CuSO4/KI as catalyst for the synthesis of 1,4-disubstituted-1,2,3-triazolo-nucleosides

Article abstract of DOI:10.1080/15257770.2015.1014047

A simple and inexpensive procedure has been developed for the selective formation of 1, 4-disubstituted-1,2,3-triazolo-nucleosides starting from organic azides and terminal alkynes, mediated by in situ generated copper(I) catalyst from readily available C

Full text of DOI:10.1080/15257770.2015.1014047

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CuSO4/KI As Catalyst for the Synthesis
of 1,4-Disubstituted-1,2,3-Triazolo-
Nucleosides
Hanane Elayadia & Hassan Bihi Lazreka
a Laboratory of Biomolecular and Medicinal Chemistry, Faculty of
Science Semlalia, Cadi Ayyad University, Marrakech, Morocco
Published online: 12 May 2015.
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To cite this article: Hanane Elayadi & Hassan Bihi Lazrek (2015) CuSO4/KI As Catalyst for the Synthesis
of 1,4-Disubstituted-1,2,3-Triazolo-Nucleosides, Nucleosides, Nucleotides and Nucleic Acids, 34:6,
433-441, DOI: 10.1080/15257770.2015.1014047
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Nucleosides, Nucleotides and Nucleic Acids, 34:433–441, 2015
Copyright ꢀC Taylor and Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770.2015.1014047
CuSO4/KI AS CATALYST FOR THE SYNTHESIS
OF 1,4-DISUBSTITUTED-1,2,3-TRIAZOLO-NUCLEOSIDES
Hanane Elayadi and Hassan Bihi Lazrek
Laboratory of Biomolecular and Medicinal Chemistry, Faculty of Science Semlalia,
Cadi Ayyad University, Marrakech, Morocco
A simple and inexpensive procedure has been developed for the selective formation of 1,
2
4-disubstituted-1,2,3-triazolo-nucleosides starting from organic azides and terminal alkynes, me-
diated by in situ generated copper(I) catalyst from readily available CuSO4 and KI.
Keywords Copper catalysts; click reaction; CuSO4/KI; 1,2,3-triazolyl nucleoside;
one-pot [3+2] cycloaddition
INTRODUCTION
Copper-based catalysts play an important role in the cycloaddition reac-
tion between azides and alkynes, often referred to as click chemistry.[1] The
method developed has been applied in organic synthesis, chemical biology
and materials science.[2,3] Generally, the copper source used comes from
direct addition of Cu(I) species[4] or reduction of Cu (II) salt to Cu (I),[5]
oxidation of copper metal turnings to give Cu(I) species,[6] or copper com-
plexes with suitable ligands.[7] The above approaches involve homogeneous
system.
Despite, the above advantages of these catalytic processes, some draw-
backs still remain, an oxidant agent is required[6] and a significant amount
of catalyst is necessary. Also, copper (I) salts are prone to redox processes,
thus nitrogen or phosphorus-based ligands must be used to protect and sta-
bilize the active copper catalyst during the cycloaddition reaction.[8] As a
complement to the previous methods, and in continuation to our research
Received 6 September 2014; accepted 28 January 2015.
Address correspondence to Hassan Bihi Lazrek, Laboratory of Biomolecular and Medicinal
Chemistry, Faculty of Science Semlalia, Cadi Ayyad University BO 2390, 40001 Marrakech, Morocco.
E-mail: hblazrek50@gmail.com
Color versions of one or more of the figures in the article can be found online at
www.tandfonline.com/lncn.
433

434
H. Elayadi and H. B. Lazrek
SCHEME 1 Screening of copper catalysts in the synthesis of compound 3a.
work on click reactions,[9] we describe herein, a simple, efficient, and inex-
pensive method for the formation of 1,4-disubstituted 1,2,3-triazole starting
from organic azide and terminal alkyne, mediated by in situ generated cop-
per(I) catalyst from readily available CuSO4 and KI.
RESULTS AND DISCUSSION
The condensation between benzyl azide 2a and propargyluracil 1 was
selected as a model reaction for optimization of the reaction conditions
(Scheme 1, Table 1).
a = U : Uracil
As shown in Table 1 (entries 1, 2) when CuSO4 was used alone low
yields of the desired product were obtained. In addition, to find the most
suitable solvent for this reaction, we investigated the use of different organic
solvents (i.e., MeOH, or dioxane), as well as mixed solvents (dioxane/water,
dioxane/EtOH, dioxane/iPrOH, dioxane/t-BuOH, dioxane/Ionic Liquid).
The yields obtained were rather poor (Table 1, entries 1, 5, 19, and 20). The
effect of the amount of the CuSO4/KI mixture was also studied increasing the
amount of catalyst mixture used from 0.1 to 1eq. The best result was obtained
with ratio 0.1eq/0.1eq (Table 1, entries 10–16). Preliminary experiments
allowed us to select 90◦C as the optimal reaction temperature to achieve
high conversions (Table 1, entry 9).
On the basis of the observation previously reported by Yamamoto
et al.[10a] that Cu(II) can be reduced to Cu(I) in MeOH, and the observation
reported by G. R. Dey[10b] that Copper (II) sulfate reacts with potassium
iodide to afford copper (II) iodide, which decomposes immediately to yield
CuI and I2. Reactions (1) to (3) (Scheme 2).
Taking these reactions into account and considering the easy prepara-
tion of the catalyst, the commercial availability of CuSO4 and KI, we carried

