Cu-mediated selective N-arylation of aminotriazole acyclonucleosides

Article abstract of DOI:10.1002/hlca.200900033

Novel N-aryltriazole nucleosides were synthesized via a Cu-mediated C-N cross-coupling reaction, using 3-aminotriazole acyclonucleosides and various boronic acid reagents. Interestingly, N-arylation proceeded much more rapidly on the amide group than on t

Full text of DOI:10.1002/hlca.200900033

Helvetica Chimica Acta – Vol. 92 (2009)
1503
Cu-Mediated Selective N-Arylation of Aminotriazole Acyclonucleosides
by Wei Li a), Yuting Fana), Yi Xiab), Palma Rocchic), Ruizhi Zhua), Fanqi Qua), Johan Neytsd),
Juan L. Iovannac), and Ling Peng*a)b)
a) State Key Laboratory of Virology, College of Chemistry and Molecular Sciences, Wuhan University,
Wuhan 430072, P. R. China
) Departement de Chimie, CNRS UPR 3118, 163, avenue de Luminy, F-13288 Marseille cedex 09
b
´
(phone: þ 33491829154; fax: þ 33491829301; e-mail: ling.peng@univmed.fr)
c) INSERM U624, 163, avenue de Luminy, F-13288 Marseille
d) Rega Institute for Medical Research, Minderbroedersstraat 10, B-3000 Leuven
Novel N-aryltriazole nucleosides were synthesized via a Cu-mediated CꢀN cross-coupling reaction,
using 3-aminotriazole acyclonucleosides and various boronic acid reagents. Interestingly, N-arylation
proceeded much more rapidly on the amide group than on the amine group, leading to selective N-
arylation of the amide functionality on nucleosides containing both groups on the triazole nucleobase.
Introduction. – Nucleoside analogs are of considerable importance in the search of
promising candidates endowed with potent antiviral, anticancer, and antibacterial
activities [1]. We have been actively engaged in a program to develop structurally novel
and diverse triazole nucleosides [2 – 8]. These nucleosides contain triazole, an
unnatural heterocycle, as nucleobase. Because of its broad H-bonding scope and its
unique geometrical size between pyrimidine and purine, triazole is considered as a
universal base [9] for base pairing in nucleoside chemistry. One important triazole
nucleoside is ribavirin (Fig. 1), representing the first synthetic nucleoside drug to have
antiviral activity against many DNA and RNA viruses [10], and remaining the only
small-molecular-weight drug available to date for treating viral infections caused by
hepatitis C virus (HCV) [11]. Recently, we have synthesized a series of triazole
nucleosides substituted with aromatic moieties on the triazole ring, such as aryltriazolyl
[3][4], bitriazolyl [5][6], and arylethynyltriazolyl nucleosides [7][8], with the rationale
that these nucleosides may combine the intrinsic properties of the triazole ring with the
enlarged aromatic systems to form special nucleobases, leading to advantageous
binding properties with the corresponding biological targets via base pairing and/or
base stacking. Indeed, some of these nucleosides have displayed potent and promising
antiviral [5 – 8] and anticancer activity [8]. In our continuing efforts to further develop
novel triazole nucleoside analogs, we are interested in synthesizing N-aryltriazole
acyclonucleosides of types A and B (Fig. 1). The aryl group is introduced at the amine
functionality on nucleosides of type A and at the amide moiety on those of type B.
The main challenge faced when synthesizing N-aryltriazole nucleosides A and B is
the formation of a CꢀN bond between the aryl moieties and the N-atom on the amine
functionality. CꢀN Bond construction has been a research subject of considerable
ꢀ 2009 Verlag Helvetica Chimica Acta AG, Zꢁrich

1504
Helvetica Chimica Acta – Vol. 92 (2009)
Fig. 1. Structure of ribavirin and proposed N-arylated triazole acyclonucleosides A and B
interest relating to bioactive nucleoside derivatives [12], and numerous methods exist
for CꢀN cross-coupling [13]. The direct nucleophilic aromatic substitution of amine
with aryl halides is one of the most commonly used methods for constructing a CꢀN
bond. However, this approach requires special aryl halides and may result in several N-
arylation products in an uncontrollable way, thereby severely limiting its scope. The
traditional Ullman-type coupling is performed at high temperatures in the presence of
strong bases, and gives varying yields. Although various methods using arylleads [14],
arylstannanes [15], arylsiloxanes [16], etc. have been reported for N-arylation, the
toxicity and/or the availability of the reagents makes these methods less attractive. The
recently developed Pd-catalyzed CꢀN cross-coupling by Buchwald, Hartwig, and
others has provided considerable improvements: the reaction can be carried out
conveniently at reasonably elevated temperatures and is efficient enough to give
various products [17]. Furthermore, Cu-mediated N-arylation, discovered by Chan and
Lam [18], employs various arylboronic acids and is performed at room temperature
under very mild conditions, constituting an important progress for N-arylation. Based
on the mild reaction conditions and the simple reaction protocols, as well as the ready
availability of starting materials in our laboratories, we decided to choose the Pd-
catalyzed and Cu-mediated CꢀN cross-coupling reactions to synthesize N-aryltriazole
nucleoside analogs A and B.
Results and Discussion. – To perform Pd-catalyzed and Cu-mediated N-arylation
for the synthesis of the nucleoside analogs A and B, we used the bromotriazole
nucleosides 1 and 1’, and the aminotriazole nucleosides 2, 2’, 3, and 3’ as starting
materials (Fig. 2). Both 3- and 5-bromotriazole nucleosides 1 and 1’ were prepared
according to our previously reported protocol [4]. 3- and 5-aminotriazole nucleosides 2
and 2’ were obtained with almost quantitative yields via catalytic hydrogenation of the
corresponding 3- and 5-azidotriazole nucleosides [6]. Subsequent ammonolysis of 2
and 2’ in NH3/MeOH led to the deprotection of the ꢂsugar moietyꢃ and transformation
of the exocyclic Me ester into the amide functionality, giving 3- and 5-aminotriazole
nucleosides 3 and 3’, respectively.
We first attempted to perform Pd-catalyzed N-arylation of bromotriazole nucleo-
sides 1 and 1’ with aniline. We have tried different conditions using various catalysts
(Pd(OAc)2, Pd(OAc)2/DPDBP, Pd2(dba)3, Pd(PPh3)4, etc.), bases (K2CO3, Li2CO3,
tBuONa, etc.), solvents (MeCN, MeCN/H2O, DME, toluene, etc.), reaction temper-

Helvetica Chimica Acta – Vol. 92 (2009)
1505
Fig. 2. Triazole acyclonucleosides as starting materials for CꢀN coupling reactions.
atures and times, as well as with or without microwave irradiation etc. (data not shown).
