Synthesis of new C5-(1-substituted-1,2,3-triazol-4 or 5-yl)-2′- deoxyuridines and their antiviral evaluation

Article abstract of DOI:10.1016/j.ejmech.2010.12.017

The synthesis and antiviral evaluation of a series of C5-(1,4- and 1,5-disubstituted-1,2,3-triazolo)-nucleoside derivatives is described. The key steps of this synthesis are regioselective Huisgen's 1,3-dipolar cycloaddition, using either copper-catalyzed azide-alkyne cycloaddition (CuAAC) or ruthenium-catalyzed azide-alkyne cycloaddition (RuAAC) under microwave activation. Some compounds among the 5a-l series possess activity against herpes simplex viruses 1 and 2, varicella-zoster virus, human cytomegalovirus and vaccinia virus. Their cytostatic activities were determined against murine leukemia cells, human T-lymphocyte cells and cervix carcinoma cells. Compounds were also evaluated on a wide panel of RNA viruses, including Vesicular stomatitis virus, influenza viruses type A (H1N1 and H3N2) and B in MDCK cell cultures, parainfluenza-3 virus, reovirus-1, Sindbis virus and Punta Toro virus in Vero cell cultures and Vesicular stomatitis, Coxsackie B4 and respiratory syncytial virus, with no specific antiviral

Full text of DOI:10.1016/j.ejmech.2010.12.017

European Journal of Medicinal Chemistry 46 (2011) 778e786
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis of new C5-(1-substituted-1,2,3-triazol-4 or 5-yl)-20-deoxyuridines and
their antiviral evaluation
Aurélien Montagu a, Vincent Roya, Jan Balzarini b, Robert Snoeck b, Graciela Andrei b,
,
Luigi A. Agrofoglio a
*
a Institut de Chimie Organique et Analytique, UMR 6005, Université d’Orléans, 45067 Orléans, France
b Rega Institute for Medical Research, K.U. Leuven, 3000 Leuven, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis and antiviral evaluation of a series of C5-(1,4- and 1,5-disubstituted-1,2,3-triazolo)-nucle-
oside derivatives is described. The key steps of this synthesis are regioselective Huisgen’s 1,3-dipolar
cycloaddition, using either copper-catalyzed azide-alkyne cycloaddition (CuAAC) or ruthenium-catalyzed
azide-alkyne cycloaddition (RuAAC) under microwave activation. Some compounds among the 5ael series
possess activity against herpes simplex viruses 1 and 2, varicella-zoster virus, human cytomegalovirus and
vaccinia virus. Their cytostatic activities were determined against murine leukemia cells, human
T-lymphocyte cells and cervix carcinoma cells. Compounds were also evaluated on a wide panel of RNA
viruses, including Vesicular stomatitis virus, influenza viruses type A (H1N1 and H3N2) and B in MDCK cell
cultures, parainfluenza-3 virus, reovirus-1, Sindbis virus and Punta Toro virus in Vero cell cultures and
Vesicular stomatitis, Coxsackie B4 and respiratory syncytial virus, with no specific antiviral effect.
Ó 2010 Elsevier Masson SAS. All rights reserved.
Received 19 August 2010
Received in revised form
9 December 2010
Accepted 10 December 2010
Available online 21 December 2010
Keywords:
C5-(1,4- and 1,5-disubstituted-1,2,3-
triazolo)-nucleosides
Copper-catalyzed azide-alkyne
cycloaddition
Ruthenium-catalyzed azide-alkyne
cycloaddition
Microwave activation
Antiviral activity
1. Introduction
and chemo-selective and offer complete regioselectivity. Thus,
based on these aforementioned C5-substituted nucleoside deriva-
C5-substituted pyrimidine nucleosides have taken up an
important role in the therapy of virus infection and cancer [1]. For
instance, significant progress in the study of anti-herpes nucleo-
sides has been made by the advent of 5-substituted pyrimidine
nucleosides such as 5-iodo-, 5-(2-chloroethyl)-, and (E)-5-(2-bro-
movinyl)- derivatives of 20-deoxyuridine.
In recent years, our group reported [2] and patented [3] a series
of C5-monohalogenated ethynyl or dihalogenated vinyl-modified
nucleosides as antiviral drugs against flaviviridae viruses, and
especially HCV, meanwhile some 5-isoxazol-5-yl were recently
developed by Kim’s group [4] (Fig. 1). Nearly at the same time, we
became interested in [3 þ 2] cycloaddition reaction pioneered by
Huisgen [5] between acetylenes and azides. The copper-catalyzed
(CuAAC) [6] or ruthenium-catalyzed (RuAAC) [7] Huisgen azide-
alkyne cycloadditions, recently reviewed by Amblard et al. [8]
allowed us to synthesize several base- or sugar-modified nucleo-
sides [9]. These catalyzed reactions are highly specific, irreversible
tives and their antiviral activity, we designed and synthesized some
C5-triazolo-20-deoxyuridines (Fig. 2) starting from our previously
described C5-ethynyl-20-deoxyuridine through either a CuAAC and
RuAAC reaction [10] with various substituted phenyl azides
generated in situ.
The influence of the substituted at the phenyl group and the
effect of the regioselectivity (1,4 and 1,5) on the antiviral data will
be discussed. Among all synthesized compounds (5ael and 7b, d, h,
l), 5a was already described [11] to study the effect of a stacking
triazole and aromatic groups in the major grooves of nucleic acid
duplex stability, but not for its antiviral properties.
2. Results and discussion
2.1. Chemistry
To introduce the 1,2,3-triazol scaffold, we decided that the
Huisgen reaction would be carried out from C5-ethynyl-20-deoxy-
uridine [2a] and a variety of substituted phenyl azides (chosen from
polar to apolar and bulky substituents). Thus, treatment of known
* Corresponding author. Tel.: þ33 2 3849 4582; fax: þ33 2 3841 7281.
E-mail address: luigi.agrofoglio@univ-orleans.fr (L.A. Agrofoglio).
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.12.017

A. Montagu et al. / European Journal of Medicinal Chemistry 46 (2011) 778e786
779
O
O
N
R
O
N
O
N
O
N
O
Br
I
I
NH
NH
NH
NH
NH
Cl
NH
O
O
O
AcO
N
AcO
AcO
O
O
O
a
b
O
O
O
N
HO
HO
HO
O
O
O
90%
84%
OAc
1
OAc
2
OAc
c
3a R = TMS
3b R = H
OH
BVDU
OH
IDU
OH
5-(2-Chloroethyl)-
2'deoxyuridine
Anti-tumoral
Idoxuridine
Anti-viral
Brivudin
Scheme 1. Synthesis of acetylated 3b. Reagents and conditions: (a) I2, CAN, CH3CN,
reflux; (b) TMS-acetylene, CuI, PdCl2(PPh3)2, DMF, Et3N; (c) n-Bu4NF, CH3CN.
Anti-viral
R
O
O
N
X
Therefore we decided to study the regioisomeric 1,5 or 1,4 influ-
ences on biological activity of the some active 5b, 5h, 5l and inactive
5d 1,4-regioisomers. We have previously investigated the optimal
conditions [9d] for microwaves-assisted [13] RuAAC synthesis of 1,5-
disubstituted-1,2,3-triazolo-nucleosides (Scheme 3). Thus, the pro-
tected C5-ethynyl-uridine (3b) was reacted with freshly synthesized
aromatic azides [12], 5 mol% Cp*RuCl(PPh3)2 catalyst (8) in THF at
100 ꢀC, during 5 min under microwave irradiation. The correspond-
ing nucleosides 6b, 6d, 6h and 6l were obtained in good yields
(70e80%), respectively. A purification bycolumn chromatography, on
silica gel was necessary to remove the small amount of 1,4-
regioisomers formed (4e5%) as observed by TLC. The final deacyla-
tion by ammoniac in methanol during 5 h at 0 ꢀC gave the corre-
sponding nucleosides 7b, 7d, 7h and 7l in good yields, respectively.
N
NH
NH
O
O
X
O
N
HO
HO
O
O
OH
(5-isoxazol-5-yl )-
OH
5-(1,2-Dihalovinyl)-
2'deoxyuridine
2'deoxyuridine
potential anti-viral
Fig. 1. Antiviral or anticancer C5-substituted nucleosides.
acetylated 20-deoxyuridine (1) with elemental iodine and ceric
ammonium nitrate (CAN) at 80 ꢀC gave the corresponding pro-
tected 5-iodouracil nucleoside 2. After reaction, under Sonogashira
conditions, of 2 with trimethylsilylacetylene (TMS) in the presence
of Et3N, CuI and PdCl2(PPh3)2 in anhydrous DMF at room temper-
ature (3a), and following removal of the trimethylsilyl group with
n-Bu4NF, the corresponding protected 5-ethynyl-20-deoxyuridine
(3b) was obtained in good yields (Scheme 1).
Since all aromatic azides are not commercially available, we
decided to convert commercial substituted anilines into their cor-
responding azides, which were directly engaged into the CuAAC
reaction following a procedure reported in 2007 by Barral et al. [12]
Thus azidation is achieved by treatment of substituted aniline with
tert-butyl-O-nitrite and an equimolar quantity of azido-
trimethylsilane in acetonitrile, respectively (Scheme 2).
2.2. Antiviral activity
Compounds 5ael and 7b, 7d, 7h, and 7l were evaluated against
a wide variety of viruses, to determine their antiviral activity, as the
effective concentration required to reduce virus-induced cytopa-
thicity by 50% (EC50). Data for vaccinia virus (VV), herpes simplex
virus-1(KOS) (HSV-1), HSV-1(TKꢁ), HSV-2(G), varicella-zoster virus
(VZV TKþ and TKꢁ), human cytomegalovirus (AD-169 and Davis
strains) in HEL cell cultures are summarized in Table 1.
Several of the synthesized compounds showed activities against
several DNA viruses. Especially, the EC50 against VZV was 3.1
mM for
5b, 2.6 M for 5h and 1.4 M for 5l. None of compounds 5ael dis-
m
m
played a specific antiviral effect against a wide panel of other viral
strains including Vesicular stomatitis virus, influenza viruses type
A (H1N1 and H3N2) and B in MDCK cell cultures, parainfluenza-3
virus, reovirus-1, Sindbis virus and Punta Toro virus in Vero cell
cultures and Vesicular stomatitis, Coxsackie B4 and respiratory
syncytial virus in HeLa cell cultures and HIV-1(IIIB) or HIV-2(ROD)
in CEM cell cultures (data not shown). However, the active
compounds are also endowed with a pronounced cytostatic
activity. The compounds’ active against DNA virus replication is also
quite cytostatic. Therefore, it is currently unclear whether the
activity observed for these compounds is due to a specific antiviral
effect or to an a-specific cellular toxic activity. It is interesting to
quote that the (1,5)-regioisomers, 7b, 7d, 7h, 7l were found inactive
against this wide panel of viruses and not toxic.
