Tandem azide-alkyne 1,3-dipolar cycloaddition/electrophilic addition: A concise three-component route to 4,5-disubstituted triazolyl-nucleosides

Article abstract of DOI:10.1055/s-0029-1217560

A one-pot, three-component approach to a new family of 4,5-functionalized triazolyl-nucleosides is described. The method relies on the one-pot azide-alkyne 1,3-cycloaddition/electrophilic addition tandem reaction, which affords good yields of the correspo

Full text of DOI:10.1055/s-0029-1217560

LETTER
2123
Tandem Azide–Alkyne 1,3-Dipolar Cycloaddition/Electrophilic Addition: A
Concise Three-Component Route to 4,5-Disubstituted Triazolyl-Nucleosides
4
, 5-Disubstituted T
i
riazoly
n
l-Nucleosid
c
es ent Malnuit, Maria Duca, Anwar Manout, Khalid Bougrin,1 Rachid Benhida*
Laboratoire de Chimie des Molécules Bioactives et des Arômes, UMR 6001 CNRS, Institut de Chimie de Nice, Université de Nice-Sophia
Antipolis (UNS), 28 Avenue de Valrose, 06108 Nice Cedex 2, France
Fax +33(4)92076151; E-mail: benhida@unice.fr
Received 29 April 2009
N
N
Abstract: A one-pot, three-component approach to a new family of
4,5-functionalized triazolyl-nucleosides is described. The method
relies on the one-pot azide–alkyne 1,3-cycloaddition/electrophilic
addition tandem reaction, which affords good yields of the corre-
sponding 4,5-disubstituted nucleosides.
O
O
O
O
N
N
N
HO
HO
NH2
NH2
OH
Ribavirin
OH
HO
HO
Eicar
Key words: click, 3CR, tandem reaction, nucleosides
N
O
O
N
HO
NH2
For many years, naturally occurring and synthetic ana-
logues of nucleosides have attracted wide interest in view
of the importance of their biological activity.2 Recently,
renewed interest in such analogues has also arisen because
of their high potential value as biochemical probes and as
building blocks in artificial DNA and RNA synthesis fol-
lowing the well-known phosphoramidite chemistry.3
Among the bioactive nucleosides, those anchoring a five-
membered heterocyclic ring are of particular interest.
Thus, Ribavirin is a synthetic triazolyl-nucleoside en-
dowed with a broad-spectrum of antiviral activity against
many RNA and DNA viruses (Figure 1).4 It is still the
only small-molecule drug available to date for treatment
of hepatitis C virus (HCV). Eicar is an imidazole nucleo-
side with potent antiviral and antitumor activity
(Figure 1).5 Mizoribine is another five-membered nucleo-
side produced by Eupenicillium brefedianum, with anti-
biotic, cytotoxic and immunosuppressive activity.6 4-
Substituted triazolyl-nucleosides were recently reported
in both carbocyclic7 and acyclic series,8 and some of these
showed promising antiviral activities. However, only a
few examples were reported in the 1,4,5-trisubstituted se-
ries and most of these involved multistep processes and
have limited application scope. Ackermann described the
synthesis of 1,4,5-trisubstituted triazole using an interest-
ing sequential process.9 Very recently, during the prepara-
tion of this manuscript, Zhang and co-workers reported a
similar procedure using a CuI/NBS couple as both catalyst
and iodination agent.10
OH
OH
HO
Mizoribine
Figure 1 Structure of bioactive five-membered-ring nucleosides
cal activity. As a continuation of our interest in the
synthesis of new nucleoside analogues,12 we describe
herein a one-pot, three-component strategy for the synthe-
sis of new triazolyl-nucleosides bearing two appended
groups at positions 4 and 5 of the triazole ring (Scheme 1),
which allows a new approach to the synthesis of Eicar and
Mizoribine five-membered analogues. The methodology
is highly efficient and involves, as the key step, a tandem
azide–alkyne cycloaddition/electrophilic addition. We
also report a short and expeditious synthesis of an Eicar
analogue by applying this new synthetic strategy.