Neither the 3- nor the 5-bromotriazole nucleoside yielded the expected N-arylation
products, whereas the starting materials could be recovered with yields up to 80%. In
some cases, a cyclization product1) was obtained when starting from 1’ due to the
intramolecular nucleophilic substitution of the Br-atom at the triazole moiety by the
free OH group in the ꢂsugar moietyꢃ of 1’. The same cyclization reaction was previously
observed by us when 1’ was subjected to Suzuki [4] and Sonogashira [7] reactions. The
particularly favorable electronic and geometric properties of 1’ explain its readiness for
intramolecular cyclization via nucleophilic substitution [4].
We further tried to perform Pd-catalyzed CꢀN coupling between aminotriazole
nucleosides (2, 2’, 3, and 3’) and bromobenzene using similar conditions as mentioned
above. No N-arylation product could be identified, and only starting materials were
recovered (data not shown). We, therefore, concluded that neither bromotriazole
nucleosides 1 and 1’ nor aminotriazole nucleosides 2, 2’, 3, and 3’ are reactive enough to
undergo Pd-catalyzed CꢀN coupling under those experimental conditions. It is worthy
to note that, due to poor availability and the high price, we did not try the various types
of new generation ligands reported for Pd-catalyzed CꢀN coupling [17].
We then focused our attention to performing Chan – Lam modified Cu-mediated N-
arylation with arylboronic acid using aminotriazole nucleosides (2, 2’, 3, and 3’)
(Scheme). Reaction between 2 and phenylboronic acid (PhB(OH)2) gave the
corresponding N-arylation product 4a with a good yield of 70% (Scheme, path a,
Table 1). Surprisingly, reaction with 5-aminotriazole nucleoside 2’, an isomer of 2, did
1
)
The cycling product has been previously identified by NMR, MS, and X-ray analysis as follows [4]:

1506
Helvetica Chimica Acta – Vol. 92 (2009)
Scheme. N-Arylation on Aminotriazole Acyclonucleosides via Cu-Mediated CꢀN Cross-Coupling
not yield the corresponding N-arylation product, and more than 80% of the starting
material 2’ was recovered after three days of reaction (data not shown). Neither did N-
arylation with the deprotected 5-aminotriazole nucleoside 3’ deliver any desired
product (data not shown), and the starting material 3’ was recovered almost
quantitatively. To our delight, the reaction of 3-aminotriazole nucleoside 3 with
various arylboronic acids resulted in the CꢀN coupling products, with N-arylation
occurring, however, selectively on the amide instead of the amine functionality
(Scheme, path b, Table 2). The different reactivity noticed for N-arylation of 3- and 5-
aminotriazole nucleosides may mainly result from the unfavorable steric congestion
created between the amino group at the 5-position and the adjacent acyclic ꢂsugar
moietyꢃ in 2’ and 3’, since steric hindrance is an important factor affecting N-arylation.
Another factor may be the different electronic properties of 3- and 5-aminotriazole
nucleosides, as we have already reported previously for 3- and 5-bromotriazole
ribonucleosides [2], and for 3- and 5-azidotriazole nucleosides [5a][6]. Finally, it is not
totally surprising that N-arylation was occurred selectively at the amide functionality
instead of the amino group in 3 (Scheme, path b, Table 2), because similar cases are also
reported in the literature [19]. This may be mainly due to the different reactivity of the
amide and the amine functionalities in 3, since the amino group in 3 is directly
conjugated with the triazole ring, and consequently, is less reactive to Cu-mediated
CꢀN coupling under our experimental conditions. Additionally, N-arylation at the
amide functionality is less sterically hindered than at the amino group in 3.
We tried to optimize the N-arylation reaction between the aminotriazole nucleoside
2 and PhB(OH)2 by varying the catalysts (Cu(OAc)2, Cu(OAc)2 · H2O, CuBr2, CuI,
CuCl, Cu(PPh3)3Br, etc.), bases (Et3N, EtN(i-Pr)2, pyridine, NaH, pyridine/Et3N, etc.),
solvents (CH2Cl2, DMF, toluene, MeOH/ H2O, etc.), reaction temperature and
duration, etc. (data not shown). The best results were obtained with Cu(OAc)2 and
pyridine in the presence of freshly prepared molecular sieves, in CH2Cl2 at room
temperature and open air for three days (Table 1). Importantly, using excess
equivalents of arylboronic acid reagent is necessary to obtain acceptable yields. It is

Helvetica Chimica Acta – Vol. 92 (2009)
Table 1. Cu-Mediated N-Arylation of 2
1507
Entry
R
Product
Yield [%]
1
2
3
4
5
6
7
8
9
H
4a
4b
4c
4d
4e
4f
4g
4h
4i
70
31
24
35
0
46
64
0
p-Me
p-MeO
m-MeO
o-MeO
p-F
m-F
o-F
p-Cl
m-Cl
o-Cl
35
77
0
10
11
4j
4k
Table 2. Cu-Mediated N-Arylation of 3
Entry
R
H
Product
Yield [%]
1
2
3
4
5
6
7
8
9
5a
75
60
51
40
21
36
57
47
48
32
41
p-Me
p-MeO
m-MeO
o-MeO
p-F
m-F
o-F
p-Cl
m-Cl
o-Cl
5b
5c
5d
5e
5f
5g
5h
5i
10
11
5j
5k
noteworthy that the Cu-mediated N-arylation reaction of 2 was significantly affected
by the electronic properties and the steric hindrance of the substituents in the
arylboronic reagents (Table 1). The presence of electron-donating groups at the phenyl
ring was not favorable for N-arylation, yielding the corresponding products with low

1508
Helvetica Chimica Acta – Vol. 92 (2009)
yields (Table 1, Entries 2 – 4). It seems that electron-withdrawing groups at the meta-
position of the phenyl ring promoted the reaction, giving the corresponding products
with up to 2-fold yields compared to those at the para-position. However, any
substituent at the ortho-position of the phenyl ring, regardless of electron-donating or
electron-withdrawing (Table 1, Entries 5, 8, and 11), prevented product formation. This
is mainly due to the strong steric hindrance created by the substituent at the ortho-
position, which strongly impedes the CꢀN coupling reaction.
We have further carried out an optimization process on the N-arylation reaction
with 3. Under optimized conditions, Cu(OAc)2 was used as the catalyst, pyridine as the
base, and MeOH as the solvent under open air at 408. Most importantly, the quantity of
boronic acid required could be reduced considerably to two equivalents, and the
reaction time shortened significantly to three hours, compared to the N-arylation of 2,
which required six equivalents of boronic acid reagent, and three days of reaction time.
In contrast to N-arylation with 2, N-arylation of 3 showed no considerable correlation
between reactivity and electronic properties of the substituents on the phenyl ring of
the boronic acid reagents (Table 2, Entries 2, 3, 6, and 9). Furthermore, no noticeable
steric effect was observed, since similar yields were obtained regardless of whether the
substituents were in ortho-, meta- or para-position (Table 2, Entries 3 – 5, 6 – 8, and 9 –
11). This may be attributed to the presence of the CO group of the amide function in 3,
which can ease the steric congestion and facilitate CꢀN coupling.
