Synthesis of 6-aryluridines via Suzuki-Miyaura cross-coupling reaction at room temperature under aerobic ligand-free conditions in neat water

Article abstract of DOI:10.1016/j.tetlet.2013.04.066

A new and efficient ligandless cross-coupling reaction of 6-iodouridine with various boronic acids in the presence of Na₂PdCl₄ was performed at room temperature in aerobic water. The target 6-aryl analogues were obtained in moderate to good yields depending on the boronic acid nature.

Full text of DOI:10.1016/j.tetlet.2013.04.066

Tetrahedron Letters 54 (2013) 3374–3377
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Tetrahedron Letters
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Synthesis of 6-aryluridines via Suzuki–Miyaura cross-coupling reaction
at room temperature under aerobic ligand-free conditions in neat water
⇑
Gérald Enderlin, Guillaume Sartori, Gwénaëlle Hervé, Christophe Len
Transformations Intégrées de la Matière Renouvelable, UTC-ESCOM, Centre de recherche de Royallieu, BP 20529, 60205 Compiègne, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A new and efficient ligandless cross-coupling reaction of 6-iodouridine with various boronic acids in the
presence of Na2PdCl4 was performed at room temperature in aerobic water. The target 6-aryl analogues
were obtained in moderate to good yields depending on the boronic acid nature.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 15 January 2013
Revised 12 April 2013
Accepted 16 April 2013
Available online 24 April 2013
Keywords:
Nucleoside
Suzuki–Miyaura
Green chemistry
Homogeneous catalysis
Research on nucleoside and nucleotide analogues has led to the
discovery of very potent drugs against a huge range of diseases as
they act as antivirals, antibiotics, or anti-tumorals.1–3 In addition
they have proved to be very efficient tools for diagnostic and exam-
ination of biological processes. To have a structure–activity rela-
tionship, three main modifications of the canonical nucleosides
and nucleotides either on the phosphate part, on the sugar moiety,
or on the nucleobase are generally considered. Among the nucleo-
side analogues, those having C-aryl group on the glycone moiety
(e.g., d4T analogues 1,4 benzo[c]furan derivative 25) or on the agly-
cone moiety (e.g., compound 36) have been particularly studied
(Fig. 1).
In particular, the C-5-aryl nucleoside analogues were studied for
their potent activities as fluorescent probes,7–11 as antiviral drugs
(e.g., Brivudin, BVDU),12–14 and for the study of electron-transfer
in DNA.15–17,6,18–20 In the case of C-5 modification, different success-
ful techniques were performed such as photochemical route,21 C–H
activation22,23 or palladium cross-coupling methodologies,24
mainly Stille10,13,25–32 or Suzuki–Miyaura7,15,16,6,33–40 reactions.
Concerning the 6-position, only few examples were reported in
the literature.41–49 In general, the main methodologies have been
developed in organic solvent starting from fully protected uridine
such as 6-stannyl42,44 and 6-iodo nucleoside analogues.43,45–48 In
2011, Shih et al. have also reported the synthesis of 6- and 5-arylu-
ridine via the Suzuki–Miyaura reaction in refluxing toluene or DME
starting from fully protected 6- or 5-halouridine with Pd(OAc)2 as
the catalyst, PPh3 as the ligand, and sodium carbonate as the base.48
Recently, Nencka et al. described a methodology starting from fully
protected vinylphosphonate 6-iodouridine by standard Suzuki–
Miyaura cross-coupling with Pd(OAc)2 and K3PO4 under aerobic
and ligandless conditions in a mixture of propanol and water (ratio
1:1).45 Finally very recently Kögler et al. reported the synthesis of 6-
aryl-20-deoxyuridine nucleosides under base free conditions via a
Liebeskind cross-coupling methodology which necessitates stoichi-
ometric use of copper thiophene carboxylate as the co-reagent at
slightly elevated temperatures (50 °C).43 Taking advantage of our
first reports concerning the synthesis of 5-aryl nucleoside analogues
via Suzuki–Miyaura cross-coupling in neat water,40 development of
a new green methodology for the substitution in position six was
investigated. The aim of the presented work was to develop green
and economic conditions starting from totally deprotected 6-iodo-
uridine (4)47,50,51 for the synthesis of 6-aryl nucleoside analogues
having no protection/deprotection steps, no ligand, aerobic condi-
tions in water as sole solvent.
First, application of our general procedure optimized for the
synthesis of 5-arylnucleoside analogues was attempted:40 nucleo-
side
4 (1.0 equiv), phenylboronic acid (1.3 equiv), Na2PdCl4
(0.1 mol %), and KOH (2.0 equiv) in the presence or not of TPPTS
(0.25 mol %) at 100 °C with degassing of neat water (18.2 M).
Unfortunately those previously described methods were not trans-
posable to the 6-iodo analogue 4. It is noteworthy that under these
conditions the substitution of KOH by K3PO4 did not permit to ob-
tain the cross-coupling analogue. The instability of the starting
material 4 under thermal conditions and alkaline media could be
the cause of this non reactivity.43,45,48,52,53 In order to avoid this
phenomenon and to develop greener conditions, room tempera-
ture without addition of any ligand has been explored. First,
⇑
Corresponding author. Tel.: +33 344 23 8 828; fax: +33 644 971 591.
E-mail address: christophe.len@utc.fr (C. Len).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.04.066