Based on the remarkable discovery of copper-catalyzed
azide–alkyne 1,3-dipolar cycloaddition,13 we envisioned,
following our previous procedure, that the targeted 4,5-
disubstituted triazolyl-nucleosides could be obtained
through trapping of the triazolyl-copper intermediate I by
electrophiles during the reaction (Scheme 2).14 Therefore,
the main challenge in this investigated one-pot reaction
was to overcome the concomitant proteolysis reaction of I
leading to 5-H-triazole.
N
N
R2
CuI, DIPEA
N3
X
R2
+
+
N
R1
R3
R1
We recently reported that azido-furanose and terminal
alkynes undergo fast 1,3-dipolar cycloaddition under the
cooperative effect of microwave activation and copper(I)
catalysis, to give high yields of triazolyl-nucleoside cy-
cloadducts.11 Some of these displayed promising biologi-
R3
Scheme 1 The proposed click–electrophilic addition tandem pro-
cess
In our previously reported work,11a we observed that the
rate of the 1,3-dipolar cycloaddition reaction between
azido-ribose and terminal alkynes was significantly in-
creased when acetic acid or silica gel were used in the re-
action. This acceleration could be explained by the
SYNLETT 2009, No. 13, pp 2123–2128
x
x
.x
x
.2
0
0
9
Advanced online publication: 15.07.2009
DOI: 10.1055/s-0029-1217560; Art ID: G10609ST
© Georg Thieme Verlag Stuttgart · New York

2124
V. Malnuit et. al
LETTER
entry 11). We also briefly explored the effect of changing
the ligand/base from DIPEA to Et3N or pyridine and con-
firmed the efficiency of DIPEA over the latter two
(Table 2, entries 3, 6 and 7).
N
N
O
N3
R
O
N
R
AcO
CuI, DIPEA
AcO
CuL
OAc
AcO
OAc
AcO
In contrast to Zhang’s work10 and as shown in Table 1, in
our case, reactions using I2 worked well (Table 1, entries
1–7) and dichloromethane was found to be an efficient
solvent since it also gave good yields of 2a (Table 1).
I
proteolysis
H+
electrophilic addition
E+
With these optimized reaction conditions in hand, the
scope and limitations of this methodology were explored
with various alkynes, azido-sugars and electrophiles
(Table 2). It should be noted that we used CuCl/NCS and
CuBr/NBS couples as sources of Cl+ and Br+, respective-
ly. In general, all reactions of NIS, NBS and NCS with
various azido-sugars (a- and b-deoxy-ribose, D- and L-ri-
bose and pyranose series) were clean and the 4,5-disubsti-
tuted triazolyl nucleosides were obtained in good yields
(Table 2).
N
N
N
N
O
O
N
N
R
R
AcO
AcO
H
E
OAc
OAc
AcO
AcO
5H-triazole
Scheme 2 Electrophilic addition vs proteolysis key steps
protonation of the triazolyl-copper intermediate I (pro-
teolysis step, Scheme 2). Therefore, in this present work,
in order to increase the efficiency of the electrophilic ad-
dition vs proteolysis (E+ vs H+) all sources of H+ were
avoided (acids and protic solvents).