We next assessed the above synthesized N-aryltriazole acyclonucleosides for their
antiviral activity against hepatitis C virus and their anticancer activity against human
cancer cell lines such as prostate cancer PC-3 cells, pancreatic cancer MiaPaCa-2, and
Capan-2 cells. The anti-HCV assay was performed using a HCV subgenomic RNA
replicon assay in Huh-5-2 cells [20], and the anticancer evaluation was carried out using
a MTT (¼ 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay to
determine the inhibition effect on cell proliferation. Unfortunately, none of the
synthesized compounds elicited any notable antiviral activity or anticancer activity.
Conclusions. – We have attempted both Pd-catalyzed and Cu-mediated CꢀN cross-
coupling reactions to synthesize N-arylated triazole nucleoside analogs. No N-arylation
product could be obtained via Pd-catalyzed CꢀN coupling starting with either
bromotriazole nucleosides (1 and 1’) or aminotriazole nucleosides (2, 2’, 3, and 3’)
under our experimental conditions. This may be due to the limited reactivity of these
triazole nucleosides when subjected to the Pd-catalyzed reaction conditions used in the
present study. Gratifyingly, we succeeded in achieving N-arylation via Cu-mediated
CꢀN cross-coupling using 3-aminotriazole nucleosides (2 and 3) as starting materials.
However, 5-aminotriazole nucleosides (2’ and 3’), the isomers of 3-aminotriazole
nucleosides (2 and 3), could not deliver the corresponding N-arylation products under
similar conditions. This is mainly due to the unfavorable steric congestion and/or
electronic properties of 5-aminotriazole nucleosides. Even between the 3-amino-
triazole nucleosides 2 and 3, very different reactivity was observed: N-arylation at the
amide functionality in 3 proceeded much faster than arylation at the amine group in 2,
and required a much reduced quantity of boronic acid reagent. This may be the direct
consequence of the different reactivity of amide and amine functionalities. Accord-
ingly, selective N-arylation at the amide group in 3 was achieved easily. Although none

Helvetica Chimica Acta – Vol. 92 (2009)
1509
of the N-arylated triazole nucleosides disclosed here elicited any significant antiviral
and anticancer activity, the syntheses presented in this study may offer alternative
methods to prepare structurally diverse triazole nucleoside analogs, for which we are
actively working.
Financial support from the Ministry of Science and Technology of China (N82003CB114400,
N82003AA2Z3506), the National Science Foundation of China (N820372055, N820473112), Wuhan
University, CNRS, INSERM, and the Geconcerteerde Onderzoeksactie (KU Leuven) are gratefully
¨
acknowledged. We thank Mrs. Katrien Geerts for anti-HCV evaluation, Mr. Joel Tardivel-Lacombe for
assistance in cell culture, and Mrs. Emily Witty for English correction of manuscript. Y. X. is supported by
´
a post-doctoral fellowship from la Fondation pour la Recherche Medicale.
Experimental Part
General. Flash chromatography (FC): silica gel (SiO2; 200 – 300 mesh) from Qingdao Ocean
1
1
Chemicals, P. R. China. H- and 13C-NMR spectra: at 300 MHz for H, and at 75 MHz or 150 MHz for
13C; Varian Mercury-VX300 and Varian Inova-600 spectrometers; d in ppm; J in Hz; chemical shifts
recorded in parts per million [ppm], with TMS as internal reference. ESI-MS: Finnigan LCQ Advantage
mass spectrometer; in m/z. MALDI-MS and HR-MS: by Matrix-assisted laser desorption/ionization
mass spectrometry (MALDI-MS) using an IonSpec 4.7 Tesla fourier transform mass spectrometer; in
m/z.
Methyl 3-Amino-1-({2-[(phenylcarbonyl)oxy]ethoxy}methyl)-1H-1,2,4-triazole-5-carboxylate (2).
To a soln. of 1.00 g of methyl 3-azido-1-({2-[phenylcarbonyl)oxy]ethoxy}methyl)-1H-1,2,4-triazole-5-
carboxylate (2.9 mmol) in 50 ml MeOH, 0.10 g Pd/C catalyst (5 wt-% of Pd, 25.6 mmol) was added. The
reaction was then carried out with H2 at a pressure of 1.01 MPa. After the complete consumption of the
starting material (detected with TLC), the mixture was filtered over Celite, the filtrate was concentrated
under reduced pressure, and the residue was purified through a SiO2 column with CH2Cl2/MeOH (30 :1),
giving 0.86 g of 2 as white powder in the yield of 93%. White solid. Rf (CH2Cl2/MeOH, 30 :1) 0.47.
1H-NMR (300 MHz, CDCl3): 8.03 (d, J ¼ 7.5, 2 arom. H); 7.57 (t, J ¼ 7.4, 1 arom. H); 7.44 (t, J ¼ 7.8, 2
arom. H); 5.83 (s, 2 CH2); 4.48 – 4.43 (m, CH2); 4.26 (br. s, NH2); 3.97 – 3.92 (m, CH2, MeO). 13C-NMR
(75 MHz, CDCl3): 173.6; 158.8; 129.6; 126.2; 124.8; 74.7; 64.3; 59.9; 49.6. MALDI-MS: 321.1 ([M þ H]þ),
343.1 ([M þ Na]þ). HR-MS: 321.1198 ([M þ H]þ, C14H17N4Oþ5 ; calc. 321.1199).
Methyl 5-Amino-1-({2-[(phenylcarbonyl)oxy]ethoxy}methyl)-1H-1,2,4-triazole-3-carboxylate (2’).
Similar to 2, 2’ was obtained as white powder (0.88 g, 95%) starting with 1.00 g methyl 5-azido-1-({2-
[(phenylcarbonyl)oxy]ethoxy}methyl)-1H-1,2,4-triazole-3-carboxylate (2.9 mmol). White solid. Rf
1
(CH2Cl2/MeOH, 30 :1) 0.23. H-NMR (300 MHz, CDCl3): 8.01 (d, J ¼ 7.2, 2 arom. H); 7.57 (t, J ¼ 7.4,
1 arom. H); 7.44 (t, J ¼ 7.7, 2 arom. H); 5.48 (s, CH2); 5.34 (br. s, NH2); 4.49 – 4.46 (m, CH2); 3.95 (s,
MeO); 3.92 – 3.89 (m, CH2). 13C-NMR (150 MHz, CDCl3): 166.6; 160.6; 156.2; 151.4; 133.5; 129.8; 128.7;
77.7; 67.6; 63.2; 52.9. MALDI-MS: 321.1 ([M þ H]þ), 343.1 ([M þ Na]þ). HR-MS: 321.1196 ([M þ H]þ,
C14H17N4Oþ5 ; calc. 321.1199).
