Copper/graphene/clay nanohybrid: A highly efficient heterogeneous nanocatalyst for the synthesis of novel 1,2,3-triazolyl carboacyclic nucleosides via 'Click' Huisgen 1,3-dipolar cycloaddition

Article abstract of DOI:10.1002/hlca.201500149

A very mild and highly efficient synthesis of some novel 1H-1,2,3-triazolyl carboacyclic nucleosides via a 'Click' Huisgen cycloaddition of N-propargyl nucleobases and azido alcohols using Cu/aminoclay/reduced graphene oxide nanohybrid (Cu/AC/r-GO nanohybrid) as nanocatalyst is described. The preparation and characterization of Cu/AC/r-GO nanohybrid are discussed. This catalyst was characterized by X-ray diffraction, FT-IR, TEM, and energy-dispersive analysis of X-ray techniques. Cu/AC/r-GO nanohybrid is a stable and highly efficient heterogeneous nanocatalyst that can be easily prepared, used, and restored from the reaction mixture by simple filtration, and reused for many consecutive trials without significant decrease in activity.

Full text of DOI:10.1002/hlca.201500149

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Helvetica Chimica Acta – Vol. 98 (2015)
Copper/Graphene/Clay Nanohybrid: A Highly Efficient Heterogeneous
Nanocatalyst for the Synthesis of Novel 1,2,3-Triazolyl Carboacyclic
Nucleosides via ꢀClickꢁ Huisgen 1,3-Dipolar Cycloaddition
by Mohammad Navid Soltani Rad*a), Somayeh Behrouz*a), S. Jafar Hoseinib), Hasan Nasrabadib), and
Maryam Saberi Zarea)
a) Medicinal Chemistry Research Laboratory, Department of Chemistry, Shiraz University of
Technology, Shiraz 71555-313, Iran
(phone: þ 98-71-37261392; fax: þ 98-71-37354523; e-mail: soltani@sutech.ac.ir, behrouz@sutech.ac.ir)
b) Department of Chemistry, Faculty of Sciences, Yasouj University, Yasouj 7591874831, Iran
A very mild and highly efficient synthesis of some novel 1H-1,2,3-triazolyl carboacyclic nucleosides
via a ꢀClickꢁ Huisgen cycloaddition of N-propargyl nucleobases and azido alcohols using Cu/aminoclay/
reduced graphene oxide nanohybrid (Cu/AC/r-GO nanohybrid) as nanocatalyst is described. The
preparation and characterization of Cu/AC/r-GO nanohybrid are discussed. This catalyst was
characterized by X-ray diffraction, FT-IR, TEM, and energy-dispersive analysis of X-ray techniques.
Cu/AC/r-GO nanohybrid is a stable and highly efficient heterogeneous nanocatalyst that can be easily
prepared, used, and restored from the reaction mixture by simple filtration, and reused for many
consecutive trials without significant decrease in activity.
Introduction. – Drug design and synthesis based on non-natural nucleosides are
prominence strategies to overcome miscellaneous infections and diseases caused by
viruses, bacteria, cancer, etc. [1]. Three main strategies are normally applied on natural
nucleosides to access a great deal of diverse non-natural nucleosides, encompassing i)
modification of functionalities on nucleobases and/or replacement of nucleobases with
their similar heterocyclic analogs or isosteres; ii) alteration of the sugar residueꢁs
backbone, and finally iii) conversion, as well as conjugation of free OH groups to
various functionalities [2]. In connection with the first strategy, it is well demonstrated
and fully established that the replacement of purine and pyrimidine nucleobases in
natural nucleosides with those of azole derivatives not only doesnꢁt abolish the
biological activity, but also endows the leading properties [3]. This inspiration in
nucleobase change has been emerged in the design and synthesis of well-established
non-natural nucleosides, i.e., ribavirin (virazole), mizoribine (bredinin), pyrazofurine,
and tert-butyldimethylsilylspiroaminooxathioledioxide (TSAO), which exhibit anti-
viral, antitumor, and immunosuppressive activities (Fig. 1) [4].
Since the discovery of zidovudine (AZT; Fig. 1) as potent anti-HIV drug [5],
enormous efforts were conducted to conjugate the AZT scaffold with various naturally
occurring molecules or drugs [6]. In this regard, the Huisgen azideÀalkyne cyclo-
addition was found to be a highly efficient and reliable tool for tethering AZT to
diverse molecules [6]. This became the starting point for extensive endeavors to
incorporate 1H-1,2,3-triazolyl cores into the nucleoside framework [7]. In general, the
ꢂ 2015 Verlag Helvetica Chimica Acta AG, Zürich

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Fig. 1. Structures of some famous non-natural nucleosides
incorporation of the 1H-1,2,3-triazolyl group into a molecular scaffold is an interesting
task, since the 1H-1,2,3-triazolyl moiety involves remarkable biological activities, as
well as recognition by enzymes and receptors in the cell [8]. Moreover, 1H-1,2,3-
triazolyl cores are known as the non-classical isostere of amide because of having
considerable topological and electronic similarities. Given the biological importance of
1H-1,2,3-triazolyl cores, they have been extensively used in the design of new
nucleosides as surrogate moieties in different fragments of the nucleosides, comprising
i) a nucleobase surrogate; ii) a single substituent linked to sugar or nucleobase
residues; iii) a splicer between nucleoside (from sugar or nucleobase sites) and other
biomolecules to access nucleosideÀnucleoside, nucleosideÀdrug conjugates, etc.; and
iv) a spacer between nucleobase and sugar or sugar mimic moieties. Among the
aforementioned 1,2,3-triazolyl-nucleoside analogs, the fourth status has recently
received extensive attention because of their noticeable biological activities like anti-
viral, antitumor, and antimicrobial activities, and binding affinity to enzymes [9].
Huisgenꢁs CuI-catalyzed azideÀalkyne cycloaddition (CuAAC) has emerged as a
powerful tool for introducing the 1H-1,2,3-triazolyl residue into a molecular structure
[10]. Active CuI as the catalytic species plays a crucial role in the regioselectivity of the
Huisgen cycloaddition, providing only 1,4-disubstituted isomers. Active CuI can be
prepared in miscellaneous ways, encompassing in situ reduction of CuII salts mostly in
the presence of vitamin C [11], oxidation of Cu0 [12], and/or CuII/Cu0 comproportio-
nation [13]. Due to several drawbacks by the use of CuI salts, especially the formation
of undesired alkyneÀalkyne homocoupling side products, their application in simple
form was limited [14]. To overcome this problem, active CuI is complexed to N- or P-
based ligands, or immobilized on various solid supports [15]. Different solid materials
were used to support the Cu species, comprising silica gel, zeolites, alumina, charcoal,
montmorillonite, amine-functionalized silica or polymer, etc. [16]. Among the solid
supports, those with covalently bonded amine residues are more satisfactory because of
their capability to chelate with the Cu species [17]. This chelation not only causes an
enhancement of CuI-catalytic activity, but also largely prevents desorption of the Cu

