of the starting material
was observed. Our results clearly show that the presence
of TPPTS in the mixture is not necessary at 100 °C. What-
ever the amount of palladium (0.01–0.5 mol%), the ab-
sence of TPPTS had no inhibiting effect on the reaction
course. In our hands, no significant differences in reaction
time and/or yields were observed with 0.5 mol%, 0.1
mol% and 0.05 mol% of palladium(II). Indeed, using
those catalytic conditions (Table 1, entries 1–6), the de-
sired cross-coupling products were obtained in very good
yields (79–86%) within 30 minutes maximum. Upon dra-
matically decreasing the amount of palladium, the expect-
O
N
NH
O
O
HO
3
Figure 1 Nucleoside analogues 1–3 having an aryl group
The synthesis of 5-aryluridines and the corresponding 2′-
deoxyuridines was usually readily achieved by the palla-
dium-catalyzed Suzuki–Miyaura10,17,18 or Stille reaction
SYNTHESIS 2013, 45, 0330–0333
Advanced online publication: 04.01.2013
DOI: 10.1055/s-0032-1317847; Art ID: SS-2012-Z0801-OP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

SHORT PAPER
Ligand-Free Suzuki–Miyaura Reaction of 5-Iodo-2′-deoxyuridine
331
ed increase in reaction times was observed, but 5-phenyl- presence of a methyl group in the para position of the ar-
2′-deoxyuridine (5) was still obtained after 24 hours in omatic ring does not change the reaction result much,
good yield even with only 0.01 mol% of palladium (Table since compound 6 was isolated in a similar range of yield
1, entries 9 and 10). These encouraging preliminary ex- and time (Table 2, entries 1–4). On the contrary, when a
periments (Table 1, entries 4 and 6) led us to define two heteroatom is directly bound to the arylboronic acid in the
ligand-free methods in order to (i) establish different opti- para position, an extended reaction time was needed to
mized reaction conditions (variation of the nature of the reach completion (Table 2, entries 5 and 6). Due to less
boronic acids having different electronic and steric de- nucleophilic properties, reactions using arylboronic acids
mands, and the time) and (ii) have a large and coherent with electron-withdrawing groups, particularly with ni-
library of nucleoside analogues.
trile and formaldehyde groups, were less efficient (Table
2, entries 7–12). In our hands, no hydrolysis was detected
with our basic reaction conditions (Table 2, entries 7–10).
Among the reactions of arylboronic acids with an elec-
tron-withdrawing group, product 10 is an exception and
was obtained in a 69% yield in 30 minutes when 0.1 mol%
of palladium was used (Table 2, entry 11). Its formation
was slowed in the presence of only 0.05 mol% of palladi-
um as a reaction time of 24 hours was necessary to reach
a full conversion of starting material (Table 2, entry 12),
compared to five hours for compounds 8 and 9 (Table 2,
entries 8 and 10).
Table 1 Coupling of 5-Iodo-2′-deoxyuridine (4) and Phenylboronic
Acid with or without Ligand (TPPTS)
PhB(OH)2 (1.3 equiv)
O
N
Na2PdCl4 (0.01–0.5 mol%)
TPPTS (0–1.25 mol%)
KOH (2 equiv)
O
N
I
NH
NH
O
H2O
O
O
O
100 °C
HO
HO
HO
HO
4
5
Entry
Na2PdCl4 (mol%)
Time (h)
Yielda (%)
Table 2 Variation of the Nature of the Boronic Acid for the Ligand-
Free Suzuki–Miyaura Coupling of 5-Iodo-2′-deoxyuridine (4)
1
2
3
4
5
6
7
8
9
10
0.5
0.25
0.08
0.25
0.25
0.50
0.50
4
79b
82c
80b
80c
84b
86c
73b
72c
60b
58c
O
O
ArB(OH)2 (1.3 equiv)
Na2PdCl4 (0.05–0.1 mol%)
KOH (2 equiv)
0.5
Ar
I
NH
NH
0.1
O
N
O
H2O
100 °C
O
N
O
0.1
HO
HO
0.05
0.05
0.02
0.02
0.01
0.01
HO
HO
4
5–13
Entry
Ar
Ph
Product
Time (h)
Yielda (%)
1
2
0.25
0.50
80b
86c
4
5
24
3
4
0.50
2
79b
80c
4- MeC6H4
4-MeOC6H4
4-NCC6H4
4-HC(O)C6H4
4-AcC6H4
6
24
5
6
7
24
64b
57c
a Isolated yields.