Without any purification, the freshly synthesized substituted
phenyl azides were directly reacted with alkynyl nucleoside 3b in
the presence of copper sulfate and ascorbic acid sodium salt. Tri-
azolo-appended nucleosides 4ael were obtained in moderate to
good yields (from 60 to 92%). No traces of 1,5-regioisomer were
observed. After deacylation (MeOH/NH3), compounds 5ael were
evaluated against various viral strains. It appears that compounds
5b, 5e, 5h and 5l exhibited interesting biological activities against
DANN viruses, respectively, (see Table 1 hereafter).
R
R
N
N
N
O
N
O
N
N
N
2.3. Cytostatic activity
N
NH
NH
O
HO
O
HO
The in vitro inhibitory effects of 5ael on the proliferation of
murine leukemia cells (L1210), human T-lymphocyte cells (CEM)
and cervix carcinoma cells (HeLa) are reported in Table 2. Several
O
O
OH
OH
compounds showed a cytostatic activity with an IC50 ∼ ꢂ1
5h and 5l) or an IC50 between 1 and 10 M (5deg). The 4-phenoxy-
phenyl triazolyl derivative 5l exhibits a pronounced cytostatic
activity with all IC50 values <1 M for L1210,
M (IC50 ¼ 0.5
IC50 ¼ 0.8 M for CEM, IC50 ¼ 0.28 M for HeLa), whereas the
mM (5b,
m
Target compounds
(1,5-regioisomers)
Target compounds
(1,4-regioisomers)
m
m
Fig. 2. C5-(1,2,3)-triazoles-20-deoxyuridines obtained.
m
m

780
A. Montagu et al. / European Journal of Medicinal Chemistry 46 (2011) 778e786
NH2
R2
a
R2
N3
N
O
N
O
N
R2
N
NH
N
NH
b
O
AcO
O
R1O
O
O
60-90%
OAc
OR1
3b
4a-l R1 = Ac
5a-l R1 = H
c
NH2
NH2
NH2
NH2
NH2
NH2
NH2
R2
F
F
=
F
F
a
b
c
d
e
f
NH2
NH2
NH2
NH2
NH2
NH2
Br
Cl
S
OCF3
NO2
O
g
h
i
j
k
l
Scheme 2. CuAAC synthesis of triazoles 5ael. Reagents and conditions: (a) t-BuONO, TMSN3, CH3CN; (b) CuSO4, sodium ascorbate, tBuOH/H2O; (c) NH3, MeOH.
regioisomer 7l displays no cytostatic activity. Compound 5l has
a comparable antiproliferative activity as 5-fluorouracil (5-FU)
against L1210 and HeLa cells. It is superior to 5-FU against CEM cells.
compounds bound in the enzyme active sites. Also, it will be of
interest to investigate the properties of their monophosphorylated
derivativesagainst thymidylatesynthaseandtheir triphosphorylated
derivatives against the viral and cellular DNA polymerases to reveal
the mechanism of biological action.
3. Conclusion
A set of C5-(1,4- and 1,5-disubstituted-1,2,3-triazolo) nucleoside
derivatives were designed and synthesized through a regioselective
CuAAC or RuAAC, as potential antiviral agents. Both series were low
molecular weight compounds with leadlike properties suitable for
a medicinal chemistry optimization program. They have been eval-
uated against several DNA viruses and their cytostatic activities were
determined against murine leukemia cells, human T-lymphocyte
cells and cervix carcinoma cells. Some cellular activity was observed,
which most likely implies that the compounds are able to penetrate
into cells. Several of the synthesized compounds showed activities
against several DNA viruses in the micromolar range. Whereas the
1,4-regioisomers exhibited antiviral activity, it is interesting to quote
that the (1,5)-regioisomers, were found inactive against this wide
panel of viruses and display notoxicity. Inorder to designcompounds
with a significantly increased potency, it will be necessary to study
their phosphorylation by human and viral kinases; this process
would be greatly aided by a co-crystal structure of the best
4. Experimental
4.1. Chemistry
Commercially available chemicals were of reagent grade and
used as received. Acetonitrile was distilled from CaH2. The reactions
were monitored by thin layer chromatography (TLC) analysis using
silica gel plates (Kieselgel 60F254, E. Merck). Column chromatog-
raphy was performed on Silica Gel 60M (0.040e0.063 mm,
E. Merck). Melting points are uncorrected and were measured on
a Kofler apparatus. The 1H and 13C NMR spectra were recorded on
a Varian InovaUnity 400 spectrometer (400 MHz) in (d4) methanol,
CDCl3 and DMSO, shift values in parts per million relative to SiMe4
as internal reference. High Resolution Mass spectra were per-
formed by the Mass Spectrometry Center of Blaise Pascal University
(Program Masslynx 4.0) (Aubière, France). The purity was deter-
mined by HRMS, 1H, 13C and a semi-preparative HPLC (Hypersil

A. Montagu et al. / European Journal of Medicinal Chemistry 46 (2011) 778e786
781
Table 1
Antiviral and cytotoxic activity of compounds 5ael and 7b, d, h, l against vaccinia (VV), herpes simplex virus-1(KOS) (HSV-1), varicella-zoster virus (VZV TKþ and TKꢁ), human
cytomegalovirus (AD-169 strain and Davis strain) in HEL cells.
Compound
Antiviral activity EC50
(
m
M)a
Cytotoxicity (mM)
c
HSV-1 (KOS)
HSV-1 (TKꢁ KOS ACVR)
HSV-2 (G)
VZV
HCMV
VV
(MCC)b
(CC50)
(TKþ) OKA
(TKꢁ) 07-1
AD-169 strain
Davis strain
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
7b
7d
7h
7l
>50
36
>50
31
>50
ꢄ50
>220
>10
>50
>50
>240
ꢄ100
>50
>50
>50
ꢄ43
>100
>100
>100
>100
180
>270
3.1
>50
20
7.7
>50
41
2.6
27
>50
>50
1.4
e
>270
6.1
>50
97
35
>50
48
>270
29
>270
18
>50
38
>220
>10
37
>50
>240
31
>50
>50
>50
4.3
>100
>100
>100
>100
2.0
270
270
1.5
36
7.4
12.4
147
7.4
1.0
27
ꢄ10
>220
>10
>50
>50
>240
132
>50
>50
>50
31
>100
>100
>100
>100
0.02
0.8
>220
>10
>50
>50
>240
132
>50
>50
>50
8.6
>100
>100
>100
>100
6.0
>50
240
>50
>50
>240
45
>50
>220
>50
19.4
e
>50
185
>50
>50
>131
25
>50
>220
>50
16.4
e
220
>240
230
230
>240
ꢄ44
14
>50
>50
>50
5.7
e
>230
>220
240
47
136
0.45
e
130
>100
>100
>100
>100
>250
>250
>50
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
Brivudin
Cidofovir
Acyclovir
Ganciclovir
Ribavirin
0.003
e
54.4
e
e
e
>250
>250
>130
>250
>250
0.8
10
0.1
>250
1.4
0.2
0.04
>250
0.3
e
0.4
e
6.0
0.4
0.01
>250
1.0
e
16.5
e
>250
>100
>250
e
e
>250
>250
e
e
>100
>100
a
Effective concentration required to reduce virus-induced cytopathicity by 50%.
Minimum cytotoxic concentration that causes a microscopically detectable alteration of cell morphology.
Cytotoxic concentration required to reduce cell growth by 50%.
b
c
100; C-18; 5
mm); with an appropriate gradient of acetonitrile:H2O
afford pure iodinated 2. The physico-chemical data of 2 are in
and was found >98%.
accordance to those previously published.
4.1.2. 30,50-Di-O-acetyl-5-trimethylsilylethynyl-20-deoxyuridine (3a)
Iodinated nucleoside 2 (5 mmol) was dissolved in a mixture of
dry DMF (15 mL), dry Et3N (2.06 mL, 3 eq) and trimethylsilylace-
tylene (2.06 mL, 3 eq). CuI (190 mg, 0.2 eq) and PdCl2(PPh3)2
(350 mg, 0.1 eq) were then added and the reaction mixture was
stirred at room temperature until completion (typically 5e20 h,
checked by TLC). Solvents were evaporated under reduced pres-
sure. The oily residue was dissolved in AcOEt (250 mL) then washed
with water (5 ꢃ 40 mL) and brine (40 mL). The organic layer was
dried over MgSO4 and the solvents were evaporated under reduced
pressure to dark oil. A purification using a short path flash
4.1.1. 30,50-Di-O-acetyl-5-iodo-20-deoxyuridine (2)
A solution of acetylated 20-deoxyuridine (1) (15 mmol) in dry
CH3CN (150 mL), CAN (4.94 g, 0.6 eq) and I2 (2.28 g, 0.6 eq) was
refluxed until completion (typically 1 h, checked by TLC). After
cooling to room temperature, solvents were evaporated under
reduced pressure and the dark oily residue was dissolved in AcOEt
(300 mL) and H2O (50 mL). The biphasic mixture was cooled in an
ice bath and a saturated Na2S2O3 solution was smoothly added until
complete decolouration. The organic layer was washed with water
(2 ꢃ 50 mL) and brine (50 mL), dried over MgSO4 and concentrated
under reduced pressure. The white foam was triturated with
pentane (50 mL), filtrated and dried under reduced pressure to
Table 2
Cytostatic activity of compounds 5ae5l and 7b, d, h, l against murine leukemia cells
(L1210), human T-lymphocyte cells (CEM) and human cervix carcinoma cells (HeLa).