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species from the surface of the support, whilst simple surface absorption of Cu species
on the surface of a raw support is accompanied with major leaching during the course of
reaction. This current drawback extensively diminishes the reusability and recover-
ability of the catalyst.
Graphene oxide (GO) as synthetic precursor of graphene is a unique substance that
can be regarded as a single monomolecular layer of graphite with various O-bearing
functionalities such as OH, C¼O, COOH, and epoxide groups [18]. The presence of
theses functionalities allows grafting of GO with many biomolecules, organic materials,
drugs, etc., that found extensive applications in electronics, energy storage, biomedical
applications (drug delivery), and biosensors [19]. After functionalizing or modifying
GO with desired molecules, the modified GO is reduced to graphene (r-GO) to
retrieve the exclusive mechanical, electrical, thermal, and optical properties known
from graphene [20].
In continuation of our ongoing research on the preparation of heterogeneous nano-
Cu catalysts and their application in organic transformation [16][21], hereby, we have
explained the preparation and characterization of Cu/aminoclay/reduced graphene
oxide nanohybrid (Cu/AC/r-GO nanohybrid) as highly efficient novel nanohybrid
catalyst for the very mild synthesis of some 1H-1,2,3-triazolyl carboacyclic nucleosides
via a ꢀClickꢁ Huisgen cycloaddition of N-propargyl nucleobases and azido alcohols in
THF/H2O at room temperature (Scheme).
Results and Discussion. – The powder X-ray diffraction pattern of the Cu/AC/r-GO
nanohybrid obtained by precipitation from freshly prepared aqueous Cu/AC/r-GO
suspension (Fig. 2) shows peaks corresponding to (111), (200), and (220) planes
associated with the fcc structure of Cu. The observation of low-angle peaks
corresponding to the interlayer spacing of AC suggest the possible coexistence of
staked nanostructures made up of few layers of AC. AC/GO hybrid has been converted
to AC/r-GO hybrid by reduction via N2H4 · H2O. r-GO shows a diffraction peak for
C(002) at 2q ¼ 278 similar to that of carbon black [22].
The Cu/AC/r-GO nanohybrid was further examined by an energy-dispersive
analysis of X-ray (EDAX) where Cu, Mg, Si, and O along with carbon elements, which
could be attributed to the synthesis of the Cu/AC/r-GO nanohybrid, were observed
(Fig. 3).
For TEM, the aqueous Cu/AC/r-GO suspension was first precipitated by the
addition of excess EtOH and then re-dispersed in EtOH by sonication before drop
casting on a carbon-coated Cu grid. The TEM images show the presence of clay
nanoparticles ranging from 10 to 70 nm in size distributed on the r-GO sheet (Fig. 4,a
and b). Also, the TEM image of a freshly prepared sample shows Cu particles of less
than 15 nm in size on the backdrop of the AC/r-GO hybrid (Fig. 4,c).
The IR spectrum of the Cu/AC/r-GO nanohybrid clearly indicated the formation of
the catalyst. As shown in Fig. 5, the peaks at 2854 and 2925 cmÀ1 correspond to
symmetric ns. CH2 and asymmetric ns. CH2 of the alkyl chains, respectively, which are
assigned to aminoclay. Moreover, the bands at 1116 (SiÀC) and 1034 cmÀ1 (SiÀOÀSi)
provide more evidence for the presence of aminoclay [23]. The IR spectrum also shows
bands at 3405, 1731, 1621, and 1216 cmÀ1, indicating that r-GO sheets are present as the
prepared hybrid [24].

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Scheme. Synthesis of Novel 1H-1,2,3-Triazolyl Carboacyclic Nucleosides via the ꢀClickꢁ Huisgen Cyclo-
addition Using the Cu/AC/r-GO Nanohybrid

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Fig. 2. XRD Pattern of the Cu/AC/r-GO nanohybrid
Fig. 3. EDAX Spectrum of the Cu/AC/r-GO nanohybrid
Having prepared the Cu/AC/r-GO nanohybrid, we initiated the synthesis of 1H-
1,2,3-triazolyl carboacyclic nucleosides by selective N-propargylation of nucleobases
and other N-heterocyclic compounds, 1a – 1h. Due to the ambident nature of
nucleobases, N-alkylation should be conducted regioselectively under mild reaction
conditions. In this context, among the established methods so far, a mild method
reported by Lazrek and co-workers [25] has shown better selectivity and efficiency. In
this method, N-propargylation of nucleobases is achieved in the presence of K2CO3 in

