Synthesis of coumarin-nucleoside conjugates via Huisgen 1,3-dipolar cycloaddition

Article abstract of DOI:10.1016/j.tet.2006.10.075

An efficient synthesis of fluorescent coumarin-nucleoside conjugates via Cu(I) catalysed Huisgen 1,3-dipolar cycloaddition is described. Starting from azidonucleosides and coumarin derivatives, products are obtained in good yields. The fluorescent properties of the newly prepared coumarin-nucleoside conjugates are determined.

Full text of DOI:10.1016/j.tet.2006.10.075

Tetrahedron 63 (2007) 312–320
Synthesis of coumarin–nucleoside conjugates via
Huisgen 1,3-dipolar cycloaddition
*
Ivana Kosiova, Sona Kovackova and Pavol Kois
Comenius University, Faculty of Natural Sciences, Department of Organic Chemistry, Mlynska dolina,
Pavilon CH2, SK-84215 Bratislava, Slovak Republic
Received 22 August 2006; revised 5 October 2006; accepted 27 October 2006
Available online 20 November 2006
Abstract—An efficient synthesis of fluorescent coumarin–nucleoside conjugates via Cu(I) catalysed Huisgen 1,3-dipolar cycloaddition is
described. Starting from azidonucleosides and coumarin derivatives, products are obtained in good yields. The fluorescent properties of
the newly prepared coumarin–nucleoside conjugates are determined.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
azidonucleoside (50-azido-50-deoxyuridine) was prepared
by Horwitz et al.21 by azidation reaction of 50-tosylnucleo-
side and lithium azide. In general, azidoanalogs have been
used mostly as intermediates in the preparation of amino-
nucleosides. But finding that 30-azido-30-deoxythymidine
(AZT), as an inhibitor of HIV reverse transcriptase,22 is an
efficient therapeutic agent has triggered explosive develop-
ments in the synthetic chemistry of azidonucleosides.
Many azidonucleosides exhibit cytotoxic and antiviral
properties23 and are convenient photoaffinity probes.24
Covalent linking of two molecular entities for preparing new
bioconjugates with desirable properties is a great challenge
for chemists. Bioconjugates, biomolecules bearing unnatu-
ral organic structures, have found during the past two
decades an increasing number of applications in molecular
and cell biology.1 Conjugated groups provide biomolecules
with novel properties, such as fluorescence emission,
catalytic activity, altered hydrophobicity or bioaffinity,
resistance towards biodegradation or the ability to carry
metal ions.
Coumarin derivatives are widely used as fluorescent probes,
labels and pigments,25–28 laser dyes29–34 and signalling units
in sensors.35,36 They are also attractive molecules due to
their extended spectral range, high emission quantum yields,
photostability and good solubility in safe solvents.37
One of the most powerful linking reactions for developing an
expanding set of new structures is Cu(I) catalysed Huisgen
1,3-dipolar cycloaddition,2–9 the formation of 1,4-disubsti-
tuted 1,2,3-triazoles from azides and terminal alkynes.
This reaction is unique due to its complete specificity,
biocompatibility of the reactants and high degree of depend-
ability. Cu(I) catalysed or the so-called Huisgen–Sharpless
1,3-dipolar cycloaddition is premiere example of a click
reaction10–13 employed in a wide range of applications,
including modification of cell surfaces,14 specific labelling
of virus particles,15 proteins,16 oligonucleotides17 and the
synthesis of new glycoproteins,8 neoglycoconjugates,18 den-
drimers6 or fluorescent labels.19,20
Here, we report on the efficient synthesis of fluorescent
triazole linked coumarin–nucleoside conjugates via Cu(I)
catalysed Huisgen 1,3-dipolar cycloaddition. The spectral
characteristics of new conjugates and the corresponding
coumarin derivatives will be compared.
2. Results and discussion
A very promising area for the preparation of new bio-
conjugates is the synthesis of azidonucleosides. The first
Huisgen–Sharpless 1,3-dipolar cycloaddition to form 1,4-
disubstituted triazole bridges is a very popular and unique
reaction for the preparation of bioconjugates. The stereo-
specific reaction gives very high yields and generates
inoffensive byproducts only. The triazole bridge serves as
a rigid linking unit that places the carbon atom, attached to
Keywords: Huisgen 1,3-dipolar cycloaddition; Bioconjugate; Nucleoside;
Coumarin; Fluorescent probe.
* Corresponding author. Tel.: +421 2 60296 341/338; e-mail: kois@fns.
uniba.sk
˚
the 4-position of 1,2,3-triazole ring, at a distance of 5.0 A
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.10.075

I. Kosiova et al. / Tetrahedron 63 (2007) 312–320
313
O
N
from N1. It cannot be cleaved hydrolytically or otherwise
and is almost impossible to oxidise or reduce.
O
N
O
N
NH
NH
NH
O
O
We prepared novel coumarin–nucleoside conjugates by
Huisgen–Sharpless 1,3-dipolar cycloaddition. Our key
substrates for this reaction were coumarin derivatives with
terminal alkyne function and azidonucleosides. Most of
the coumarin derivatives are commercially available25 and
have very good fluorescent properties. Among them
7-hydroxycoumarin derivatives 1a–b are the most often
used due their fluorescent quantum yields. Coumarin-4-
acetic acids 1c–e were synthesised in our laboratory in the
scope of new coumarins studies. Further functionalization
of basic coumarin skeleton of 1a–e was necessary, and the
coumarin derivatives with terminal alkynes 2a–e (Scheme 1)
were prepared. The synthesis of prop-2-yn-1-yloxy deriva-
tives 2a–b was achieved via an established method.38 Reac-
tion of 7-hydroxycoumarins 1a–b with propargylbromide
gives products 2a–b in excellent yields. The synthesis of
N-(prop-2-yn-1-yl)acetamide derivatives 2c–e was achieved
via a method common to the peptide synthesis.39–41 The
carboxylic acid was activated by 1-hydroxybenzotriazole
(HOBt) in the presence of dicyclohexylcarbodiimide
(DCC) as a coupling agent. Further reaction of the reactive
intermediates with propargylamine led to acetamides 2c–e.
Although, the conversion of substrates 1c–e was almost
quantitative in all the cases (Table 1), the lengthy separation
of products from contaminating dicyclohexylurea (DCU)
lowered the yields. As simple filtration of DCU was not
sufficient, the isolated yields of the corresponding products
were between 62 and 78%.
O
N3
N3
O
HO
O
O
OH
OH
OH
N3
3
4
5
Figure 1. Azidonucleosides for coumarin–nucleoside conjugates prepara-
tion.
Azidonucleosides are our key substrates for the synthesis of
new coumarin–nucleoside conjugates via Cu(I) catalysed
Huisgen 1,3-dipolar cycloaddition. They are available by
several methods;23 however, azidation reactions are usually
efficient and afford products in good yields. We prepared
azidonucleoside 3 (Fig. 1) via Mitsunobu type reaction,42
along with azidonucleosides 4 and 5 (Fig. 1) from 50-tosy-
lated intermediates.43
We chose Cu(I) catalysed Huisgen 1,3-dipolar cycloaddition
as a simple and efficient method for the synthesis of our
tailored bioconjugates possessing the desired properties.