Table 1 Survey of the Reaction Conditions
N
N
O
O
CO2Et, E+
conditions
N
N3
R
AcO
As a model reaction, we investigated the reactivity of azi-
do-ribose 1, ethyl propiolate and various sources of I+
(Table 1). First, condensation of azido-ribose 1 with ethyl
propiolate, in the presence of CuI/DIPEA and iodine (1
equiv), produced the desired 5-iodo-triazolyl adduct 2a,
together with triazole 3a, resulting from a concomitant
proteolysis, in 85% combined yield and 1:3 ratio in favor
of 3a (2a/3a = 25:75; Table 1, entry 1).15 Although the
yield of 2a was low, this result showed that the one-pot
transformation was feasible, and prompted us to under-
take a deeper study in order to increase the ratio of 2a. Dif-
ferent conditions were then evaluated for this
transformation, including the nature of solvent, source of
I+, stoichiometry and the use of additives. Thus, increas-
ing the amount of I2 from one to three equivalents resulted
in an increased ratio in favor of 2a (2a/3a = 70:30;
Table 1, entry 3). The low efficiency observed in the pro-
duction of 2a is thus due to the slow iodonium addition
step. The best results were obtained using iodine/
iodosobenzene diacetate (I2/IBD) or iodine/cerium(IV)
ammonium nitrate (I2/CAN) couples, both of which gave
high yields of the desired compound 2a, while minimizing
the formation of 3a (Table 1, entries 8 and 9). CAN and
IBD were used as oxidizing agents in order to generate
more reactive iodonium species.16 We found that tetra-
hydrofuran and dichloromethane were both effective as
solvents in this multi-component process. Furthermore,
the ratio of DIPEA/I2 was crucial in this transformation,
AcO
I
(see table)
OAc
AcO
OAc
AcO
2a
+
N
N
O
N
CO2Et
AcO
OAc
AcO
3a
Entry Ratio alkyne/CuI/ Source of I+
Solvent Yield Ratio
DIPEAa (equiv)
(equiv)
I2 (1)
I2 (2)
I2 (3)
I2 (3)
I2 (3)
I2 (3)
I2 (3)
(%)b 2a/3ac
1
2
2:2:5
CH2Cl2 85 25:75
CH2Cl2 93 40:60
CH2Cl2 92 70:30
2:2:5
3
2:2:5
4
2:2:5
THF
90 68:32
5
2:2:5
toluened 32e 70:30
CH2Cl2 35e 65:35
CH2Cl2 68 70:30
6
2:2:5 (pyridine)
2:2:5 (Et3N)
1.2:1.2:5
1.2:1.2:5
1.2:1.2:1.5
1.2:1.2:1.5
7
8
I2 / IBD (2:1) CH2Cl2 92 90:10
I2 / CAN (2:1) THF 95 >95:5
9
10
NIS (1)
NIS (3)
CH2Cl2 65 60:40
CH2Cl2 82 90:10
since DIPEA served as a base, copper ligand and HI 11
quencher (HI acid released from I2).17 Therefore, when I2
a DIPEA: N,N-diisopropylethylamine.
was used, an excess of DIPEA was required in order to
avoid proteolysis (HI). This result was also confirmed by
using N-iodosuccinimide (NIS) instead of I2. Under these
conditions, only 1.5 equivalents of DIPEA were required
to achieve complete transformation of 1 into 2a (Table 1,
b Combined isolated yield. In general, reactions were complete after 1
h.
c Ratio based on 1H NMR of the crude product.
d Reaction time = 16 h.
e The starting material was recovered.
Synlett 2009, No. 13, 2123–2128 © Thieme Stuttgart · New York

LETTER
4,5-Disubstituted Triazolyl-Nucleosides
2125
Table 2 Extension of the Three-Component Procedure
N
N
N
N
R2
conditions
N3
R1
+
+
R2
electrophile
N
R2
N
+
R1
R1
see table
H
E
2b–j
3b–j
Entrya Azide
Alkyne
E+
Conditions
(equiv)
Time Product
(h)
Ratio 2/3b,
Yield (%)c
N
N
N
N
CO2Et
O
O
O
O
N3
CuBr, DIPEA
(1.2:1.2)
75:25
(85)
AcO
1
2
NBS
NCS
1
2
AcO
CO2Et
Br
AcO
OAc
AcO
AcO
OAc
2b
N
N
CO2Et
N3
CuCl, DIPEA
(1.2:1.2)
70:30
(82)
AcO
AcO
AcO
CO2Et
Cl
AcO
AcO
OAc
OAc
2c
N
N
N
N
CO2Et
CO2Et
CO2Et
O
O
O
O
O
N3
CuI, DIPEA
(1.2:3)
30:70
(74)
3d
PhSeBr
4-Me-
1
AcO
CO2Et
Se
OAc
AcO
AcO
TolO
OAc
2d
N
N
N3
CuI, DIPEA
C6H4COCl (2:5)
>95:5
(91)
AcO
4d,e
0.5
AcO
CO2Et
AcO
O
N
OAc
OAc
2e
N
N
O
N3
TolO
CuBr, DIPEA
(1.2:1.2)
68:32
(83)
5
TolO
CO2Et
CO2Et
NBS
NCS
NCS
1
1
Br
TolO
a/b = 2:3
2f (a/b = 2:3)
N
N
N
O
O
O
CO2Et
N3
CuCl, DIPEA
(1.2:1.2)
70:30
(86)
BzO
BzO
BzO
6
Cl
N
OBz
BzO
OBz
2g
N
N
O
N3
CuCl, DIPEA
(2:5)
OMe 50:50
BzO
BzO
BzO
7d
16
1
OMe
(60)
Cl
BzO
OBz
OBz
2h
AcO
N
N
AcO
O
CO2Et
I2, CAN
(2:1)
CuI, DIPEA
(1.2:5)
>95:5
(92)
AcO
AcO
N
8
O
CO2Et
AcO
AcO
N3
OAc
I
OAc
2i
N
AcO
N
N
AcO
O
AcO
AcO
CuBr, DIPEA
(1.2:1.2)
30:70
(58)
O
AcO
AcO
9
NBS
8
N3
OAc
Br
OAc
2j
a Reactions were performed at r.t. in CH2Cl2 (azide/alkyne/E+ = 1:1.2:3).