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Fig. 4. TEM Images of the Cu/AC/r-GO nanohybrid. a), b) Clay nanoparticles (10 – 70 nm in size)
distributed on the r-GO sheet. c) Cu particles (less than 15 nm in size) on the backup of the AC/r-GO
hybrid.
DMF at ambient temperature. To our experience, addition of a catalytic amount of
Bu4NBr (TBAB) can largely enhance the efficiency and shorten the reaction time
while retaining the regioselectivity trend. Thus, the desired alkynes, N1-propargylur-
acils 1a and 1b, N9-propargyladenine (1c), N7-propargyltheophylline (1d), N1-
propargyltheobromine (1e), N1-propargylbenzimidazoles 1f and 1g, and N1-proparg-
yl-2-methyl-4-nitroimidazole (1h) were obtained in good to excellent yields.
After the preparation of alkynes 1a – 1h, azido alcohols were prepared in the next
step. Azido alcohols in the preparation of 1H-1,2,3-triazolyl carboacyclic nucleosides
have an apparent privilege compared with simple alkyl azide analogs, since the
application of azido alcohols introduces a OH group as a crucial site for potential
phosphorylation via phosphate kinases in the cell [26]. In this regard, two different

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Fig. 5. FT-IR Spectrum of the Cu/AC/r-GO nanohybrid
types of azido alcohols, including branched and unbranched (linear) structures, were
prepared for ꢀClickꢁ Huisgen cycloaddition with 1a – 1h. Branched azido alcohols 2a –
2h were prepared by regioselective ring opening of epoxides via NÀ3 in acetone/H2O
solution under reflux, whereas unbranched azido alcohols 2i and 2j were prepared from
2-bromoethanol and 3-bromopropan-1-ol, respectively, under similar conditions and
almost in quantitative yields.
To find the optimized reaction conditions, the cycloaddition of 1a with 2d was
designated as a sample reaction and the influence of factors like solvent and catalyst
was investigated.
Due to the polar nature of the ꢀClickꢁ Huisgen cycloaddition, the solvent plays a
critical role in this reaction. To our experience [16][21], the combination of H2O with
H2O-miscible organic solvents often progresses the reaction satisfactorily. As can be
seen in Table 1, a 1 :1 mixture of organic solvents in H2O was tested for cycloaddition of
1a and 2d in the presence of a catalytic amount of Cu/AC/r-GO nanohybrid at room
temperature. The most appropriate result was obtained when a THF/H2O mixture was
applied (Table 1, Entry 8). However, other mixtures also afforded moderate to good
yields of 3d after longer times (Table 1, Entries 1 – 7). When H2O was used alone, the
low yield of 3d was attained after a much longer time. The low yield obtained for 3d
using pure H2O, is attributed to a lack of solubility of the starting materials in H2O
under the examined conditions.
Inductively coupled plasma (ICP) analysis indicated that in each gram of catalyst,
there are 0.013 g of active Cu catalyst (0.02 mol-%). To determine the optimized
amount of Cu/AC/r-GO nanohybrid, different amounts of catalyst were examined in
the model reaction (Table 2). As depicted in Table 2, the best result was obtained when
0.008 or 0.010 mol-% of catalyst were applied (Table 2, Entries 4 and 5). The use of an
excess amount of catalyst has a negligible effect on the progress of the reaction. To
investigate the catalytic potency of Cu/AC/r-GO nanohybrid in the synthesis of 1H-
1,2,3-triazolyl carboacyclic nucleosides, we tested the model reaction using other Cu
catalysts and compared the results with that of Cu/AC/r-GO nanohybrid (Table 3).

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Table 1. Influence of H2O Mixture with Some H2O-Miscible Organic Solvents on Cycloaddition of 1a with
2d Using Cu/AC/r-GO Nanohybrid at Room Temperaturea)
Entry
Solventb)
Time [h]
Yield [%]c)
1
2
3
4
5
6
7
8
9
H2O/MeCN
H2O/DMF
H2O/DMSO
H2O/EtOH
H2O/acetone
H2O/dioxane
H2O/HMPAd)
H2O/THF
10
8
7
10
8
6
9
5
12
68
77
70
58
66
75
61
84
53
H2O
a) Reagents and conditions: 1a (0.01 mol), 2d (0.012 mol), Cu/AC/r-GO nanohybrid (0.008 mol-%),
c
solvent (30 ml), room temperature. b) A 1 : 1 mixture of solvents was used. ) Yield of isolated product.
d) HMPA, hexamethylphosphoramide.
Table 3 shows that despite favorable activities assessed for different examined Cu salts
(CuI or CuII), however, the most satisfactory result was observed when the Cu/AC/r-
GO nanohybrid was applied. The improved performance of the Cu/AC/r-GO
nanohybrid in comparison with other Cu catalysts is rationalized to potential p ··· p*
interaction of electron-enriched r-GO as a polynuclear aromatic sheet with electron-
deficient nucleobases [27].
To determine the scope of the Cu/AC/r-GO nanohybrid in the synthesis of other
1H-1,2,3-triazolyl carboacyclic nucleosides, the optimized conditions were screened to
other N-propargylated nucleobases, 1a – 1h, and azido alcohols 2a – 2j (Table 4). As
depicted in Table 4, diverse N-propargylated nucleobases, comprising purines, pyrimi-
dines, and azoles with branched or unbranched azido alcohols, were regioselectively
and efficiently converted to their corresponding 1,4-disubstituted triazolyl carboacyclic
adducts by the ꢀClickꢁ Huisgenꢁs cycloaddition using the Cu/AC/r-GO nanohybrid in
excellent yields under very mild conditions. Compounds 3a – 3o were fully charac-
terized, and their structures were confirmed by physical and spectroscopic techniques
including IR, 1H- and 13C-NMR, MS, and elemental analysis. In general, the presence of
a singlet at d(H) 7.50 – 8.20 in the 1H-NMR spectra is a main criterion for a H-atom at
C(5) of the 1H-1,2,3-triazole moiety in all synthesized triazolyl carboacyclic nucleo-
sides.

