Efficient synthesis of unprotected C-5-Aryl/Heteroaryl-2'-deoxyuridine via a suzuki-miyaura reaction in aqueous media

Article abstract of DOI:10.3390/molecules171214409

Following our previous results on an environmentally benign one-pot Sonogashira-cyclization protocol to obtain substituted furopyrimidine nucleosides under aqueous conditions, we investigate herein the Suzuki-Miyaura cross-coupling reactions of aryl and h

Full text of DOI:10.3390/molecules171214409

Molecules 2012, 17, 14409-14417; doi:10.3390/molecules171214409
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Efficient Synthesis of Unprotected
C-5-Aryl/Heteroaryl-2'-deoxyuridine via a
Suzuki-Miyaura Reaction in Aqueous Media
Nathalie Fresneau, Marie-Aude Hiebel, Luigi A. Agrofoglio and Sabine Berteina-Raboin *
Institut de Chimie Organique et Analytique, Université d’Orléans, UMR CNRS 7311, BP 6759,
45067 Orléans Cedex 2, France
* Author to whom correspondence should be addressed;
E-Mail: sabine.berteina-raboin@univ-orleans.fr; Tel.: +33-2-3849-4856; Fax: +33-2-3841-7281.
Received: 8 October 2012; in revised form: 20 November 2012 / Accepted: 23 November 2012 /
Published: 5 December 2012
Abstract: Following our previous results on an environmentally benign one-pot
Sonogashira-cyclization protocol to obtain substituted furopyrimidine nucleosides under
aqueous conditions, we investigate herein the Suzuki-Miyaura cross-coupling reactions of
aryl and heteroaryl derivatives at the C5 position of unprotected 2'-deoxyuridine in the
same media with a common catalyst system avoiding exotic ligands, since palladium
acetate and triphenylphosphine afforded the expected products in moderate to good yields.
Keywords: unnatural nucleosides; Suzuki-Miyaura coupling; aqueous conditions
1. Introduction
Nucleosides attract attention due to the central role they play in all living systems. Therefore
synthesis of unnatural nucleosides arises continuous interest because of their wide biological potential.
For instance, 5-substituted 2'-deoxyuridines have been reported as efficient candidates in DNA
labeling, modification, and other studies [1–17], and they also exhibit significant antiviral [18–23],
antibacterial [24], and anticancer activities [25–27]. Due to the importance of modified nucleosides, all
major classes of palladium-catalyzed reactions have been extensively developed to introduce various
substituents [28–38]. Among them, the Suzuki-Miyaura reaction is a powerful and widely used method
for carbon-carbon cross coupling reactions. Until lately, this reaction would be carried out in lipophilic
media that required working with protected nucleosides. However protection/deprotection sequences