Starting from azidonucleosides 3–5 and coumarin deriva-
tives 2a–e, with interesting fluorescent properties, we
obtained the conjugates in good yields. The reaction is regio-
selective only in the presence of Cu(I) salts as a catalyst, to
give the desired 1,4-disubstituted triazole bridge. In the liter-
ature Cu(I) catalysed Huisgen cycloaddition was studied
using various (1–30%, in most cases 5%) concentrations of
CuSO4 in the presence of sodium ascorbate.5–9,20,44–46 Using
0.05 molar equiv of catalyst in our preliminary experiments,
we observed incomplete reaction even after 72 h. Our ana-
logous experiments with different Cu(I) sources—CuI in
the presence of DIPEA,3 did not improve the conversion,
but reactions were not optimised. The best results we ob-
tained using 0.15 molar equiv of CuSO4$5H2O in aqueous
tert-BuOH (Schemes 2 and 3). The reaction was complete
after 6–7 h in the case of substrates 2a–b. We used 0.15
molar equiv of catalyst also for substrates 2c–e, but the
R1
(i)
(ii), (iii)
R1
R1
X
OH
1a-b
COOH
1c-e
R1 = coumarin derivative
X = O, CONH
2a-e
Scheme 1. Preparation of coumarin derivatives with terminal alkyne func-
tionality. Reaction conditions: (i) 1.0 molar equiv K2CO3, 1.0 molar equiv
propargylbromide, abs acetone; (ii) 1.0 molar equiv HOBt, 2.0 molar equiv
DCC, abs dioxane; (iii) 1.0 molar equiv propargylamine.
Table 1. Isolated yields of coumarin derivatives 2a–e with terminal alkyne functionality
Functionalized coumarin derivative
Yield (%)
Functionalized coumarin derivative
Yield (%)
O
N
H
2a
2b
95
2c
2d
2e
62
O
O
O
O
O
O
HO
O
O
N
H
OMe
93
69
78
O
O
MeO
O
O
N
H
O
O

314
I. Kosiova et al. / Tetrahedron 63 (2007) 312–320
O
R2
O
N
NH
R2
NH
O
N
N3
R1
O
O
R1
(i)
N
O
+
X
X
N
N
OH
R3
R3
R1 = coumarin derivative
X= O, CO-NH
2a-e
OH
6a-e
7a-e
4 R2 = H, R3 = OH
5 R2 = CH3 R3 = H
,
Scheme 2. Preparation of 50-triazole bridged nucleoside conjugates via Cu(I) catalysed Huisgen 1,3-dipolar cycloaddition. Reaction conditions: (i) 0.15 molar
equiv CuSO4$5H2O, 0.30 molar equiv sodium ascorbate, tert-BuOH/H2O¼1/1 (v/v).
O
O
NH
NH
O
N
N
O
HO
R1
HO
N
O
(i)
O
+
X
R1
N3
R1 = coumarin derivative
X= O, CO-NH
N
X
N
2a-e
3
8a-e
Scheme 3. Preparation of 30-triazole bridged nucleoside conjugates via Cu(I) catalysed Huisgen 1,3-dipolar cycloaddition. Reaction conditions: (i) 0.15 molar
equiv CuSO4$5H2O, 0.30 molar equiv sodium ascorbate, tert-BuOH/H2O¼1/1 (v/v).
reactions were slower (12–16 h) in comparison with 2a–b.
Higher concentrations of catalyst (0.30 molar equiv) accel-
erated the reaction, but the work-up of reaction mixture
was more complicated. The conversion of all the reactions
was almost quantitative and isolated yields of the products
are summarised in the Table 2. As detected by TLC and con-
with the desired products 6a–b, 7a–b and 8a–b. We suppose
that under the influence of Cu(I) polarisation of the C–O
bond between the coumarin and propargyl group causes
the fragmentation of 2a–b to 1a–b. Our isolated yields
were in the range 81–89%. Derivatives 6c–e, 7c–e and
8c–e were isolated in 69–87% yields, due to less straightfor-
ward separation of the products from the reaction mixture.
Emulsions were created during the ethyl acetate washings,
with polar products in both phases. Initially products were
purified most effectively by chromatography on silica. Later,
we realised that simple filtration and subsequent chromato-
graphy of crude reaction mixture was the most convenient
procedure.
1
firmed by H NMR, minor byproducts 7-hydroxycoumarin
1a and 7-hydroxy-4-methylcoumarin 1b were formed along
Table 2. Isolated yields and characteristics of prepared conjugates 6a–e to
8a–e
Compda Yield Mp
labs
(nm)
3
lems FI
(nm) (A.U.)
(%)
(ꢀC)
(cmꢁ1 Mꢁ1
)
The structure of isolated products 6a–e, 7a–e and 8a–e
1a
6a
7a
8a
—
83
85
89
—
325
14,509
9552
10,761
14,076
392
388
381
385
748
183
178
143
1
1
(Fig. 2), determined by H, 13C, H–1H COSY, 13C–1H,
HSQC and 13C–1H HMBC measurements, confirmed
only the expected regioisomer. Only one characteristic
signal for the triazole hydrogen was observed. The spectral
137–142 320
249–253 319
188–192 320
1b
6b
7b
8b
—
81
86
88
—
322
15,552
3725
10,398
12,903
387 1530
226–230 319
267–272 321
154–157 319
381
387
381
379
451
389
O
1c
6cb
7c
8c
—
69
75
79
—
326
12,487
4274
6923
7196
392 1955
395 1930
396 2394
397 2214
O
R2
4
3
11
231–235 326
260–263 326
187–191 326
12
NH
23
10
5
2
24
13
22
21
N
H
14
N
7
6
N
O
5'
1
24a
N
O
N
9
16
15
1'
2'
15a
4'
8
20a
20
1d
6d
7db
8d
—
78
81
82
—
323
323
3032
2028
9260
7590
418 2260
427 1471
428 2453
429 2524
189c
O
3'
17
19a
O
19
18
R3
O
193–197 323
322
200c
11
12
10
1e
6e
7e
8e
—
83
87
74
—
318/349
7444
7764
5315
6108
417 719/930
417 869/1080
419 822/952
419 785/881
R
18
14 13
N
R''
19
N
247–251 319/350
178–179 319/350
183–185 319/350
H
22
7
20
11
17
16
22a
N
18a
14a
N
10
21
9
12
15 16
8
N
O
7
13
O
O
15
O
14
R'
20
17
N
N
8
19a
O
c¼10ꢁ4 M in methanol.
c¼0.5ꢂ10ꢁ4 M in methanol.
Compound decomposed.
19
a
9
18
b
c
Figure 2. Designation of atoms for interpretation of NMR data.

I. Kosiova et al. / Tetrahedron 63 (2007) 312–320
315
characteristics of the isolated products are summarised in
Table 2. We found that all newly prepared conjugates display
only one peak in the fluorescence spectrum in methanol. The
process of conjugation did not cause a shift in the absorption
and fluorescence maxima of our compounds in comparison
with maxima of 1a–e. The fluorescence intensity of conju-
gates depends on the position of coumarin modification.
We observed only slight changes in fluorescence intensity
in the series of coumarin-4-acetic acid derivatives (6c–e,
7c–e and 8c–e). In contrast, the coumarin C7-hydroxy group
modification (6a–b, 7a–b and 8a–b) caused decrease in
intensity in comparison with the intensity of the correspond-
ing unmodified coumarins 1a–b.
1.00 g (5.68 mmol) of ascorbic acid (Across Organics) to
which 11.25 mL of distilled water and 0.48 g (5.68 mmol)
of sodium bicarbonate were added.
4.2. General procedure A
To a solution of coumarins 1a,b in dry acetone, anhydrous
potassium carbonate (1.0 molar equiv) and propargylbro-
mide (1.0 molar equiv) were added. The resultant mixture
was stirred at 50 ꢀC for 18 h, then the mixture was cooled
and the solvent was removed under reduced pressure. The
residue was treated with 15 mL of water and extracted
with ethyl acetate. The combined organic phases were
washed with water, dried over anhydrous sodium sulfate
and evaporated in vacuum. The crude product was purified
by crystallisation from ethyl acetate/hexane mixture.