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Table 2. Influence of Catalyst Amount on Cycloaddition of 1a with 2d Using Cu/AC/r-GO Nanohybrid at
Room Temperaturea)
Entry
Cu/AC/r-GO Nanohybrid [mol-%]
Time [h]
Yield [%]b)
1
2
3
4
5
6
7
8
0.002
0.004
0.006
0.008
0.010
0.012
0.014
0.016
11
9
8
5
5
6
7
7
58
64
68
84
84
81
80
80
a) Reagents and conditions: 1a (0.01 mol), 2d (0.012 mol), Cu/AC/r-GO nanohybrid (x mol-%), THF/
H2O 1 : 1 (30 ml), room temperature. b) Yield of isolated product.
Table 3. Comparison of Various Cu Catalysts with Cu/AC/r-GO Nanohybrid on Cycloaddition of 1a with
2d at Room Temperaturea)
Entry
Cu Catalyst
Time [h]
Yield [%]b)
1
2
3
4
5
6
7
Cu/AC/r-GO Nanohybrid
Cu2O
5
9
5
11
8
8
84
67
78
59
68
63
70
CuI
c
Cu(acac)2
)
CuSO4 · 5 H2Oc)
(AcO)2Cuc)
c
Cu(OTf)2
)
7
a) Reagents and conditions: 1a (0.01 mol), 2d (0.012 mol), Cu catalyst (0.008 mol-%), THF/H2O 1 : 1
c
(30 ml), room temperature. b) Yield of isolated product. ) The reaction was carried out in the presence
of sodium ascorbate (0.1 mol-%).

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Table 4. Cu/AC/r-GO Nanohybrid-Catalyzed Synthesis of 1H-1,2,3-Triazolyl Carboacyclic Nucleosidesa)
Entry Alkyne (Nu)
Azido alcohol (R)
Productb) Time Yield
[h]
[%]c)
1
N1-Uracilyl
7
88
3a
8
2
3
4
5
6
7
8
9
10
11
12
13
14
15
N1-uracilyl
Me(CH2)5CH(OH)CH2
MeCH2CH(OH)CH2
3b
3c
3d
3e
3f
92
90
84
81
93
90
94
80
82
85
86
80
87
91
N1-uracilyl
7
5
4
3
3
N1-uracilyl
4-ClÀC6H4ÀOCH2CH(OH)CH2
2,4-Cl2ÀC6H3ÀOCH2CH(OH)CH2
4-MeÀC6H4ÀOCH2CH(OH)CH2
N1-6-azauracilyl
N7-theophyllinyl
N7-theophyllinyl
N7-theophyllinyl
N1-theobrominyl
N9-adeninyl
4-MeOÀC6H4ÀOCH2CH(OH)CH2 3g
HO(CH2)2
3h
3i
3j
3k
3l
3m
3n
3o
4
8
HO(CH2)2
HO(CH2)2
HO(CH2)3
HO(CH2)2
PhOCH2CH(OH)CH2
HO(CH2)2
10
10
9
12
8
N9-adeninyl
N-benzimidazolyl
N-benzimidazolyl
N-2-methylbenzimidazolyl
N1-2-methyl-4-nitroimidazolyl HO(CH2)3
10
a) Reagents and conditions: 1a (0.01 mol), 2d (0.012 mol), Cu catalyst (0.008 mol-%), THF/H2O 1 : 1
b
(30 ml), room temperature. ) All products were characterized by IR, 1H- and 13C-NMR, MS, and elemental
analysis. c) Yield of isolated product.
The reusability and recoverability of the Cu/AC/r-GO nanohybrid in the sample
reaction was also evaluated. In this regard, before using and also final testing of the
catalyst for its activity in many successive runs, the catalyst was recycled from the
reaction mixture through a sintered glass funnel by vacuum-filtering. Afterwards, the
catalyst was washed successively with anhydrous THF or acetone (10 ml) and dried in a
vacuum oven at 808 for 1 h. The catalyst was tested in five consecutive runs, and no
fresh catalyst was added. As can be seen in Table 5, the Cu/AC/r-GO nanohybrid can be
recycled and reused for many consecutive trials without significant loss of activity.
Furthermore, the ICP analysis has confirmed the reusability of the Cu/AC/r-GO
nanohybrid without significant desorption of Cu species from AC/r-GO matrix. As it is
well indicated, the amount of leached Cu from Cu/AC/r-GO nanohybrid is extremely
negligible (0.008% after five consecutive runs), and it is rationalized due to a powerful
binding present between the Cu species and AC group on the surface of r-GO.
In summary, the fabrication and characterization of a novel Cu/AC/r-GO nano-
hybrid as a highly efficient heterogeneous nanocatalyst in the synthesis of some 1,2,3-
triazolyl carboacyclic nucleosides has been discussed. The Cu/AC/r-GO nanohybrid

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Table 5. Reusability of Cu/AC/r-GO Nanohybrid in Successive Runs for the Synthesis of 3da)
Run
Time [h]
Yield [%]b)
1
2
3
4
5
5
5
6
7
7
84
84
82
81
80
a) Reagents and conditions: 1a (0.01 mol), 2d (0.012 mol), Cu catalyst (0.008 mol-%), THF/H2O 1 : 1
(30 ml), room temperature. b) Yield of isolated product.
was efficiently utilized in the mild synthesis of 1,4-disubstituted 1H-1,2,3-triazolyl
carboacyclic nucleosides through regioselective ꢀClickꢁ Huisgen cycloaddition of N-
propargylated nucleobases and azido alcohols in H2O/THF 1:1 at room temperature,
and the products were obtained in excellent yields. The Cu/AC/r-GO nanohybrid was
shown to be a chemically and thermally stable, cheap, and environmentally benign
heterogeneous nanocatalyst that could be reused for many consecutive experiments
without significant loss of its activity.
We thank the Shiraz University of Technology and Yasouj University Research Councils for partial
support of this work.
Experimental Part
General. All reagents were purchased from either Fluka or Merck. GO was prepared using a
modified Hummersꢁ method from flake graphite [28]. N-Propargylated nucleobases 1a – 1h were
prepared according to a modified Lazrek and co-workersꢁ method (note: a small amount of TBAB, i.e.,
0.1 g, was added for 10 mmol reactionꢁs scale) [25]. Azido alcohols 2a – 2h were prepared according to
our previously reported method [29]. Solvents were purified and stored over 3-Š molecular sieves.
Ultrasonication was performed in a TECNO-GAZ Tecna 3 ultrasonic bath. M.p.: Electrothermal IA 9000
melting point apparatus; in open capillary tubes; uncorrected. Thin layer chromatography (TLC): SILG/
UV 254 silica gel plates (SiO2). Column chromatography (CC): SiO2 60 (0.063 – 0.200 mm, 70 – 230 mesh
1
ASTM). IR Spectra: Shimadzu FT-IR-8300 spectrophotometer; n˜ in cmÀ1. H- and 13C-NMR spectra:
Bruker Avance-DPX-250 spectrometer (250 and 62.5 MHz, resp.); d in ppm rel. to Me4Si as internal
standard, J in Hz. GC/MS: Shimadzu GC/MS-QP 1000-EX apparatus; in m/z (rel. %). Elemental
analyses: PerkinElmer 240-B microanalyzer. TEM: Philips CM-10 TEM microscope; at 100 kV. Powder
X-ray diffraction (XRD): Bruker AXS D8 Advance instrument employing reflection BraggÀBrentano
geometry with CuKa radiation. Energy-dispersive analysis of X-ray (EDAX): PHILIPS XL30
instrument; accelerating voltage, 20 kV.