Catalyst for Synthesis of 1,4-Disubstituted-1,2,3-Triazolo-Nucleosides
435
TABLE 1 Effects of copper source and solvent on click reaction yield of 3a after 2 h at 90◦C
Entry
Copper source
Copper loading (eq) solvent
Time(h) Yield%
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
CuSO4
CuSO4
0.1
0.1
Dioxane/water
Dioxane/MeOH
MeOH
2
2
2
2
2
2
2
2
16
20
21
18
0
CuSO4/KI
CuSO4/KI
CuSO4/KI
CuSO4/KI
CuSO4/KI
CuSO4/KI
CuSO4/KI
CuSO4/KI
CuSO4/KI
CuSO4/KI
CuSO4/KI
CuSO4/KI
CuSO4/KI
CuSO4/KI
CuSO4/KF
CuI
0.1/0.1
0.1/0.1
0.1/0.1
0.1/0.1
0.1/0.1
0.1/0.1
0.1/0.1
0.1/0.1
0.25/0.25
0.5/0.5
0.75/0.75
1/1
0.1/0.05
0.1/excess
0.1/0.1
0.1
0.1/0.1
0.1/0.1
0.1/0.2
Dioxane
Dioxane/water
Dioxane/EtOH
Dioxane/tBuOH
Dioxane/iPrOH
Dioxane/MeOH
Dioxane/MeOH
Dioxane/MeOH
Dioxane/MeOH
Dioxane/MeOH
Dioxane/MeOH
Dioxane/MeOH
Dioxane/MeOH
Dioxane/MeOH
Dioxane/MeOH
Dioxane/ILb
15
5
11
68
72
69
62
41
35
32
38
0
12a
2
2
2
2
2
2
2
2
2
2
2
2
0
CuSO4/KI
CuSO4/KI
CuSO4/Na ascorbate
28
17
71
MeOH/ILb
Dioxane/water
aReaction carried out at room temperature.
bIL: Ionic liquid (1-butyl-3methyl imidazolium chloride).
out the reaction between propargyluracil 1 and phenylazide 2a (Scheme 1)
in Dioxane/MeOH at 90◦C (Table 1, entry 10) the yield increased to 72%.
Remarkably, the use of a base or additive was not necessary to ensure good
yield.
When the reaction is carried out using the standard conditions, for
instance, CuSO4/Na Ascorbate (0.1eq/0.2eq) and Dioxane/H2O, the 1,2,3-
triazole derivative 3a is obtained with 71% yield (Table 1, entry 21).On
SCHEME 2 Balanced redox reaction of CuSO4+KI.
SCHEME 3 Reactions taking place using the CuSO4/KI dioxane/MeOH system.

436
H. Elayadi and H. B. Lazrek
SCHEME 4 One-pot tandem reactions.
the other hand, no 1,2,3-triazole formation was observed when CuI and
Dioxane/MeOH were used (Table 1, entry 18) highlighting the key role of
the CuSO4/KI as catalyst.
With an optimized catalytic system in hand, we next investigated the
scope of the reaction. Three reactions were studied using alkyl azide, benzyl
azide, and azido sugar with ethyl propiolate. The CuSO4/KI catalyst mixture
showed the same activity giving the 1,2,3-triazole 4a, 4b, and 4c (Scheme 3)
in good yield (Tables 2 and 3) after simple extraction and purification by
flash column.
It is worthy to note that azido sugar could be also used as the azide pre-
cursor in the reaction with alkynes substituted with nucleobases (Uracil,
Thymine, 6-Azauracil, Adenine) Scheme 3, Table 4. As expected, in all