R2
Compound
Cytostatic activity [IC50
L1210
(
m
M)a]
CEM
75 ꢅ 8
N
N
O
N
O
N
N
HeLa
NH
NH
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
7b
7d
7h
7l
204 ꢅ 0
2.9 ꢅ 0.5
nd
56 ꢅ 0
1.5 ꢅ 0.5
0.51 ꢅ 0.09
R1O
AcO
O
O
O
O
nd
nd
a
29 ꢅ 7
15 ꢅ 11
15 ꢅ 1
14.8 ꢅ 0.2
4.6 ꢅ 0.6
62 ꢅ 0
50 ꢅ 0
>100
22 ꢅ 0.2
11 ꢅ 5
6.2 ꢅ 0.7
9 ꢅ 0
OR1
71-80%
OAc
60 ꢅ 49
13 ꢅ 4
23 ꢅ 21
4 ꢅ 3
6b, d, h, l R1 = Ac
7b, d, h, l R1 = H
3b
b
1.8 ꢅ 0.2
50 ꢅ 0
1.37 ꢅ 0.02
23 ꢅ 10
37 ꢅ 2
>100
35 ꢅ 4
>100
0.5 ꢅ 0.4
10 ꢅ 2
>200
0.8 ꢅ 0.3
0.28 ꢅ 0.02
12 ꢅ 1
5 ꢅ 3
>200
>200
Ru
61 ꢅ 5
47 ꢅ 2
8 ꢅ 4
PPh3
Cl
134 ꢅ 6
107 ꢅ 70
42 ꢅ 6
PPh3
5-FUb
0.56 ꢅ 0.31
14 ꢅ 2
0.57 ꢅ 0.23
(8) RuAAC catalyst [Cp*RuCl(PPh3)2]
a
50% Inhibitory concentration, or compound concentration required to inhibit
tumor cell proliferation by 50%.
Scheme 3. RuAAC synthesis of triazoles 7b, 7d, 7h and 7l. Reagents and conditions: (a)
R-N3, [Ru] Catalyst, CH2Cl2, MW; (b) NH3, MeOH.
b
5-fluorouracil as reference compound.

782
A. Montagu et al. / European Journal of Medicinal Chemistry 46 (2011) 778e786
chromatography (eluent: hexanes/AcOEt 7/3 then 1/1) afforded the
desired compound 3a. The physico-chemical data of 3a are in
accordance to those previously published [2a].
according to the corresponding procedure as a white solid with
a yield of 71%. mp ¼ 217 ꢀC. 1H NMR (400 MHz, CDCl3)
d 9.00 (s, 1H,
NH), 8.72 (s, 1H, Htriazol), 8.68 (s, 1H, H6), 7.44 (dd, J ¼ 2.1, 7.2 Hz, 2H,
0
Harom), 6.89 (m,1H, Harom), 6.48 (dd, J ¼ 5.7, 8.5 Hz,1H, H1 ), 5.33 (dt,
4.1.3. 30,50-Di-O-acetyl-5-ethynyl-20-deoxyuridine (3b)
0
0
J ¼ 1.5, 6.4 Hz, 1H, H3 ), 4.44 (dd, J ¼ 2.8, 12.0 Hz, 1H, H5 a), 4.38 (dd,
Compound 3a (2 mmol) was dissolved in dry CH3CN (20 mL).
TBAF monohydrate (583 mg, 1.05 eq) was added and the resulting
solution was stirred at room temperature until completion (typi-
cally 30 min to 2 h, checked by TLC). Solvents were evaporated
under reduced pressure at room temperature and the oily residue
was submitted to a flash column chromatography (eluent: hexanes/
AcOEt 1/1 then AcOEt then MeOH/AcOEt 98/2) to afford pure
5-ethynyl nucleoside 3b as white solid in 74% yield. mp ¼ 183 ꢀC. 1H
0
0
J ¼ 2.4, 12.0 Hz, 1H, H5 b), 4.34 (q, J ¼ 2.4 Hz, 1H, H4 ), 2.57 (ddd,
0
J ¼ 1.5, 6.0, 14.0 Hz, 1H, H2 a), 2.37 (ddd, J ¼ 6.4, 8.5, 14.0 Hz, 1H,
H2 b), 2.32 (s, 3H, OAc), 2.13 (s, 3H, OAc); 13C NMR (400 MHz, CDCl3)
0
d
171.08, 170.60, 160.86, 149.53, 140.17, 136.24, 120.03, 106.46,
104.23, 104.15, 103.93, 85.53, 82.95, 74.74, 64.19, 38.34, 21.24, 21.13.
IR (cmꢁ1): 1740.1, 1693.2, 1481.0, 1235.6, 754.6. HRMS (MþH) found
492.1313, calcd for C21H20N5O7F2 492.1331.
NMR (400 MHz, CDCl3)
d 9.04 (s, 1H, NH), 7.93 (s, 1H, H6), 6.30
4.1.4.4. 30,50-Di-O-acetyl-5-(1-[4-iso-propyl]phenyl-1,2,3-triazol-4-
yl)-20-deoxyuridine (4d). Compound 4d has been synthesized
according to the corresponding procedure as a white solid with
0
0
0
(t, J ¼ 7.1 Hz, 1H, H1 ), 5.25 (m, 1H, H3 ), 4.30e4.45 (m, 3H, H4 and
0
0
0
H5 ), 3.21 (s, 1H, CH alkyne), 2.55 (m, 1H, H2 a), 2.25 (m, 1H, H2 b),
2.07 (s, 3H, OAc), 2.05 (s, 3H, OAc); 13C NMR (400 MHz, CDCl3)
a yield of 89%. mp ¼ 137 ꢀC. 1H NMR (400 MHz, CDCl3)
d 9.78 (s, 1H,
d
170.5, 170.3, 161.1, 149.2, 142.9, 99.8, 85.7, 82.4, 74.6, 74.0, 63.9,
NH), 8.59 (s, 1H, Htriazol), 8.57 (s, 1H, H6), 7.61 (d, J ¼ 8.5 Hz, 2H,
38.5, 21.0, 20.9. HRMS (MþH) found 336.3048 calculated for
C15H17N2O7 336.3052.
0
Harom), 7.29 (d, J ¼ 8.5 Hz, 2H, Harom), 6.42 (dd, J ¼ 5.7, 8.6 Hz,1H, H1 ),
0
0
5.26 (dt, J ¼ 1.4, 6.7 Hz, 1H, H3 ), 4.37 (dd, J ¼ 3.1, 12.3 Hz, 1H, H5 a),
0
0
4.30 (dd, J ¼ 2.7, 12.3 Hz, 1H, H5 b), 4.25 (q, J ¼ 2.3 Hz, 1H, H4 ), 2.90
4.1.4. General procedure to compounds 4ael
0
(sept, 1H, CH), 2.48 (ddd, J ¼ 1.3, 5.7, 14.5 Hz, 1H, H2 a), 2.33 (ddd,
Aniline derivative (1 eq) was dissolved, in anhydrous acetoni-
trile (4 mL by mmol of aniline derivative) in a round-bottom flask
and cooled to 0 ꢀC. To this mixture, t-BuONO (1.5 eq) followed by
TMSN3 (1.2 eq) was added dropwise and the resulting solution was
stirred at room temperature for 2 h. To the crude mixture con-
taining the azido derivative, compound 3b (1 eq), aqueous solution
of CuSO4 (0.05 eq) and sodium ascorbate (0.2 eq) were added and
the reaction was stirred overnight at room temperature. After
evaporation of all volatiles, the residue was purified on silica gel
eluting with (petroleum ether/ethyl acetate, 4/6) to give pure
compounds 4ael, respectively.
0
J ¼ 6.6, 8.6,14.5 Hz,1H, H2 b), 2.25 (s, 3H, OAc), 2.06 (s, 3H, OAc), 1.21
(d, J ¼ 6.9 Hz, 6H, CH3); 13C NMR (400 MHz, CDCl3)
d 171.45, 170.57,
161.38, 149.83, 135.71, 134.6, 127.82, 120.69, 107.07, 85.47, 82.94,
74.30, 64.26, 38.15, 33.99, 24.05, 21.22, 21.11; IR (cmꢁ1): 1710.1,
1227.9, 1032.9, 835.8. HRMS (MþH) found 498.1994, calcd for
C24H28N5O7 498.1989.
4.1.4.5. 30,50-Di-O-acetyl-5-(1-[4-tert-butyl]phenyl-1,2,3-triazol-4-
yl)-20-deoxyuridine (4e). Compound 4e has been synthesized
according to the corresponding procedure as a white solid with
a yield of 90%. mp ¼ 143 ꢀC. 1H NMR (400 MHz, CDCl3)
d 9.57 (s, 1H,
4.1.4.1. 30,50-Di-O-acetyl-5-(1-phenyl-1,2,3-triazol-4-yl)-20-deoxyur-
idine (4a). Compound 4a has been synthesized according to the
corresponding procedure as a white solid in 80% yield. mp ¼ 201 ꢀC.
NH), 8.67 (s, 1H, Htriazol), 8.64 (s, 1H, H6), 7.74e7.64 (m, 2H, Harom),
0
7.57e7.48 (m, 2H, Harom), 6.50 (dd, J ¼ 5.7, 8.7 Hz, 1H, H1 ), 5.34 (dt,
0
0
J ¼ 1.3, 6.8 Hz, 1H, H3 ), 4.37 (dd, J ¼ 3.1, 12.3 Hz, 1H, H5 a), 4.30 (dd,
1H NMR (400 MHz, CDCl3)
d 9.48 (s,1H, NH), 8.61 (s,1H, Htriazol), 8.60
0
0
J ¼ 2.8, 12.3 Hz, 1H, H5 b), 4.25 (q, J ¼ 2.4 Hz, 1H, H4 ), 2.56 (ddd,
0
J ¼ 1.6, 5.6, 14.5 Hz, 1H, H2 a), 2.33 (ddd, J ¼ 6.5, 8.6, 14.5 Hz, 1H,
(s, 1H, H6), 7.77e7.66 (m, 2H, Harom), 7.45 (t, J ¼ 7.8 Hz, 2H, Harom),
H2 b), 2.33 (s, 3H, OAc), 2.14 (s, 3H, OAc), 1.36 (s, 9H, CH3); 13C NMR
0
0
7.36 (t, J ¼ 7.4 Hz, 1H, Harom), 6.42 (dd, J ¼ 5.7, 8.6 Hz, 1H, H1 ), 5.33
0
0
(400 MHz, CDCl3)
d 171.16, 161.26, 152.23, 149.57, 139.59, 135.88,
(dt, J ¼ 1.5, 6.5 Hz, 1H, H3 ), 4.44 (dd, J ¼ 3.0, 12.3 Hz, 1H, H5 a), 4.38
0
0
134.70,126.80, 120.37, 107.10, 85.41, 82.86, 74.81, 64.18, 38.07, 34.97,
31.45, 21.25, 21.14; IR (cmꢁ1): 1710.1, 1230.6, 754.2 cmꢁ1. HRMS
(MþH) found 512.2151, calcd for C25H30N5O7 512.2145.