Molecules 2012, 17
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induce generally a loss of material and increase the waste production. Recently, Suzuki-Miyaura
reactions on unprotected 2'-deoxyuridines in an aqueous-organic solvent system were described, where
tetrahydrofuran, acetonitrile, methanol or dimethylformamide was used as co-solvent [1–27,39,40]. To
the best of our knowledge, only two examples in the 5-iodouridine [41,42] and one in the 2'-deoxy-
uridine [43] series are reported in the literature where the experimental conditions required either
tris(3-sulfonatophenyl)phosphine trisodium salt (TPPTS) as a specific ligand or palladium supported on
reverse phase glass beads. This induced us to disclose herein a similar straightforward method as a
natural extension of the current available methods. Based on our interest in environmentally sound
processes [44,45], we investigated the development of a Suzuki-Miyaura reaction with 2'-deoxyuridines
in a completely aqueous medium using a readily available and inexpensive catalyst/ligand system.
2. Results and Discussion
The conditions of the reaction were optimized using the unprotected 5-iodo-2'-deoxyuridine 1
(5-IdU) and 4-methoxyphenylboronic acid. We started by using a mixture of water and acetonitrile in
presence of palladium acetate (3 mol %), triphenylphosphine (5 mol %), and sodium carbonate (1.5 equiv)
at 80 °C. After 4 hours under these conditions, the starting material 1 was completely consumed and
the expected product was isolated in 62% yield. Then, we were pleased to observe that a complete
aqueous medium did not prevent the reaction from proceeding but even slightly improved the yield
(Table 1, entry 2). An increase in the catalyst loading induced no noticeable change. However the
concentration of the reaction mixture appeared to be significant, since 2b was obtained in 75% yield
(entry 4). Further optimizations showed that increasing the amount of boronic acid or replacing the
ligand by tri(4,6-dimethyl-3-sulfonatophenyl)phosphine trisodium (TXTPS) [46,47], CataXCium F.
Sulf. [48] or tris[bis(N-2-hydroxyethyl)aminomethyl]phosphine [49], which are well-known to be highly
hydrophilic, did not improve the reaction outcome (entries 4–7) [50].
Table 1. Suzuki-Miyaura cross coupling optimization.
MeO
O
O
I
Pd(OAc)2 (3 mol %), Ligand L,
pMeOPhB(OH)2 (1.5 equiv),
Na2CO3 (1.5 equiv), solvant
NH
NH
HO
HO
N
O
N
O
O
O
OH
OH
1
2b
Entry
Ligand (L) a
PPh3
Solvent
Conditions
80 °C, 4 h
80 °C, 4 h
80 °C, 4 h
80 °C, 4 h
80 °C, 4 h
80 °C, 4 h
80 °C, 4 h
Yield (%) b
62
1
2
3
4
5
6
7
8
9
H2O:CH3CN 2:1
H2O (5 mL)
PPh3
67
c
PPh3
H2O (5 mL)
69
PPh3
TXPTS
H2O (2.5 mL)
H2O (2.5 mL)
H2O (2.5 mL)
H2O (2.5 mL)
H2O (2.5 mL)
75 (74) d
71
CataCXium F sulf
P(CH2N(C2H4OH)2)3
PPh3
traces
70
75 (66) e
70 f
120 °C, 10 min MW
120 °C, 10 min MW
PPh3
H2O (2.5 mL)
a
b
c
d
Ratio Pd/L: 1/1.8; Isolated yield; Pd(OAc)2 (10 mol %) and PPh3 (25 mol %); with 2 equiv. of
R-B(OH)2; e with 1 mL H2O; f with Na2PdCl4.

Molecules 2012, 17
14411
Then, under the best conditions, the use of microwave irradiation significantly reduced the reaction
time with the same yield. Concentrating the media and changing the catalyst induced no positive
changes (entries 8 and 9).
To probe the scope of the reaction, the use of different arylboronic acids was examined (Table 2).
The expected products were cleanly obtained in good yields with substrates that contained electron
withdrawing and donating groups in the para and meta positions (entries 1 and 2). It is worth noting
that the use of potassium trifluoroborate is compatible with these experimental conditions as a strict
stoichiometric amount of potassium phenyltrifluoroborate gave 2a with the same range of yields (entry 1).
Table 2. Substrates scope.
Entry
RB(OH)2
Products
2a: R1 = H
Yield (%) a
70 (62) b
R1
2b: R1 = OMe
2c: R1 = Ac
2d: R1 = CHO
2e: R1 = F
75
72
79
74
68
O
N
R1
NH
HO
1
O
O
OH
2f: R1 = NO2
O
NC
NH
HO
2
3
2g
70
N
O
NC
O
OH
R2
2h: R2 = Me
2i: R2 = OMe
-
-
O
NH
R2
HO
N
O
O
OH
OMe
F
O
N
OMe
F
NH
4
5
2j
53 c
HO
O
O
OH
O
N
NH
HO
O
2k
30
O
OH
O
2l: X = O
67 (73) d
81
X
NH
HO
X
N
O
6
7
O
2m: X = S
OH
O
O
NH
HO
N
O
2n
44c
O
O
OH
a Isolated yield; b with 1 equiv. Ph-BF3K; c with 3 equiv. of R-B(OH)2; d with 2 equiv. of R-B(OH)2.