3. Conclusion
New coumarin–nucleoside conjugates were prepared via
Cu(I) catalysed Huisgen 1,3-dipolar cycloaddition. This
smooth and convenient reaction combines the fluorescent
coumarin and biospecific nucleoside to the new molecule
with promising fluorescent properties. Products were ob-
tained in good yields and their spectral characteristics were
determined. Work is in progress to extend this flexible ap-
proach for the preparation of different types of bioconjugates,
including oligonucleotides, and substrates forenzymeassays.
4.2.1. 7-(Prop-2-yn-1-yloxy)-2H-chromen-2-one (2a).
Light yellow solid product, 586 mg (2.93 mmol, 95%),
1
mp¼118–120 ꢀC (lit.49 119 ꢀC). H NMR (DMSO): 8.01
(1H, d, J3–4¼9.4 Hz, H-4), 7.66 (1H, d, J5–6¼8.6 Hz, H-5),
7.06 (1H, d, J6–8¼2.5 Hz, H-8), 7.00 (1H, dd, J5–6¼8.6 Hz,
J6–8¼2.5 Hz, H-6), 6.33 (1H, d, J3–4¼9.4 Hz, H-3), 4.94
(2H, d, J9–11¼2.3 Hz, H-9), 3.67 (1H, t, J9–11¼2.3 Hz,
H-11); 13C NMR (DMSO): 160.19 (2), 160.18 (7), 155.13
(8a), 144.24 (4), 129.53 (5), 112.98 (3), 112.86 (4a), 112.83
(6), 101.78 (8), 78.94 (10), 78.52 (11), 56.11 (9).
4. Experimental
4.2.2. 4-Methyl-7-(prop-2-yn-1-yloxy)-2H-chromen-2-one
(2b). Light yellow solid product, 565 mg (2.64 mmol,
1
4.1. General methods
93%), mp¼130–134 ꢀC (lit.49 134 ꢀC). H NMR (CDCl3):
7.51 (1H, dd, J4–5¼7.5 Hz, H-4), 6.93 (1H, d, J5–6¼2.6 Hz,
H-6), 6.91 (1H, dd, J4–5¼7.5 Hz, J5–6¼2.6 Hz, H-5), 6.15
(1H, d, J3-Me¼1.2 Hz, H-3), 4.75 (2H, d, J9–11¼2.3 Hz,
Solvents were distilled and dried via established methods.47
Melting points were measured on a Kofer hot stage and are
uncorrected. NMR spectra were recorded in CDCl3 and
DMSO with Varian VX UNITY spectrometer (300 MHz/
75 MHz for 1H/13C). Chemical shifts are referenced to
Me4Si (1H) or the residual solvent signal (13C). All measure-
H-9), 2.56 (1H, t, J9–11¼2.5 Hz, H-11), 2.39 (3H, d, J3-Me
¼
1.1 Hz, CH3-4); 13C NMR (CDCl3): 161.34 (2), 160.36 (7),
155.08 (4), 152.40 (8a), 125.62 (5), 114.29 (4a), 112.75 (6),
112.47 (3), 102.17 (8), 76.50 (11), 56.17 (9), 18.70 (CH3-4).
ments were carried out at room temperature. The 1H and 13
C
1
assignments were based on H–1H COSY, 13C–1H HSQC
and 13C–1H HMBC experiments. Infrared spectra were ob-
tained on Perkin–Elmer Spectrum GX FT-IR spectrometer
with ATR sampling accessory. Absorption spectra were re-
corded using UV–Vis spectrophotometer Agilent 8453,
cuvette length 1 cm. Fluorescence spectra were recorded
using Hitachi F-2000. TLC was performed on precoated
plates of silica gel 60 F254 (Merck) using chloroform/meth-
anol (9/1) as eluent. The crude products were purified using
column chromatography on silica gel using chloroform/
methanol (9/1) as eluent. 30-Azido-30-deoxythymidine42 3,
50-azido-50-deoxyuridine43 4 and 50-azido-50-deoxythy-
midine43 5 were prepared as described in the literature.
CAUTION: the handling of low-molecular weight azides
is dangerous, due to their potential explosive character. Neat
azidonucleosides must not be heated and all the reactions
should be carried out on a small scale. 7-Hydroxy-2H-chro-
men-2-one (7-hydroxycoumarin) and 7-hydroxy-4-methyl-
2H-chromen-2-one (7-hydroxy-4-methylcoumarin) were
obtained from Aldrich and 2-(2-oxo-2H-chromen-4-yl)-
acetic acids were prepared as described in the literature.48
Propargylamine and propargylbromide (80% solution in
toluene) were obtained from Across Organics. Stock solu-
tion of sodium ascorbate (100 mg/mL) was prepared from
4.3. General procedure B
To a solution of 2-(2-oxo-2H-chromen-4-yl)acetic acids
1c–e and 1-hydroxybenzotriazole (HOBt, 1.0 molar equiv)
in dry dioxane, 1,3-dicyclohexylcarbodiimide (DCC,
2.0 molar equiv) in dry dioxane was added. The resultant
mixture was stirred at room temperature for 4 h. Then prop-
argylamine (1.0 molar equiv) was added and the mixture was
stirred at room temperature for 5 h. The DCU byproduct was
filtered off, the solvent was removed under reduced pressure
and the crude product was purified by column chromato-
graphy.
4.3.1. 2-(7-Hydroxy-2-oxo-2H-chromen-4-yl)-N-(prop-2-
yn-1-yl)acetamide (2c). White solid product, 362 mg
(1.04 mmol, 62%), mp¼249–253 ꢀC. C14H11NO4 (257.24),
calculated: 65.37% C, 4.31% H, 5.44% N, 24.88% O; found:
65.22% C, 4.42% H, 5.53% N. 1H NMR (DMSO): 8.67 (1H,
t, JNH-11¼6.6 Hz, HN–CO), 7.57 (1H, t, J5–6¼8.8 Hz, H-5),
6.79 (1H, dd, J5–6¼8.8 Hz, J6–8¼2.2 Hz, H-6), 6.72 (1H, t,
J6–8¼2.5 Hz, H-8), 6.17 (1H, s, H-3), 3.87 (1H, dd, J11-NH
¼
5.8 Hz, J11–13¼2.5 Hz, H-11), 3.66 (2H, s, H-9), 2.47 (1H, t,
J11–13¼2.5 Hz, H-13); 13C NMR (DMSO): 167.50 (10),
161.26 (2), 160.19 (7), 154.99 (4), 150.87 (8a), 126.66 (5),

316
I. Kosiova et al. / Tetrahedron 63 (2007) 312–320
0
0
0
112.92 (6), 111.70 (3), 111.35 (4a), 102.29 (8), 80.78 (12),
73.24 (13), 40.34 (9), 28.19 (11); IR (neat, cmꢁ1): 1694,
1622, 1609, 1565, 1326, 1143, 999, 740.