(dd, J ¼ 2.8, 12.3 Hz, 1H, H5 b), 4.34 (q, J ¼ 2.7 Hz, 1H, H4 ), 2.57 (ddd,
0
0
J ¼ 1.6, 5.7,14.6 Hz,1H, H2 a), 2.37 (ddd, J ¼ 6.5, 8.6,14.6 Hz,1H, H2 b),
2.26 (s, 3H, OAc), 2.07 (s, 3H, OAc); 13C NMR (400 MHz, CDCl3)
d
171.16,170.59,161.26,149.85,139.64,137.15,135.85,129.93,128.94,
4.1.4.6. 30,50-Di-O-acetyl-5-(1-[4-butyl]phenyl-1,2,3-triazol-4-yl)-20-
deoxyuridine (4f). Compound 4f has been synthesized according to
the corresponding procedure as a white solid with a yield of 84%.
120.68, 120.39, 106.97, 85.46, 82.88, 74.79, 64.19, 38.20, 21.25, 21.14.
IR (cmꢁ1): 1713.0,1228.7, 749.3. HRMS (MþH) found 456.1538, calcd
for C21H22N5O7 456.1519.
mp ¼ 140 ꢀC. 1H NMR (400 MHz, CDCl3)
d 9.71 (s, 1H, NH), 8.66
4.1.4.2. 30,50-Di-O-acetyl-5-(1-[2,6-difluoro]phenyl-1,2,3-triazol-4-
yl)-20-deoxyuridine (4b). Compound 4b has been synthesized
according to the corresponding procedure as a white solid with
(s, 1H, Htriazol), 8.63 (s, 1H, H6), 7.66 (d, J ¼ 8.4 Hz, 2H, Harom), 7.31
0
(d, J ¼ 8.4 Hz, 2H, Harom), 6.49 (dd, J ¼ 5.7, 8.6 Hz, 1H, H1 ), 5.32 (dt,
0
0
J ¼ 1.4, 6.7 Hz, 1H, H3 ), 4.44 (dd, J ¼ 3.1, 12.3 Hz, 1H, H5 a), 4.37 (dd,
a yield of 67%. mp ¼ 215 ꢀC. 1H NMR (400 MHz, CDCl3)
d 9.11 (s, 1H,
0
0
J ¼ 2.8, 12.3 Hz, 1H, H5 b), 4.32 (q, J ¼ 2.6 Hz, 1H, H4 ), 2.66
NH), 8.70 (s, 1H, Htriazol), 8.49 (s, 1H, H6), 7.50 (td, J ¼ 4.3, 8.6 Hz, 1H,
0
(t, J ¼ 7.6 Hz, 2H, CH2), 2.54 (ddd, J ¼ 1.3, 5.5, 14.5 Hz, 1H, H2 a), 2.39
0
Harom), 7.14 (t, J ¼ 8.1 Hz, 2H, Harom), 6.50 (dd, J ¼ 5.6, 8.7 Hz,1H, H1 ),
0
(ddd, J ¼ 6.6, 8.6, 14.5 Hz, 1H, H2 b), 2.32 (s, 3H, OAc), 2.13 (s, 3H,
0
0
5.33 (dt, J ¼ 1.5, 6.5 Hz, 1H, H3 ), 4.44 (dd, J ¼ 2.9, 13.0 Hz, 1H, H5 a),
OAc), 1.62 (dt, J ¼ 7.6, 12.9 Hz, 2H, CH2), 1.36 (tq, J ¼ 7.3, 14.8 Hz, 2H,
CH2), 0.93 (t, J ¼ 7.4 Hz, 3H, CH3); 13C NMR (400 MHz, CDCl3)
0
0
4.37 (dd, J ¼ 2.6, 13.0 Hz, 1H, H5 b), 4.32 (q, J ¼ 2.3 Hz, 1H, H4 ), 2.55
0
(ddd, J ¼ 2.0, 5.6,14.0 Hz,1H, H2 a), 2.38 (ddd, J ¼ 6.5, 8.7,14.0 Hz,1H,
d
171.15, 170.58, 161.32, 149.93, 144.05, 139.49, 135.72, 134.98,
H2 b), 2.33 (s, 3H, OAc), 2.13 (s, 3H, OAc); 13C NMR (400 MHz, CDCl3)
0
129.77, 120.61, 120.39, 107.08, 85.41, 82.85, 74.80, 64.18, 38.16,
35.56, 33.63, 22.43, 21.23, 21.12, 14.09. IR (cmꢁ1): 1710.1, 1231.5,
755.0. HRMS (MþH) found 512.2144, calcd for C25H30N5O7 512.2145.
d
171.16,170.59,160.92,155.97,149.69,139.05,135.96,131.69,124.99,
112.84, 112.61, 106.81, 85.31, 82.88, 74.79, 64.20, 38.24, 21.21, 21.14;
IR (cmꢁ1): 1739.9, 1694.6, 1234.3, 755.7. HRMS (MþH) found
492.1334, calcd for C21H20N5O7F2 492.1331.
4.1.4.7. 30,50-Di-O-acetyl-5-(1-[4-chloro]phenyl-1,2,3-triazol-4-yl)-
20-deoxyuridine (4g). Compound 4g has been synthesized accord-
ing to the corresponding procedure as a white solid with a yield of
4.1.4.3. 30,50-Di-O-acetyl-5-(1-[3,5-difluoro]phenyl-1,2,3-triazol-4-
yl)-20-deoxyuridine (4c). Compound 4c has been synthesized
60%. mp ¼ 192 ꢀC. 1H NMR (400 MHz, CDCl3)
d 9.80 (s, 1H, NH), 8.70

A. Montagu et al. / European Journal of Medicinal Chemistry 46 (2011) 778e786
783
(s, 1H, Htriazol), 8.66 (s, 1H, H6), 7.75 (d, J ¼ 8.7 Hz, 2H, Harom), 7.48
d 171.09,170.57,160.87,149.38,149.21,139.73,136.01,135.38,122.51,
0
(d, J ¼ 8.7 Hz, 2H, Harom), 6.47 (dd, J ¼ 5.7, 8.5 Hz, 1H, H1 ), 5.33
122.05, 120.24, 106.67, 85.48, 82.90, 74.74, 64.18, 38.26, 21.13, 21.12.
IR (cmꢁ1): 1708.5, 1526.7, 1342.7, 1227.4, 1024.5, 854.3. HRMS
(MþH) found 501.1385, calcd for C21H21N6O9 501.1370.
0
0
(dt, J ¼ 1.4, 6.9 Hz, 1H, H3 ), 4.44 (dd, J ¼ 3.0, 12.4 Hz, 1H, H5 a), 4.40
0
0
(dd, J ¼ 2.8, 12.4 Hz, 1H, H5 b), 4.30 (q, J ¼ 2.6 Hz, 1H, H4 ), 2.50 (ddd,
0
J ¼ 1.8, 5.4, 14.5 Hz, 1H, H2 a), 2.40 (ddd, J ¼ 6.5, 8.6, 14.5 Hz, 1H,
4.1.4.12. 30,50-Di-O-acetyl-5-(1-[4-phenoxy]phenyl-1,2,3-triazol-4-yl)-
20-deoxyuridine (4l). Compound 4l has been synthesized according
to the corresponding procedure as a white solid with a yield of 79%.
H2 b), 2.31 (s, 3H, OAc), 2.14 (s, 3H, OAc); 13C NMR (400 MHz, CDCl3)
0
d
171.10, 170.59, 149.85, 135.98, 135.64, 135.64, 134.59, 130.06,
121.74, 85.91, 82.91, 74.79, 64.17, 60.59, 38.23, 21.22, 21.14, 14.39. IR
(cmꢁ1): 1715.4, 1232.9, 756.6. HRMS (MþH) found 490.1131, calcd
for C21H21N5O7Cl 490.1130.
mp ¼ 191 ꢀC.1H NMR (400 MHz, CDCl3)
d 9.32 (s,1H, NH), 8.66 (s,1H,
Htriazol), 8.62 (s, 1H, H6), 7.71 (d, J ¼ 8.9 Hz, 2H, Harom), 7.38 (t,
J ¼ 7.9 Hz, 2H, Harom), 7.21e7.01 (m, 5H, Harom), 6.49 (dd, J ¼ 5.7,
4.1.4.8. 30,50-Di-O-acetyl-5-(1-[4-bromo]phenyl-1,2,3-triazol-4-yl)-
20-deoxyuridine (4h). Compound 4h has been synthesized accord-
ing to the corresponding procedure as a white solid with a yield of
0
0
8.6 Hz, 1H, H1 ), 5.33 (dt, J ¼ 1.5, 6.6 Hz, 1H, H3 ), 4.44 (dd, J ¼ 3.0 Hz,
0
0
12.3 Hz, 1H, H5 a), 4.38 (dd, J ¼ 2.8 Hz, 12.3 Hz, 1H, H5 b), 4.33 (q,
0
0
J ¼ 2.3 Hz,1H, H4 ), 2.56 (ddd, J ¼ 1.2, 5.6,14.3 Hz,1H, H2 a), 2.39 (ddd,
J ¼ 6.5, 8.6, 14.9 Hz, 1H, H2 b), 2.33 (s, 3H, OAc), 2.13 (s, 3H, OAc). 13
C
62%. mp ¼ 198 ꢀC. 1H NMR (400 MHz, CDCl3)
d 9.00 (s, 1H, NH), 8.67
(s, 1H, Htriazol), 8.65 (s, 1H, H6), 7.72e7.62 (m, 4H, Harom), 6.48 (dd,
0
NMR (400 MHz, CDCl3) d 171.14,170.59,161.15,158.06,156.56,149.76,
139.61, 135.81, 132.36, 130.22, 124.32, 122.44, 120.53, 119.58, 119.53,
106.98, 85.43,82.88,74.79, 64.19,38.34,21.24,21.13.IR(cmꢁ1):1717.0,
1260.7, 1230.0, 756.4. HRMS (MþH) found 548.1799, calcd for
C27H26N5O8 548.1781.
