Direct synthesis of 5-aryltriazole acyclonucleosides via Suzuki coupling in aqueous solution

Article abstract of DOI:10.1016/j.tetlet.2007.01.154

5-Aryltriazole acyclonucleosides with various aromatic groups on the triazole ring were synthesized via the Suzuki coupling reaction in aqueous solution and promoted by microwave irradiation. Careful optimization of the reaction conditions led in good to

Full text of DOI:10.1016/j.tetlet.2007.01.154

Tetrahedron Letters 48 (2007) 2389–2393
Direct synthesis of 5-aryltriazole acyclonucleosides
via Suzuki coupling in aqueous solution
a
a
b
a,b,
*
´ ´
Ruizhi Zhu, Fanqi Qu, Gilles Quelever and Ling Peng
aCollege of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, PR China
bCNRS UMR 6114, De´partement de Chimie, 163, avenue de Luminy, 13288 Marseille, France
Received 14 December 2006; revised 22 January 2007; accepted 23 January 2007
Available online 2 February 2007
Abstract—5-Aryltriazole acyclonucleosides with various aromatic groups on the triazole ring were synthesized via the Suzuki cou-
pling reaction in aqueous solution and promoted by microwave irradiation. Careful optimization of the reaction conditions led in
good to excellent yields to the Suzuki products, while the cyclization side-reaction could be completely suppressed.
Ó 2007 Elsevier Ltd. All rights reserved.
Nucleoside derivatives occupy a pivotal position in the
arsenal of drug candidates for combating various
viruses.1,2 Acyclic nucleosides belong to an important
class of biologically active nucleosides. Acyclovir
(Scheme 1) was the first acyclic nucleoside to be success-
fully tested and developed.3 It has become the gold
standard for the treatment of herpes simplex viral
infections.3 Since then, various acyclonucleosides, such
as ganciclovir, tenofovir, and cidofovir, have been devel-
oped for use as antiviral agents.4 Acyclic nucleoside
derivative HEPT, of which the pyrimidine nucleobase
bears a phenylthio group at the 6-position, was recently
reported to show anti-HIV activity and to be less toxic
than the clinical drug AZT.5 Meanwhile, 6-arylpurine
ribonucleosides have also been found to show promising
antiviral and cytostatic characteristics.6 The large aro-
matic systems, present in the scaffold of such com-
pounds, may recognize their biological targets more
selectively and specifically because of the stronger and
more efficient interactions occurring between their
respective aromatic units. The biaryl motif is known to
be a widely occurring structural feature in biologically
active compounds.7 However, relatively few attempts
have been made so far to develop biaryl nucleoside
derivatives.8
In our ongoing project, which focuses on novel triazole
compounds of medicinal and agrochemical potentials,9
we are interested in developing aryl-triazole nucleoside
derivatives. We recently synthesized 5-aryltriazole ribo-
nucleosides9b by employing a synthetic sequence involv-
ing a Suzuki coupling reaction.10,11 Here, we report on
the synthesis of novel acyclic aryltriazole nucleoside
analogues 1 (Scheme 1), using a simple and efficient
one-step procedure involving the direct Suzuki coupling
of the unprotected 5-bromotriazole acyclonucleoside 5
with Suzuki reagents in aqueous solution under micro-
wave irradiation. Good to excellent yields were obtained
without requiring any yield-limiting and time-consum-
ing protection/deprotection steps.
O
O
N
O
Me
N
N
N
NH2
NH
NH2
HN
Ar
N
N
O
S
N
HO
HO
HO
O
O
O
HEPT
Acyclovir
Scheme 1. Acyclovir, HEPT, 5-aryltriazole acyclonucleoside 1.
1
*
Corresponding author. Tel.: +33 491 82 91 54; fax: +33 491 82 93 01; e-mail: ling.peng@univmed.fr
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.154