3-Amino-1-[(2-hydroxyethoxy)methyl]-1H-1,2,4-triazole-5-carboxamide (3). A soln. of 1.00 g of 2
(3.1 mmol) in 25 ml of NH3/MeOH soln. (10 wt-%) was stirred at r.t. After complete consumption of
starting material (detected with TLC), the soln. was concentrated under reduced pressure, and the
residue was purified on a SiO2 column with CH2Cl2/MeOH (10 :1), giving 0.53 g of product 3 as white
powder in the yield of 85%. White solid. Rf (CH2Cl2/MeOH, 10 :1) 0.15. 1H-NMR (300 MHz,
(D6)DMSO): 7.85 (br. s, C(O)NH2); 5.67 (s, CH2); 5.55 (s, NH2); 4.64 (t, J ¼ 5.6, OH); 3.53 – 3.50 (m,
CH2); 3.47 – 3.42 (m, CH2). 13C-NMR (75 MHz, (D6)DMSO): 162.9; 159.5; 146.3; 77.9; 71.6; 60.5.
MALDI-MS: 224.1 ([M þ Na]þ). HR-MS: 224.0756 ([M þ Na]þ, C6H11N5NaOþ3 ; calc. 224.0760).
5-Amino-1-[(2-hydroxyethoxy)methyl]-1H-1,2,4-triazole-3-carboxamide (3’). Similar to 3, 3’ was
obtained as a white powder (0.56 g, 89%) starting with 1.00 g of 2’ (3.1 mmol). White solid. Rf (CH2Cl2/
MeOH, 10 :1) 0.05. 1H-NMR (300 MHz, (D6)DMSO): 7.40 (br. s, C(O)NH2); 6.62 (br. s, NH2); 5.33 (s,
CH2); 4.72 (t, J ¼ 4.8, OH); 3.57 – 3.46 (m, 2 CH2). 13C-NMR (75 MHz, (D6)DMSO): 161.9; 157.0; 154.4;

1510
Helvetica Chimica Acta – Vol. 92 (2009)
75.9; 71.0; 60.6. MALDI-MS: 202.1 ([M þ H]þ), 224.1 ([M þ Na]þ). HR-MS: 202.0937 ([M þ H]þ,
C6H12N5Oþ3 ; calc. 202.0940).
General Procedure for the Preparation of 4 via Cu-Mediated N-Arylation with Arylboronic Acid. To
a mixture of 32.0 mg 2 (0.10 mmol), 6 equiv. arylboronic acid (0.60 mmol), and 27.2 mg anh. Cu(OAc)2
(0.15 mmol) was added 5 ml CH2Cl2 (dist. freshly over CaH2). Then, 16.1 ml freshly distilled pyridine
(0.20 mmol) and ca. 20 mg powder of 4 ꢄ molecular sieve (activated at 5008 for 5 h) were added rapidly.
The mixture was stirred at r.t. for 3 d, and then filtered over Celite. The filtrate was concentrated under
reduced pressure, and the obtained residue was purified on SiO2 with petroleum ether (PE)/AcOEt
(2 :1), giving the corresponding product 4 as powder.
Methyl 3-(Phenylamino)-1-({2-[(phenylcarbonyl)oxy]ethoxy}methyl)-1H-1,2,4-triazole-5-carboxy-
1
late (4a). White solid (70%). Rf (PE/AcOEt, 1:1) 0.54. H-NMR (300 MHz, CDCl3): 8.01 (d, J ¼ 7.2,
2 arom. H); 7.54 (t, J ¼ 7.7, 1 arom. H); 7.46 – 7.26 (m, 6 arom. H); 6.97 (t, J ¼ 7.4, 1 arom. H); 6.75 (br. s,
NH); 5.93 (s, CH2); 4.48 (t, J ¼ 4.7, CH2); 4.03 (t, J ¼ 4.8, CH2); 3.97 (s, MeO). 13C-NMR (150 MHz,
CDCl3): 166.7; 159.5; 158.0; 142.9; 140.2; 133.3; 130.0; 129.9; 129.4; 128.6; 121.5; 116.7; 78.8; 68.3; 63.7;
53.5. ESI-MS: 397 ([M þ H]þ). HR-MS: 397.1514 ([M þ H]þ, C20H21N4Oþ5 ; calc. 397.1512).
Methyl 3-[(4-Methylphenyl)amino]-1-({2-[(phenylcarbonyl)oxy]ethoxy}methyl)-1H-1,2,4-triazole-
5-carboxylate (4b). White solid (31%). Rf (PE/AcOEt, 1:1) 0.56. 1H-NMR (300 MHz, CDCl3): 8.02
(d, J ¼ 7.2, 2 arom. H); 7.55 (t, J ¼ 7.2, 1 arom. H); 7.43 – 7.33 (m, 4 arom. H); 7.11 (d, J ¼ 8.7, 2 arom. H);
6.76 (br. s, NH); 5.92 (s, CH2); 4.48 (t, J ¼ 4.4, CH2); 4.03 (t, J ¼ 4.7, CH2); 3.98 (s, MeO); 2.31 (s, Me).
13C-NMR (75 MHz, CDCl3): 166.7; 159.9; 158.0; 142.9; 137.8; 133.3; 130.9; 130.1; 129.9; 129.8; 128.6;
117.0; 78.8; 68.2; 63.8; 53.4; 20.9. ESI-MS: 411.2 ([M þ H]þ), 433.1 ([M þ Na]þ). HR-MS: 411.1660
([M þ H]þ, C21H23N4Oþ5 ; calc. 411.1668).
Methyl 3-[(4-Methoxyphenyl)amino]-1-({2-[(phenylcarbonyl)oxy]ethoxy}methyl)-1H-1,2,4-tria-
zole-5-carboxylate (4c). White solid (24%). Rf (PE/AcOEt, 1:1) 0.38. 1H-NMR (300 MHz, CDCl3):
8.02 (d, J ¼ 8.1, 2 arom. H); 7.55 (t, J ¼ 7.4, 1 arom. H); 7.43 – 7.35 (m, 4 arom. H); 6.87 (d, J ¼ 9.0, 2 arom.
H); 6.52 (br. s, NH); 5.91 (s, CH2); 4.48 (t, J ¼ 4.8, CH2); 4.02 (t, J ¼ 4.8, CH2); 3.97 (s, MeO); 3.79 (s,
MeO). 13C-NMR (150 MHz, CDCl3): 166.6; 160.0; 158.0; 154.7; 142.9; 133.7; 133.3; 130.1; 129.9; 128.6;
118.5; 114.7; 78.7; 68.2; 63.7; 55.8; 53.5. ESI-MS: 427.2 ([M þ H]þ), 449.1 ([M þ Na]þ). HR-MS: 427.1611
([M þ H]þ, C21H23N4Oþ6 ; calc. 427.1618).