0
0
J ¼ 5.6, 8.7 Hz, 1H, H1 ), 5.33 (dt, J ¼ 1.5, 6.9 Hz, 1H, H3 ), 4.44 (dd,
0
0
J ¼ 3.1, 12.3 Hz, 1H, H5 a), 4.38 (dd, J ¼ 2.8, 12.3 Hz, 1H, H5 b), 4.33
0
0
(q, J ¼ 2.3 Hz, 1H, H4 ), 2.56 (ddd, J ¼ 1.7, 5.6, 14.6 Hz, 1H, H2 a), 2.38
0
(ddd, J ¼ 6.5, 8.6,14.6 Hz,1H, H2 b), 2.32 (s, 3H, OAc), 2.14 (s, 3H, OAc);
13C NMR (400 MHz, CDCl3)
d 171.10, 170.59, 160.95, 149.59, 139.93,
4.1.5. General procedure to 5ael
135.99, 133.12, 122.60, 122.02, 120.07, 106.73, 85.49, 82.92, 74.78,
Compounds4aelwererespectivelydissolved in asolution ofNH3
in methanol 7N. The mixture was stirred at 0 ꢀC overnight. After
evaporation of the solvents, the residual solid was purified on silica
gel eluting with ethyl acetate to give compounds 5ael, respectively.
64.20, 38.27, 21.26, 21.15; IR (cmꢁ1): 1715.4, 1230.6, 757.8 cmꢁ1
.
HRMS (MþH) found 534.0612, calcd for C21H21N5O779Br 534.0624.
4.1.4.9. 30,50-Di-O-acetyl-5-(1-[4-thiomethyl]phenyl-1,2,3-triazol-4-
yl)-20-deoxyuridine (4i). Compound 4i has been synthesized
according to the corresponding procedure as a white solid with
4.1.5.1. 5-(1-Phenyl-1,2,3-triazol-4-yl)-20-deoxyuridine (5a). Compou-
nd 5a has been synthesized according to the corresponding procedure
and obtained to give a white solid with a yield of 99%. mp ¼ 244 ꢀC. 1H
a yield of 67%. mp ¼ 161 ꢀC. 1H NMR (400 MHz, CDCl3)
d 8.66 (s, 1H,
Htriazol), 8.60 (s,1H, H6), 8.30 (s,1H, NH), 7.69 (d, J ¼ 8.7 Hz, 2H, Harom),
NMR (400 MHz, MeOD) d 8.80 (s, 1H, Htriazol), 8.75 (s, 1H, H6), 7.88 (d,
0
7.38 (d, J ¼ 8.7 Hz, 2H, Harom), 6.48 (dd, J ¼ 5.7, 8.7 Hz, 1H, H1 ), 5.33
J ¼ 8.1 Hz, 2H, Harom), 7.64e7.55 (m, 2H, Harom), 7.54e7.46 (m, 1H,
0
0
(dt, J ¼ 1.5, 6.6 Hz, 1H, H3 ), 4.44 (dd, J ¼ 3.0, 12.3 Hz, 1H, H5 a), 4.38
0
Harom), 6.38 (dt, J ¼ 6.6, 9.0 Hz, 1H, H1 ), 4.46 (dt, J ¼ 3.3, 5.6 Hz, 1H,
0
0
(dd, J ¼ 2.8, 12.3 Hz, 1H, H5 b), 4.35 (q, J ¼ 2.7 Hz, 1H, H4 ), 2.55 (ddd,
0
0
0
H3 ), 4.00 (q, J ¼ 3.6 Hz, 1H, H4 ), 3.87 (dd, J ¼ 3.4, 12.0 Hz, 1H, H5 a),
0
J ¼ 1.6, 5.6, 14.5 Hz, 1H, H2 a), 2.54 (s, 3H, SMe), 2.38 (ddd, J ¼ 6.5, 8.7,
3.79 (dd, J ¼ 4.0, 12.0 Hz, 1H, H5 b), 2.47e2.27 (m, 2H, H2 ). 13C NMR
0
0
14.5 Hz, 1H, H2 b), 2.33 (s, 3H, OAc), 2.14 (s, 3H, OAc); 13C NMR
0
(400 MHz, DMSO)
d 171.71, 161.10, 149.68, 140.08, 138.68, 136.81,
(400 MHz, CDCl3)
d 171.16, 170.65, 160.94, 149.46, 149.29, 139.81,
136.56, 129.89, 128.64, 120.15, 120.05, 111.42, 104.70, 87.68, 84.86,
70.62, 61.36. IR (cmꢁ1): 3133.7, 1680.6, 1475.4, 1246.3, 1051.8, 759.7.
HRMS (MþH) found 372.1316, calcd for C17H18N5O5 372.1308.
136.08, 135.45, 122.59, 122.12, 120.31, 106.74, 85.55, 82.98, 74.82,
64.25, 38.33, 21.30, 21.20. IR (cmꢁ1): 1716.6, 1261.6, 1229.9, 757.2.
HRMS (MþH) found 502.1412, calcd for C22H24N5O7S 502.1396.
4.1.5.2. 5-(1-[2,6-Difluoro]phenyl-1,2,3-triazol-4-yl)-20-deoxyuridine
(5b). Compound 5b has been synthesized according to the cor-
responding procedure and obtained to give a white solid with
4.1.4.10. 30,50-Di-O-acetyl-5-(1-[4-trifluoromethoxy]phenyl-1,2,3-tri-
azol-4-yl)-20-deoxyuridine (4j). Compound 4j has been synthesized
according to the corresponding procedure as a white solid with
a yield of 92%. mp ¼ 256 ꢀC. 1H NMR (400 MHz, MeOD)
d 8.82 (s,
a yield of 71%. mp ¼ 200 ꢀC. 1H NMR (400 MHz, CDCl3)
d 8.82 (s, 1H,
1H, Htriazol), 8.61 (s, 1H, H6), 7.67 (tt, J ¼ 6.2, 8.6 Hz, 1H, Harom),
0
NH), 8.67 (s,1H, Htriazol), 8.66 (s,1H, H6), 7.84 (d, J ¼ 9.0 Hz, 2H, Harom),
7.32 (t, J ¼ 8.4 Hz, 2H, Harom), 6.38 (t, J ¼ 6.7 Hz, 1H, H1 ), 4.48 (dt,
0
0
0
7.39 (d, J ¼ 8.5 Hz, 2H, Harom), 6.48 (dd, J ¼ 5.6, 8.6 Hz, 1H, H1 ), 5.33
J ¼ 3.5, 6.8 Hz, 1H, H3 ), 4.00 (q, J ¼ 3.5 Hz, 1H, H4 ), 3.88 (dd,
0
0
0
0
(dt, J ¼ 1.5, 6.6 Hz,1H, H3 ), 4.44 (dd, J ¼ 3.1,12.3 Hz,1H,H5 a), 4.38(dd,
J ¼ 3.4, 11.9 Hz, 1H, H5 a), 3.80 (dd, J ¼ 4.0, 11.9 Hz, 1H, H5 a),
2.44e2.34 (m, 2H, H2 ). 13C NMR (400 MHz, MeOD)
d 163.36,
0
0
0
J ¼ 2.7,12.3 Hz,1H, H5 b), 4.35(q, J ¼ 2.4 Hz,1H, H4 ), 2.56 (ddd, J ¼ 1.5,
0
0
5.6, 14.9 Hz, 1H, H2 a), 2.38 (ddd, J ¼ 6.5, 8.6, 14.9 Hz, 1H, H2 b), 2.32
157.47, 151.78, 151.57, 141.23, 138.78, 133.81, 126.46, 113.92, 113.72,
106.40, 89.32, 87.23, 72.50, 63.06, 41.75. IR (cmꢁ1): 3328.1, 1693.4,
1087.0, 1045.5, 881.8. HRMS (MþH) found 408.1125, calcd for
C17H16N5O5 408.1120.
(s, 3H, OAc), 2.14 (s, 3H, OAc). 13C NMR (400 MHz, CDCl3)
d
171.11,
170.59, 160.89, 149.40, 149.23, 139.75, 136.03, 135.40, 122.53, 122.07,
120.26, 106.69, 85.50, 82.92, 74.76, 64.20, 38.28, 21.15, 21.14. IR
(cmꢁ1): 1715.4, 1261.9, 1230.8, 759.1. HRMS (MþH) found 540.1339,
calcd for C22H21N5O8F3 540.1342.
4.1.5.3. 5-(1-[3,5-Difluoro]phenyl-1,2,3-triazol-4-yl)-20-deoxyuridine
(5c). Compound 5c has been synthesized according to the corre-
sponding procedure and obtained to give a white solid with a yield
4.1.4.11. 30,50-Di-O-acetyl-5-(1-[4-nitro]phenyl-1,2,3-triazol-4-yl)-20-
deoxyuridine (4k). Compound 4k has been synthesized according
to the corresponding procedure as a white solid with a yield of 60%.
of 94%. mp ¼ 258 ꢀC. 1H NMR (400 MHz, DMSO)
d 11.75 (s, 1H, NH),
9.05 (s, 1H, Htriazol), 8.70 (s, 1H, H6), 7.87 (dd, J ¼ 2.0, 7.9 Hz, 2H,
mp ¼ 212 ꢀC 1H NMR (400 MHz, CDCl3)
d 8.77 (s, 1H, Htriazol), 8.70
0
Harom), 7.48e7.37 (m, 1H, Harom), 6.25 (t, J ¼ 6.7 Hz, 1H, H1 ), 5.30
0
0
(d, J ¼ 4.1 Hz, 1H, H3 ), 3.88 (q, J ¼ 3.1 Hz, 1H, H4 ), 3.67e3.56 (m, 2H,
(s, 1H, H6), 8.47 (s, 1H, NH), 8.43 (d, J ¼ 9.1 Hz, 2H, Harom), 8.03
H5 ), 2.21 (dd, J ¼ 4.7, 6.5, 2H, H2 ). 13C NMR (400 MHz, MeOD)
0
0
0
(d, J ¼ 9.1 Hz, 2H, Harom), 6.48 (dd, J ¼ 5.6, 8.6 Hz, 1H, H1 ), 5.34
d
163.36, 157.47, 151.78, 151.57, 141.23, 138.78, 133.81, 126.46, 113.92,
0
0
(dt, J ¼ 1.5, 6.6 Hz, 1H, H3 ), 4.45 (dd, J ¼ 3.1, 12.3 Hz, 1H, H5 a), 4.40
113.72, 106.40, 89.32, 87.23, 72.50, 63.06, 41.75. IR (cmꢁ1): 3327.5,
1695.6, 1087.8, 1046.4, 880.2. HRMS (MþH) found 408.1104, calcd
for C17H16N5O5F2 408.1120.