7
b In the presence of TPPTS (2.5 equiv/Pd).
c Without TPPTS.
7
8
1
5
39b
13c
8
All reactions were performed using 5-iodo-2′-deoxyuri-
dine (4, 0.28 mmol), an arylboronic acid (1.3 equiv) and
potassium hydroxide (2 equiv) at 100 °C with degassing
of neat water (18.2 MΩ) prior to use. Coupling products
were all isolated from the crude reaction mixtures by flash
chromatography on C18-phase silica gel.
9
10
6
5
17b
13c
9
11
12
0.5
24
69b
49c
10
11
12
13
13
14
24
24
22b
19c
2- MeC6H4
2-MeOC6H4
2-Naph
Using various boronic acids (Table 2), the reaction times
and yields in the presence of Na2PdCl4 (0.1 mol%) were
often shorter and higher, respectively, than those observed
in the presence of a lower loading of Na2PdCl4 (0.05
mol%) (Table 2, entries 3–18). Arylboronic acids with an
electron-donating substituent in the para position deliv-
ered the cross-coupling products, 6 and 7, in good yields
either with 0.1 mol% or with 0.05 mol% Na2PdCl4 (Table
2, entries 3–6). When comparing with compound 5, the
15
16
24
24
23b
18c
17
18
2
24
80b
70c
a Isolated yields.
b In the presence of Na2PdCl4 (0.1 mol%).
c In the presence of Na2PdCl4 (0.05 mol%).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 330–333

332
G. Sartori et al.
SHORT PAPER
target 5-arylated nucleoside 5–13. All the synthesized compounds
have been reported in the literature and were characterized by com-
paring the corresponding spectroscopic data.41
The sterically demanding 2-methyl- and 2-methoxy-
phenylboronic acid proved to be difficult substrates for
the Suzuki–Miyaura cross-coupling reaction of nucleo-
sides even under ‘standard’ conditions. Both methods per-
mitted isolation of the product in modest yields (Table 2,
entries 13–16); however, this time, no matter what the
atom directly bound to the aromatic part of the boronic
acid (methyl or methoxy group), no difference in the
length of the reaction time was observed. Steric restric-
tions may take over from electronic effects in these cases.
Once again, an exception has to be mentioned as 2-naph-
thylboronic acid reacted with 5-iodo-2′-deoxyuridine (4)
in the presence of 0.1 mol% of Na2PdCl4 to give com-
pound 13 in a very good yield (80%) within two hours
(Table 2, entry 17). The use of 0.05 mol% of Na2PdCl4
gave the corresponding nucleoside analogue 13 in 70%
yield, with an extended reaction time (Table 2, entry 18).
Our group was the first to describe this compound41 and,
at that time, our optimized reaction catalyst was Na2PdCl4
(0.1 mol%)–TPPTS (0.25 mol%). Under these previous
conditions, a reaction time of five hours was necessary to
observe a full conversion of 5-iodo-2′-deoxyuridine (4)
and compound 13 was isolated in 77% yield.
Acknowledgment
G.S. thanks Dr G. Santini and ESCOM for financial support. This
work was supported in part by the regional program of Région
Picardie, France.
References
(1) (a) Agrofoglio, L. A.; Gillaizeau, I.; Saito, Y. Chem. Rev.
