Synthesis of 1,2,3-triazolyl nucleoside analogs as potential anti-influenza A (H3N2 subtype) virus agents

Article abstract of DOI:10.1002/ardp.201300260

Montmorillonite K10 impregnated with copper dichloride and potassium iodide (CuCl₂/KI/K10) was used as catalyst in the cycloaddition of azides and propargylnucleobases, to provide the corresponding 1,4-disubstituted 1,2,3-triazoles in good yiel

Full text of DOI:10.1002/ardp.201300260

134
Arch. Pharm. Chem. Life Sci. 2014, 347, 134–141
Full Paper
Synthesis of 1,2,3-Triazolyl Nucleoside Analogs as Potential
Anti-Influenza A (H3N2 Subtype) Virus Agents
Hanane Elayadi1, Michael Smietana2, Jean J. Vasseur2, Jan Balzarini3, and Hassan B. Lazrek1
1
Unité de Chimie Biomoléculaire et Médicinale, Laboratoire de Chimie Biomoléculaire Substances Naturelles
et Réactivité (URAC 16), Faculty of Science Semlalia, Marrakech, Morocco
Institut des Biomolécules Max Mousseron UMR 5247 CNRS-UMI-UMII, Université Montpellier II, CC008,
2
Montpellier, France
Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
3
Montmorillonite K10 impregnated with copper dichloride and potassium iodide (CuCl2/KI/K10) was
used as catalyst in the cycloaddition of azides and propargylnucleobases, to provide the corresponding
1,4-disubstituted 1,2,3-triazoles in good yield. All compounds 16–23 were evaluated for their antiviral
activity in vitro. Compound 18 showed moderate inhibition against influenza virus A (H3N2).
Keywords: Anti-influenza A (H3N2) / Click reaction / 1,2,3-Triazolyl nucleoside
Received: July 12, 2013; Revised: August 28, 2013; Accepted: September 12, 2013
DOI 10.1002/ardp.201300260
Introduction
chemistry” is becoming one of the most important methodol-
ogies leading specifically to 1,4-substituted 1,2,3-triazoles.
Therefore, in the past years, copper catalysts have played an
important role in cycloadditions between azides and
alkynes [5]. Generally, the use of copper source comes
from direct addition of Cu(I) species or reduction of Cu(II)
salts to Cu(I) salts, oxidation of copper metal turnings to Cu(I)
salts [6, 7]. Recent research on click chemistry has concen-
trated on heterogeneous catalytic systems [8], which can have
several advantages such as faster and simpler isolation of the
reaction products by filtration, as well as recovery and
recycling of the catalyst systems. Some examples were
reported, for instance Cu(I)-Zeolite [9], Cu/C, Cu2O/C [10],
Cu(OH)x/TiO2 [11], Cu(II)-Hydrotalcite [12], and amine-
functionalized polymers [13]. The results obtained by any of
these methods are, in general, excellent. On the other hand,
CuCl2, an inexpensive, easily available reagent with low
toxicity and less corrosivity, has been widely used in organic
chemistry, but it has not been studied as a heterogeneous
catalyst with KI (CuCl2/KI) in the click reaction.
As a part of our studies on 1,3-cycloaddition [14] and as a
complement to the previous methods, we now report that the
heterogeneous (CuCl2/KI) supported on montmorillonite K10
can be used as a catalyst in [3 þ 2] cycloaddition reactions.
The condensation between benzyl azide and propargylur-
acil was selected as a model reaction for optimization of the
reaction conditions. As shown in Table 1 when CuCl2 was used
alone or supported on silica gel, low yields of the desired
Pandemic (pdm) influenza A (H1N1 or H3N2 subtype) virus
emerged in April 2009 in Mexico and rapidly spread to more
than 200 countries. Most of the circulating H1N1 pdm viruses
belong to the Eurasian swine lineage of influenza viruses and
were derived from avian influenza viruses. Human infection
with H1N1 pdm viruses is characterized by a broad spectrum
of clinical symptoms, ranging from an upper respiratory
febrile illness to diffuse pneumonia. The established treat-
ment is the use of oseltamivir or zanamavir. However, there
have been significant increases in the frequency of seasonal
oseltamivir resistance recently [1]. There is a need of
developing new antiviral strategies including new antiviral
agents to improve the outcome of influenza infections [2].