0
0
(dd, J ¼ 2.7, 12.3 Hz, 1H, H5 b), 4.35 (q, J ¼ 2.4 Hz, 1H, H4 ), 2.58 (ddd,
0
J ¼ 1.6, 5.7, 14.2 Hz, 1H, H2 a), 2.38 (ddd, J ¼ 6.5, 8.6, 14.8 Hz, 1H,
H2 b), 2.32 (s, 3H, OAc), 2.14 (s, 3H, OAc). 13C NMR (400 MHz, CDCl3)
0

784
A. Montagu et al. / European Journal of Medicinal Chemistry 46 (2011) 778e786
4.1.5.4. 5-(1-[4-i-Propyl]phenyl-1,2,3-triazol-4-yl)-20-deoxyuridine
(5d). Compound 5d has been synthesized according to the corre-
sponding procedure and obtained to give awhite solid with ayield of
40.61. IR: 3179.0, 1682.0, 1256.5, 1211.4, 1166.9, 1037.8 cmꢁ1. HRMS
(MþNa) found 472.0250; calcd for C17H16N5O759BrNa 472.0232.
4.1.5.9. 5-(1-[4-Thiomethyl]phenyl-1,2,3-triazol-4-yl)-20-deoxyuridine
(5i). Compound 5i has been synthesized according to the corre-
sponding procedure and obtained togive awhite solid with a yield of
95%. mp ¼ 183 ꢀC. 1H NMR (400 MHz, MeOD)
d 8.75 (s, 1H, Htriazol),
8.73 (s, 1H, H6), 7.77 (d, J ¼ 8.6 Hz, 2H, Harom), 7.47 (d, J ¼ 8.5 Hz, 2H,
0
0
Harom), 6.37 (t, J ¼ 6.7 Hz, 1H, H1 ), 4.46 (dt, J ¼ 3.4, 5.9 Hz, 1H, H3 ),
95%. mp ¼ 188 ꢀC. 1H NMR (400 MHz, DMSO)
d 8.84 (s, 1H, Htriazol),
0
0
3.99 (q, J ¼ 3.5 Hz, 1H, H4 ), 3.87 (dd, J ¼ 3.5, 12.0 Hz, 1H, H5 a), 3.78
8.65 (s,1H, H6), 7.88 (d, J ¼ 8.7, 2H, Harom), 7.45 (d, J ¼ 8.8, 2H, Harom),
0
(dd, J ¼ 4.0, 12.0 Hz, 1H, H5 b), 3.00 (sept, J ¼ 3.5 Hz, 1H, H-C1),
2.44e2.27 (m, 2H, H2 ),1.31 (d, J ¼ 6.9, 9H, H-C2).13C NMR (400 MHz,
0
0
6.24 (t, J ¼ 6.9 Hz, 1H, H1 ), 5.30 (d, J ¼ 4.1 Hz, 1H, H3 ), 5.10
0
0
0
(t, J ¼ 4.8 Hz,1H, H4 ), 4.34e4.26 (m,1H, H5 a), 3.90 (q, J ¼ 3.4 Hz,1H,
MeOD) d 163.31,153.70,151.66,141.61,138.50,136.03,128.00,121.74,
H5 b), 2.54 (s, 3H, HSCH3), 2.21 (dd, J ¼ 4.7, 6.7, 2H, H2 ). 13C NMR
0
0
121.27, 106.60, 89.29, 87.16, 72.47, 63.07, 41.71, 35.81, 31.78. IR:
3447.2, 1698.0, 1681.4, 1664.3, 1049.1. HRMS (MþH) found 414.1779,
calcd for C20H24N5O5 414.1777.
(400 MHz, DMSO)
d 161.19, 149.79, 147.94, 140.42, 140.40, 137.07,
135.59, 135.56, 122.69, 122.28, 120.45, 104.69, 87.73, 85.03, 70.75,
61.49. IR: 3341.1, 3192.6, 1652.4, 1387.2 cmꢁ1. HRMS (MþNa) found
440.0995, calcd for C18H19N5O5SNa 440.1005.
4.1.5.5. 5-(1-[4-t-Butyl]phenyl-1,2,3-triazol-4-yl)-20-deoxyuridine
(5e). Compound 5e has been synthesized according to the corre-
sponding procedure and obtained to give a white solid with a yield
4.1.5.10. 5-(1-[4-Trifluoromethoxy]phenyl-1,2,3-triazol-4-yl)-20-deoxy-
uridine (5j). Compound 5j has been synthesized according to the
corresponding procedure and obtained to give a white solid with
of 97%. mp ¼ 176 ꢀC. 1H NMR (400 MHz, MeOD)
d 8.73 (s, 1H,
Htriazol), 8.71 (s, 1H, H6), 7.75 (d, J ¼ 8.8 Hz, 2H, Harom), 7.63
a yield of 96%. mp ¼ 233 ꢀC. 1H NMR (400 MHz, MeOD)
d 8.84 (s, 1H,
0
(d, J ¼ 8.8 Hz, 2H, Harom), 6.36 (t, J ¼ 7.0 Hz, 1H, H1 ), 4.46 (dt, J ¼ 3.4,
Htriazol), 8.77 (s, 1H, H6), 8.01 (d, J ¼ 9.0 Hz, 2H, Harom), 7.53
0
0
6.5 Hz, 1H, H3 ), 3.99 (q, J ¼ 3.5, 1H, H4 ), 3.87 (dd, J ¼ 3.4, 12.0 Hz,
0
(d, J ¼ 8.4 Hz, 2H, Harom), 6.37 (t, J ¼ 6.7 Hz, 1H, H1 ), 4.47 (dt, J ¼ 2.8,
0
0
0
2H, H5 a), 3.79 (dd, J ¼ 4.0, 12.0 Hz, 2H, H5 b), 2.42e2.28 (m, 2H, H2 ),
0
0
5.9 Hz, 1H, H3 ), 4.00 (q, J ¼ 3.5 Hz, 1H, H4 ), 3.87 (dd, J ¼ 3.4, 12.0 Hz,
1.37 (s, 9H, H-C2). 13C NMR (400 MHz, MeOD)
d
163.31, 153.68,
0
0
0
2H, H5 a), 3.80 (dd, J ¼ 4.0, 12.0 Hz, 2H, H5 b), 2.44e2.28 (m, 2H, H2 ).
13C NMR (400 MHz, DMSO)
161.06, 149.66, 147.81, 140.27, 136.94,
135.46, 135.43, 122.56, 122.15, 120.32, 104.56, 87.70, 84.90, 70.62,
151.67, 141.63, 138.49, 136.05, 128.00, 121.72, 121.26, 106.60, 89.31,
81.17, 72.49, 63.09, 41.73, 35.81, 31.79, 24.40. IR (cmꢁ1): 3176.4;
1688.0, 1271.9, 755.4. HRMS (MþN) found 428.1945, calcd for
C21H26N5O5 428.1934.
d
61.36, 40.60; IR: 3176.4, 1685.4, 1260.4, 1211.4, 1170.4, 1041.5 cmꢁ1
.
HRMS (MþH) found 456.1148, calcd for C18H17N5O6F3 456.1131.
4.1.5.6. 5-(1-[4-Butyl]phenyl-1,2,3-triazol-4-yl)-20-deoxyuridine (5f).
Compound 5f has been synthesized according to the corresponding
procedure and obtained to give a white solid with a yield of 93%.
4.1.5.11. 5-(1-[4-Nitro]phenyl-1,2,3-triazol-4-yl)-20-deoxyuridine (5k)
. Compound 5k has been synthesized according to the corre-
sponding procedure and obtained to give a white solid with a yield
mp ¼ 179 ꢀC. 1H NMR (400 MHz, MeOD)
d 8.64 (s, 1H; Htriazol), 8.63
of 94%. mp ¼ 204 ꢀC . 1H NMR (400 MHz, MeOD)
d 8.99 (s, 1H,
(s, 1H, H6), 7.65 (d, J ¼ 8.5 Hz, 2H, Harom), 7.31 (d, J ¼ 8.4 Hz, 2H;
Htriazol), 8.83 (s, 1H, H6), 8.48 (d, J ¼ 7.1 Hz, 2H, Harom), 8.20
0
0
Harom), 6.27 (t, J ¼ 6.7 Hz, 1H, H1 ), 4.36 (m, 1H, H3 ), 3.89 (q,
0
(d, J ¼ 7.1 Hz, 2H, Harom), 6.38 (t, J ¼ 6.8 Hz, 1H, H1 ), 4.47 (dt, J ¼ 2.9,
0
0
J ¼ 3.5 Hz, 1H, H4 ), 3.77 (dd, J ¼ 3.5, 12.0 Hz, 1H, H5 a), 3.69 (dd,
0
0
6.0 Hz, 1H, H3 ), 4.00 (q, J ¼ 3.5 Hz, 1H, H4 ), 3.87 (dd, J ¼ 3.5, 12.0 Hz,
0
J ¼ 4.0, 12.0 Hz, 1H, H5 b), 2.61 (t, J ¼ 7.7 Hz, 2H, H-C1), 2.25 (dd,
0
0
0
1H, H5 a), 3.80 (dd, J ¼ 3.9, 12.0 Hz, 1H, H5 b), 2.37 (m, 2H, H2 ).
0
J ¼ 7.0, 14.2, 2H, H2 ), 1.56 (dt, J ¼ 7.7, 15.3 Hz, 2H, H-C3), 1.30 (dd,
13C NMR (400 MHz, DMSO)
d
161.00, 149.60, 147.75, 140.23, 140.21,
J ¼ 7.4, 14.9 Hz, 2H, H-C2), 0.87 (t, J ¼ 7.4, 3H, H-C4); 13C NMR
136.38, 135.40, 135.37, 122.50, 122.09, 120.26, 104.50, 87.64, 84.84,
70.56, 61.30. IR: 3323.8, 2972.7, 1088.1, 1047.1, 880.5 cmꢁ1. HRMS
(MþNa) found 439.0978, calcd for C17H16N6O7Na 439.0978
(400 MHz, DMSO)
d 161.15, 149.73, 143.16, 139.98, 136.79, 134.52,
129.66, 120.15, 104.81, 87.71, 84.90, 70.67, 61.41, 34.29, 33.00, 21.73,
13.80. IR (cmꢁ1): 3175.7, 1688.9, 1271.4, 755.0. HRMS (MþH) found
428.1922, calcd for C21H26N5O5 428.1934.