Methyl 3-[(3-Methoxyphenyl)amino]-1-({2-[(phenylcarbonyl)oxy]ethoxy}methyl)-1H-1,2,4-tria-
zole-5-carboxylate (4d). White solid (35%). Rf (PE/AcOEt, 1:1) 0.48. 1H-NMR (300 MHz, CDCl3):
8.02 (d, J ¼ 7.2, arom. H); 7.55 (t, J ¼ 7.4, 1 arom. H); 7.41 (t, J ¼ 7.7, 2 arom. H); 7.27 – 7.16 (m, 2 arom. H);
6.97 (d, J ¼ 6.6, 1 arom. H); 6.76 (br. s, NH); 6.53 (d, J ¼ 7.8, 1 arom. H); 5.93 (s, CH2); 4.48 (t, J ¼ 4.8,
CH2); 4.04 (t, J ¼ 4.5, CH2); 3.98 (s, MeO); 3.81 (s, MeO). 13C-NMR (150 MHz, CDCl3): 166.6; 160.7;
159.4; 158.0; 142.9; 141.4; 133.3; 130.14; 130.07; 129.9; 128.6; 109.4; 106.6; 103.0; 78.9; 68.3; 63.7; 55.5;
53.5. ESI-MS: 427 ([M þ H]þ), 449 ([M þ Na]þ). HR-MS: 427.1613 ([M þ H]þ, C21H23N4Oþ6 ; calc.
427.1618).
Methyl 3-[(4-Fluorophenyl)amino]-1-({2-[(phenylcarbonyl)oxy]ethoxy}methyl)-1H-1,2,4-triazole-
5-carboxylate (4f). White solid (46%). Rf (PE/AcOEt, 1:1) 0.53. 1H-NMR (300 MHz, CDCl3): 8.01
(d, J ¼ 8.1, 2 arom. H); 7.55 (t, J ¼ 7.7, 1 arom. H); 7.43 – 7.37 (m, 4 arom. H); 7.00 (t, J ¼ 8.4, 2 arom. H);
6.65 (br. s, NH); 5.92 (s, CH2); 4.48 (t, J ¼ 4.5, CH2); 4.02 (t, J ¼ 4.8, CH2); 3.98 (s, MeO). 13C-NMR
(75 MHz, CDCl3): 166.6; 159.8; 157.9; 157.8 (d, 1J(F,C) ¼ 238.4); 143.0; 136.6; 133.3; 130.0; 129.8; 128.6;
118.3 (d, 3J(F,C) ¼ 7.9); 115.7 (d, 2J(F,C) ¼ 23.6); 78.8; 68.3; 63.7; 53.3. ESI-MS: 415.1 ([M þ H]þ), 437.1
([M þ Na]þ). HR-MS: 415.1409 ([M þ H]þ, C20H20FN4Oþ5 ; calc. 415.1418).
Methyl 3-[(3-Fluorophenyl)amino]-1-({2-[(phenylcarbonyl)oxy]ethoxy}methyl)-1H-1,2,4-triazole-
5-carboxylate (4g). White solid (64%). Rf (PE/AcOEt, 1:1) 0.58. 1H-NMR (300 MHz, CDCl3): 8.01
(d, J ¼ 7.2, 2 arom. H); 7.54 (t, J ¼ 7.8, 1 arom. H); 7.43 – 7.38 (m, 3 arom. H); 7.26 – 7.19 (m, 1 arom. H);
7.05 (d, J ¼ 8.1, 1 arom. H); 6.80 (br. s, NH); 6.66 (t, J ¼ 8.1, 1 arom. H); 5.94 (s, CH2); 4.48 (t, J ¼ 4.4,
CH2); 4.04 (t, J ¼ 4.4, CH2); 3.98 (s, MeO). 13C-NMR (75 MHz, CDCl3): 164.1; 161.0 (d, 1J(F,C) ¼ 240.5);
2
2
156.7; 155.3; 140.3; 139.5; 130.7; 127.6; 127.3; 126.0; 109.8; 105.2 (d, J(F,C) ¼ 20.0); 101.4 (d, J(F,C) ¼
24.5); 76.4; 65.8; 61.2; 50.8. ESI-MS: 415.1 ([M þ H]þ), 437.1 ([M þ Na]þ). HR-MS: 415.1408 ([M þ
H]þ, C20H20FN4Oþ5 ; calc. 415.1418).

Helvetica Chimica Acta – Vol. 92 (2009)
1511
Methyl 3-[(4-Chlorophenyl)amino]-1-({2-[(phenylcarbonyl)oxy]ethoxy}methyl)-1H-1,2,4-triazole-
1
5-carboxylate (4i). White solid (35%). Rf (PE/AcOEt, 1 :1) 0.46. H-NMR (300 MHz, CDCl3): 8.02 –
7.99 (m, 2 arom. H); 7.55 (t, J ¼ 7.7, 1 arom. H); 7.43 – 7.36 (m, 4 arom. H); 7.28 – 7.24 (m, 2 arom. H);
6.66 (br. s, NH); 5.93 (s, CH2); 4.48 (t, J ¼ 4.4, CH2); 4.03 (t, J ¼ 4.4, CH2); 3.99 (s, MeO). 13C-NMR
(75 MHz, CDCl3): 166.6; 159.4; 157.9; 143.0; 139.0; 133.3; 130.0; 129.9; 129.2; 128.6; 126.0; 118.1; 78.9;
68.3; 63.7; 53.4. ESI-MS: 431.1, 433.1 ([M þ H]þ), 453.1, 455.1 ([M þ Na]þ). HR-MS: 431.1110 ([M þ
H]þ, C20H20ClN4Oþ5 ; calc. 431.1122).
Methyl 3-[(3-Chlorophenyl)amino]-1-({2-[(phenylcarbonyl)oxy]ethoxy}methyl)-1H-1,2,4-triazole-
5-carboxylate (4j). White solid (77%). Rf (PE/AcOEt, 1:1) 0.74. 1H-NMR (300 MHz, CDCl3): 8.01
(d, J ¼ 8.1, 2 arom. H); 7.60 – 7.51 (m, 2 arom. H); 7.40 (t, J ¼ 7.4, 2 arom. H); 7.30 (t, J ¼ 9.5, 1 arom. H);
7.21 (t, J ¼ 8.1, 1 arom. H); 7.10 (br. s, NH); 6.93 (d, J ¼ 7.5, 1 arom. H); 5.94 (s, CH2); 4.49 (t, J ¼ 4.5,
CH2); 4.05 (t, J ¼ 4.8, CH2); 3.96 (s, MeO). 13C-NMR (75 MHz, CDCl3): 166.6; 159.3; 157.7; 142.9; 141.8;
134.7; 133.3; 130.2; 130.0; 129.8; 128.6; 121.0; 116.7; 114.9; 78.9; 68.3; 63.8; 53.3. ESI-MS: 431.1, 433.1
([M þ H]þ), 453.1, 455.1 ([M þ Na]þ). HR-MS: 431.1114 ([M þ H]þ, C20H20ClN4Oþ5 ; calc. 431.1122).
General Procedure for the Preparation of 5 via Cu-Mediated N-Arylation with Arylboronic Acid. To
a mixture of 20.1 mg 3 (0.10 mmol), 2.0 equiv. of arylboronic acid (0.20 mmol), and 27.2 mg of anh.
Cu(OAc)2 (0.15 mmol) was added 5 ml MeOH (freshly dist. over Mg turning and I2), followed by rapid
addition of 16.1 ml freshly dist. pyridine (0.20 mmol). The mixture was stirred at 408 until complete
consumption of 3 (detected by TLC). The mixture was filtered over Celite, and the filtrate was
concentrated under reduced pressure. The obtained residue was purified on SiO2 with CH2Cl2/MeOH
(20 :1), giving the corresponding product 5 as a powder.