b Based on 1H NMR of the crude product.
c Combined isolated yield.
d Alkyne (2 equiv) was used.
e The reaction was performed in THF with E+ (5 equiv).
Synlett 2009, No. 13, 2123–2128 © Thieme Stuttgart · New York

2126
V. Malnuit et. al
LETTER
O
As we previously observed, the rate of the 1,3-dipolar cy-
cloaddition step was increased with more polar alkynes
(polar transition state) since aryl-alkynes required longer
reaction times and led to moderate yields compared to
those obtained with ethyl propiolate (Tables 2, 6 vs 7 and
8 vs 9).11 Interestingly, we found that the three-component
reaction was also applicable to other electrophiles. Thus,
when PhSeBr was used in the reaction, the desired 5-phe-
nylselenide-substituted triazole 2d was obtained in mod-
erate yield, which is probably due to the low reactivity of
the electrophile (Table 2, entry 3). Fortunately, the three-
component, one-pot reaction of azido-ribose 1, ethyl pro-
piolate and toluoyl chloride, which was used as the elec-
trophile, led to 5-toluoyl-triazolyl-nucleoside 2e in
excellent yield (Table 2, entry 4).18
N
N
O
N
OMe
HO
O
4
OH
HO
(ii) NH3, MeOH, 1 h
87% (two steps)
(i) 2-tributyltin-furan, CuI, Et3N
Pd(PPh3)2Cl2, toluene, 80 °C
0.5 h
N
N
CO2Et
O
N
AcO
I
2a
OAc
AcO
(i) TMS-acetylene, CuI, Et3N
Pd(PPh3)2Cl2, r.t. then 70 °C
(ii) NH3, MeOH, 48 h
62% (two steps)
In summary, we have developed an efficient, one-pot,
three-component synthesis of 4,5-disubstituted triazolyl-
nucleosides using a tandem process based on copper-
catalyzed 1,3-dipolar cycloaddition and trapping with
electrophiles. This methodology offers access to various
triazoles functionalized at positions 1, 4 and 5. Generally
moderate to good yields were obtained. Moreover, the
process is compatible with many functional groups and
offers several possibilities for further post-synthetic trans-
formations. For example, the iodo-derivative 2a was sub-
jected to palladium cross-coupling reactions in order to
evaluate its reactivity (Scheme 3). Thus, treatment of 2a
with 2-tributyltin-furan under Stille conditions followed
by treatment with ammonia in methanol for one hour in
order to induce acetyl group cleavage/trans-esterification
(OEt to OMe) reactions, afforded the free nucleoside 4 in
87% overall yield.19 In a similar way, the new Eicar ana-
logue 520 was prepared in 62% overall yield through
Sonogashira coupling between 2a and TMS-protected
acetylene, and subsequent aminolysis (NH3, MeOH, 48
h); this approach efficiently allowed three transformations
in one operation, i.e., acetyl, TMS-cleavage and ester into
amide conversion.
4 h
O
N
N
O
N
NH2
HO
HO
5
OH
Eicar analogue
Scheme 3 Post-synthetic transformations of 2a
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Taken together, our results illustrate the efficiency of the
given synthetic methodology for the supply of a variety of
4,5-disubstituted triazolyl nucleosides for further bio-
physical and biological applications. The evaluation of the
antiviral activity of these analogues is under investigation.