1,2,3-Triazoles are versatile compounds that have been
applied for a variety of purposes and they represent diverse
biologically active substances displaying antimicrobial effica-
cy [3], including anti-human immunodeficiency virus
(HIV) [4a] and anti-influenza virus activity [4b]. Simple
methods that can quickly and easily generate large libraries
of compounds have become more and more in demand. “Click
Correspondence: Dr. Hassan B. Lazrek, Unité de Chimie Biomoléculaire
et Médicinale, Laboratoire de Chimie Biomoléculaire Substances Nature-
lles et Réactivité (URAC 16), Faculty of Science Semlalia, Marrakech
40000, Morocco.
E-mail: hblazrek50@gmail.com
Fax: þ212-524-43 74 08
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Arch. Pharm. Chem. Life Sci. 2014, 347, 134–141
1,2,3-Triazolyl Nucleoside Analogs as Influenza A Inhibitors
135
Table 1. Effects of copper source and solvent on click reaction and yield of 3 after 2 h.
Entry
Compound 1
Catalyst
Solvent
Yield (%)
1
2
3
4
5
6
7
8
Uracil
Uracil
Uracil
Uracil
Uracil
Uracil
Uracil
Uracil
Uracil
Uracil
Uracil
Uracil
Uracil
Uracil
Uracil
Uracil
Uracil
Uracil
Uracil
Uracil
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2/SiO2
CuCl2/KI
CuCl2/KI
CuCl2/KI/SiO2
CuCl2/KI/SiO2
CuCl2/KI/SiO2
CuCl2/KI/K10
CuCl2/KI/K10
CuCl2/KI/K10
CuCl2/KI/K10
CuCl2/KI/C
CuCl2/KI/Al2O3
CuCl2/KI/NP
MeOH
EtOH
t-BuOH
12
10
0
i-PrOH
MeOH (one night)
Dioxane
6
21
14
0
40
35
0
49
17
67
72
0
0
0
69
21
44
Dioxane/water
Dioxane/water
Dioxane/MeOH
Dioxane/water
Dioxane/water
Dioxane
Dioxane/MeOH
Dioxane/MeOH
Dioxane/water
Dioxane/EtOH
THF
9
10
11
12
13
14
15
16
17
18
19
20
Dioxane/MeOH
Dioxane/MeOH
Dioxane/MeOH
Reaction condition: 1 (1.1 mmol), 2a (1 mmol) catalysts, solvent, reflux 90°C, 2 h.
product were obtained. To find the most suitable solvent for
this catalyst, we used organic solvents (i.e. EtOH, t-BuOH, i-
PrOH, MeOH, dioxane, and THF). The reaction failed to retain
the desirable product by thin-layer chromatography (TLC).
When mixed solvents were used (dioxane/water, dioxane/
EtOH), the results showed that the yield is rather poor (Table 1,
entries 1–6).