Helvetica Chimica Acta – Vol. 98 (2015)
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Synthesis of AC/GO Hybrid. In this method, aminoclay nanostructures were allowed to form on the
surface of GO sheets dispersed in H2O. In a typical procedure, for the preparation of AC/GO hybrid 0.2 g
of GO were dispersed in 25 ml H2O by sonication for 10 min. To the dispersion, 0.84 g (3.62 mmol) of
MgCl2 was added followed by dropwise addition of 1.0 ml (5.85 mmol) of 3-(trimethoxysilyl)propan-1-
amine. The soln. was stirred for 48 h to form a brown-black slurry, which was dried at 1008. The solid thus
obtained was dispersed in H2O (20 ml) and precipitated from EtOH (30 ml). The precipitate was
centrifuged and subsequently dried at 608 to obtain the AC/GO hybrid [30].
Synthesis of the Cu/AC/r-GO Nanohybrid. AC/GO (40 mg) was first dispersed in 4 ml of deionized
H2O by sonication. To this transparent AC/GO suspension, 1 ml of 10 mm CuSO4 · 5 H2O soln. was added
followed by dropwise addition of 2 ml of 1m N2H4 · H2O soln. Then, Cu/AC/r-GO nanohybrid was
precipitated from EtOH (30 ml). The precipitate was centrifuged and subsequently dried in vacuo for 1 d
at ambient temp. to obtain the Cu/AC/GO nanohybrid [31].
Synthesis of 1,2,3-Triazolyl Carboacyclic Nucleosides 3a – 3o. To a 50-ml round-bottom flask was
added a mixture of alkyne (0.01 mol), azido alcohol (0.012 mol), and Cu/AC/r-GO nanohybrid (0.4 g,
0.008 mol-%) in H2O/THF 1:1 (30 ml). The mixture was stirred at r.t. until TLC monitoring indicated no
further progress in the conversion. The catalyst was filtered off and washed with THF, and the filtrate was
evaporated in vacuo to remove the solvent. The remaining foam was dissolved in CHCl3 (100 ml) and
subsequently washed with H2O (3 Â 100 ml). The org. layer was dried (Na2SO4) and evaporated. The
crude product was purified by CC (SiO2) and eluted with proper solvents described below.
1-{[1-(2-Hydroxycyclohexyl)-1H-1,2,3-triazol-4-yl]methyl}pyrimidine-2,4(1H,3H)-dione (3a).
Yield: 2.56 g (88%; CC (SiO2; AcOEt)). Colorless solid. M.p. 229 – 2308. IR (KBr): 3233 (br.), 3058s,
2930m, 1718s, 1707s, 1657m, 1495s. 1H-NMR ((D6)DMSO): 11.34 (s, NH, exchangeable with D2O); 8.08
(s, HÀC(5) of triazol); 7.79 (d, J ¼ 7.8, HÀC(6) of uracil); 5.65 (d, J ¼ 7.8, HÀC(5) of uracil); 5.11 – 4.94
(m, NCH2C¼C, CHOH); 4.24 – 4.22 (m, NCH); 3.75 (s, OH, exchangeable with D2O); 2.02 – 1.73 (m, 4
CH2). 13C-NMR ((D6)DMSO): 163.59; 150.69; 145.45; 141.46; 122.66; 101.15; 71.16; 65.84; 63.09; 42.31;
34.78; 31.79; 24.53. MS: 291 (16.1, Mþ). Anal. calc. for C13H17N5O3 (291.31): C 53.60, H 5.88, N 24.04;
found: C 53.52, H 5.76, N 23.95.
1-{[1-(2-Hydroxyoctyl)-1H-1,2,3-triazol-4-yl]methyl}pyrimidine-2,4(1H,3H)-dione (3b). Yield:
2.95 g (92%; CC (SiO2; AcOEt)). Colorless solid. M.p. 146 – 1478. IR (KBr): 3300 (br.), 3080s,
2978m, 1720s, 1708s, 1663m, 1475s. 1H-NMR ((D6)DMSO): 11.36 (s, NH, exchangeable with D2O); 8.04
(s, HÀC(5) of triazol); 7.77 (d, J ¼ 7.7, HÀC(6) of uracil); 5.65 (d, J ¼ 7.7, HÀC(5) of uracil); 5.12 – 5.02 (m,
CHOH); 4.98 (s, NCH2C¼C); 4.42 – 4.20 (m, NCH2CH); 3.83 (s, OH, exchangeable with D2O); 1.39 –
1.28 (m, 5 CH2); 0.90 (t, J ¼ 6.7, Me). 13C-NMR ((D6)DMSO): 163.51; 150.68; 145.40; 141.81; 124.25;
101.13; 68.85; 55.40; 42.23; 34.26; 31.16; 28.58; 24.71; 21.97; 13.87. MS: 321 (12.5, Mþ). Anal. calc. for
C15H23N5O3 (321.38): C 56.06, H 7.21, N 21.79; found: C 55.98, H 7.15, N 21.85.
1-{[1-(2-Hydroxybutyl)-1H-1,2,3-triazol-4-yl]methyl}pyrimidine-2,4(1H,3H)-dione (3c). Yield:
2.38 g (90%; CC (SiO2; AcOEt)). Colorless solid. M.p. 142 – 1438. IR (KBr): 3400 (br.), 3028s,
2956m, 1714s, 1701s, 1662m, 1472s. 1H-NMR ((D6)DMSO): 10.07 (s, NH, exchangeable with D2O); 8.11
(s, HÀC(5) of triazol); 7.66 (d, J ¼ 7.5, HÀC(6) of uracil); 5.92 (d, J ¼ 7.5, HÀC(5) of uracil); 5.52 (s,
NCH2C¼C); 4.94 – 4.97 (m, CHOH); 4.28 (dd, J ¼ 13.6, 3.2, 1 H of NCH2CH); 4.12 (dd, J ¼ 13.6, 7.4, 1 H
of NCH2CH); 3.68 (s, OH, exchangeable with D2O); 1.35 – 1.13 (m, MeCH2); 0.85 (t, J ¼ 7.2, MeCH2).
13C-NMR ((D6)DMSO): 163.62; 150.77; 143.28; 141.39; 123.84; 102.86; 71.84; 61.52; 50.21; 28.01; 9.79.
MS: 265 (13.8, Mþ). Anal. calc. for C11H15N5O3 (265.27): C 49.81, H 5.70, N 26.40; found: C 49.89, H 5.64,
N 26.48.
1-({1-[3-(4-Chlorophenoxy)-2-hydroxypropyl]-1H-1,2,3-triazol-4-yl}methyl)pyrimidine-2,4(1H,3H)-
dione (3d). Yield: 3.17 g (84%; CC (SiO2; AcOEt)). Colorless solid. M.p. 165 – 1668. IR (KBr): 3260
(br.), 3035s, 2968m, 1716s, 1704s, 1659m, 1461s, 1210s, 768s. 1H-NMR ((D6)DMSO): 11.12 (s, NH,
exchangeable with D2O); 7.85 (s, HÀC(5) of triazol); 7.48 (d, J ¼ 7.5, HÀC(6) of uracil); 7.11 (m, 2 arom.
H); 6.78 (m, 2 arom. H); 5.42 (d, J ¼ 7.5, HÀC(5) of uracil); 4.74 (s, NCH2C¼C); 4.40 – 4.23 (m, CHOH,
CH2O); 4.01 (s, OH, exchangeable with D2O); 3.77 – 3.70 (m, NCH2CH). 13C-NMR ((D6)DMSO):
163.71; 157.10; 150.93; 145.40; 141.98; 134.53; 129.16; 124.58; 116.19; 101.19; 69.79; 67.62; 52.58; 42.29.
MS: 377 (10.3, Mþ). Anal. calc. for C16H16ClN5O4 (377.78): C 50.87, H 4.27, Cl 9.38, N 18.54; found: C
50.81, H 4.32, Cl 9.46, N 18.48.