2390
R. Zhu et al. / Tetrahedron Letters 48 (2007) 2389–2393
In order to prepare the bromotriazole acyclonucleosides
for use as starting material for the Suzuki coupling reac-
tion, we first attempted to synthesize bromotriazole
acyclonucleoside 3 via alkylation12 of bromotriazole 2
with 2-(chloromethoxy)ethyl benzoate (Scheme 2a).13
However, the reaction yielded the expected 5-bromo-
triazole derivative 3 and its 3-bromo isomer 30, as well
as two unexpected chlorotriazole derivatives 4 and 40.
We were only able, by performing flash chromato-
graphy, to separate the mixture of 5-halogeno isomers
(3 and 4) from the mixture of 3-halogeno ones (30 and
40), while the bromo isomers 3 and 30 were resolutely
inseparable from their corresponding chloro analogues
4 or 40, due to their very similar silica gel column behav-
ior. Evidence of the presence of 5-chloro derivative 4 as
an impurity in 5-bromotriazole 3 was provided by 13C
NMR analysis and further confirmed by mass spectral
analysis due to the noticeable differences observed for
the chemical shift of the anomeric carbons and the
molecular mass between 3 and 4. Further ammonolysis
of the mixture of 3 and 4 led to the mixture of the
corresponding products 5 and 6, from which 6 could
be isolated by careful crystallization in CH3OH/CH2Cl2.
X-ray structural analysis of both 5 and 6 (Fig. S1 in Sup-
plementary data)14 confirmed the unexpected finding
that the chlorotriazole derivative 4 was formed in the
preparation of 3 during the alkylation step.
In order to prepare pure halogenated triazole derivatives
to further confirm the obtained reaction mixtures as well
as to serve as starting material for the subsequent Suzuki
coupling reaction, we performed the alkylation reaction
of 2-(chloromethoxy)ethyl benzoate, by replacing bromo-
triazole 2 with the corresponding chlorotriazole 7
(Scheme 2b).15 The corresponding pure chlorotriazole
products 4 and 40 could be obtained after column sepa-
ration. Bromotriazole acyclonucleosides 8 and 80 were
further synthesized using the fusion method16 by cou-
pling bromotriazole 3 with 2-(acetoxymethoxy)ethyl
acetate (Scheme 2c).17 Further ammonolysis of 8, 80, 4,
40 gave the corresponding products 5, 50, 6 and 60,
respectively, in good to excellent yields.
We attempted to perform the Suzuki coupling reactions
with the 5-bromo derivative 8 under similar experimen-
tal conditions to those previously used for the synthesis
of 5-aryltriazole ribonucleosides.9b However, the results
were not satisfactory because the reaction was not com-
plete and the yields were very low (data not shown). The
low reactivity of 8 toward the Suzuki reaction might be
O
O
Br
Cl
O
C
N
N
N
OCH3
N
N
OCH3
+
O
OCH3
O
Br
Cl
N
N
O
Cl
N
N
N
BzO
N
N
N
OCH3
OCH3
N
BzO
BzO
BzO
BzO
Br
N
H
NaH,CH3CN, RT
+
+
O
O
O
O
3
3'
4'
4
2
NH3 CH3OH
NH2
NH3 CH3OH
O
O
Br
Cl
N
N
N
N
N
NH2
O
NH2
O
Br
Cl
N
N
N
N
N
N
N
NH2
HO
HO
HO
HO
+
O
O
O
O
+
5
5'
6'
6
O
Cl
O
C
N
OCH3
N
O
Cl
OCH3
N
O
N
Cl
BzO
N
N
N
OCH3
+
BzO
BzO
N
NaH,CH3CN, RT
Cl
N
O
O
H
4'
7
4
O
Br
O
N
N
OCH3
N
O
OCH3
Br
N
N
O
N
OAc
N
AcO
OCH3
+
N
AcO
AcO
Br
TsOH, Vacuum, 140 °C
N
H
O
O
2
8
8'
Scheme 2. Synthesis of triazole acyclonucleoside starting materials for Suzuki coupling.