H-17), 5.75 (1H, d, J1 –2 ¼5.5 Hz, H-1 ), 5.63 (1H, d, J5–6
¼
8.1 Hz, H-5), 5.53 (1H, d, J2 -OH¼5.5 Hz, OH-20), 5.41 (1H,
0
d, J3 -OH¼5.0 Hz, OH-30), 5.26 (2H, s, H-12), 4.79–4.64 (2H,
0
m, H-50), 4.16 (1H, m, H-40), 4.10 (1H, m, H-20), 3.99 (1H,
m, H-30); 13C NMR (DMSO): 163.0 (4), 161.2 (16), 160.3
(13), 156.3 (14a), 150.6 (2), 144.3 (18), 141.9 (10), 141.1
(6), 129.5 (19), 125.7 (11), 112.9 (020), 112.6 (18a), 102.2
(14), 101.6 (5), 88.8 (10), 81.7 (4 ), 72.1 (20), 70.6 (30),
61.6 (12), 51.3 (50); IR (neat, cmꢁ1): 1689, 1612, 1260,
1079, 1019, 795.
4.3.2. 2-(5,7-Dimethoxy-2-oxo-2H-chromen-4-yl)-
N-(prop-2-yn-1-yl)acetamide (2d). Light yellow solid
product, 237 mg (0.79 mmol, 69%), mp¼108–111 ꢀC.
C16H15NO5 (301.29), calculated: 63.78% C, 5.02% H,
4.65% N, 26.55% O; found: 63.54% C, 4.93% H, 4.58%
1
N. H NMR (DMSO): 8.31 (1H, t, JNH-11¼5.8 Hz, HN–
CO), 6.60 (1H, d, J6–8¼2.2 Hz, H-6), 6.45 (1H, d, J6–8
2.2 Hz, H-8), 6.09 (1H, s, H-3), 3.87 (1H, dd, J11-NH
¼
¼
4.4.2. 50-{4-[(4-Methyl-2-oxo-2H-chromen-7-yloxy)-
methyl]-1H-1,2,3-triazol-1-yl}uridine (6b). White solid
product, 160 mg (0.33 mmol, 81%), mp¼226–230 ꢀC.
C22H21N5O8 (483.1), calculated: 54.66% C, 4.38% H,
14.49% N, 26.48% O; found: 54.45% C, 4.63% H,
5.8 Hz, J11–13¼2.5 Hz, H-11), 3.71 (2H, s, H-9), 3.11 (1H,
t, J11–13¼2.5 Hz, H-13); 13C NMR (DMSO): 168.48 (10),
162.71 (7), 159.79 (2), 158.32 (5), 156.32 (4), 150.74 (8a),
113.36 (3), 103.71 (4a), 95.41 (8), 93.62 (6), 81.32 (12),
72.80 (13), 56.12 (CH3O-5), 55.92 (CH3O-7), 42.68 (9),
27.87 (11); IR (neat, cmꢁ1): 1731, 1626, 1611, 1310,
1259, 1081, 1016, 795.
1
14.67% N. H NMR (DMSO): 8.26 (1H, s, H-11), 7.69
(1H, d, J19–20¼8.8 Hz, H-19), 7.53 (1H, d, J5–6¼8.0 Hz,
H-6), 7.15 (1H, d, J14–20¼2.5 Hz, H-14), 7.04 (1H, dd,
J14–20¼2.5 Hz, J19–20¼8.8 Hz, H-20), 6.23 (1H, d, J17-Me
¼
0
0
0
4.3.3. 2-(3-Oxo-3H-benzo[f]chromen-1-yl)-N-(prop-2-
yn-1-yl)acetamide (2e). White solid product, 443 mg
(1.52 mmol, 78%), mp¼185–189 ꢀC. C18H13NO3 (291.3),
calculated: 74.22% C, 4.50% H, 4.81% N, 16.48% O; found:
74.38% C, 4.34% H, 4.53% N. 1H NMR (DMSO): 8.73 (1H,
t, JNH-13¼5.2 Hz, HN–CO), 8.38 (1H, d, J7–8¼7.9 Hz, H-7),
8.20 (1H, d, J9–10¼9.3 Hz, H-9), 8.07 (1H, dd, J6–7¼7.4 Hz,
J7–8¼1.7 Hz, H-7), 7.66 (1H, dd, J5–6¼7.1 Hz, J6–7¼1.9 Hz,
1.4 Hz, H-17), 5.75 (1H, d, J1 –2 ¼5.2 Hz, H-1 ), 5.63 (1H,
d, J5–6¼8.0 Hz, H-5), 5.54 (1H, d, J2 -OH¼5.5 Hz, OH-20),
0
5.42 (1H, d, J3 -OH¼5.5 Hz, OH-30), 5.26 (2H, s, H-12),
0
4.80–4.65 (2H, m, H-50), 4.17 (1H, m, H-40), 4.10 (1H, m,
H-20), 4.00 (1H, m, H-30), 2.40 (3H, s, CH3-18); 13C NMR
(DMSO): 162.98 (4), 161.03 (16), 160.14 (13), 154.66
(18), 153.43 (14a), 150.63 (2), 142.01 (10), 141.09 (6),
126.51 (19), 125.70 (11), 113.37 (19a), 112.58 (17),
111.31 (20), 102.10 (14), 101.56 (5), 88.78 (10), 81.71 (40),
72.06 (20), 70.56 (30), 61.56 (12), 51.32 (50); IR (neat,
cmꢁ1): 1730, 1652, 1621, 1555, 1430, 1287, 1138, 1056,
835, 753.
H-6), 7.61 (1H, d, J5–6¼7.1 Hz, H-5), 7.59 (1H, d, J9–10
¼
8.8 Hz, H-10), 6.59 (1H, s, H-3), 4.21 (2H, s, H-11), 3.87
(1H, dd, J13-NH¼5.5 Hz, J13–15¼2.3 Hz, H-13), 3.12 (1H, t,
J13–15¼2.5 Hz, H-15); 13C NMR (DMSO): 167.92 (12),
159.22 (2), 154.22 (4), 151.35 (10a), 133.90 (9), 130.88
(5a), 129.60 (8), 129.08 (8a), 128.04 (6), 125.49 (7),
124.61 (5), 118.05 (10), 117.51 (3), 113.80 (4a), 80.79
(15), 73.13 (14), 43.42 (11), 28.12 (13); IR (neat, cmꢁ1):
1703, 1625, 1573, 1311, 1260, 1087, 1018, 798.
4.4.3. 50-{4-[2-(7-Hydroxy-2-oxo-2H-chromen-4-yl)acet-
amidomethyl]-1H-1,2,3-triazol-1-yl}uridine (6c). Light
yellow product, 120 mg (0.23 mmol, 69%), mp¼231–
235 ꢀC. C23H22N6O9 (526.1), calculated: 52.47% C, 4.21%
H, 15.96% N, 27.35% O; found: 52.19% C, 4.52% H,
1
4.4. General procedure C
16.21% N. H NMR (DMSO): 11.38 (1H, s, H-3), 10.55
(1H, s, HO-21), 8.72 (1H, t, JNH-12¼5.5 Hz, HN–C]O),
To a solution of compounds 2a–e in tert-BuOH/H2O 1/1
(v/v), CuSO4$5H2O (0.15 molar equiv) and sodium ascor-
bate (0.30 molar equiv) were added. The mixture was stirred
at room temperature for 15 min. Then nucleoside (3, 4 or 5,
1.0 molar equiv) was added and the resulting reaction mix-
ture was stirred at room temperature until the starting mate-
rial was consumed as judged by TLC. Then the reaction
mixture was washed with ethyl acetate, the combined
organic phases were washed with water, dried over anhy-
drous sodium sulfate and evaporated in vacuum. The crude
product was purified by column chromatography and crys-
tallised from ethyl acetate/hexane mixture.