G. Enderlin et al. / Tetrahedron Letters 54 (2013) 3374–3377
3375
Table 1
O
N
O
N
Variation of the nature of the base for the Suzuki–Miyaura cross-coupling starting
from 6-iodouridine (4)
O
N
NH
NH
NH
O
O
O
O
O
PhB(OH)2 1.3 equiv.
Na2PdCl4 10 mol%
Base 2.0 equiv.
O
O
HO
O
HO
HN
HN
HO
O
N
I
O
N
HO
OH
O
O
H2O
20°C, 0.5-2 h
3
1
2
HO
HO
HO
OH
HO
OH
Figure 1. Nucleoside analogues 1–3 having an aryl group.
4
5
Entry
Base
Time (h)
Yielda (%)
variation of the palladium loadings was realized to develop the
cross-coupling reaction in water. At 20 °C, the ligandless cross-cou-
pling Suzuki–Miyaura reaction starting from nucleoside analogue 4
was effective with phenylboronic acid (1.3 equiv), Na2PdCl4
(10 mol %), KOH (2.0 equiv) in aerobic water. The target 6-aryl uri-
dine derivative 5 was obtained in 81% yield (Scheme 1).54 Unfortu-
nately, lower amount of palladium did not furnish the target
compound 5 in acceptable yield. Compared with our previous
work,40 the actual amount of palladium (10 mol % vs 0.1 mol %) is
due to both lower temperature (rt vs 100 °C) and less reactive
starting nucleoside analogue 4. In the presented work, the time
of reaction was determined by monitoring the reaction until full
conversion of the starting material was observed.
1
2
3
4
5
6
7
8
Na2CO3
K2CO3
CsCO3
NaOH
KOH
CsF
AcONa
K3PO4
1
2
2
1
0.5
2
2
73
60
73
75
81
23
10
75
1
a
Isolated yield.
Table 2
Variation of the nature of palladium-based species for the Suzuki–Miyaura cross-
coupling starting from 6-iodouridine (4)
Different bases, including Na2CO3, K2CO3, CsCO3, NaOH, KOH,
CsF, AcONa, and K3PO4, were tested with the optimized conditions
described above. Interestingly in all cases the yields were moderate
to good (60–81%) (Table 1, entries 1–5 and 8) with the exception of
CsF and AcONa (Table 1, entries 6 and 7). In those cases, compound
5 was isolated only in respectively, 23% and 10% yields. The best re-
sult was obtained when using KOH (Table 1, entry 5). This base
permitted both a full conversion in a shorter reaction time (0.5 h
vs 1.5–2.0 h) and a higher yield. It is noteworthy that the use of
such a strong base did not furnish a detrimental effect on the sta-
bility of C-6 iodouridine such as deglycosylation or dehalogenation
at this temperature (20 °C).
In search of a more efficient catalyst, the next step consisted in
examining different palladium sources which are soluble or give
colloidal suspensions in water. For this purpose Pd(OAc)2, PdI2,
PdCl2, Pd(PPh3)4, Pd/C, Na2PdCl4, PdCl2(PPh3)2, PdCl2(PhCN)2,
Pd2((PhCHCH)2CO)3 were screened by using each time the same
amount of catalyst (10 mol %). Even though all the water soluble
palladium derivatives promoted the formation of the target nucle-
oside 5, slight differences were observed in reaction times (0.5–
1.5 h) for similar yields (76–80%) (Table 2, entries 1–3, 6, and 8).
In our hands, PdI2, PdCl2, Na2PdCl4 afforded the 6-phenyl analogue
5 in 0.5 h while in the presence of Pd(OAc)2 and PdCl2(PhCN)2 the
reaction was completed in , 1 and 1.5 h, respectively. On the other
hand, when water insoluble catalysts such as Pd(PPh3)4, Pd/C,
PhB(OH)2 1.3 equiv.
O
O
PdII 10 mol%
HN
HN
KOH 2.0 equiv.
O
N
I
O
N
O
H2O
20°C, 0.5-6 h
O
HO
HO
HO
OH
HO
OH
4
5
Entry
Pd
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
9
Pd(OAc)2
PdI2
1
80
76
79
0
62
81
0
0.5
0.5
5
PdCl2
Pd(PPh3)4
Pd/C
Na2PdCl4
PdCl2(PPh3)2
PdCl2(PhCN)2
Pd2((PhCHCH)2CO)3
6
0.5
6
1.5
6
77
0
a
Isolated yield.
in water, fast reaction time, and good yield (Table 2, entry 6). In our
hands, the catalytic system cannot be recycled due to the polarity
of the target nucleoside analogues.
PdCl2(PPh3)2,
and
Pd2((PhCHCH)2CO)3
were
employed,
In order to validate the utility of the method, a series of arylbo-
ronic acids with different electronic and steric demands were
tested. Application of our optimized conditions using 6-iodouri-
dine (4) as the starting material, Na2PdCl4 (10 mol %) as the
catalyst in the presence of KOH (2 equiv) and arylboronic acid
(1.3 equiv) in water as the sole solvent was performed at 20 °C
without taking care of an inert atmosphere. It is interesting to note
that starting from arylboronic acid having either electron-donating
(Table 3, entries, 1, 2, 4, and 10) or electron-withdrawing substitu-
ents (Table 3, entries 5 and 6) in para position the catalyst system
was very efficient. Using our optimized method, the less hydrosol-
uble 2-naphthylboronic acid furnished the corresponding nucleo-
side analogue in 84% yield. The presence of a withdrawing group
in para position gave similar yield (Table 3, entry 6) with the
exception of the methylketone (Table 3, entry 5). To the best of
our knowledge, the cross-coupling Suzuki–Miyaura reaction in
heterogeneous cross-coupling catalysis failed even after longer
reaction time (Table 2, entries 4, 5, 7, and 9). Among the palladium
sources, Na2PdCl4 (10 mol %) was kept due to its greatest solubility
O
O
HN
HN
i
O
N
I
O
N
O
O
HO
HO
HO
OH
HO
OH
4
5
Scheme 1. Reagents and conditions: (i) PhB(OH)2 (1.3 equiv), Na2PdCl4 (10 mol %),
KOH (2.0 equiv), H2O, rt, 81% yield.