R. Zhu et al. / Tetrahedron Letters 48 (2007) 2389–2393
2391
due to the formation of a stable Pd-complex with the
oxygen atoms in both the ether and acyl functions in
the side chain of 8. The flexible feature of the side chain
of 8 may greatly favor the formation of such complex.
order to obtain the optimized reaction conditions. First,
the choice of solvent was crucial. The use of dioxane/
H2O system significantly improved the reaction yields,
while either pure water or pure organic solvents gave
the desired product in very low amounts (Table 1, entries
1–4). The beneficial effects of this solvent system may
have resulted from the fact that substrate 5 is water
soluble, while the Pd catalytic systems usually prefer
organic solvents. Polar solvents favor nucleophilic
substitution, and thus promote the intramolecular cycli-
zation of 5 into 9, while the less polar solvent system
dioxane/H2O (3:1) gave better Suzuki product yields
(Table 1, entries 5–6). Second, the nature of the Pd cata-
lyst also played an important role. Three common Pd
catalysts, Pd(PPh3)4, Pd2(dba)3 and Pd(OAc)2/TBAB,
were used. Among them, Pd(PPh3)4 was the only catalyst
that was able to efficiently catalyze the Suzuki coupling,
while both Pd2(dba)3 and Pd(OAc)2/TBAB showed no
catalytic activity under our experimental conditions
(Table 1, entries 6–8). Higher loading of Pd(PPh3)4 did
not significantly improve the yields of 1, nor could the
cyclization reaction be further suppressed (data not
shown). Finally, the influence of a suitable base was of
greatest importance. Stronger bases, such as NaOH,
accelerated the cyclization reaction and therefore gave
9 as the main product. Weaker organic bases, such as tri-
ethylamine, efficiently suppressed the cyclization, but it
was not in favor of the Suzuki coupling. Better results
were obtained using K2CO3, with which products 1a–m
were obtained in yields ranging from good to excellent
(Table 1, entry 6, and Table 2). Further spectacular
results were obtained using Li2CO3: 1a–m were obtained
in nearly quantitative yields in most cases, while the
cyclization side reaction was completely suppressed
(Table 1, entry 11, and Table 2). These results may be
attributable to the formation of a Li+-complex with the
It has been reported that in some cases, aqueous solvents
can significantly promote Suzuki coupling reactions.18
Besides, the use of water as a solvent for transition-
metal-catalyzed reactions is of particular interest in
organic chemistry for economical, environmental, and
safety reasons. We therefore performed the Suzuki reac-
tion in aqueous solution, using the water soluble sub-
strate 5. Good to excellent results were obtained with 5
when the Suzuki reaction was performed in aqueous
solution under microwave irradiation (Tables 1 and 2).
During our efforts to optimize the experimental condi-
tions of the Suzuki coupling reaction (Table 1) a side
product 9 was isolated, the structure of which was con-
firmed by X-ray analysis (Fig. S2 in Supplementary
data).19 Compound 9 resulted from the intra-molecular
nucleophilic substitution of 5, mainly due to the partic-
ularly favorable structure and reactivity of 5 for such
cyclization. This was supported by further experimental
results: in the presence of a weak base such as K2CO3,
the 5-bromo derivative 5 underwent cyclization and
gave product 9 in excellent yields (87%). Under the same
conditions, 3-bromo isomer 50 did not undergo any such
intra-molecular cyclization, probably due to its unfavor-
able molecular geometry and low chemical reactivity.
Since the undesired cyclization of 5 competes with the
Suzuki coupling reaction, we decided to optimize the
reaction conditions by promoting the Suzuki coupling
while suppressing the cyclization reaction. Various
parameters were studied and judiciously adjusted in
Table 1. Optimizing the Suzuki coupling reaction
O
O
O
NH2
NH2
N
NH2
N
N
B(OH)2
N
Br
N
O
N
N
N
+
N
Pd catalyst, Base
HO
HO
O
O
MW, 120 °C,15min
O
5
1
9
Entrya
Solvent
Base
Pd catalyst
1 (%)
9 (%)
b
1
2
3
4
5
6
7
8
9
H2O
CH3OH
CH3CN
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd2(dba)3
Pd(OAc)2, TBAB
Pd(PPh3)4
Pd(PPh3)4
21
13
0
21
5
0
11
25
20
41
41
55
5
b
b
b
Dioxane
6
b
Dioxane/H2O (1:1)
Dioxane/H2O (3:1)
Dioxane/H2O (3:1)
Dioxane/H2O (3:1)
Dioxane/H2O (3:1)
Dioxane/H2O (3:1)
Dioxane/H2O (3:1)
42
79
0
0
9
b
b
b
NaOHc
d
10
11
NEt3
47
97
e
Li2CO3
Pd(PPh3)4
0
a 1.1 equiv PhB(OH)2, 0.05 equiv Pd catalyst.
b 1.2 equiv K2CO3.
c 2.0 equiv NaOH.
d 2.0 equiv NEt3.
e 2.0 equiv Li2CO3.