On the basis of the observation done by Kirai and
Yamamoto [15] that Cu(II) can be reduced to Cu(I) in MeOH,
we carried out the reaction between propargyluracil 1 and
benzyl azide 2a in dioxane/MeOH (Table 1, entry 13). The yield
increased to 67%. When the silica gel was changed to
montmorillonite K10, charcoal, Al2O3, and natural phos-
phate, the best yield was obtained with montmorillonite K10
(72%) (Table 1, entries 14, 18–20). Addition of some ligands
such as P(Ph)3, DMAP, or DIPEA was not required to improve
both conversion and selectivity. Thus, having in hand the
standard conditions: 1.1 mmol of 1 and 1.0 mmol of 2
(Scheme 1), CuCl2/KI/K10 (0.5 equiv./0.5 equiv.), dioxane–
MeOH (2:1 v/v), and the mixture refluxed for 2 h at 90°C,
we investigated the possibility of the application in cyclo-
additions with benzyl azide and azidosugar with a variety of
organic alkynes (Table 2). It is known that terminal alkynes
may undergo Cu(II)-catalyzed oxidative homocoupling reac-
tions to afford diynes (Glaser reaction) [16]. Moreover, in the
classical Eglinton protocol [17] Cu(OAc)2 is the most active
Cu(II) agent. The fact that only readily oxidizable alcohol
(dioxane/MeOH) (Table 1, entry 14) allowed the formation
U
N
N
N
U
N3
Conditions
2a
3
1
Scheme 1. Synthesis of compound 3.
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H. Elayadi et al.
Arch. Pharm. Chem. Life Sci. 2014, 347, 134–141
Table 2. 1,2,3-Triazole products 8–23 generated under CuCl2/KI/K10 dioxane/MeOH conditions.
Entry
Products
Yield
Entry
Products
Yield
O
O
NH
HN
N
O
1
70
9
72
O
N
N
N
N
N
N
N
O
BzO
BzO
OBz
8
16
NH2
NH2
N
N
N
N
N
N
N
N
2
65
10
66
N
N
N
N
N
N
O
BzO
BzO
OBz
17
9
O
N
O
N
NH
HN
N
N
O
O
3
69
11
66
N
N
N
N
N
O
BzO
N
BzO
OBz
10
18
O
N
O
N
NH
HN
O
O
4
67
12
70
N
N
N
N
N
N
O
BzO
19
BzO
OBz
11
O
N
O
N
F
F
NH
HN
O
O
5
68
13
65
N
N
N
N
N
N
O
BzO
20
BzO
OBz
12
(Continued)
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Arch. Pharm. Chem. Life Sci. 2014, 347, 134–141
Table 2. (Continued)
1,2,3-Triazolyl Nucleoside Analogs as Influenza A Inhibitors
137
Entry
Products
Yield
Entry
Products
Yield
O
O
Cl
Cl
NH
HN
N
O
O
N
O
6
72
14
72
N
N
N
N
N
N
BzO
BzO
HN
OBz
13
21
O
O
N
I
I
NH
N
O
O
7
74
15
69
N
N
N
N
N
N
O
BzO
BzO
HN
OBz
Br
22
14
O
O
N
Br
NH
N
O
O
8
71
16
74
N
N
N
N
N
N
O
BzO
OBz
15 BzO
23
Reaction conditions: 1 (1.1 mmol), 2 (1 mmol), catalyst CuCl2/KI/K10, dioxane–MeOH (3 mL, 2:1 v/v) reflux 90°C, 2 h.
of the 1,2,3-triazole in good yield supported the hypothesis
that a catalytic Cu(I) species was generated via the reduction
of CuCl2/KI (Scheme 2).
triazole nucleosides 8–15 (Scheme 4, Table 2). In all the cases, a
very good yield of a single regioisomer is obtained. The
structures of the title compounds 8–15 were established
on the basis of their spectroscopic data (1H and 13C NMR,
mass) [20].
Having in hand these new conditions, we investigated the
possibility of the application in cycloadditions with benzyl
azide 2a for a variety of terminal alkynes (Table 2, entries
9–16) such as propargylated uracil, 5-fluorouracil, 5-chloro-
uracil, 5-bromouracil, 5-iodouracil, thymine, 6-azauracil,
and adenine (Scheme 5). In all the cases, very good yields of
a single regioisomer, namely 1,4-disubstituted 1,2,3-triazole
acyclonucleosides, are obtained. The structures of the title
compounds 16–23 were established on the basis of their
spectroscopic data (1H and 13C NMR, mass).