7.91 (1H, s, H-11), 7.57 (1H, d, J21–22¼8.8 Hz, H-22),
7.52 (1H, d, J5–6¼8.2 Hz, H-6), 6.77 (1H, dd, J21–22
¼
8.8 Hz, J19–21¼2.2 Hz, H-21), 6.71 (1H, d, J19–21¼2.2 Hz,
0
0
H-19), 6.17 (1H, s, H-16), 5.74 (1H, d, J1 –2 ¼5.5 Hz,
H-10), 5.65 (1H, d, J5–6¼8.0 Hz, H-5), 5.53 (1H, d, J2 -OH
¼
0
5.5 Hz, OH-20), 5.40 (1H, d, J3 -OH¼5.5 Hz, OH-30), 4.73–
4.58 (2H, m, H-50), 4.32 (2H, d, J12-NH¼5.5 Hz, H-12),
4.12 (1H, m, H-40), 4.07 (1H, m, H-20), 3.96 (1H, m, H-30),
3.67 (2H, s, H-14); 13C NMR (DMSO): 168.30 (13),
163.66 (4), 161.82 (17), 160.89 (20), 155.66 (15), 151.73
(19a), 151.30 (2), 145.06 (10), 141.72 (6), 127.41 (22),
113.54 (19), 112.44 (16), 112.15 (22a), 102.94 (19),
102.78 (5), 89.41 (10), 82.40 (40), 72.73 (20), 71.20 (30),
51.84 (50), 39.00 (14), 35.05 (12); IR (neat, cmꢁ1): 1707,
1673, 1605, 1389, 1262, 1096, 1079, 1053, 857, 818, 740.
0
4.4.1. 50-{4-[(2-Oxo-2H-chromen-7-yloxy)methyl]-1H-
1,2,3-triazol-1-yl}uridine (6a). White solid product,
144 mg (0.31 mmol, 83%), mp¼137–142 ꢀC. C21H19N5O8
(469.1), calculated: 53.73% C, 4.08% H, 14.92% N,
27.27% O; found: 53.38% C, 3.95% H, 14.74% N. 1H
NMR (DMSO): 11.37 (1H, s, H-3), 8.26 (1H, s, H-11),
4.4.4. 50-{4-[2-(5,7-Dimethoxy-2-oxo-2H-chromen-4-
yl)acetamidomethyl]-1H-1,2,3-triazol-1-yl}uridine (6d).
Light yellow product, 76 mg (0.13 mmol, 78%), mp¼
189 ꢀC–decomposed. C25H26N6O10 (570.2), calculated:
52.63% C, 4.59% H, 14.73% N, 28.04% O; found: 52.37%
C, 4.74% H, 14.39% N. H NMR (DMSO): 11.40 (1H, s,
H-3), 8.40 (1H, t, J12-NH¼5.4 Hz, HN–C]O), 7.88 (1H, s,
7.99 (1H, d, J17–18¼9.7 Hz, H-18), 7.64 (1H, d, J19–20
8.6 Hz, H-19), 7.53 (1H, d, J5–6¼8.1 Hz, H-6), 7.17
(1H, d, J14–20¼2.5 Hz, H-14), 7.02 (1H, dd, J19–20
8.6 Hz, J14–20¼2.5 Hz, H-20), 6.30 (1H, d, J17–18¼9.5 Hz,
¼
1
¼

I. Kosiova et al. / Tetrahedron 63 (2007) 312–320
317
H-11), 7.56 (1H, d, J5–6¼8.2 Hz, H-6), 6.58 (1H, d, J19–21
¼
4.4.7. 50-{4-[(4-Methyl-2-oxo-2H-chromen-7-yloxy)-
methyl]-1H-1,2,3-triazol-1-yl}thymidine (7b). Light yel-
low solid product, 153 mg (0.32 mmol, 86%), mp¼267–
272 ꢀC. C23H23N5O7 (481.5), calculated: 57.38% C, 4.82%
H, 14.55% N, 23.26% O; found: 57.21% C, 4.93% H,
2.3 Hz, H-21), 6.39 (1H, d, J19–21¼2.3 Hz, H-19), 6.07
0
0
0
(1H, s, H-16), 5.74 (1H, d, J1 –2 ¼5.4 Hz, H-1 ), 5.65 (1H,
d, J5–6¼8.1 Hz, H-5), 5.55 (1H, d, J2 -OH¼5.6 Hz, HO-20),
0
5.42 (1H, d, J3 -OH¼5.3 Hz, HO-30), 4.74–4.57 (2H, m,
0
1
H-50), 4.30 (2H, d, J12-NH¼5.4 Hz, H-12), 4.13 (1H, m,
H-40), 4.07 (1H, m, H-20), 3.96 (1H, m, H-30), 3.84 (3H, s,
CH3O-22), 3.71 (2H, s, H-14), 3.59 (3H, s, CH3O-20); 13C
NMR (DMSO): 168.71 (13), 163.06 (4), 162.72 (17),
159.87 (20), 158.37 (22), 156.34 (15), 151.04 (19a),
150.69 (2), 144.85 (10), 141.18 (6), 123.80 (11), 113.36
(16), 103.80 (22a), 102.15 (5), 95.33 (19), 93.62 (21),
88.83 (10), 81.84 (40), 72.14 (30), 70.58 (2’), 55.96 (CH3O-
22), 55.82 (CH3O-20), 51.27 (50), 42.82 (14), 34.15 (12);
IR (neat, cmꢁ1): 1707, 1673, 1605, 1389, 1262, 1096,
1079, 1053, 857, 818, 740.
14.74% N. H NMR (DMSO): 8.26 (1H, s, H-11), 7.68
(1H, d, J19–20¼8.6 Hz, H-19), 7.35 (1H, d, J6-Me¼1.1 Hz,
H-6), 7.15 (1H, d, J14–20¼2.5 Hz, H-14), 7.03 (1H, dd,
J19–20¼8.8 Hz, J14–20¼2.3 Hz, H-20), 6.22 (1H, d, J17-Me
¼
0
0
0
1.1 Hz, H-17), 6.16 (1H, t, J1 –2 ¼6.6 Hz, H-1 ), 5.52 (1H,
d, J3 -OH¼4.1 Hz, HO-30), 5.26 (2H, s, H-12), 4.78–4.61
0
(2H, m, H-50), 4.29 (1H, m, H-30), 4.09 (1H, m, H-40), 2.40
(3H, d, J17-Me¼1.1 Hz, CH3-18), 2.39–2.13 (2H, m, H-20),
1.79 (3H, d, J6-Me¼0.8 Hz, CH3-5); 13C NMR (DMSO):
163.47 (4), 160.83 (16), 159.94 (13), 154.47 (18), 153.23
(14a), 150.21 (2), 141.86 (10), 135.86 (6), 126.32 (19),
125.42 (11), 113.19 (18a), 112.43 (17), 111.13 (20),
109.70 (5), 101.42 (14), 83.88 C (10), 83.77 (30), 70.61
(40), 61.41 (12), 51.12 (50), 37.70 (20), 17.97 (CH3-18),
11.90 (CH3-5); IR (neat, cmꢁ1): 1720, 1656, 1616, 1478,
1270, 1199, 1079, 1019, 840, 792.
4.4.5. 50-{4-[2-(3-Oxo-3H-benzo[f]chromen-1-yl)acet-
amidomethyl]-1H-1,2,3-triazol-1-yl}uridine (6e). Yellow
solid product, 130 mg (0.23 mmol, 83%), mp¼249–
253 ꢀC. C27H24N6O8 (560.5), calculated: 57.86% C, 4.32%
H, 14.99% N, 22.84% O; found: 57.59% C, 4.12% H,
1
14.57% N. H NMR (DMSO): 11.38 (1H, s, H-3), 8.80
4.4.8. 50-{4-[2-(7-Hydroxy-2-oxo-2H-chromen-4-yl)acet-
amidomethyl]-1H-1,2,3-triazol-1-yl}thymidine (7c).