Acknowledgment
Financial support from UNS, Région PACA, MAEE, Ministère de
la Recherche (doctoral fellowship to V.M.) and CNRS is gratefully
acknowledged. We also thank Egide (PAI 20538WC) and ARCUS-
CERES for funding this project. We are grateful to Dr. Jean-Marie
Guigonis for HRMS data.
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References and Notes
(1) Present address: Laboratoire de Chimie des Plantes et de
Synthèse Organique et Bioorganique, Faculté des Sciences,
Université Mohamed-V Rabat-Agdal, Morocco
Synlett 2009, No. 13, 2123–2128 © Thieme Stuttgart · New York

LETTER
4,5-Disubstituted Triazolyl-Nucleosides
2127
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13C NMR (50 MHz, CDCl3): d = 14.3, 20.5, 20.6, 20.8, 61.7,
62.7, 71.0, 74.3, 81.2, 88.9, 128.3, 128.7, 129.9, 132.6,
136.8, 160.3, 169.2, 169.5, 170.7, 172.0. HRMS (ESI):
m/z [M + H]+ calcd for C22H26N3O9Se: 556.0834; found:
526.0829.
2e: 1H NMR (200 MHz, CDCl3): d = 0.93 (t, J = 7.1 Hz, 3 H,
CH3), 1.96 (s, 3 H, Ac), 2.02 (s, 3 H, Ac), 2.03 (s, 3 H, Ac),
2.37 (s, 3 H, CH3Ph), 3.99 (dd, J = 12.3, 4.5 Hz, 1 H, H-5¢),
4.07 (q, J = 7.1 Hz, 2 H, CH2 ester), 4.17 (dd, J = 12.3, 3.3
Hz, 1 H, H-5¢), 4.31 (dd, J = 7.9, 4.5 Hz, 1 H, H-4¢), 5.59 (t,
J = 4.7 Hz, 1 H, H-3¢), 6.07 (m, 2 H, H-1¢ and H-2¢), 7.23 (d,
J = 8.1 Hz, 2 H, H-Ar), 7.59 (d, J = 8.1 Hz, 2 H, H-Ar). 13
NMR (50 MHz, CDCl3): d = 13.6, 20.3, 20.4, 20.6, 21.9,
C
61.6, 62.5, 70.8, 73.7, 81.7, 89.4, 129.7, 133.7, 137.6, 138.8,
146.5, 159.4, 169.1, 169.4, 170.4, 185.4. HRMS (ESI):
m/z [M + H]+ calcd for C24H28N3O10: 518.1775; found:
518.1781.
2h: 1H NMR (200 MHz, CDCl3): d = 3.86 (s, 3 H, OCH3),
4.61 (dd, J = 12.2, 4.9 Hz, 1 H, H-5¢), 4.78 (dd, J = 12.2, 3.7
Hz, 1 H, H-5¢), 4.94 (dd, J = 10.9, 5.3 Hz, 1 H, H-4¢), 6.35
(dd, J = 7.0, 5.1 Hz, 1 H, H-3¢), 6.40 (d, J = 2.0 Hz, 1 H, H-
1¢), 6.50 (dd, J = 5.1, 2.0 Hz, 1 H, H-2¢), 7.00 (d, J = 8.9 Hz,
2 H, H-Ar), 7.30–7.65 (m, 9 H, H-Ar), 7.85–8.10 (m, 8 H,
H-Ar). 13C NMR (50 MHz, CDCl3): d = 55.4, 63.7, 71.9,
75.1, 81.2, 88.2, 114.3, 121.5, 128.1, 128.5, 128.6, 128.7,
130.0, 133.3, 133.7, 134.0, 142.3, 160.1, 165.2, 166.3.
MS (ES): m/z = 75.8 [M + Na].
(19) To a solution of 2a (1 mmol) in toluene (10 mL) were
successively added 2-(tributylstannyl)furan (2 equiv),
Pd(PPh3)2Cl2 (5 mol%), CuI (5 mol%) and Et3N (1 equiv).