The same result was observed by Brotherton et al. [18] in
their catalytic AAC processes using CuCl2 or Cu(OAc)2.
To further understand the relationship between structure
and promotion activity of CuCl2/KI/K10 as catalyst, two
reactions were tested: benzyl azide 2a and azidosugar 2b [19]
with ethyl propiolate 8b (Scheme 3). To our delight, CuCl2/KI/
K10 showed the same activity giving the 1,2,3-triazole 5 and 6
in good yield (Table 3).
The application of this new synthetic protocol was explored
by using various propargylated nucleobases, namely: uracil,
5-fluorouracil, 5-chlorouracil, 5-bromouracil, 5-iodouracil,
thymine, 6-azauracil, and adenine and protected azidosugar
2b as building blocks to construct 1,4-disubstituted-1,2,3-
Biological testing
(Cu(II)) + CH3OH → (Cu(I)) + CH2O
Scheme 2. Process by which Cu(I) might have been generated.
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Target compounds 16–23 were evaluated for their inhibitory
activities against parainfluenza virus-3, reovirus-1, sindbis,
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138
H. Elayadi et al.
Arch. Pharm. Chem. Life Sci. 2014, 347, 134–141
CuCl2/KI/K10
N3
N
CO2Et
CO2Et
N
N
Dioxane/MeOH
2a
5
CO2Et
BzO
BzO
N
N
N3
O
N
CuCl2/KI/K10
O
CO2Et
OBz OBz
OBz OBz
Dioxane/MeOH
2b
6
Scheme 3. Reaction of either benzyl azide 2a or azidosugar 2b with ethyl propiolate 8b.
inhibitory against the broad range of viruses except
compound 18 that proved moderately inhibitory against
the H3N2 strain of influenza virus A at subtoxic concen-
trations (Table 4).
Table 3. Reactions of benzyl azide 2a and sugar azide 2b with
ethyl propiolate 4.
Entry
Product
Time (h)
Yield (%)
1
2
5
6
2
2
68
70
In conclusion, we have reported for the first time CuCl2/KI/
K10 as an active species in the Huisgen [3 þ 2] cycloaddition of
azides with terminal alkynes in dioxane/MeOH. Furthermore,
CuCl2/KI/K10 serves as a novel environmentally benign, highly
reactive, and efficient heterogeneous catalyst without any
additives under aerobic conditions. Compound 18 may be
regarded as a potential lead compound against influenza
virus A.
Coxsackie B4, and Punta Toro virus in Vero cell cultures;
herpes simplex virus type 1 (HSV-1, strain KOS), HSV-1 (TKꢀ
KOS ACVr), herpes simplex virus type 2 (HSV-2, strain G),
vaccinia virus, and vesicular stomatitis virus in human
embryonic lung (HEL) cell cultures; vesicular stomatitis virus,
respiratory syncytial virus, and Coxsackie B4 virus in human
epithelial (HeLa) cell cultures; feline corona and feline herpes
virus in Crandell-Rees feline kidney (CRFK) cells; cytomegalo-
virus (CMV, Davis strain) in HEL cell cultures; influenza virus
A(H1N1/H3N2) and B in MDCK cell cultures; and HIV-1 and
HIV-2 in MT4 cell cultures. None of the compounds were
Experimental
General remarks
The NMR spectra were recorded on a Bruker spectrometer (AC
300 MHz). Chemical shifts are reported as d values (ppm) relative
to TMS as a standard, and the coupling constants J values are
B
N
N
BzO
BzO
N
O
B
N3
O
CuCl2/KI/K10
OBz OBz
OBz OBz
2b
Dioxane/MeOH
_
8 15
BH = base: uracil 8, adenine 9, 6-azauracil 10, thymine 11, 5-F-uracil 12, 5-Cl-uracil 13, 5-
I- uracil 14, 5-Br-uracil 15
Scheme 4. Synthesis of compounds 8–15.