3376
G. Enderlin et al. / Tetrahedron Letters 54 (2013) 3374–3377
Table 3
Supplementary data
Suzuki–Miyaura cross-coupling starting from various arylboronic acids and 6-
iodouridine (4)
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.04.066.
O
O
ArB(OH)2 1.3 equiv.
Na2PdCl4 10 mol%
KOH 2.0 equiv.
HN
HN
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O
N
I
O
N
Ar
H2O
20°C, 0.5-24 h
O
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Acknowledgments
G.S. thank Dr. G. Santini and ESCOM for their financial support.
This work was supported in part by Regional Program of Region
Picardie, France.

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54. General procedure for 5: 51 6-iodouridine (50 mg, 0.135 mmol), Na2PdCl4, 3H2O
(3.9 mg, 0.013 mmol), phenylboronic acid (25 mg, 0.202 mmol), and KOH
(18 mg, 0.270 mmol) were dissolved and stirred in 1 ml of water. The reaction
was performed at room temperature during 30 min. Then the solvent was
evaporated or lyophilized. The residue was purified on flash reverse phase
column chromatography (water/MeOH = 1:0–3:7) to yield 6-phenyluridine (5)
(35 mg, 80%). 1H NMR (DMSO-d6, 400 MHz) d 11.49 (s, 1H, NH), 7.54–7.50 (m,
5H, Ph), 5.51 (s, 1H, H-5), 5.06–5.04 (m, 2H, H-10 and OH), 4.82 (d, 1H,
J = 6.0 Hz, OH), 4.62–4.57 (m, 2H, OH, and H-20), 4.01 (dd, 1H, J = 5.9 and
11.7 Hz, H-30), 3.59–3.52 (m, 2H, H-40 and H-50), 3.46–3.42 (m, 1H, H-50); 13C
NMR (DMSO-d6, 100 MHz) d 162.1, 156.1, 150.6, 133.1, 130.2 (CH), 128.8 (CH),
128.05 (CH), 103.6 (CH), 93.6 (CH), 84.9 (CH), 70.9 (CH), 69.9 (CH), 62.15 (CH2).