Molecules 2012, 17
14412
The effects of steric hindrance were also tested with mono- and di-ortho-substituted boronic acids
showing a limitation of the method by causing a moderate and drastic loss of yield, respectively (entries
3 and 4). Then the challenging styrene-4-boronic acid was also tried to compare the reaction with the
competitive Heck cross-coupling. In this case, the desired product was isolated in 30% yield with no
trace of the alkenyl compound [51]. To expend the range of applicable substrates, 5-iodo-2'-
deoxyuridine 1 was coupled with a variety of heteroarylboronic acids (Table 2, entries 6 and 7).
Moderate to good yields were observed with thiophene-3-, furan-2-, and furan-3-boronic acids requiring
occasionally a larger excess of the boronic moiety (entries 6 and 7). Unfortunately, with pyridin-2- and
pyridin-3-boronic acids no reaction was observed, and the same result was obtained with the more
stable potassium pyridin-3-trifluoroborate.
3. Experimental
3.1. General
Solvents and reagents were purchased from commercial suppliers and used without further
1
purification. H-NMR and 13C-NMR were recorded on a Bruker Avance DPX 250 or 400 MHz
spectrometers. High-resolution mass spectra (HRMS) were recorded with a TOF spectrometer in the
electrospray ionisation (ESI) mode or with a Finnigan MAT 95 XL in the chemical ionisation (CI)
mode at the Regional Center of Physical Measurement University Blaise Pascal. All commercial
solvents were used without further purification. Column chromatography was carried out using Silica
gel 60N (spherical, neutral, 40–63 µm, Merck). Melting point was measure on Thermo Scientific 9200.
Intfrared (IR) spectra were obtained on FT-IR Thermo Scientific Nicolet iS10. Thin layer
chromatography (TLC) was carried out on Merck silica gel 60F254 precoated plates. Visualization was
made with ultraviolet light.
3.2. General procedure
Under nitrogen, 5-IdU 1 (100 mg, 0.282 mmol), PPh3 (4.1 mg, 0.016 mmol), sodium carbonate
(44.8 mg, 0.423 mmol), and ary/hetarylboronic acid (0.423 mmol) were dissolved in water (2.5 mL).
Then Pd(OAc)2 (2.5 mg, 0.011 mmol) was added to the mixture before sealing the vial. Then the
mixture was irradiated for 10 min at 120 °C. After completion, water was added (5 mL) and the pH
was adjusted to 7 using aqueous HCl 10%. The solution was concentrated under reduced pressure and
the residue was finally purified by silica gel chromatography to afford the desired product.
5-Phenyl-2'-deoxyuridine (2a). DCM/MeOH (96/4), spectroscopic data conformed to the literature [40].
5-(4-Methoxyphenyl)-2'-deoxyuridine (2b). DCM/MeOH (96/4), spectroscopic data conformed to the
literature [40].
5-(4-Acetylphenyl)-2'-deoxyuridine (2c). DCM/MeOH (96/4), white solid (72% yield); mp >250 °C
(slow degradation); 1H-NMR (250 MHz, DMSO-d6) δ 11.60 (bs, 1H), 8.41 (s, 1H), 7.96 (d, J = 8.5 Hz,
2H), 7.75 (d, J = 8.5 Hz, 2H), 6.24 (t, 1H, J = 6.5 Hz), 5.28 (d, 1H, J = 2.7 Hz), 5.19 (t, 1H, J = 3.2 Hz),
4.37–4.26 (m, 1H), 3.88–4.81 (m, 1H), 3.69–3.60 (m, 2H), 2.59 (s, 3H), 2.35–2.12 (m, 2H); 13C-NMR