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Arch. Pharm. Chem. Life Sci. 2014, 347, 134–141
1,2,3-Triazolyl Nucleoside Analogs as Influenza A Inhibitors
139
B
N
N
N
B
CuCl2/KI/K10
N3
Dioxane/MeOH
_
16 23
2a
BH = base: uracil 16, adenine 17, 6-azauracil 18, thymine 19, 5-F-uracil 20, 5-Cl-uracil 21, 5-
I-uracil 22, 5-Br-uracil 23,
Scheme 5. Synthesis of compounds 16–23.
given in Hz. FAB mass spectra were recorded on a Varian MAT
311A spectrometer. TLC was performed on 60 F254 precoated
plastic plates silica gel (Merck). Column chromatography was
performed on silica gel (30–60 mm). All solvents were distilled and
dried before using.
2-[1-Benzyl-1,2,3-triazol-4-yl-methyl]uracil 16
1H NMR (300 MHz, CDCl3): d (ppm) ¼ 5.04 (s, 2H, CH2), 5.44 (s, 2H,
CH2), 5.73 (d, J ¼ 7.78 Hz, 1H, H5), 7.24 (m, Ar–H), 7.29 (s, 1H,
CH C), 7.69 (d, J ¼ 7.77 Hz, 1H, H6), 12.48 (s, 1H, NH). 13C NMR
–
–
(CDCl3, 75 MHz): d (ppm) ¼ 48.65 (CH2), 50.71 (CH2), 102.99 (C5),
124.01 (C9), 128.44–133.87 (Ar–C), 143.78 (C6), 143.78 (C8), 150.59
(2C O), 163.99 (4C O). MS/ESIþ m/z 284.28 (MþH)þ. HMRS calcd.
–
–
–
–
Preparation of the catalyst
for C14H13N5O2 283.2853. Found: 283.2859.
1mmol (166mg) of KI and 1mmol (134mg) of CuCl2 are dissolved in
5 mL of water. To the mixture was added 1 g of montmorillonite K10.
The mixture was stirred for 15 min and evaporated to dryness.
7-[1-Benzyl-1,2,3-triazole-4-yl-methyl]adenine 17
1H NMR (300 MHz, CDCl3) d (ppm) ¼ 4.3 (s, 2H, NH2), 5.53 (s, 2H,
General experimental procedure
CH2), 8.10 (s, 1H, H8), 7.50 (m, Ar–H), 8.15 (m, Ar–H), 8.20 (s, 1H,
H2), 8.30 (s, 1H, CH C). 13C NMR (CDCl3, 75 MHz): d (ppm) ¼ 57.00
–
–
Propargylated base (1.1 mmol), benzyl azide (1 mmol), and CuCl2/
KI/K10 (0.5 equiv./0.5 equiv., 650 mg) were suspended in 3 mL of
dioxane–MeOH (2:1 v/v) and stirred at reflux 90°C for 2 h. The
solution was evaporated, and the residue was applied to flash
column (silica gel).
(CH2), 57.10 (CH2), 119.50 (C5), 123.27 (C Tr), 128.44–133.87 (Ar–C),
140.49 (C8), 149.59 (C6), 152.09 (C4 Tr), 156.59 (C2). MS/ESIþ m/z
307.32 (MþH)þ. HMRS calcd. for C15H14N8 306.3252. Found:
306.3260.
Table 4. Cytotoxicity and anti-influenza virus activity in MDCK cell cultures.