2003, 103, 1875. (b) Onuma, S.; Kumamoto, H.; Kawato,
M.; Tanaka, H. Tetrahedron 2002, 58, 2497. (c) Haraguchi,
K.; Itoh, Y.; Tanaka, H.; Akita, M.; Miyasaka, T.
Tetrahedron 1993, 49, 1371. (d) Len, C.; Mackenzie, G.
Tetrahedron 2006, 62, 9085. (e) Ewing, D. F.; Fahmi, N.;
Len, C.; Mackenzie, G.; Ronco, G.; Villa, P.; Shaw, G.
Nucleosides Nucleotides 1999, 18, 2613. (f) Ewing, D. F.;
Fahmi, N.; Len, C.; Mackenzie, G.; Pranzo, A. J. Chem.
Soc., Perkin Trans. 1 2000, 3561. (g) Lipka-Belloli, E.; Len,
C.; Mackenzie, G.; Ronco, G.; Bonte, J. P.; Vaccher, C.
J. Chromatogr., A 2001, 943, 91. (h) Ewing, D. F.; Len, C.;
Mackenzie, G.; Ronco, G.; Villa, P. Tetrahedron:
Asymmetry 2000, 11, 4995. (i) Selouane, A.; Vaccher, C.;
Villa, P.; Postel, D.; Len, C. Tetrahedron: Asymmetry 2002,
13, 407. (j) Pilard, S.; Riboul, D.; Glacon, V.; Moitessier, N.;
Chapleur, Y.; Postel, D.; Len, C. Tetrahedron: Asymmetry
2002, 13, 529. (k) Egron, D.; Périgaud, C.; Gosselin, G.;
Aubertin, A.-M.; Faraj, A.; Sélouane, M.; Postel, D.; Len, C.
Bioorg. Med. Chem. Lett. 2003, 13, 4473.
It is important to note that, using our current reaction con-
ditions, we have never observed any loss of the aglycone
moiety of compounds 5–13.
In summary, a simple and efficient procedure for the
Suzuki–Miyaura cross-coupling reaction of 5-iodo-2′-de-
oxyuridine (4) in neat water has been developed using a li-
gandless palladium catalyst. The ligand was not necessary
even with very low loadings of palladium (0.05 mol%
Na2PdCl4). Our new reaction conditions allowed us to ob-
tain 5-arylated nucleoside derivatives with substituents
with various steric and electronic demands in yields which
are at least equal to those previously reported reactions us-
ing organic solvents or a mixture of water/organic sol-
vents in the presence of higher loadings of palladium and
expensive ligands. To the best of our knowledge, this is
the first time in nucleoside chemistry that the Suzuki–Mi-
yaura reaction has been used under such green and eco-
nomical conditions.
(2) Pesnot, T.; Wagner, G. K. Org. Biomol. Chem. 2008, 6,
2884.
(3) Segal, M.; Fischer, B. Org. Biomol. Chem. 2012, 10, 1571.
(4) Naus, P.; Pohl, R.; Votruba, I.; Dzubak, P.; Hajduch, M.;
Ameral, R.; Birkus, G.; Wang, T.; Ray, A. S.; Mackman, R.;
Cihlar, T.; Hocek, M. J. Med. Chem. 2010, 53, 460.
(5) Fukuda, M.; Nakamura, M.; Takada, T.; Yamana, K.
Tetrahedron Lett. 2010, 51, 1732.
(6) Jacobsen, M. F.; Ferapontova, E. E.; Gothelf, K. V. Org.
Biomol. Chem. 2009, 7, 905.
(7) Wanninger-Weiß, C.; Wagenknecht, H.-A. Eur. J. Org.
Chem. 2008, 64.
(8) Ehrenschwender, T.; Wagenknecht, H.-A. Synthesis 2008,
3657.
(9) Capobianco, M. L.; Cazzato, A.; Alesi, S.; Barbarella, G.
Bioconjugate Chem. 2008, 19, 171.
(10) Okamoto, A.; Tainaki, K.; Unzai, T.; Saito, I. Tetrahedron
2007, 63, 3465.