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Helvetica Chimica Acta – Vol. 98 (2015)
2-({1-[3-(2,4-Dichlorophenoxy)-2-hydroxypropyl]-1H-1,2,3-triazol-4-yl}methyl)-1,2,4-triazine-
3,5(2H,4H)-dione (3e). Yield: 3.34 g (81%; CC (SiO2; AcOEt)). White solid. M.p. 202 – 2038. IR (KBr):
3345 (br.), 3100s, 2971m, 1720s, 1705s, 1663m, 1459s, 1215s, 775s. 1H-NMR ((D6)DMSO): 12.54 (s, NH,
exchangeable with D2O); 7.88 (s, HÀC(5) of triazol); 7.42 (s, HÀC(5) of azauracil, 1 arom. H); 7.25 – 7.20
(m, 1 arom. H); 7.05 (d, J ¼ 7.5, 1 arom. H); 5.50 (s, OH, exchangeable with D2O); 4.87 (s, NCH2C¼C);
4.49 – 4.26 (m, CHOH, CH2O); 3.95 – 3.84 (m, NCH2CH). 13C-NMR ((D6)DMSO): 155.84; 152.77;
148.81; 141.30; 134.70; 129.20; 128.03; 124.68; 124.55; 122.46; 115.17; 70.64; 67.52; 52.47; 34.40. MS: 413
(15.7, Mþ). Anal. calc. for C15H14Cl2N6O4 (413.22): C 43.60, H 3.41, Cl 17.16, N 20.34; found: C 43.67, H
3.35, Cl 17.24, N 20.29.
3,7-Dihydro-7-({1-[2-hydroxy-3-(4-methylphenoxy)propyl]-1H-1,2,3-triazol-4-yl}methyl)-1,3-di-
methyl-1H-purine-2,6-dione (3f). Yield: 3.95 g (93%; CC (SiO2; AcOEt)). Colorless solid. M.p. 116 –
1
1178. IR (KBr): 3250 (br.), 3100s, 2945m, 1723s, 1711s, 1657m, 1461s, 1223s. H-NMR ((D6)DMSO):
8.02 (s, HÀC(8) of theophenyl); 7.97 (s, HÀC(5) of triazol); 6.91 (d, J ¼ 8.2, 2 arom. H); 6.65 (d, J ¼ 8.2, 2
arom. H); 5.43 (s, NCH2C¼C); 4.61 – 4.41 (m, CH2O); 4.34 – 4.25 (m, CHOH); 4.09 (br. s, OH,
exchangeable with D2O); 3.79 – 3.72 (m, NCH2CH); 3.32 (s, MeÀN(1)); 3.24 (s, MeÀN(3)); 2.07 (s,
ArÀMe). 13C-NMR ((D6)DMSO): 162.23; 156.08; 154.30; 150.83; 148.15; 134.47; 133.00; 129.37; 124.76;
114.15; 105.70; 69.36; 67.73; 52.67; 41.02; 29.25; 27.39; 19.92. MS: 425 (9.5, Mþ). Anal. calc. for
C20H23N7O4 (425.45): C 56.46, H 5.45, N 23.05; found: C 56.40, H 5.41, N 23.14.
3,7-Dihydro-7-({1-[2-hydroxy-3-(4-methoxyphenoxy)propyl]-1H-1,2,3-triazol-4-yl}methyl)-1,3-di-
methyl-1H-purine-2,6-dione (3g). Yield: 3.97 g (90%; CC (SiO2; AcOEt)). Colorless solid. M.p. 183 –
1
1848. IR (KBr): 3222 (br.), 3127s, 2931m, 1725s, 1710s, 1657m, 1439s, 1236s. H-NMR ((D6)DMSO):
8.13 (s, HÀC(8) of theophenyl); 8.07 (s, HÀC(5) of triazol); 6.83 – 6.75 (m, 4 arom. H); 5.54 (s,
NCH2C¼C); 5.51 – 5.49 (m, CHOH); 4.51 (dd, J ¼ 13.8, 3.3, 1 H of CH2O); 4.35 (dd, J ¼ 13.8, 7.5, 1 H of
CH2O); 4.15 (s, OH, exchangeable with D2O); 3.83 – 3.80 (m, NCH2CH); 3.65 (s, MeO); 3.35 (s,
MeÀN(1)); 3.16 (s, MeÀN(3)). 13C-NMR ((D6)DMSO): 154.29; 153.43; 152.22; 150.85; 148.17; 142.27;
141.99; 124.77; 115.31; 114.40; 105.72; 69.96; 67.75; 55.21; 52.68; 41.04; 29.28; 27.42. MS: 441 (10.3, Mþ).