The reaction mixture was stirred for 30 min at 80 °C. After
the reaction was complete (1H NMR monitoring), the
mixture was filtered through Celite and the solvent was
removed. The crude product was purified by flash silica gel
chromatography (cyclohexane–EtOAc, 9:1→1:1) to afford
the desired compound in 95% isolated yield. 1H NMR (200
MHz, CDCl3): d = 1.37 (t, J = 7.1 Hz, 3 H, CH3), 2.00 (s,
3 H, Ac), 2.09 (s, 3 H, Ac), 2.10 (s, 3 H, Ac), 4.11 (dd,
J = 12.1, 4.4 Hz, 1 H, H-5¢), 4.30–4.50 (m, 4 H, H-4¢, H-5¢
and CH2 ester), 5.82 (t, J = 6.2 Hz, 1 H, H-3¢), 6.17 (dd,
J = 5.2, 2.9 Hz, 1 H, H-2¢), 6.39 (d, J = 2.9 Hz, 1 H, H-1¢),
6.60 (dd, J = 3.4, 1.8 Hz, 1 H, H-furan), 7.45 (d, J = 3.4 Hz,
1 H, H-furan), 7.66 (d, J = 1.8 Hz, 1 H, H-furan). 13C NMR
(50 MHz, CDCl3): d = 14.4, 20.6, 20.8, 61.6, 62.9, 71.2,
74.4, 81.4, 89.7, 112.4, 117.6, 139.0, 145.3, 151.5, 157.9,
160.8, 169.4, 169.5, 170.7. HRMS (ESI): m/z [M + H]+
calcd for C20H24N3O10: 466.1462; found: 466.1456. This
compound was then dissolved in MeOH (8 mL) and the
solution was saturated with ammonia at 0 °C and stirred for
1 h at r.t. The crude product was evaporated and purified by
flash silica gel chromatography (CH2Cl2–MeOH, 9:1) to
afford nucleoside 4 in 91% yield. Free nucleoside 4: 1H
NMR (200 MHz, CD3OD): d = 3.60 (dd, J = 12.1, 5.6 Hz,
1 H, H-5′), 3.75 (dd, J = 12.2, 3.7 Hz, 1 H, H-5′), 3.88 (s,
3 H, OMe), 4.13 (dd, J = 9.2, 5.5 Hz, 1 H, H-4′), 4.51 (t,
J = 5.4 Hz, 1 H, H-3′), 4.87 (t, J = 1.7 Hz, 1 H, H-2′), 6.17
(d, J = 2.9 Hz, 1 H, H-1′), 6.69 (dd, J = 3.4, 1.8 Hz, 1 H, H-
furan), 7.36 (d, J = 3.4 Hz, 1 H, H-furan), 7.82 (d, J = 1.8
Hz, 1 H, H-furan). 13C NMR (50 MHz, CD3OD): d = 52.6,
63.3, 72.2, 76.0, 87.3, 93.3, 113.0, 118.0, 139.8, 147.0,
159.0, 161.7, 162.2. HRMS (ESI): m/z [M + Na]+ calcd for
C13H15N3O7Na: 348.0808; found: 348.0807.
(15) 2a: 1H NMR (200 MHz, CDCl3): d = 1.36 (t, J = 7.1 Hz, 3 H,
CH3), 1.97 (s, 3 H, Ac), 2.07 (s, 6 H, Ac), 4.07 (dd, J = 12.3,
4.2 Hz, 1 H, H-5¢), 4.25–4.50 (m, 4 H, H-4¢, H-5¢ and CH2
ester), 5.72 (t, J = 5.5 Hz, 1 H, H-3¢), 6.07 (dd, J = 5.5, 3.1
Hz, 1 H, H-2¢), 6.12 (d, J = 3.1 Hz, 1 H, H-1¢). 13C NMR (50
MHz, CDCl3): d = 14.2, 20.4, 20.5, 20.6, 61.6, 62.5, 70.9,
73.9, 81.5, 90.3, 142.2, 159.9, 169.2, 169.4, 170.4. HRMS
(ESI): m/z [M+H]+ calcd for C16H21N3O9I: 526.0322; found:
526.0317.
(16) (a) Benhida, R.; Blanchard, P.; Fourrey, J.-L. Tetrahedron
Lett. 1998, 39, 6849. (b) Wirth, T.; Hirt, U. H. Synthesis
1999, 1271. (c) Zhdankin, V. V.; Stang, P. J. Chem. Rev.