3-Amino-1-[(2-hydroxyethoxy)methyl]-N-phenyl-1H-1,2,4-triazole-5-carboxamide (5a). White solid
1
(75%). Rf (CH2Cl2/MeOH, 20 :1) 0.34. H-NMR (300 MHz, (D6)DMSO): 10.50 (br. s, C(O)NH); 7.78
(d, J ¼ 8.1, 2 arom. H); 7.35 (t, J ¼ 8.0, 2 arom. H); 7.14 (t, J ¼ 7.4, 1 arom. H); 5.70 (s, CH2); 5.65 (s, NH2);
4.66 (t, J ¼ 5.1, OH); 3.56 (t, J ¼ 5.1, CH2); 3.53 – 3.41 (m, CH2). 13C-NMR (150 MHz, (D6)DMSO):
162.7; 155.9; 146.2; 138.0; 129.5; 125.4; 121.1; 78.1; 71.5; 60.4. ESI-MS: 278.1 ([M þ H]þ), 300.1 ([M þ
Na]þ). HR-MS: 278.1250 ([M þ H]þ, C12H16N5Oþ3 ; calc. 278.1253).
3-Amino-1-[(2-hydroxyethoxy)methyl]-N-(4-methylphenyl)-1H-1,2,4-triazole-5-carboxamide (5b).
White solid (60%). Rf (CH2Cl2/MeOH, 20 :1) 0.23. 1H-NMR (300 MHz, (D6)DMSO): 10.42 (br. s,
C(O)NH); 7.66 (d, J ¼ 8.1, 2 arom. H); 7.15 (d, J ¼ 8.7, 2 arom. H); 5.69 (s, CH2); 5.64 (s, NH2); 4.66 (t, J ¼
5.6, OH); 3.56 – 3.54 (m, CH2); 3.48 – 3.45 (m, CH2); 2.27 (s, Me). 13C-NMR (75 MHz, (D6)DMSO):
162.9; 156.0; 146.4; 136.0; 134.2; 129.8; 121.2; 78.1; 71.7; 60.6; 21.2. ESI-MS: 292.1 ([M þ H]þ), 314.1
([M þ Na]þ). HR-MS: 292.1414 ([M þ H]þ, C13H18N5O3þ ; calc. 292.1410).
3-Amino-1-[(2-hydroxyethoxy)methyl]-N-(4-methoxyphenyl)-1H-1,2,4-triazole-5-carboxamide (5c).
White solid (51%). Rf (CH2Cl2/MeOH, 20 :1) 0.18. 1H-NMR (300 MHz, (D6)DMSO): 10.40 (s,
C(O)NH); 7.69 (d, J ¼ 8.7, 2 arom. H); 6.92 (d, J ¼ 9.6, 2 arom. H); 5.70 (s, CH2); 5.63 (s, NH2); 4.66 (t,
J ¼ 5.6, OH); 3.74 (s, MeO); 3.56 (t, J ¼ 4.8, CH2); 3.48 – 3.45 (m, CH2). 13C-NMR (75 MHz,
(D6)DMSO): 163.7; 157.5; 156.6; 147.2; 132.3; 123.6; 115.3; 78.8; 72.5; 61.4; 56.7. ESI-MS: 308.1
([M þ H]þ), 330.1 ([M þ Na]þ). HR-MS: 308.1346 ([M þ H]þ, C13H18N5Oþ4 ; calc. 308.1359).
3-Amino-1-[(2-hydroxyethoxy)methyl]-N-(3-methoxyphenyl)-1H-1,2,4-triazole-5-carboxamide
1
(5d). White solid (40%). Rf (CH2Cl2/MeOH, 20 :1) 0.45. H-NMR (300 MHz, (D6)DMSO): 10.46 (s,
C(O)NH); 7.46 (s, 1 arom. H); 7.39 (d, J ¼ 9.0, 1 arom. H); 7.25 (t, J ¼ 8.4, 1 arom. H); 6.72 (d, J ¼ 8.1, 1
arom. H); 5.69 (s, CH2); 5.65 (s, NH2); 4.66 (t, J ¼ 5.6, OH); 3.74 (s, MeO); 3.56 (t, J ¼ 4.7, CH2); 3.49 –
3.45 (m, CH2). 13C-NMR (75 MHz, (D6)DMSO): 162.9; 160.1; 156.2; 146.3; 139.7; 130.2; 113.4; 110.6;
107.0; 78.1; 71.7; 60.6; 55.8. ESI-MS: 308.1 ([M þ H]þ), 330.1 ([M þ Na]þ). HR-MS: 308.1356 ([M þ
H]þ, C13H18N5Oþ4 ; calc. 308.1359).
3-Amino-1-[(2-hydroxyethoxy)methyl]-N-(2-methoxyphenyl)-1H-1,2,4-triazole-5-carboxamide (5e).
White solid (21%). Rf (CH2Cl2/MeOH, 20 :1) 0.18. 1H-NMR (300 MHz, (D6)DMSO): 9.56 (s,
C(O)NH); 8.23 (d, J ¼ 8.1, 1 arom. H); 7.14 (br. s, 2 arom. H); 7.02 – 6.98 (m, 1 arom. H); 5.84 (s,
NH2); 5.74 (s, CH2); 4.67 (t, J ¼ 5.1, OH); 3.90 (s, MeO); 3.62 – 3.56 (m, CH2); 3.49 – 3.46 (m, CH2).
13C-NMR (150 MHz, (D6)DMSO): 165.0; 157.1; 151.4; 147.7; 129.0; 127.9; 123.5; 122.4; 114.1; 80.5; 74.0;
62.8; 59.0. ESI-MS: 308.1 ([M þ H]þ), 330.1 ([M þ Na]þ). HR-MS: 308.1357 ([M þ H]þ, C13H18N5Oþ4 ;
calc. 308.1359).

1512
Helvetica Chimica Acta – Vol. 92 (2009)
3-Amino-N-(4-fluorophenyl)-1-[(2-hydroxyethoxy)methyl]-1H-1,2,4-triazole-5-carboxamide (5f).
White solid (36%). Rf (CH2Cl2/MeOH, 20 :1) 0.35. 1H-NMR (300 MHz, (D6)DMSO): 10.63 (s,
3
4
3
C(O)NH); 7.81 (dd, J(H,H) ¼ 8.1, J(F,H) ¼ 6.0, 2 arom. H); 7.20 (t, J(H,H) ¼ 3J(F,H) ¼ 8.7, 2 arom.
H); 5.69 (s, CH2); 5.65 (s, NH2); 4.66 (t, J ¼ 5.6, OH); 3.56 – 3.54 (m, CH2); 3.49 – 3.45 (m, CH2).