Antiviral EC50
Influenza A H3N2
subtype (A/HK/7/87)
Influenza virus A H1N1
subtype (A/PR/8/34)
Influenza virus B
(B/HK/5/72)
Cytotoxicity
Minimum cytotoxic
concentrationb
(MCC)
Visual
CPE
score
Visual
CPE
score
Visual
CPE
score
Concentration
unit
Compound
CC50 a
MTS
MTS
MTS
16
17
18
19
20
21
22
23
mM
mM
mM
mM
mM
mM
mM
mM
mM
mM
mM
mM
>100
>100
>100
15
>100
>100
>100
>100
>100
43
ꢁ100
ꢁ100
ꢁ100
20
>100
>100
20
>100
>100
>100
>100
>100
>100
>100
>100
0.44
>100
>100
>100
>100
>100
>100
>100
>100
0.48
>100
>100
11 ꢂ 9
>100
>100
>100
>100
>100
0.043
8.9
>100
>100
13 ꢂ 10
>100
>100
>100
>100
>100
0.012
13
>100
>100
>100
>100
>100
>100
>100
>100
20
>100
>100
>100
>100
>100
>100
>100
>100
10
100
Zanamivir
Ribavirin
Amantadine
Rimantadine
>100
ꢁ20
500
8.4
124
2.7
6.7
201
7 2.5
8.9
>500
>500
11
>500
>500
>500
212
0.80
0.044
0.70
0.042
100
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2-[1-Benzyl-1,2,3-triazol-4-yl-methyl]thymine 18
cell cultures. Confluent cell cultures in microtiter 96-well plates
were inoculated with 100 cell culture inhibitory dose-50 (CCID50)
of virus (1 CCID50 being the virus dose to infect 50% of the cell
cultures) in the presence of varying concentrations of the test
compounds. Viral cytopathicity was recorded as soon as it
reached completion in the control virus-infected cell cultures that
were not treated with the test compounds.
1H NMR (300 MHz, CDCl3): d (ppm) ¼ 2.10 (s, 3H, CH3), 7.25 (m,
–
–
Ar–H), 7.50 (m, Ar–H), 7,70 (d, 1H, H6), 8.12 (s, 1H, CH C), 10.70
(s, 1H, NH). 13C NMR (CDCl3, 75 MHz): d (ppm) ¼ 20.12 (C10), 53.47
(CH2), 57.00 (CH2), 110.39 (C5), 124.01 (C–Tr), 128.38–133.87
–
–
–
(Ar–C), 137.46 (C6), 151.19 (C8), 151.59 (2C O), 163.29 (4C O).
–
MS/ESIþ m/z 297.30 (MþH)þ. HMRS calcd. for C15H15N5O2
The anti-HIV activity and cytotoxicity of the compounds were
evaluated against wild-type HIV-1 strain IIIB and HIV-2 strain ROD
in MT-4 cell cultures using the 3-(4,5-dimethylthiazol-2-yl)-2,5-
diphenyltetrazolium bromide (MTT) method. Briefly, stock
solutions (10 ꢃ final concentration) of test compounds were
added in 25 mL volumes to two series of triplicate wells. Serial
fivefold dilutions of test compounds were made directly in flat-
bottomed 96-well microtiter trays using a Biomek 3000 robot
(Beckman instruments). Untreated control HIV- and mock-
infected cell culture samples were included. Virus stock (50 mL)
at 100–300 CCID50 (50% cell culture infective dose) or culture
medium was added to either the infected or mock-infected wells
of the microtiter tray. Mock-infected cells were used to evaluate
the effect of test compound on uninfected cells in order to assess
the cytotoxicity of the test compound. Exponentially growing
MT-4 cells were centrifuged for 5 min at 1000 rpm (220 g) and the
supernatant was discarded. The MT-4 cells were resuspended at
6 ꢃ 105 cells mLꢀ1 and 50-mL volumes were transferred to the
microtiter tray wells. Five days after infection, the viability of
mock- and HIV-infected cells was examined spectrophotometri-
297.3119. Found: 297.3113.
2-[1-Benzyl-1,2,3-triazol-4-yl-methyl]6-azauracil 19
1H NMR (300 MHz, CDCl3): d (ppm) ¼ 4.04 (s, 2H, CH2), 5.44 (s, 2H,
–
–
CH ), 5.73 (s, 1H, H5), 7.24 (m, Ar–H), 8.24 (s, 1H, CH C), 10.48
2
(s, 1H, NH). 13C NMR (CDCl3, 75 MHz): d (ppm) ¼ 48.65 (CH2), 50.57
(CH2), 102.47 (C5), 120.01 (C9), 128.44–133.87 (Ar–C), 143.88 (C8),
150.59 (2C O), 163.99 (4C O). MS/ESIþ m/z 285.27 (MþH)þ. HMRS
–
–
–
–
calcd. for C13H12N6O2 284.2733. Found: 284.2721.