Light yellow solid product, 98 mg (0.19 mmol, 75%),
mp¼260–263 ꢀC. C24H24N6O8 (524.2), calculated: 54.96%
C, 4.61% H, 16.02% N, 24.40% O; found: 54.83% C,
4.74% H, 15.92% N. 1H NMR (DMSO): 11.39 (1H, s,
H-3), 10.64 (1H, s, HO-20), 8.79 (1H, t, J12-NH¼5.8 Hz,
(1H, t, J12-NH¼5.5 Hz, HN–C]O), 8.35 (1H, d, J21–22
¼
8.8 Hz, H-21), 8.20 (1H, d, J19–20¼9.1 Hz, H-20), 8.05
(1H, d, J23–24¼8.0 Hz, H-24), 7.74 (1H, s, H-11), 7.59 (1H,
dd, H-23), 7.57 (1H, d, J19–20¼9.1 Hz, H-19), 7.53 (1H,
dd, H-22), 7.52 (1H, d, J5–6¼8.0 Hz, H-6), 6.59 (1H, s,
0
0
0
H-16), 5.74 (1H, d, J1 –2 ¼5.2 Hz, H-1 ), 5.64 (1H, d,
J5–6¼8.0 Hz, H-5), 5.53 (1H, d, J2 -OH¼5.5 Hz, OH-20),
HN–C]O), 7.99 (1H, s, H-11), 7.63 (1H, d, J21–22
¼
0
5.41 (1H, d, J3 -OH¼5.5 Hz, OH-30), 4.70–4.55 (2H, m,
8.9 Hz, H-22), 7.44 (1H, d, J6-Me¼1.0 Hz, H-6), 6.82
0
H-50), 4.32 (2H, d, J12-NH¼5.2 Hz, H-12), 4.22 (1H, s,
H-14), 4.12 (m, 1H, H-40), 4.07 (1H, m, H-20), 3.97 (1H,
m, H-30); 13C NMR (DMSO): 168.11 (13), 163.07 (4),
159.34 (17), 154.27 (15), 151.56 (2), 150.68 (19a), 144.55
(10), 141.16 (6), 133.92 (20), 130.89 (20a), 129.61 (24a),
129.13 (24), 127.94 (22), 125.53 (23), 124.72 (21), 123.52
(11), 118.26 (16), 117.58 (15a), 113.92 (19), 102.18 (5),
88.67 (10), 81.75 (40), 72.15 (20), 70.57 (30), 51.27 (50),
43.62 (14), 34.37 (12); IR (neat, cmꢁ1): 1698, 1674, 1623,
1542, 1457, 1271, 1221, 1112, 1017, 836, 772, 751.
(1H, dd, J21–22¼8.8 Hz, J19–21¼2.3 Hz, H-21), 6.77 (1H,
0
0
0
d, J19–21¼2.3 Hz, H-19), 6.23 (1H, t, J1 –2 ¼7.0 Hz, H-1 ),
6.22 (1H, s, H-16), 5.57 (1H, s, HO-30), 4.78–4.61 (2H, m,
H-50), 4.37 (2H, d, J12-NH¼5.6 Hz, H-12), 4.32 (1H, m,
H-30), 4.11 (1H, m, H-40), 3.72 (2H, s, H-14), 2.26–2.17
(2H, m, H-20), 1.85 (3H, d, J6-Me¼0.9 Hz, CH3-5); 13C
NMR (DMSO): 168.05 (13), 164.1 (4), 161.60 (17),
160.66 (20), 155.40 (15), 151.50 (19a), 150.84 (2), 144.80
(10), 136.52 (6), 127.16 (22), 113.28 (19), 112.19 (16),
111.87 (22a), 110.31 (5), 102.69 (19), 84.45 (10), 71.16
(30), 51.61 (50), 39.00 (14), 38.27 (20), 34.81 (12), 12.52
(CH3-5); IR (neat, cmꢁ1): 1703, 1683, 1611, 1397, 1260,
1079, 1056, 1020, 794, 668.
4.4.6. 50-{4-[(2-Oxo-2H-chromen-7-yloxy)methyl]-1H-
1,2,3-triazol-1-yl}thymidine (7a). Light yellow solid
product, 146 mg (0.31 mmol, 85%), mp¼247–251 ꢀC.
C22H21N5O7 (467.1), calculated: 56.53% C, 4.53% H,
14.98% N, 23.96% O; found: 56.28% C, 4.42% H, 15.05%
4.4.9. 50-{4-[2-(5,7-Dimethoxy-2-oxo-2H-chromen-4-
yl)acetamidomethyl]-1H-1,2,3-triazol-1-yl}thymidine
(7d). Light yellow solid product, 78 mg (0.14 mmol, 81%),
mp¼193–197 ꢀC. C26H28N6O9 (568.2), calculated: 54.93%
C, 4.96% H, 14.78% N, 25.33% O; found: 55.21% C,
4.87% H, 14.92% N. 1H NMR (DMSO): 11.34 (1H, s,
H-3), 8.39 (1H, t, J12-NH¼5.5 Hz, HN–C]O), 7.90 (1H,
s, H-11), 7.40 (1H, d, J6-Me¼1.1 Hz, H-6), 6.58 (1H, d,
1
N. H NMR (DMSO): 8.26 (1H, s, H-11), 8.00 (1H, d,
J17–18¼9.6 Hz, H-18), 7.64 (1H, d, J19–20¼8.8 Hz, H-19),
7.36 (1H, d, J6-Me¼1.1 Hz, H-6), 7.16 (1H, d, J14–20
2.5 Hz, H-14), 7.01 (1H, dd, J19–20¼8.8 Hz, J14–20
¼
¼
2.2 Hz, H-20), 6.30 (1H, 0d, J17–18¼9.3 Hz, H-17), 6.17
0
0
0
(1H, t, J1 –2 ¼6.8 Hz, H-1 ), 5.52 (1H, d, J3 -OH¼4.4 Hz,
HO-30), 5.26 (2H, s, H-12), 4.78–4.61 (2H, m, H-50), 4.29
(1H, m, H-30), 4.09 (1H, m, H-40), 2.23–2.06 (2H, m,
H-20), 1.79 (3H, d, J6-Me¼0.8 Hz, CH3-5); 13C NMR
(DMSO): 164.32 (4), 161.78 (16), 160.92 (13), 155.97
(14a), 151.06 (2), 144.96 (18), 142.67 (10), 136.73 (6),
130.18 (19), 126.28 (11), 113.57 (20), 113.26 (18a),
111.72 (17), 110.56 (5), 102.23 (14), 84.73 (10), 84.62 (30),
71.45 (40), 62.27 (12), 51.97 (50), 38.54 (20), 12.75
(CH3-5); IR (neat, cmꢁ1): 1719, 1656, 1613, 1478, 1263,
1199, 1079, 1019, 859, 802, 651.