Molecules 2012, 17
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(125 MHz, DMSO-d6) δ 197.8, 162.3, 150.2, 139.7, 138.5, 135.6, 128.5, 128.1, 112.6, 88.0, 85.2, 70.5,
61.3, 27.1 (one peak under the DMSO-d6 signal); IR (neat): 3421, 3162, 3054, 2921, 2831, 1671, 1657,
1598, 1558, 958 cm−1; HRMS (ESI) calcd. for C17H18N2O6Na (M+Na) 369.1063, Found 369.1077.
5-(4-Formylphenyl)-2'-deoxyuridine (2d). DCM/MeOH (96/4), spectroscopic data conformed to the
literature [7].
5-(4-Fluorophenyl)-2'-deoxyuridine (2e). DCM/MeOH (96/4), spectroscopic data conformed to the
literature [40].
5-(4-Nitrosophenyl)-2'-deoxyuridine (2f). DCM/MeOH (96/4), spectroscopic data conformed to the
literature [52].
5-(3-Cyanophenyl)-2'-deoxyuridine (2g). DCM/MeOH (96/4), white solid (70% yield); mp 179.2–180.5 °C;
1H-NMR (250 MHz, DMSO-d6) δ 11.63 (bs, 1H), 8.34 (s, 1H), 8.01 (s, 1H), 7.89 (d, J = 7.9 Hz, 1H),
7.76 (d, J = 7.9 Hz, 1H), 7.58 (t, J = 7.9 Hz, 1H), 6.22 (t, J = 6.5 Hz, 1H), 5.26 (d, J = 3.9 Hz, 1H),
5.17 (t, J = 4.7 Hz, 1H), 4.35–4.24 (m, 1H), 3.81 (q, J = 3.9 Hz, 1H), 3.65 (dd, J = 8.6, 4.7 Hz, 1H),
13
3.58 (dd, J = 8.6, 3.9 Hz, 1H), 2.35–2.12 (m, 2H); C-NMR (125 MHz, DMSO-d6) δ 162.3, 150.2,
139.7, 135.0, 133.0, 131.6, 131.1, 129.8, 119.3, 111.8, 111.8, 88.0, 85.1, 70.3, 61.2 (one peak under
DMSO d6 signal); IR (neat): 3468, 3336, 3207, 3071, 2236, 1682, 1263, 1086, 945, 817 cm−1; HRMS
(ESI) calcd. for C16H15N3O5Na (M+Na) 352.0909, Found 352.0906.
5-(2-Fluoro-3-methoxyphenyl)-2'-deoxyuridine (2j). DCM/MeOH (96/4), white solid (53% yield); mp
1
173.2–174.2 °C; H-NMR (250 MHz, DMSO-d6) δ 11.52 (bs, 1H), 8.05 (s, 1H), 7.13 (m, 2H), 6.91
(dt, J = 6.3, 2.8 Hz, 1H), 6.22 (t, J = 6.7 Hz, 1H), 5.25 (d, J = 3.6 Hz, 1H), 4.97 (t, J = 4.7 Hz, 1H),
4.23–4.25 (m, 1H), 3.84 (s, 3H), 3.81–3.75 (m, 1H), 3.60–3.45 (m, 2H), 2.21–2.12 (m, 2H); 13C-NMR
(125 MHz, DMSO-d6) δ 161.8, 150.5, 148.6, 147.7, 140.1, 124.3, 123.1, 121.9, 113.7, 109.3, 88.0,
84.9, 70.8, 61.5, 56.5 (one peak under the DMSO-d6 signal); IR (neat): 3411, 3040, 2943, 2837, 1697,
1663, 1480, 1271, 1096, 1043, 1021, 790 cm−1; HRMS (ESI) calcd. for C16H17N2O6FNa (M+Na)
375.0968, Found 375.0971.
1
5-(4-Vinylphenyl)-2'-deoxyuridine (2k). DCM/MeOH (96/4), pale yellow gel (30% yield); H-NMR
(400 MHz, DMSO-d6) δ 11.57 (bs, 1H), 8.31 (s, 1H), 7.62 (d, J = 8.3 Hz, 2H), 7.53 (d, J = 8.3 Hz,
2H), 6.80 (dd, J = 17.7, 10.8 Hz, 1H), 6.30 (t, J = 6.5 Hz, 1H), 5.91 (d, J = 17.7 Hz, 1H), 5.33 (d,
J = 10.8 Hz, 1H), 5.32 (d, J = 3.6 Hz, 1H), 5.19 (t, J = 4.8 Hz, 1H), 4.38–4.34 (m, 1H), 3.91–3.82 (m,
13
1H), 3.71–3.59 (m, 2H), 2.37–2.14 (m, 2H); C-NMR (125 MHz, DMSO-d6) δ 162.5, 150.3, 138.4,
136.7, 136.4, 128.4, 126.3, 114.7, 113.4, 88.0, 85.0, 70.6, 61.4 (one peak under the DMSO-d6 signal);
IR (neat): 3395, 3056, 2961, 1667, 1262, 1088, 1047, 1027, 792 cm−1; HRMS (ESI) calcd. for
C17H18N2O5Na (M+Na) 353.1113, Found 353.1112.
5-(Furan-3-yl)-2'-deoxyuridine (2l). DCM/MeOH (96/4), spectroscopic data conformed to the
literature [53].

Molecules 2012, 17
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5-(Thiophen-3-yl)-2'-deoxyuridine (2m). DCM/MeOH (96/4), spectroscopic data conformed to the
literature [53].
5-(Furan-2-yl)-2'-deoxyuridine (2n). DCM/MeOH (96/4), spectroscopic data conformed to the
literature [54].
4. Conclusions
In summary, we disclose herein a successful Suzuki-Miyaura reaction with 5-iodo-2'-deoxyuridine
in a completely aqueous medium. The inexpensive and common triphenylphosphine combined with
palladium acetate gave rise to the expected products in moderate to good yields. Furthermore, the
variety of aryl and heteroaryl derivatives introduced demonstrates the generality of this method.
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Sample Availability: Samples of the compounds 2a–g, j, l, m are available from the authors.
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