4.1.5.12. 5-(1-[4-Phenoxy]phenyl-1,2,3-triazol-4-yl)-20-deoxyuridine
(5l). Compound 5l has been synthesized according to the corre-
sponding procedure and obtained to give a white solid with a yield of
4.1.5.7. 5-(1-[4-Chloro]phenyl-1,2,3-triazol-4-yl)-20-deoxyuridine
(5g). Compound 5g has been synthesized according to the corre-
sponding procedure and obtained to give a white solid with a yield
94%. mp ¼ 277 ꢀC.1H NMR (400 MHz, DMSO)
d 11.70 (s,1H, NH), 8.81
(s, 1H, Htriazol), 8.66 (s, 1H, H6), 8.05 (d, J ¼ 9.0 Hz, 2H, Harom), 7.45
(t, J ¼ 2.1 Hz, 2H, Harom), 7.25e7.15 (m, 3H, Harom), 7.10 (d, J ¼ 7.6 Hz,
of 97%. mp ¼ 230 ꢀC. 1H NMR (400 MHz, DMSO)
d 11.74 (s, 1H, NH),
8.92 (s, 1H, Htriazol), 8.67 (s, 1H, H6), 8.00 (d, J ¼ 8.8 Hz, 2H, Harom),
0
0
2H, Harom), 6.25 (t, J ¼ 6.7 Hz,1H, H1 ), 5.32 (d, J ¼ 4.0 Hz,1H, H3 ), 5.07
0
7.66 (d, J ¼ 8.8 Hz, 2H, Harom), 6.25 (t, J ¼ 6.7 Hz, 1H, H1 ), 4.30
0
0
(t, J ¼ 4.7 Hz, 1H, H4 ), 4.34e4.26 (m, 1H, H5 a), 3.87 (q, J ¼ 3.6 Hz, 1H,
H5 b), 2.21 (dd, J ¼ 4.7, 6.6, 2H, H2 ). 13C NMR (400 MHz, DMSO)
0
0
0
(m, 1H, H3 ), 3.87 (q, J ¼ 3.0 Hz, 1H, H4 ), 3.62 (q, J ¼ 2.7 Hz, 2H, H5 ),
0
0
2.21 (dd, J ¼ 4.8, 6.3 Hz, 2H, H2 ). 13C NMR (400 MHz, DMSO)
0
d
161.17, 156.96, 156.03, 149.74, 140.05, 136.81, 132.03, 130.31, 124.21,
d
161.06, 149.66, 147.61, 140.23, 135.36, 129.81, 124.50, 121.87,
122.26, 119.29, 119.23, 104.77, 87.72, 84.91, 70.62, 61.41. IR: 3175.9,
1681.0, 1258.6, 1210.9, 1166.1, 1038.9 cmꢁ1. HRMS (MþH) found
464.1555, calcd for C23H22N5O6 464.1570.
121.24, 120.15, 104.57, 87.68, 84.88, 70.60, 61.34, 27.11. IR (cmꢁ1):
3179.0, 5160.4, 1679.1, 1044.4. HRMS (MþNa) found 427.6250; calcd
for C17H16N5O5ClNa 427.6232.
4.1.6. General procedure to compounds 6
4.1.5.8. 5-(1-[4-Bromo]phenyl-1,2,3-triazol-4-yl)-20-deoxyuridine (5h)
. Compound 5h hasbeen synthesized accordingtothe corresponding
procedure and obtained to give a white solid with a yield of 90%.
d 8.81 (s,1H, Htriazol), 8.75 (s,
1H, H6), 7.87e7.79 (m, 2H, Harom), 7.79e7.72 (m, 2H, Harom), 6.28 (t,
In a microwave sealed reactor, a mixture of azide (1.5 mmol),
nucleoside 3b (1 mmol) and Cp*RuCl(PPh3)2 (0.05 mmol) in THF is
irradiated during 5 min at 100 ꢀC (200 W, normal mode). The
mixture is then evaporated and purified by silica gel column chro-
matography (Petroleum Ether/AcOEt 3:7) to give pure product 6.
mp ¼ 228 ꢀC.1H NMR (400 MHz, MeOD)
0
0
0
J ¼ 6.7 Hz, 1H, H1 ), 4.31 (m, 1H, H3 ), 3.94 (q, J ¼ 3.1 Hz, 1H, H4 ), 3.78
(q, J ¼ 2.9 Hz, 2H, H5 ), 2.26 (dd, J ¼ 5.0, 6.3 Hz, 2H, H2 ). 13C NMR
4.1.6.1. 30,50-Di-O-acetyl-5-(1-[2,6-difluoro]phenyl-1,2,3-triazol-5-yl)-
20-deoxyuridine (6b). Compound 6b has been synthesized according
to the corresponding procedure as a white solid with a yield of 71%.
0
0
(400 MHz, DMSO)
d 161.04, 150.40, 149.66, 142.26, 140.24, 136.91,
135.75, 122.10,121.23,120.08,104.56, 87.68, 84.88, 70.59, 61.33, 41.11,

A. Montagu et al. / European Journal of Medicinal Chemistry 46 (2011) 778e786
785
mp ¼ 208 ꢀC. 1H NMR (400 MHz, CDCl3)
d
9.10 (s, 1H, NH), 8.65 (s, 1H,
4.1.7.1. 5-(1-[2,6-Difluoro]phenyl-1H-1,2,3-triazol-5-yl)-20-deoxyur-
idine (7b). Compound 7b has been synthesized according to the
corresponding procedure and obtained to give a white solid with
Htriazol), 8.52 (s, 1H, H6), 7.48 (td, J ¼ 4.2, 8.6 Hz, 1H, Harom), 7.12
0
(t, J ¼ 8.1 Hz, 2H, Harom), 6.50 (dd, J ¼ 5.7, 8.6 Hz, 1H, H1 ), 5.25
(dt, J ¼ 1.5, 6.5 Hz, 1H, H3 ), 4.40 (dd, J ¼ 2.7, 13.0 Hz, 1H, H5 a), 4.36 (dd,
a yield of 94%. mp ¼ 265 ꢀC. 1H NMR (400 MHz, d6-acetone)
d 8.89
0
0
0
0
J ¼ 2.7, 13.0 Hz, 1H, H5 b), 4.25 (q, J ¼ 2.7 Hz, 1H, H4 ), 2.48 (ddd, J ¼ 2.1,
(s,1H, Htriazol), 8.57 (s,1H, H6), 7.66 (tt, J ¼ 6.4, 8.5 Hz,1H, Harom), 7.30
0
0
0
5.8, 14.0 Hz, 1H, H2 a), 2.33 (ddd, J ¼ 6.5, 8.6, 14.0 Hz, 1H, H2 b), 2.30
(t, J ¼ 8.4 Hz, 2H, Harom), 6.30 (t, J ¼ 6.5 Hz, 1H, H1 ), 4.52 (dt, J ¼ 3.4,
(s, 3H, OAc), 2.08 (s, 3H, OAc); 13C NMR (400 MHz, CDCl3)
d
171.16,
7.0 Hz, 1H, H3 ), 3.97 (q, J ¼ 3.4 Hz, 1H, H4 ), 3.85 (dd, J ¼ 3.5, 11.9 Hz,
0
0
0
0
0
170.59, 160.92, 155.97, 149.69, 139.05, 135.96, 131.69, 124.99, 113.68,
111.58, 107.49, 84.32, 82.88, 73.72, 63.10, 38.44, 21.66, 21.21; IR:
1741.2,1700.1,1245.2, 754.3 cmꢁ1;HRMS(MþNa) found 514.1136, calcd
for C21H20N5O7F2Na 514.1150.
1H, H5 a), 3.77 (dd, J ¼ 4.2, 11.9 Hz, 1H, H5 a), 2.43e2.30 (m, 2H, H2 );
13C NMR (400 MHz, d6-acetone)
d
163.36, 156.39, 152.03, 151.42,
141.04, 137.54, 133.71, 126.46, 114.65, 113.29, 106.40, 90.00, 87.69,
73.07, 62.86, 42.13; IR: 3330.3, 1702.6, 1087.0, 1047.9, 884.8 cmꢁ1
HRMS (MþH) found 408.1116, calcd for C17H16N5O5 408.1120.
;
4.1.6.2. 30,50-Di-O-acetyl-5-(1-[4-iso-propyl]phenyl-1,2,3-triazol-5-
yl)-20-deoxyuridine (6d). Compound 6d has been synthesized
according to the corresponding procedure as a white solid with
4.1.7.2. 5-(1-[4-i-Propyl]phenyl-1,2,3-triazol-5-yl)-20-deoxyuridine
(7d). Compound 7d has been synthesized according to the corre-
sponding procedure and obtained to give a white solid with a yield
a yield of 80%. mp ¼ 162 ꢀC. 1H NMR (400 MHz, CDCl3)
d
9.82 (s, 1H,
NH), 8.57 (s, 1H, Htriazol), 8.50 (s, 1H, H6), 7.59 (d, J ¼ 8.7 Hz, 2H,
of 93%. mp ¼ 201 ꢀC. 1H NMR (400 MHz, d6-acetone)
d 8.75 (s, 1H,
0
Harom), 7.32(d, J ¼ 8.7 Hz, 2H, Harom), 6.49 (dd, J ¼ 5.5, 8.6 Hz,1H, H1 ),
Htriazol), 8.70 (s, 1H, H6), 7.68 (d, J ¼ 8.7 Hz, 2H, Harom), 7.51
0
0
0
5.29 (dt, J ¼ 1.5, 6.9 Hz, 1H, H3 ), 4.40 (dd, J ¼ 3.0, 12.3 Hz, 1H, H5 a),
(d, J ¼ 8.7 Hz, 2H, Harom), 6.36 (t, J ¼ 6.5 Hz, 1H, H1 ), 4.44 (dt, J ¼ 3.3,
0
0
0
0
4.28 (dd, J ¼ 2.6, 12.3 Hz, 1H, H5 b), 4.28 (q, J ¼ 2.2 Hz, 1H, H4 ), 2.88
5.9 Hz, 1H, H3 ), 4.00 (q, J ¼ 3.4 Hz, 1H, H4 ), 3.88 (dd, J ¼ 3.6,
0
0
0
(sept, 1H, H-C1), 2.51 (ddd, J ¼ 1.4, 5.7, 14.4 Hz, 1H, H2 a), 2.30 (ddd,
12.0 Hz, 1H, H5 a), 3.76 (dd, J ¼ 4.0, 12.0 Hz, 1H, H5 b), 2.99 (sept,
0
0
J ¼ 6.5, 8.7, 14.5 Hz, 1H, H2 b), 2.26 (s, 3H, OAc), 2.01 (s, 3H, OAc), 1.19
J ¼ 3.6 Hz, 1H, H-C1), 2.47e2.29 (m, 2H, H2 ), 1.25 (d, J ¼ 6.5, 9H, H-
(d, J ¼ 6.8 Hz, 6H, H-C2); 13C NMR (400 MHz, CDCl3)
d
171.54,171.02,
C2); 13C NMR (400 MHz, d6-acetone)
d 163.31, 154.23, 152.00,
163.52, 150.10, 136.21, 133.99, 127.62, 121.03, 107.90, 85.33, 83.01,
74.87, 64.00, 39.20, 34.01, 24.51, 21.33, 21.13; IR: 1709.6, 1228.9,
1031.3, 842.6 cmꢁ1; HRMS (MþNa) found 520.1824, calcd for
C24H28N5O7Na 520.1808.