J19–21¼2.5 Hz, H-21), 6.38 (1H, d, J19–21¼2.5 Hz, H-19),
0
0
0
6.16 (1H, t, J1 –2 ¼7.1 Hz, H-1 ), 6.07 (1H, s, H-16), 5.52
(1H, d, J3 -OH¼3.9 Hz, HO-30), 4.73–4.54 (2H, m, H-50),
0
4.30 (2H, J12-NH¼6.1 Hz, H-14), 4.26 (1H, m, H-30), 4.06
(1H, m, H-40), 3.83 (3H, s, CH3O-22), 3.70 (2H, s, H-14),
3.58 (3H, s, CH3O-20), 2.3–2.05 (2H, m, H-20), 1.79 (3H,
s, CH3-5); 13C NMR (DMSO): 168.57 (13), 163.64 (4),
162.64 (17), 159.72 (20), 158.72 (22), 156.29 (15), 150.94
(19a), 150.39 (2), 144.77 (10), 136.06 (6), 123.68 (11),
113.29 (16), 109.83 (5), 103.74 (22a), 95.31 (19), 93.54

318
I. Kosiova et al. / Tetrahedron 63 (2007) 312–320
(21), 84.09 (10), 84.07 (40), 70.78 (30), 55.89 (CH3O-22),
55.71 (CH3O-20), 51.2 (50), 42.77 (14), 37.89 (20), 34.11
(12), 12.04 (CH3-5); IR (neat, cmꢁ1): 1723, 1656, 1599,
1274, 1163, 1079, 1038, 794, 668.
m, H-30), 5.29 (2H, s, H-12), 5.29 (1H, m, HO-50), 5.24 (1H,
m, H-40), 3.75–3.59 (2H, m, H-50), 2.8–2.6 (2H, m, H-20),
2.41 (3H, d, J17-Me¼1.1 Hz, CH3-18), 1.81 (3H, d, J6-Me
¼
0.8 Hz, CH3-5); 13C NMR (DMSO): 163.71 (4), 161.01
(16), 160.10 (13), 154.66 (14a), 153.40 (18), 150.42 (2),
142.22 (10), 136.22 (6), 126.53 (19), 124.57 (11), 113.40
(18a), 112.56 (17), 111.32 (20), 109.62 (5), 101.56 (14),
84.41 (10), 83.89 (40), 61.62 (12), 60.75 (30), 59.35 (50),
37.16 (20), 18.13 (CH3-18), 12.71 (CH3-5); IR (neat,
cmꢁ1): 1695, 1622, 1293, 1271, 1146, 1100, 1072, 839,
771, 618.
4.4.10. 50-{4-[2-(3-Oxo-3H-benzo[f]chromen-1-yl)acet-
amidomethyl]-1H-1,2,3-triazol-1-yl}thymidine (7e).
Light yellow solid product, 189 mg (0.34 mmol, 87%),
mp¼178–179 ꢀC. C28H26N6O7 (558.2), calculated: 60.21%
C, 4.69% H, 15.05% N, 20.05% O; found: 60.34% C,
4.81% H, 14.88% N. 1H NMR (DMSO): 11.33 (1H, s,
H-3), 8.82 (1H, t, J12-NH¼5.4 Hz, HN–C]O), 8.36 (1H, d,
J21–22¼8.7 Hz, H-21), 8.19 (1H, d, J19–20¼8.9 Hz, H-20),
8.06 (1H, dd, J23–24¼7.9 Hz, J22–24¼1.5 Hz, H-24), 7.77
(1H, s, H-11), 7.58 (d, 1H, J19–20¼8.9 Hz, H-19), 7.56
4.4.13. 30-{4-[2-(7-Hydroxy-2-oxo-2H-chromen-4-yl)acet-
amidomethyl]-1H-1,2,3-triazol-1-yl}thymidine (8c).
Light yellow solid product, 240 mg (0.44 mmol, 79%),
mp¼187–191 ꢀC. C24H24N6O8 (524.2), calculated: 54.96%
C, 4.61% H, 16.02% N, 24.40% O; found: 54.78% C,
4.76% H, 16.33% N. 1H NMR (DMSO): 11.43 (1H, s,
H-3), 8.84 (1H, t, J12-NH¼5.4 Hz, HN–C]O), 8.16
(1H, s, H-11), 7.88 (1H, d, J6-Me¼0.9 Hz, H-6), 7.64 (1H,
d, J21–22¼8.6 Hz, H-22), 6.83 (1H, dd, J19–21¼2.2 Hz,
(1H, dd, J22–23¼7.3 Hz, H-23), 7.50 (1H, dd, J22–23
¼
7.1 Hz, J22–24¼1.5 Hz, H-22), 7.39 (1H, d, J6-Me¼1.0 Hz,
0
0
0
H-6), 6.58 (1H, s, H-16), 6.16 (1H, t, J1 –2 ¼6.8 Hz, H-1 ),
5.53 (1H, s, HO-30), 4.71–4.50 (2H, m, H-50), 4.32 (2H, d,
J12-NH¼5.4 Hz, H-12), 4.26 (1H, m, H-30), 4.22 (2H, s,
H-14), 4.04 (1H, m, H-40), 2.3–2.1 (2H, m, H-20), 1.79
(3H, d, J6-Me¼0.9 Hz, CH3-5); 13C NMR (DMSO): 168.44
(13), 164.09 (4), 159.69 (17), 155.75 (15), 154.65 (2),
151.96 (19a), 144.89 (10), 136.58 (6), 134.28 (20), 131.28
(20a), 129.97 (21), 129.52 (24a), 128.30 (23), 125.87 (22),
125.13 (24), 123.88 (11), 118.60 (19), 117.95 (15a),
114.32 (16), 110.29 (5), 84.46 (10), 71.18 (30), 51.63 (50),
43.98 (14), 38.33 (20), 34.77 (12), 12.62 (CH3-5); IR (neat,
cmꢁ1): 1717, 1698, 1654, 1542, 1508, 1272, 1207, 1097,
1018, 1043, 812, 753.
J21–22¼8.6 Hz, H-21), 6.78 (1H, d, J19–21¼2.2 Hz, H-19),
0
0
0
6.47 (1H, t, J1 –2 ¼6.6 Hz, H-1 ), 6.23 (1H, s, H-16), 5.42
(1H, m, H-30), 5.40 (1H, m, HO-50), 4.40 (2H, d, J12-NH
¼
5.4 Hz, H-12), 4.25 (1H, m, H-40), 3.78 (1H, m, H-50),
3.75 (1H, m, H-50), 3.75 (2H, s, H-14), 2.82–2.64 (2H, m,
H-20), 1.87 (3H, s, CH3-5); 13C NMR (DMSO): 168.10
(13), 164.17 (4), 161.60 (17), 160.66 (20), 155.44 (19a),
151.47 (22a), 150.88 (15), 145.10 (10), 136.67 (6), 127.16
(22), 123.10 (11), 113.28 (21), 112.25 (16), 111.90 (22a),
110.08 (5), 102.71 (19), 84.88 (10), 84.29 (40), 61.13 (50),
59.57 (30), 39.00 (14), 37.57 (20), 34.83 (12), 12.71
(CH3-5); IR (neat, cmꢁ1): 1684, 1638, 1620, 1567, 1267,
1141, 1100, 1046, 847, 776, 681, 633.
4.4.11. 30-{4-[(2-Oxo-2H-chromen-7-yloxy)methyl]-1H-
1,2,3-triazol-1-yl}thymidine (8a). White solid product,
154 mg (0.33 mmol, 89%), mp¼188–192 ꢀC. C22H21N5O7
(467.1), calculated: 56.53% C, 4.53% H, 14.98% N,
23.96% O; found: 56.42% C, 4.29% H, 15.21% N.