13C-NMR (150 MHz, (D6)DMSO): 165.1; 161.7 (d, 1J(F,C) ¼ 265.4); 158.3; 148.4; 137.0; 125.4; 118.1 (d,
2J(F,C) ¼ 21.2); 80.3; 73.9; 62.8. ESI-MS: 296.1 ([M þ H]þ), 318.1 ([M þ Na]þ). HR-MS: 296.1152
([M þ H]þ, C12H15FN5Oþ3 ; calc. 296.1159).
3-Amino-N-(3-fluorophenyl)-1-[(2-hydroxyethoxy)methyl]-1H-1,2,4-triazole-5-carboxamide (5g).
White solid (57%). Rf (CH2Cl2/MeOH, 20 :1) 0.32. 1H-NMR (300 MHz, (D6)DMSO): 10.77 (s,
C(O)NH); 7.73 (d, 3J(F,H) ¼ 11.7, 1 arom. H); 7.64 (d, 3J(H,H) ¼ 8.1, 1 arom. H); 7.39 (dd, 3J(F,H) ¼ 15.6,
3J(H,H) ¼ 8.1, 1 arom. H); 7.01 – 6.95 (m, 1 arom. H); 5.70 (s, CH2); 5.67 (s, NH2); 4.67 (t, J ¼ 5.6, OH);
3.57 (t, J ¼ 5.1, CH2); 3.49 – 3.44 (m, CH2). 13C-NMR (75 MHz, (D6)DMSO): 162.9; 162.6 (d, 1J(F,C) ¼
3
3
2
239.0); 156.4; 146.0; 140.3 (d, J(F,C) ¼ 10.7); 131.0 (d, J(F,C) ¼ 8.6); 117.1; 111.6 (d, J(F,C) ¼ 21.5);
108.1 (d, 2J(F,C) ¼ 26.8); 78.2; 71.8; 60.6. ESI-MS: 296.1 ([M þ H]þ), 318.1 ([M þ Na]þ). HR-MS:
296.1154 ([M þ H]þ, C12H15FN5Oþ3 ; calc. 296.1159).
3-Amino-N-(2-fluorophenyl)-1-[(2-hydroxyethoxy)methyl]-1H-1,2,4-triazole-5-carboxamide (5h).
White solid (47%). Rf (CH2Cl2/MeOH, 20 :1) 0.43. 1H-NMR (300 MHz, (D6)DMSO): 10.03 (s,
C(O)NH); 7.84 – 7.79 (m, 1 arom. H); 7.35 – 7.21 (m, 3 arom. H); 5.76 (s, NH2); 5.71 (s, CH2); 4.67 (t, J ¼
5.6, OH); 3.57 (t, J ¼ 4.8, CH2); 3.47 (t, J ¼ 5.1, CH2). 13C-NMR (75 MHz, (D6)DMSO): 163.0; 155.8;
3
2
145.5; 127.5 (d, J(F,C) ¼ 6.7); 125.6; 125.4; 125.3; 116.4 (d, J(F,C) ¼ 18.9); 78.1; 71.8; 60.6. ESI-MS:
296.1 ([M þ H]þ), 318.1 ([M þ Na]þ). HR-MS: 296.1151 ([M þ H]þ, C12H15FN5Oþ3 ; calc. 296.1159).
3-Amino-N-(4-chlorophenyl)-1-[(2-hydroxyethoxy)methyl]-1H-1,2,4-triazole-5-carboxamide (5i).
White solid (48%). Rf (CH2Cl2/MeOH, 20 :1) 0.30. 1H-NMR (300 MHz, (D6)DMSO): 10.71 (s,
C(O)NH); 7.83 (d, J ¼ 8.1, 2 arom. H); 7.42 (d, J ¼ 8.7, 2 arom. H); 5.82 (s, CH2); 5.66 (s, NH2); 4.66 (t, J ¼
5.7, OH); 3.56 – 3.54 (m, CH2); 3.47 – 3.45 (m, CH2). 13C-NMR (75 MHz, (D6)DMSO): 162.9; 156.3;
146.1; 137.5; 129.3; 128.8; 122.9; 78.1; 71.7; 60.6. ESI-MS: 312.1, 314.1 ([M þ H]þ), 334.1, 336.1 ([M þ
Na]þ). HR-MS: 312.0854 ([M þ H]þ, C12H15ClN5O3þ ; calc. 312.0863).
3-Amino-N-(3-chlorophenyl)-1-[(2-hydroxyethoxy)methyl]-1H-1,2,4-triazole-5-carboxamide (5j).
White solid (32%). Rf (CH2Cl2/MeOH, 20 :1) 0.38. 1H-NMR (300 MHz, (D6)DMSO): 10.76 (s,
C(O)NH); 7.97 (s, 1 arom. H); 7.74 (d, J ¼ 7.8, 1 arom. H); 7.38 (t, J ¼ 8.1, 1 arom. H); 7.20 (d, J ¼ 7.2, 1
arom. H); 5.70 (s, CH2); 5.67 (s, NH2); 4.66 (t, J ¼ 5.6, OH); 3.56 (t, J ¼ 4.8, CH2); 3.49 – 3.44 (m, CH2).
13C-NMR (75 MHz, (D6)DMSO): 162.9; 156.4; 145.9; 140.0; 133.7; 131.1; 124.8; 120.7; 119.8; 78.2; 71.7;
60.6. ESI-MS: 312.1, 314.1 ([M þ H]þ), 334.1, 336.1 ([M þ Na]þ). HR-MS: 312.0859 ([M þ H]þ,
C12H15ClN5Oþ3 ; calc. 312.0863).
3-Amino-N-(2-chlorophenyl)-1-[(2-hydroxyethoxy)methyl]-1H-1,2,4-triazole-5-carboxamide (5k).
White solid (41%). Rf (CH2Cl2/MeOH, 20 :1) 0.40. 1H-NMR (300 MHz, (D6)DMSO): 9.93 (s,
C(O)NH); 8.04 (d, J ¼ 8.1, 1 arom. H); 7.58 (d, J ¼ 8.1, 1 arom. H); 7.41 (t, J ¼ 6.6, 1 arom. H); 7.26 (t,
J ¼ 7.2, 1 arom. H); 5.82 (s, NH2); 5.72 (s, CH2); 4.67 (t, J ¼ 5.6, OH); 3.58 (t, J ¼ 4.8, CH2); 3.50 – 3.44 (m,
CH2). 13C-NMR (75 MHz, (D6)DMSO): 162.9; 155.5; 145.3; 134.3; 130.2; 128.6; 127.3; 126.0; 124.6; 78.3;
71.8; 60.6. ESI-MS: 312.1, 314.1 ([M þ H]þ), 334.1, 336.1 ([M þ Na]þ). HR-MS: 312.0858 ([M þ H]þ,
C12H15ClN5Oþ3 ; calc. 312.0863).