2-[1-Benzyl-1,2,3-triazol-4-yl-methyl]5-chlorouracil 20
1H NMR (300 MHz, CDCl3): d (ppm) ¼ 4.34 (s, 2H, CH2), 5.44 (s, 2H,
–
CH ), 7.24 (m, Ar–H) 7.29 (s, 1H, CH C), 7.97 (s, 1H, H6), 10.38
–
2
(s, 1H, NH). 13C NMR (CDCl3, 75 MHz): d (ppm) ¼ 48.65 (CH2), 50.71
(CH2), 106.49 (C5), 124.01 (C9), 128.44–133.87 (Ar–C)þ, 142.78 (C6),
–
–
–
–
143.78 (C8), 150.59 (2C O), 163.99 (4C O). MS/ESI m/z 318.37
(MþH)þ. HMRS calcd. for C14H12ClN5O2 317.7303. Found:
317.7311.
cally by the MTT assay. The 50% cytotoxic concentration (CC50
)
2-[1-Benzyl-1,2,3-triazol-4-yl-methyl]5-bromouracil 21
1H NMR (300 MHz, CDCl3): d (ppm) ¼ 5.34 (s, 2H, CH2), 5.44 (s, 2H,
was defined as the concentration of the test compound that
reduced the absorbance (OD540) of the mock-infected control
sample by 50%. The concentration achieving 50% protection from
the cytopathic effect of the virus in infected cells was defined as
the 50% effective concentration (EC50).
–
CH ), 7.54 (m, Ar–H), 7.89 (s, 1H, CH C); 8.01 (s, 1H, H6), 10.48
–
2
(s, 1H, NH). 13C NMR (CDCl3, 75 MHz): d (ppm) ¼ 48.65 (CH2), 51.71
(CH2), 102.99 (C5), 122.01 (C9), 128.44–133.87 (Ar–C)þ, 143.21 (C6),
–
–
–
–
143.78 (C8), 150.59 (2C O), 159.99 (4C O). MS/ESI m/z 363.18
(MþH)þ. HMRS calcd. for C14H12BrN5O2 362.1813. Found:
This work was supported by the CNRST Morocco (Project: RS/2011/01)
and by the K.U. Leuven (GOA 10/14). The authors thank Mrs. Leentje
Persoons, Frieda De Meyer, Wim Van Dam, Kristien Erven, and Mr. Kris
Uyttersprot for excellent technical assistance.
362.1805.
2-[1-Benzyl-1,2,3-triazol-4-yl-methyl]5-fluorouracil 22
1H NMR (300 MHz, CDCl3): d (ppm) ¼ 4.34 (s, 2H, CH2), 5.44 (s, 2H,
–
CH ), 7.54 (m, Ar–H), 7.79 (s, 1H, CH C), 8.09 (d, J ¼ 6.41 Hz, 1H,
–
2
H6); 11.48 (s, 1H, NH). 13C NMR (CDCl3, 75 MHz): d (ppm) ¼ 48.57
The authors have declared no conflict of interest.
(CH2), 50.81 (CH2), 102.41 (C5), 124.01 (C9), 128.44–133.87 (Ar–Cþ),
–
–
–
143.19 (C6), 143.08 (C8), 150.59 (2C O), 163.99 (4C O). MS/ESI
–
m/z 302.27 (MþH)þ. HMRS calcd. for C14H12FN5O2 301.2757.
Found: 301.2760.
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