Anal. calc. for C20H23N7O5 (441.45): C 54.42, H 5.25, N 22.21; found: C 54.31, H 5.39, N 22.27.
3,7-Dihydro-7-{[1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl]methyl}-1,3-dimethyl-1H-purine-2,6-dione
(3h). Yield: 2.86 g (94%; CC (SiO2; AcOEt/hexane 10 :1)). Colorless solid. M.p. 186 – 1878. IR (KBr):
3248 (br.), 3064s, 2952m, 1718s, 1706s, 1668m, 1449s. 1H-NMR (CDCl3): 8.19 (s, HÀC(8) of theophenyl);
8.09 (s, HÀC(5) of triazol); 5.59 (s, NCH2C¼C); 4.38 (t, J ¼ 5.2, CH2O); 3.77 (t, J ¼ 5.2, NCH2CH2); 3.43
(s, MeÀN(1)); 3.39 (s, OH, exchangeable with D2O); 3.24 (s, MeÀN(3)). 13C-NMR (CDCl3): 159.23;
154.41; 152.16; 148.63; 143.15; 122.54; 108.09; 63.37; 56.51; 49.53; 33.48; 29.88. MS: 305 (11.6, Mþ). Anal.
calc. for C12H15N7O3 (305.30): C 47.21, H 4.95, N 32.12; found: C 47.34, H 5.03, N 32.08.
3,7-Dihydro-1-{[1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl]methyl}-3,7-dimethyl-1H-purine-2,6-dione
(3i). Yield: 2.44 g (80%; CC (SiO2; AcOEt/MeOH 7:1)). Colorless solid. M.p. 212 – 2138. IR (KBr):
3300 (br.), 3058s, 2947m, 1720s, 1708s, 1661m, 1469s. 1H-NMR ((D6)DMSO): 8.04 (s, HÀC(8) of
theobromin); 7.94 (s, HÀC(5) of triazol); 5.12 (s, NCH2C¼C); 5.05 (s, OH, exchangeable with D2O); 4.35
(t, J ¼ 5.2, CH2O); 3.90 (s, MeÀN(7)); 3.76 (t, J ¼ 5.2, NCH2CH2); 3.43 (s, MeÀN(3)). 13C-NMR
((D6)DMSO): 155.29; 151.72; 150.80; 146.02; 143.58; 123.59; 106.59; 58.78; 56.39; 43.52; 31.28; 30.68.
MS: 305 (14.9, Mþ). Anal. calc. for C12H15N7O3 (305.30): C 47.21, H 4.95, N 32.12; found: C 47.31, H 4.90,
N 32.17.
2-{4-[(6-Amino-9H-purin-9-yl)methyl]-1H-1,2,3-triazol-1-yl}ethanol (3j). Yield: 2.13 g (82%; CC
(SiO2; AcOEt/MeOH 1:4)). Gray solid. M.p. > 2808 (dec.). IR (KBr): 3310 (br.), 3075s, 2981m, 1667m,
1458s. 1H-NMR ((D6)DMSO): 8.18 (s, HÀC(8) of adenine); 7.91 (s, HÀC(5) of triazol); 7.78 (s, HÀC(2) of
adenine); 7.21 (s, NH2, exchangeable with D2O); 4.65 (s, NCH2C¼C); 4.34 (t, J ¼ 7.0, CH2O); 4.16 (s, OH,
exchangeable with D2O); 3.78 (t, J ¼ 7.0, NCH2CH2). 13C-NMR ((D6)DMSO): 160.82; 153.63; 149.75;
144.96; 141.95; 124.60; 120.73; 60.87; 59.68; 58.49. MS: 260 (17.4, Mþ). Anal. calc. for C10H12N8O (260.26):
C 46.15, H 4.65, N 43.06; found: C 46.21, H 4.74, N 43.15.
3-{4-[(6-Amino-9H-purin-9-yl)methyl]-1H-1,2,3-triazol-1-yl}propan-1-ol (3k). Yield: 2.33 g (85%;
CC (SiO2; AcOEt/MeOH 1:4)). Gray solid. M.p. >3108 (dec.). IR (KBr): 3300 (br.), 3040s, 2973m,
1665m, 1462s. 1H-NMR ((D6)DMSO): 8.25 (s, HÀC(8) of adenine); 8.22 (s, HÀC(5) of triazol); 8.12 (s,
HÀC(2) of adenine); 7.32 (s, NH2, exchangeable with D2O); 4.96 (s, NCH2C¼C); 4.62 (s, OH,