2392
R. Zhu et al. / Tetrahedron Letters 48 (2007) 2389–2393
Table 2. Synthesis of 1 via the Suzuki coupling between 5 and various boronic acids
O
O
N
O
N
NH2
NH2
NH2
N
N
ArB(OH)2
Pd(PPh3)4
K2CO3 or Li2CO3
N
Br
N
Ar
N
N
O
N
+
HO
HO
dioxane/H2O (3:1)
MW, 120 °C,15Min
O
5
O
O
1
9
Entry
Ar
Product
1a
1/9a (%)
1b (%)
97
1
2
79/20
1b
81/13
98
F
3
4
5
6
1c
1d
1e
1f
58/18
88/0.4
77/9
92
98
92
97
F3C
Me
MeS
92/0.3
MeO
MeO
7
1g
95/5
99
OMe
8
9
1h
1i
1j
89/10
72/4
78/5
97
83
86
Cl
Cl
10
Cl
11
1k
72/7
98
12
13
1l
49/14
50/9
66
97
O
S
1m
a 1.1 equiv ArB(OH)2, 0.05 equiv Pd(PPh3)4, 1.2 equiv K2CO3.
b 1.1 equiv ArB(OH)2, 0.05 equiv Pd(PPh3)4, 2.0 equiv Li2CO3.
side chain of 5 (Scheme 3), which may have prevented the
cyclization of 5 and promoted the Suzuki coupling reac-
tion by blocking the formation of the undesirable Pd–O
complex during the oxidative insertion process.
O
N
NH2
N
H
Br
Li+
N
Under our optimized conditions, that is, with Pd(PPh3)4
and Li2CO3, using dioxane/H2O (3:1, v/v) as solvent
(Table 2), starting material 5 was completely consumed
during the Suzuki coupling reaction, which greatly sim-
O
O
Scheme 3. Proposed Li+-complex of 5.

R. Zhu et al. / Tetrahedron Letters 48 (2007) 2389–2393
2393
plified the purification procedure.20 The Suzuki coupling
reaction was not affected by the presence of either elec-
tron-donating or electron-withdrawing substituents on
the aromatic ring of the boronic acids used as Suzuki re-
agents (Table 2, entries 1–6), nor were any noteworthy
steric effects observed (Table 2, entries 6–11). To our
great surprise, 2-thienyl product 1m was obtained in a
quantitative yield, while only moderate yields were ob-
tained with the 2-furanylboronic acid (Table 2, entries
12–13). The slightly lower yields obtained for 1i and 1j
might be due to their further coupling with the corre-
sponding Suzuki reagent.21
4. De Clercq, E. J. Clin. Virol. 2004, 30, 115–133.
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In conclusion, 5-aryltriazole acyclonucleosides 1a–m
bearing various aromatic groups on the triazole ring were
synthesized. The aromatic group was introduced onto the
triazole ring via a Suzuki coupling reaction using bromo-
triazole acyclonucleoside 5. The coupling reaction was
significantly promoted in aqueous solution under micro-
wave irradiation, giving the corresponding compounds in
good to excellent yields. The method used here to directly
synthesize the aryltriazole acyclonucleosides 1a–m in
aqueous solvent involved no protection and deprotection
steps, and thus provides an efficient and convenient one-
step procedure for synthesizing various novel triazole
acyclonucleosides 1. Studies on the biological and
physico-chemical properties of these novel triazole
compounds are now under way at our laboratories.
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We are grateful to Dr. Michel Giorgi (University Paul
Cezanne, France) for performing X-ray structural anal-
ysis. Financial support from the Ministry of Science
and Technology of China (Nos. 2003CB114400,
2003AA2Z3506), National Natural Science Foundation
of China, Wuhan University, and CNRS is gratefully
acknowledged. We thank Dr. Alphonse Tenaglia for
helpful discussions and suggestions.
´
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Supplementary data
Experimental procedures, analytical data and NMR
spectra of all new compounds are included. Supplemen-
tary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2007.01.154.
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