140.87, 137.66, 136.24, 128.04, 122.54, 123.58, 106.60, 90.01, 87.96,
73.56, 63.47, 42.26, 36.02, 31.58; IR: 3449.2, 1699.5, 1670.4,
999.2 cmꢁ1
;
HRMS (MþNa) found 436.1595, calcd for
C20H24N5O5Na 436.1597.
4.1.6.3. 30,50-Di-O-acetyl-5-(1-[4-bromo]phenyl-1,2,3-triazol-5-yl)-
20-deoxyuridine (6h). Compound 6h has been synthesized according
to the corresponding procedure as a white solid with a yield of 78%.
4.1.7.3. 5-(1-[4-Bromo]phenyl-1,2,3-triazol-5-yl)-20-deoxyuridine (7h)
. Compound 7h has been synthesized according to the correspond-
ing procedure and obtained to give a white solid with a yield
mp ¼ 206 ꢀC 1H NMR (400 MHz, CDCl3)
d
8.97 (s, 1H, NH), 8.66
of 91%. mp ¼ 231 ꢀC 1H NMR (400 MHz, d6-acetone)
d 8.75
(s, 1H, Htriazol), 8.62 (s, 1H, H6), 7.70e7.62 (m, 4H, Harom), 6.45 (dd,
(s, 1H, Htriazol), 8.68 (s, 1H, H6), 7.80e7.74 (m, 2H, Harom), 7.70e7.65
0
0
0
0
J ¼ 5.5, 8.9 Hz,1H, H1 ), 5.29 (dt, J ¼ 1.4, 7.0 Hz, 1H, H3 ), 4.42 (dd, J ¼ 3.0,
(m, 2H, Harom), 6.30 (t, J ¼ 6.6 Hz, 1H, H1 ), 4.33 (m, 1H, H3 ), 3.94
0
0
0
0
12.3 Hz, 1H, H5 a), 4.37 (dd, J ¼ 2.8, 12.3 Hz, 1H, H5 b), 4.34 (q, J ¼ 2.4
(q, J ¼ 3.6 Hz, 1H, H4 ), 3.82 (q, J ¼ 3.0 Hz, 2H, H5 ), 2.32
(dd, J ¼ 5.1, 6.3 Hz, 2H, H2 ); 13C NMR (400 MHz, d6-acetone)
d 162.08,
0
0
0
Hz, 1H, H4 ), 2.56 (ddd, J ¼ 1.8, 5.7, 14.6 Hz, 1H, H2 a), 2.37 (ddd, J ¼ 6.4,
8.6, 14.7 Hz, 1H, H2 b), 2.30 (s, 3H, OAc), 2.15 (s, 3H, OAc); 13C NMR
151.45, 150.10, 142.26, 139.21, 137.54, 133.69, 123.00, 120.87, 120.07,
103.76, 86.57, 85.06, 71.24, 61.03, 40.75, 40.33. IR: 3212.0, 1682.0,
1248.7,1172.6,1042.2 cmꢁ1. HRMS (MþNa) found 472.0250; calcd for
C17H16N5O759BrNa 472.0232.
0
(400 MHz, CDCl3)d171.46,170.89,161.02,149.77,139.93,136.04,132.88,
122.50, 121.99, 119.67, 107.68, 85.78, 83.02, 74.25, 63.99, 38.25, 21.26,
21.13; IR: 1712.3, 1231.2, 1212.25 758.6 cmꢁ1; HRMS (MþNa) found
556.0460, calcd for C21H21N5O779BrNa 556.0444.
4.1.7.4. 5-(1-[4-Phenoxy]phenyl-1,2,3-triazol-5-yl)-20-deoxyuridine
(7l). Compound 7l has been synthesized according to the corre-
sponding procedure and obtained to give a white solid with a yield
4.1.6.4. 30,50-Di-O-acetyl-5-(1-[4-phenoxy]phenyl-1H-1,2,3-triazol-
5-yl)-20-deoxyuridine (6l). Compound 6l has been synthesized
according to the corresponding procedure as a white solid with
of 90%. mp ¼ 256 ꢀC. 1H NMR (400 MHz, DMSO)
d 11.65 (s, 1H, NH),
a yield of 72%. mp ¼ 202 ꢀC 1H NMR (400 MHz, CDCl3)
d
9.29 (s, 1H,
8.77 (s, 1H, Htriazol), 8.62 (s, 1H, H6), 8.12 (d, J ¼ 9.1 Hz, 2H, Harom),
7.38 (t, J ¼ 2.0 Hz, 2H, Harom), 7.29e7.17 (m, 3H, Harom), 7.10
NH), 8.61 (s, 1H, Htriazol), 8.59 (s, 1H, H6), 7.69 (d, J ¼ 8.8 Hz, 2H,
0
Harom), 7.41 (t, J ¼ 8.8 Hz, 2H, Harom), 7.25e7.01 (m, 5H, Harom OPh),
(d, J ¼ 7.7 Hz, 2H, Harom), 6.29 (t, J ¼ 6.9 Hz, 1H, H1 ), 5.39
0
0
0
6.45 (dd, J ¼ 5.8 Hz, 8.6 Hz, 1H, H1 ), 5.30 (dt, J ¼ 1.4 Hz, 6.6 Hz, 1H,
(d, J ¼ 3.8 Hz, 1H, H3 ), 5.02 (t, J ¼ 4.8 Hz, 1H, H4 ), 4.37e4.27 (m, 1H,
0
0
0
0
0
H3 ), 4.48 (dd, J ¼ 3.1 Hz, 12.3 Hz, 1H, H5 a), 4.39 (dd, J ¼ 2.9 Hz,
H5 a), 3.82 (q, J ¼ 3.7 Hz, 1H, H5 b), 2.25 (dd, J ¼ 4.8, 6.8 Hz, 2H, H2 );
13C NMR (400 MHz, DMSO)
162.25, 157.24, 155.87, 150.84, 139.22,
135.68, 131.84, 129.36, 123.99, 122.04, 118.78, 118.62, 103.89, 88.04,
0
0
12.3 Hz, 1H, H5 b), 4.27 (q, J ¼ 2.4 Hz, 1H, H4 ), 2.59 (ddd, J ¼ 1.3 Hz,
d
0
5.7 Hz, 14.3 Hz, 1H, H2 a), 2.41 (ddd, J ¼ 6.5 Hz, 8.7 Hz, 14.5 Hz, 1H,
H2 b), 2.36 (s, 3H, OAc), 2.15 (s, 3H, OAc); 13C NMR (400 MHz, CDCl3)
85.47, 70.41, 61.38. IR: 3180.9, 1704.3, 1265.9, 1202.3, 1020.7 cmꢁ1
.
0
d
171.28, 170.59, 162.37, 159.04, 156.65, 150.77, 140.40, 133.97,
HRMS (MþNa) found 486.1372, calcd for C23H22N5O6Na 486.1390.
132.37, 130.22, 124.99, 123.01, 120.00, 119.47, 119.41, 107.25, 85.98,
83.09, 75.08, 64.27, 38.45, 21.78, 21.36. IR: 1719.0, 1259.8, 1227.0,
759.8 cmꢁ1. HRMS (MþNa) found 570.1609, calcd for C27H26N5O8
570.1601.
4.2. Biology
4.2.1. Antiviral activity assays
The antiviral assays, other than the anti-HIV assays, were based
on inhibition of virus-induced cytopathicity or plaque formation in
HEL [herpes simplex virus type 1 (HSV-1) (KOS), HSV-2 (G), vaccinia
virus, vesicular stomatitis virus, cytomegalovirus (HCMV), and
varicella-zoster virus (VZV)], Vero (parainfluenza-3, reovirus-1,
Sindbis virus and Coxsackie B4), HeLa (vesicular stomatitis virus,
Coxsackie virus B4, and respiratory syncytial virus) or MDCK
4.1.7. General procedure to compounds 7
Compounds 6 were dissolved in a solution of NH3 in methanol
7N, respectively. The mixture was stirred at 0 ꢀC overnight. After
evaporation of the solvents, the residual solid was purified on
silica gel, eluting with ethyl acetate to give compound 7,
respectively.

786
A. Montagu et al. / European Journal of Medicinal Chemistry 46 (2011) 778e786
[influenza A (H1N1; H3N2) and influenza B] cell cultures. Confluent
cell cultures (or nearly confluent for MDCK cells) in microtiter 96-
well plates were inoculated with 100 CCID50 of virus (1 CCID50
being the virus dose to infect 50% of the cell cultures) or with 20
plaque forming units (PFU). After 1e2 h virus adsorption period,
residual virus was removed, and the cell cultures were incubated in
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Acknowledgements
AM received a PhD fellowship from the DGA (Direction Générale
de l’Armement). The K.U.Leuven is acknowledged for financial
support (GOA no. 10/14). We thank Mrs. Lies Van den Heurck, Mrs.
Anita Camps, Mr. Steven Carmans, Mrs. Leentje Persoons, Mrs.
Frieda De Meyer, Mrs. Leen Ingels and Mrs. Lizette van Berckelaer
for excellent technical assistance.
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