2002, 102, 2523. (d) Wirth, T. Top. Curr. Chem. 2003, 224.
(17) With excess of I2 as electrophile the reaction was sluggish
when only one equivalent of DIPEA was used.
(18) Typical procedure: To a solution of azido-sugar (1 mmol)
in CH2Cl2 (10 mL) were successively added alkyne (1.1
equiv), electrophile (3 equiv), CuX (CuI, CuBr or CuCl, 1.1
equiv) and DIPEA (see Table 1 and Table 2). The reaction
mixture was stirred at r.t. until the reaction was complete as
indicated by TLC. The mixture was filtered through Celite
and the solvent was removed. The crude product was
purified by flash silica gel chromatography (cyclohexane–
EtOAc, 9:1→1:1) to afford the desired 1,4,5-trisubstituted
triazoles.
Analytical data for selected compounds:
2d: 1H NMR (200 MHz, CDCl3): d = 1.28 (t, J = 7.1 Hz, 3 H,
CH3), 1.97 (s, 3 H, Ac), 1.98 (s, 3 H, Ac), 2.04 (s, 3 H, Ac),
4.05 (dd, J = 13.1, 5.1 Hz, 1 H, H-5¢), 4.25–4.40 (m, 4 H, H-
4¢, H-5¢ and CH2 ester), 5.72 (t, J = 5.5 Hz, 1 H, H-3¢), 5.88
(dd, J = 5.2, 3.0 Hz, 1 H, H-2¢), 6.27 (d, J = 3.0 Hz, 1 H, H-
1¢), 7.17–7.25 (m, 3 H, H-Ar), 7.31–7.40 (m, 2 H, H-Ar).
(20) The Eicar analogue 5 was prepared using standard
Sonogashira coupling to give the protected nucleoside
intermediate: 1H NMR (200 MHz, CDCl3): d = 0.27 (s, 9 H,
TMS), 1.37 (t, J = 7.2 Hz, 3 H, CH3), 2.02 (s, 3 H, Ac), 2.09
(s, 3 H, Ac), 2.10 (s, 3 H, Ac), 4.12 (dd, J = 12.9, 5.4 Hz,
Synlett 2009, No. 13, 2123–2128 © Thieme Stuttgart · New York

2128
V. Malnuit et. al
LETTER
1 H, H-5¢), 4.32–4.52 (m, 4 H, H-4, H-5¢ and CH2 ester),
5.73 (t, J = 6.2 Hz, 1 H, H-3¢), 5.90 (dd, J = 5.2, 2.8 Hz, 1 H,
H-2¢), 6.16 (d, J = 2.8 Hz, 1 H, H-1¢). 13C NMR (50 MHz,
CDCl3): d = –0.6, 14.3, 20.4, 20.5, 20.7, 61.5, 62.6, 70.7,
74.1, 81.1, 88.8, 113.6, 124.6, 140.6, 159.6, 169.2, 169.4,
170.6. HRMS (ESI): m/z [M + H]+ calcd for C21H30N3O9Si:
496.1751; found: 496.1746.
(200 MHz, CD3OD): d = 3.40 (s, 1 H, H-alkyne), 3.60 (dd,
J = 12.1, 5.7 Hz, 1 H, H-5′), 3.74 (dd, J = 12.1, 3.8 Hz, 1 H,
H-5′), 4.11 (dd, J = 9.3, 5.4 Hz, 1 H, H-4′), 4.45 (t, J = 5.4
Hz, 1 H, H-3′), 4.75 (t, J = 3.4 Hz, 1 H, H-2′), 6.09 (d,
J = 3.4 Hz, 1 H, H-1′). 13C NMR (50 MHz, CD3OD): d =
63.3, 72.2, 75.8, 87.4, 92.5, 94.5, 123.8, 144.3, 159.1, 163.3.
HRMS (ESI): m/z [M + H]+ calcd for C10H13N4O5: 269.0886;
found: 269.0882.
Methanolysis of this intermediate as described above
(MeOH, NH3, 48 h) led to the free nucleoside 5: 1H NMR
Synlett 2009, No. 13, 2123–2128 © Thieme Stuttgart · New York

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