(11) Okamoto, A.; Inasaki, T.; Saito, I. Tetrahedron Lett. 2005,
46, 791.
(12) Greco, N. J.; Tor, Y. J. Am. Chem. Soc. 2005, 127, 10784.
(13) Hubert, R.; Fiebig, T.; Wagenknecht, H.-A. Chem. Commun.
2003, 1878.
(14) Amann, N.; Wagenknecht, H.-A. Synlett 2002, 687.
(15) Amann, N.; Pandurski, E.; Fiebig, T.; Wagenknecht, H.-A.
Chem. Eur. J. 2002, 8, 4877.
(16) Amann, N.; Pandurski, E.; Fiebig, T.; Wagenknecht, H.-A.
Angew. Chem. Int. Ed. 2002, 41, 2978.
(17) Aucagne, V.; Berteina-Raboin, S.; Guenot, P.; Agrofoglio,
L. A. J. Comb. Chem. 2004, 6, 717.
(18) El Kazzouli, S.; Berteina-Raboin, S.; Agrofoglio, L. A.
Nucleosides, Nucleotides Nucleic Acids 2007, 26, 1398.
(19) Yamamoto, Y.; Seko, T.; Nemoto, H. J. Org. Chem. 1989,
54, 4734.
Reagents were purchased from either Acros or Sigma Aldrich, de-
pending on availability. All solvents were purchased from Carlo
Erba. All reactions were monitored by TLC [Merck Kieselgel
60F254 aluminum sheets, detection by UV light and/or with H2SO4
in EtOH (9:1, v/v)] and by HPLC [Shimadzu; column: Grace Pre-
vail C18; mobile phase: H2O–MeOH, 1:1; detectors: SPD-M20A
photo diode array detector (Shimadzu), LCMS-2020 mass spec-
trometer (Shimadzu) and ELSD-LTII detector (Shimadzu)].
5-Aryl-2′-deoxyuridines 5–13; General Procedure
Under nitrogen atmosphere, 5-iodo-2′-deoxyuridine (4; 100 mg,
0.28 mmol, 1 equiv), KOH (31 mg, 0.56 mmol, 2 equiv) and the ar-
ylboronic acid (0.37 mmol, 1.3 equiv) were placed in a 25 mL flask.
Nitrogen-flushed solutions of Na2PdCl4 in H2O (1 mL, 0.28 μmol,
0.1 mol%) and H2O (1 mL) were added. The mixture was then heat-
ed to 100 °C. Conversion was followed by HPLC. After complete
conversion, the mixture was cooled to r.t. and concentrated under
reduced pressure. The crude residue was purified by flash chroma-
tography on C18 silica gel (H2O–MeOH, 95:5 to 5:95) to afford the
Synthesis 2013, 45, 330–333
© Georg Thieme Verlag Stuttgart · New York

SHORT PAPER
Ligand-Free Suzuki–Miyaura Reaction of 5-Iodo-2′-deoxyuridine
333
(20) Sadler, J. M.; Ojewoye, O.; Seley-Radtke, K. L. Nucleic
Acids Symp. Ser. 2008, 52, 571.
(21) Srivatsan, S. G.; Tor, T. J. Am. Chem. Soc. 2007, 129, 2044.
(22) Peyron, C.; Benhida, R.; Bories, C.; Loiseau, P. M. Bioorg.
Chem. 2005, 33, 439.
(23) Wüst, F. R.; Kniess, T. J. Labelled Compd. Radiopharm.
2004, 47, 457.
(24) Haouz, A.; Vanheusden, V.; Munier-Lehmann, H.; Froeyen,
M.; Herdewijn, P.; Van Calenbergh, S.; Delarue, M. J. Biol.
Chem. 2003, 278, 4963.
Vries, A. H. M.; de Vries, J. G. Adv. Synth. Catal. 2004, 346,
1812. (f) de Vries, J. G.; de Vries, A. H. M. Eur. J. Org.