Anti-Cancer Assay in PC-3, MiaPaCa-2, and Capan-2 Cells. Prostate cancer PC-3 and pancreatic
cancer MiaPaCa-2 cells were cultured in DMEM medium (Gibco) supplemented with 10% fetal bovine
serum (FBS). Cells were seeded at a densitiy of 15,000 cells per well in 96 well View PlateTM (Packard) in
250 ml of medium containing the same components as described above. For Capan-2 cell lines, the cells
were cultured in RPMI 1640 medium supplemented with 10% FBS and 1% glutamine. Cells were seeded
at a densitiy of 20,000 cells per well in 96 well View PlateTM (Packard) in 250 ml of medium containing the
same components as described above. Cells were allowed to attach overnight, and then the culture
medium was removed and replaced with fresh media alone as the control or containing different
compounds. Plates were further incubated at 378 and 5% CO2 for 48 h. The number of viable cells
remaining after the appropriate treatment was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-
diphenyltetrazolium bromide (MTT) colorimetric assay.

Helvetica Chimica Acta – Vol. 92 (2009)
1513
Anti-HCVAssay in Huh-5-2 Cells. Huh 5-2 cells were seeded at a density of 5000 per well in a tissue
culture-treated white 96-well view plate (Packard, Canberra, Canada) in complete Dulbeccoꢃs modified
Eagle medium (DMEM) supplemented with 250 mg/ml G418. After incubation for 24 h at 378 (5% CO2),
the medium was removed, and 3-fold serial dilutions in complete DMEM (without G418) of the test
compounds were added in a total volume of 100 ml. After 4 d of incubation at 378, the cell culture medium
was removed and luciferase activity was determined using the Steady-Glo luciferase assay system
(Promega, Leiden, The Netherlands); the luciferase signal was measured using a Luminoskan ascent
(Thermo, Vantaa, Finland).
REFERENCES
[1] S. Claire, ꢂNucleoside mimetics: Their chemistry and biological propertiesꢃ, Gordon and Beach
Science Publishers, UK, 2001.
[2] Q. Wu, F. Qu, J. Wan, X. Zhu, Y. Xia, L. Peng, Helv. Chim. Acta 2004, 87, 811.
[3] J. Wan, R. Zhu, Y. Xia, F. Qu, Q. Wu, G. Yang, J. Neyts, L. Peng, Tetrahedron Lett. 2006, 47, 6727.
´ ´
[4] R. Zhu, F. Qu, G. Quelever, L. Peng, Tetrahedron Lett. 2007, 48, 2389.
[5] a) Y. Xia, W. Li, F. Qu, Z. Fan, X. Liu, C. Berro, E. Rauzy, L. Peng, Org. Biomol. Chem. 2007, 5, 1695;
b) Y. Xia, Z. Fan, J. Yao, Q. Liao, W. Li, F. Qu, L. Peng, Bioorg. Med. Chem. Lett. 2006, 16, 2693;
c) Y. Xia, F. Qu, W. Li, Q. Wu, L. Peng, Heterocycles 2005, 65, 345.
[6] W. Li, Y. Xia, Z. Fan, F. Qu, Q. Wu, L. Peng, Tetrahedron Lett. 2008, 49, 2804.
[7] R. Zhu, M. Wang, Y. Xia, F. Qu, J. Neyts, L. Peng, Bioorg. Med. Chem. Lett. 2008, 18, 3321.
[8] J. Wan, Y. Xia, Y. Liu, M. Wang, P. Rocchi, J. Yao, F. Qu, J. Neyts, J. L. Iovanna, L. Peng, J. Med.
Chem. 2009, 52, 1144.
[9] D. Loakes, Nucleic Acids Res. 2001, 29, 2437.
[10] R. W. Sidwell, J. H. Huffman, G. P. Khare, L. B. Allen, J. T. Witkowski, R. K. Robins, Science 1972,
177, 705.
[11] R. De Francesco, G. Migliaccio, Nature 2005, 436, 953; C. P. Gordon, P. A. Keller, J. Med. Chem.
2005, 48, 1.
ˇ
[12] M. K. Lakshman, Curr. Org. Synth. 2005, 2, 83; J. J. Strouse, M. Jeselnik, J. B. Arterburn, Acta Chim.
Slov. 2005, 52, 187.
[13] J. F. Hartwig, Acc. Chem. Res. 2008, 41, 1534; J.-P. Corbet, G. Mignani, Chem. Rev. 2006, 106, 2651;
I. P. Beletskaya, A. V. Cheprakov, Coord. Chem. Rev. 2004, 248, 2337; S. V. Ley, A. W. Thomas,
Angew. Chem., Int. Ed. 2003, 42, 5400; K. Kunz, U. Scholz, D. Ganzer, Synlett 2003, 2428; J. Lindley,
Tetrahedron 1984, 40, 1433.
[14] G. I. Elliott, J. P. Konopelski, Org. Lett. 2000, 2, 3055.
[15] P. Y. S. Lam, C. G. Clark, S. Saubern, J. Adams, K. M. Averill, D. M. T. Chan, A. Combs, Synlett 2000, 674.
[16] P. Y. S. Lam, S. Deudon, K. M. Averill, R. Li, M. Y. He, P. DeShong, C. G. Clark, J. Am. Chem. Soc.
2000, 122, 7600.
[17] C. H. Burgos, T. E. Barder, X. H. Huang, S. L. Buchwald, Angew. Chem., Int. Ed. 2006, 45, 4321; L.
Jiang, S. L. Buchwald, in ꢂMetal-Catalyzed Cross-Coupling Reactionsꢃ, 2nd edn., Eds. A. de Meijere,
F. Diederich, Wiley-VCH, Weinheim, Germany, 2004, p. 699.
[18] D. M. T. Chan, K. L. Monaco, R.-P. Wang, M. P. Winters, Tetrahedron Lett. 1998, 39, 2933; P. Y. S.
Lam, C. G. Clark, S. Saubern, J. Adams, M. P. Winters, D. M. T. Chan, A. Combs, Tetrahedron Lett.
1998, 39, 2941; P. Y. S. Lam, G. Vincent, C. G. Clark, S. Deudon, P. K. Jadhav, Tetrahedron Lett. 2001,
42, 3415; H. Bekolo, Can. J. Chem. 2007, 85, 42; M. L. Kantam, G. T. Venkanna, C. Sridhar, B.
Sreedhar, B. M. Choudary, J. Org. Chem. 2006, 71, 9522; G. Evano, N. Blanchard, M. Toumi, Chem.
Rev. 2008, 108, 3054; D. W. Ma, Q. Cai, Acc. Chem. Res. 2008, 41, 1450.
[19] M. L. Kantam, B. Neelima, C. V. Reddy, V. Neeraja, J. Mol. Catal. A: Chemical 2006, 249, 201; D. P.
Phillips, A. R. Hudson, B. Nguyen, T. L. Lau, M. H. McNeill, J. E. Dalgard, J.-H. Chen, R. J.
Penuliar, T. A. Miller, L. Zhi, Tetrahedron Lett. 2006, 47, 7137.
[20] J. Paeshuyse, A. Kaul, E. De Clercq, B. Rosenwirth, J.-M. Dumont, P. Scalfaro, R. Bartenschlager, J.
Neyts, Hepatology 2006, 43, 761.
Received January 30, 2009