Helvetica Chimica Acta – Vol. 98 (2015)
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exchangeable with D2O); 4.23 (t, J ¼ 7.7, CH2O); 3.85 (t, J ¼ 7.7, NCH2CH2); 1.90 – 1.78 (m, NCH2CH2).
13C-NMR ((D6)DMSO): 160.57; 154.24; 148.76; 145.01; 141.88; 125.09; 121.64; 63.94; 59.92; 50.69; 33.10.
MS: 274 (9.7, Mþ). Anal. calc. for C11H14N8O (274.29): C 48.17, H 5.14, N 40.85; found: C 48.25, H 5.06, N
40.80.
2-[4-(1H-Benzimidazol-1-ylmethyl)-1H-1,2,3-triazol-1-yl]ethanol (3l). Yield: 2.09 g (86%; CC
(SiO2; AcOEt)). Colorless solid. M.p. 150 – 1518. IR (KBr): 3237 (br.), 3046s, 2983m, 1670m, 1476s.
1H-NMR ((D6)DMSO): 8.33 (s, HÀC(2) of benzimidazole); 8.12 (s, HÀC(5) of triazol); 7.68 – 7.63 (m, 2
arom. H); 7.27 – 7.16 (m, 2 arom. H); 5.56 (s, NCH2C¼C); 4.34 (t, J ¼ 5.2, CH2O); 3.70 (t, J ¼ 5.2,
NCH2CH2); 3.40 (s, OH, exchangeable with D2O). 13C-NMR ((D6)DMSO): 145.65; 144.52; 141.17;
135.33; 126.98; 124.76; 123.35; 117.24; 116.10; 59.30; 57.37; 55.70. MS: 243 (9.2, Mþ). Anal. calc. for
C12H13N5O (243.27): C 59.25, H 5.39, N 28.79; found: C 59.37, H 5.31, N 28.84.
1-[4-(1H-Benzimidazol-1-ylmethyl)-1H-1,2,3-triazol-1-yl]-3-phenoxypropan-2-ol (3m). Yield:
2.79 g (80%; CC (SiO2; AcOEt)). Yellow oil. IR (film): 3283 (br.), 3052s, 2960m, 1671m, 1457s, 1225s.
1H-NMR ((D6)DMSO): 8.18 (s, HÀC(2) of benzimidazole); 8.08 (s, HÀC(5) of triazol); 7.33 – 7.04 (m, 9
arom. H); 5.59 – 5.57 (m, CHOH); 5.13 (s, NCH2C¼C); 4.56 (dd, J ¼ 13.8, 3.4, 1 H of CH2O); 4.39 (dd,
J ¼ 13.8, 7.6, 1 H of CH2O); 4.21 (s, OH, exchangeable with D2O); 3.90 – 3.85 (m, NCH2CH). 13C-NMR
((D6)DMSO): 159.15; 146.08; 143.81; 139.68; 135.22; 130.11; 124.68; 123.42; 122.12; 120.51; 118.61;
116.35; 114.78; 73.31; 65.91; 61.46; 59.84. MS: 349 (8.5, Mþ). Anal. calc. for C19H19N5O2 (349.39): C 65.32,
H 5.48, N 20.04; found: C 65.37, H 5.46, N 20.10.
2-{4-[(2-Methyl-1H-benzimidazol-1-yl)methyl]-1H-1,2,3-triazol-1-yl}ethanol (3n). Yield: 2.23 g
(87%; CC (SiO2; AcOEt)). Creamy solid. M.p. 170 – 1718. IR (KBr): 3320 (br.), 3080s, 2945m, 1668m,
1481s. 1H-NMR ((D6)DMSO): 8.05 (s, HÀC(5) of triazol); 7.25 – 7.09 (m, 4 arom. H); 4.65 (s,
NCH2C¼C); 4.40 (t, J ¼ 7.2, CH2O); 4.06 (s, OH, exchangeable with D2O); 3.74 (t, J ¼ 7.2, NCH2CH2);
2.48 (s, Me). 13C-NMR ((D6)DMSO): 147.33; 144.90; 141.87; 135.46; 127.51; 125.08; 123.54; 118.69;
117.16; 60.12; 59.20; 57.68; 18.02. MS: 257 (15.1, Mþ). Anal. calc. for C13H15N5O (257.30): C 60.69, H 5.88,
N 27.22; found: C 60.62, H 5.31, N 27.29.
3-{4-[(2-Methyl-4-nitro-1H-imidazol-1-yl)methyl]-1H-1,2,3-triazol-1-yl}propan-1-ol (3o). Yield:
2.42 g (91%; CC (SiO2; AcOEt)). Brown oil. IR (film): 3325 (br.), 3050s, 2972m, 1665m, 1537s, 1486s,
1348s. 1H-NMR ((D6)DMSO): 8.01 (s, HÀC(5) of triazol); 7.82 (s, HÀC(5) of imidazole); 4.83 (s,
NCH2C¼C); 4.17 (s, OH, exchangeable with D2O); 3.83 – 3.78 (m, CH2O, NCH2CH2); 2.47 (s, Me);
1.94 – 1.89 (m, NCH2CH2). 13C-NMR ((D6)DMSO): 152.99; 148.88; 144.83; 124.16; 119.46; 61.52; 52.13;
47.78; 29.89; 15.79. MS: 266 (10.7, Mþ). Anal. calc. for C10H14N6O3 (266.26): C 45.11, H 5.30, N 31.56;
found: C 45.17, H 5.38, N 31.49.
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Received June 14, 2015