Chem. 2003, 799. (g) Hu, H.; Ge, C.; Zhang, A.; Ding, L.
Molecules 2009, 14, 3153.
(32) (a) Polshettivar, V.; Decottignies, A.; Len, C.; Fihri, A.
ChemSusChem 2010, 3, 502. (b) Fihri, A.; Luart, D.; Len,
C.; Solhy, A.; Chevrin, C.; Polshettivar, V. Dalton Trans.
2011, 40, 3116.
(33) Riedl, J.; Pohl, R.; Rulisek, L.; Hocek, M. J. Org. Chem.
2012, 77, 1026.
(25) Netzel, T. L.; Zhao, M.; Nafisi, K.; Headrick, J.; Sigman, M.
S.; Eaton, B. E. J. Am. Chem. Soc. 1995, 117, 9119.
(26) Gutierrez, A. J.; Terhost, T. J.; Matteucci, M. D.; Froehler,
B. C. J. Am. Chem. Soc. 1994, 116, 5540.
(34) Kogler, M.; Vanderhoydonck, B.; De Jonghe, S.; Rozenski,
J.; Van Belle, K.; Herman, J.; Louat, T.; Parchina, A.;
Sibley, C.; Lescrinier, E.; Herdewijn, P. J. Med. Chem. 2011,
54, 4847.
(27) Wigerinck, P.; Kerremans, L.; Claes, P.; Snoeck, R.;
Maugdal, P.; De Clercq, E.; Herdewijn, P. J. Med. Chem.
1993, 36, 538.
(28) Hassan, M. E. Collect. Czech. Chem. Commun. 1991, 56,
1944.
(29) Crips, G. T.; Flynn, B. L. Tetrahedron Lett. 1990, 31, 1347.
(30) Saughnessy, K. H. Chem. Rev. 2009, 109, 643.
(31) (a) Del Zotto, A.; Amoroso, F.; Baratta, W.; Rigo, P. Eur. J.
Org. Chem. 2009, 110. (b) de Souza, A. L. F.; Silva, A. D.
C.; Antunes, O. A. C. Appl. Organomet. Chem. 2009, 23, 5.
(c) Silva, A. D. C.; Senra, J. D.; Aguiar, L. C. S.; Simas, A.
B. C.; de Souza, A. L. F.; Malta, L. F. B.; Antunes, O. A. C.
Tetrahedron Lett. 2010, 51, 3883. (d) Qiu, J.; Wang, L.; Liu,
M.; Shen, Q.; Tang, J. Tetrahedron Lett. 2011, 52, 6489.
(e) Alimardanov, A.; Schmieder-van de Vonderwoort, L.; de
(35) Shih, Y. C.; Chien, T. C. Tetrahedron 2011, 67, 3915.
(36) Kalachova, L.; Pohl, R.; Hocek, M. Synthesis 2009, 105.
(37) Mizuta, M.; Banba, J.-i.; Kanamori, T.; Ohkubo, A.; Sekine,
M.; Seio, K. Nucleic Acids Symp. Ser. 2007, 51, 25.
(38) Čapek, P.; Cahová, H.; Pohl, R.; Hocek, M.; Gloeckner, C.;
Marx, A. Chem. Eur. J. 2007, 13, 6196.
(39) Wagner, C.; Wagenknecht, H.-A. Chem. Eur. J. 2005, 11,
1871.
(40) Western, E. C.; Daft, J. R.; Johnson, E. M.; Gannett, P. M.;
Shaughnessy, K. H. J. Org. Chem. 2003, 68, 6767.
(41) Sartori, G.; Enderlin, G.; Hervé, G.; Len, C. Synthesis 2012,
44, 767.
(42) Lawson Daku, K. M.; Newton, R. F.; Pearce, S. P.; Vile, J.;
Williams, J. M. J. Tetrahedron Lett. 2003, 44, 5095.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 330–333