1H NMR (DMSO): 11.36 (1H, s, H-3), 8.48 (1H, s, H-11),
4.4.14. 30-{4-[2-(5,7-Dimethoxy-2-oxo-2H-chromen-4-
yl)acetamidomethyl]-1H-1,2,3-triazol-1-yl}thymidine
(8d). White solid product, 154 mg (0.28 mmol, 82%),
mp¼200 ꢀC–decomposed. C26H28N6O9 (568.2), calculated:
54.93% C, 4.96% H, 14.78% N, 25.33% O; found: 55.19%
8.01 (1H, d, J17–18¼9.3 Hz, H-18), 7.82 (1H, d, J6-Me
¼
1.1 Hz, H-6), 7.66 (1H, d, J19–20¼8.5 Hz, H-19), 7.18 (1H,
d, J14–20¼2.5 Hz, H-14), 7.04 (1H, dd, J14–20¼2.41 Hz,
1
0
0
0
J19–20¼8.5 Hz, H-20), 6.43 (1H, t, J1 –2 ¼6.6 Hz, H-1 ),
6.31 (1H, d, J17–18¼9.6 Hz, H-17), 5.41 (1H, m, H-30),
5.29 (2H, s, H-12), 5.29 (1H, m, HO-50), 4.24 (1H, m,
H-40), 3.76–3.57 (2H, m, H-50), 2.80–2.60 (2H, m, H-20),
2.08 (3H, d, J6-Me¼1.1 Hz, CH3-5); 13C NMR (DMSO):
164.15 (4), 161.56 (16), 160.70 (13), 155.76 (14a), 150.88
(2), 144.74 (18), 142.32 (10), 136.68 (6), 129.99 (19),
125.05 (11), 113.34 (18a), 113.17 (17), 113.07 (20),
110.08 (5), 102.00 (14), 84.86 (10), 84.32 (40), 62.10 (12),
61.20 (30), 59.81 (50), 37.62 (20), 12.71 (CH3-5); IR (neat,
cmꢁ1): 1716, 1670, 1616, 1630, 1276, 1093, 1050, 1008,
836, 771, 618.
C, 5.16% H, 14.92% N. H NMR (DMSO): 11.42 (1H, s,
H-3), 8.48 (1H, t, J12-NH¼5.6 Hz, HN–C]O), 8.17 (1H,
s, H-11), 7.87 (1H, d, J6-Me¼1.1 Hz, H-6), 6.64 (1H, d,
J19–21¼2.3 Hz, H-19), 6.47 (1H, d, J19–21¼2.0 Hz, H-21),
0
0
0
6.47 (1H, t, J1 –2 ¼6.7 Hz, H-1 ), 6.13 (1H, s, H-16), 5.46
(1H, m, H-30), 5.32 (m, HO-50), 4.37 (2H, d, J12-NH¼5.5 Hz,
H-12), 4.28–4.22 (1H, m, H-40), 3.89 (3H, s, CH3O-20), 3.78
(2H, s, H-14), 3.73 (1H, m, H-50), 3.68 (1H, m, H-50), 3.66
(3H, s, CH3O-22), 2.75–2.66 (2H, m, H-20), 1.87 (3H, d,
J6-Me¼0.9 Hz, H-5); 13C NMR (DMSO): 168.46 (13),
163.55 (4), 162.48 (17), 159.62 (20), 158.10 (22), 156.12
(15), 150.76 (19a), 150.26 (2), 144.81 (10), 136.04 (6),
122.70 (11), 113.14 (16), 109.46 (5), 103.56 (22a), 95.16
(21), 93.39 (19), 84.23 (10), 83.66 (40), 60.54 (50), 58.93
(30), 55.72 (CH3O-20), 55.57 (CH3O-22), 42.61 (14),
39.99 (20), 33.95 (12), 12.08 (CH3-5); IR (neat, cmꢁ1):
1707, 1655, 1630, 1261, 1098, 1061, 1015, 849, 801, 625.
4.4.12. 30-{4-[(4-Methyl-2-oxo-2H-chromen-7-yloxy)-
methyl]-1H-1,2,3-triazol-1-yl}thymidine (8b). White solid
product, 157 mg (0.33 mmol, 88%), mp¼154–157 ꢀC.
C23H23N5O7 (481.5), calculated: 57.38% C, 4.82% H,
14.55% N, 23.26% O; found: 57.62% C, 4.78% H, 14.84%
1
N. H NMR (DMSO): 11.37 (1H, s, H-3), 8.48 (1H, s,
H-11), 7.83 (1H, d, J6-Me¼1.3 Hz, H-6), 7.71 (1H, d, J19–20
4.4.15. 30-{4-[2-(3-Oxo-3H-benzo[f]chromen-1-yl)acet-
amidomethyl]-1H-1,2,3-triazol-1-yl}thymidine (8e).
White solid product, 140 mg (0.25 mmol, 74%), mp¼183–
185 ꢀC. C28H26N6O7 (558.2), calculated: 60.21% C, 4.69%
H, 15.05% N, 20.05% O; found: 60.43% C, 4.82% H,
¼
9.1 Hz, H-19), 7.17 (1H, d, J14–20¼2.5 Hz, H-14), 7.06 (1H,
0
0
d, J14–20¼2.4 Hz, J19–20¼8.8 Hz, H-20), 6.43 (1H, t, J1 –2
¼
6.6 Hz, H-10), 6.24 (1H, d, J17-Me¼1.1 Hz, H-17), 5.40 (1H,

I. Kosiova et al. / Tetrahedron 63 (2007) 312–320
319
15.35% N. 1H NMR (DMSO): 11.44 (1H, s, H-3), 8.92 (1H,
t, J12-NH¼5.8 Hz, HN–C]O), 8.40 (1H, d, J21–22¼8.2 Hz,
H-21), 8.25 (1H, d, J19–20¼9.1 Hz, H-20), 8.11 (1H, d,
J23–24¼8.0 Hz, H-24), 8.00 (1H, s, H-11), 7.88 (1H, s,
H-6), 7.66 (1H, dd, H-23), 7.63 (1H, d, J19–20¼9.1 Hz,
14. Deiters, A.; Cropp, T. A.; Mukherji, M.; Chin, J. W.; Anderson,
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H-19), 7.59 (1H, dd,0H-22), 6.64 (1H, s, H-16), 6.47 (1H,
0
0
0
t, J1 –2 ¼6.6 Hz, H-1 ), 5.42 (1H, m, H-3 ), 5.34 (1H, m,
HO-50), 4.40 (2H, d, J12-NH¼5.5 Hz, H-12), 4.29 (2H, s,
H-14), 4.21 (1H, m, H-40), 3.76 (1H, m, H-50), 3.73 (1H,
m, H-50), 2.68 (2H, t, J1 –2 ¼6.6 Hz, H-2 ), 1.88 (3H, s,
H-5); 13C NMR (DMSO): 168.03 (13), 163.72 (4), 159.23
(17), 154.22 (19a), 151.48 (15), 150.44 (2), 144.65 (10),
136.22 (6), 133.85 (20), 130.85 (20a), 129.56 (24), 129.07
(24a), 127.84 (22), 125.43 (19), 124.64 (23), 122.63 (15a),
118.22 (16), 117.53 (22), 113.86 (5), 109.62 (6), 84.42
(10), 83.89 (40), 60.70 (50), 59.10 (30), 43.57 (14), 37.14
(40), 34.32 (20), 33.35 (12), 12.27 (CH3-5); IR (neat,
cmꢁ1): 1700, 1678, 1644, 1554, 1278, 1092, 1072, 1017,
805, 737, 664, 620.
0
0
0
Acknowledgements
24. Fleming, S. A. Tetrahedron 1995, 51, 12479–12520 and refer-
ences cited therein.
The present work has been supported by the Slovak Grant
Agency VEGA 1/3559/06, Science and Technology Assis-
tance Agency under the contracts no. APVV-51-046505
and partly no. APVT-20-031904. NMR measurements
performed on the equipment supported by the Slovak State
Programme Project no. 2003SP200280203 are gratefully
acknowledged. We thank Assoc. Prof. Margita Lacova for
helpful discussion.
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