Catalyst for Synthesis of 1,4-Disubstituted-1,2,3-Triazolo-Nucleosides
437
TABLE 2 1,2,3-Triazole products 3(a–d) generated with the CuSO4/KI dioxane/MeOH mixture
Entry
RN3
R1
Yield (%)
1
2
3
4
Ph-CH2-N3
Ph-CH2-N3
Ph-CH2-N3
Ph-CH2-N3
CH2-U 3a
CH2-T 3b
CH2-A 3c
CH2-AzU
3d
72
65
69
60
a, U: Uracil; b, T: Thymine; c, A: Adenine; d, AzU: 6-Azauracil.
TABLE 3 1,2,3-Triazole products 4a–c generated under conditions CuSO4/KI, dioxane/MeOH
mixture
Entry
RN3
R1
Yield (%)
1
2
Ph-CH2-N3
CO2Et 4a
CO2Et 4b
66
77
3
CO2Et 4c
66
TABLE 4 1,2,3-Triazole5a–d products generated with the CuSO4/KI dioxane/MeOH mixture
Entry
1
RN3
R1
Yield (%)
73
CH2-U5a
2
3
4
CH2-T5b
CH2-A5c
60
65
64
CH2-AzU5d
aConditions: Azide(1,1 mmol), Alkynes(1 mmol), CuSO4/KI (0.1eq/0.1eq), 90◦C, solvent:
Dioxane/MeOH (2/1) (3 mL), 2 h.
bIsolated yield.

438
H. Elayadi and H. B. Lazrek
TABLE 5 Results for one-pot tandem reactions
Entry
Alkyne
Products
Time (h)
Yield (%)a
1
2
3
3a
3a
3c
4
4
51
27b
46
5.30
4
4a
4
49
Conditions: azide (1.1 mmol), alkynes (1 mmol), CuSO4/KI (0.1eq/0.1eq), solvent: Dioxane/MeOH
(2/1, 3 mL), 90◦C, 4 h to 5 h 30.
aIsolated yield.
bSolvent: Dioxane/H2O.
cases the prepared 1,4-substituted-1,2,3-triazolo nucleosides analogous 5a–d
were obtained in good yields as a single regioisomer. The structures of all
compounds 5a–d were established on the basis of their spectroscopic data
(1H, 13C, NMR, and Mass).[9]
RESULTS FOR ONE-POT REACTIONS
Recently, one-pot synthetic strategies have become an attractive alter-
native to traditional sequential approaches for preparing triazole com-
pounds.[11] To search for new methods for the synthesis of diverse triazole,
we studied the one-pot tandem [3 + 2] cycloaddition reactions[12] where ben-
zylbromide was reacted with propargyl derivatives and sodium azide in the
presence of CuSO4/KI as catalyst in dioxane/MeOH as solvent (Scheme 4).
The reaction mixture was refluxed for 4–5.30 h and the products were iso-
lated by simple purification using flash column chromatography. As shown
in Table 5, the one-pot reaction proceeded efficiently to provide the desired
products in fair to good yields.
CONCLUSION
In conclusion, we have reported for the first time the couple CuSO4/KI
as an active catalyst in the Huisgen [3 + 2] cycloaddition of azides (alkyl,
benzyl, sugar) with terminal alkynes (Propargyl purine and pyrimidines) in
nonaqueous medium to provide 1,4-disubstituted 1,2,3-triazolonucleoside
analogous. Furthermore, CuSO4/KI serves as a novel and efficient catalyst
without any additives under aerobic conditions.

Catalyst for Synthesis of 1,4-Disubstituted-1,2,3-Triazolo-Nucleosides
439
EXPERIMENTAL SECTION
General Methods
All starting materials for synthesis were purchased from Alfa Aesar, Fluka,
or Sigma Aldrich, Thin-layer chromatography (TLC): aluminum sheets, sil-
ica gel 60 F254. Melting points were measured using a Stuart Scientific melt-
ing point apparatus. NMR spectra were recorded with a Bruker AC-300 MHz
and AC-400 MHz in CDCl3 and DMSO-d6 with SiMe4 as an internal standard.
Chemical shifts are given in ppm and spin–spin coupling constants, J , are
given in Hz (s, singlet; d, doublet; t, triplet; m, multiplet, and br, broad). ESI-
mass spectrometry was performed on a Fisons instrument equipped with a
VG platform II with quadrupole analyzer. High-resolution mass spectrometry
was provided by a MALDI Orbitrap LTQ XL instrument (Thermo Fisher).
Synthesis of 1,2,3-Triazoles Using CuSO4/KI as Catalyst
Terminal alkynes (1 mmol), organic azides (1.1 mmol), and CuSO4/KI
(0.1eq/0.1eq) were suspended in Dioxane/MeOH (2/1, v/v) and stirred
under reflux 90◦C for 2 h. Then, the solution was evaporated, and the
residue was applied to flash column chromatography (silica gel). All the
spectroscopic data of the reaction CuAAC products were compared with
those reported in the literature.[9]
Typical Procedure for One Pot Tandem Reactions1,3-Dipolar Cycloaddition
Benzylbromide (1.1 mmol) was reacted with propargyl derivatives
(1 mmol) and sodium azide (1,1 mmol) in the presence of CuSO4/KI
(0.1eq/0.1eq) as catalyst in Dioxane/MeOH (2/1, 3 mL) as solvent. The
reaction mixture was refluxed for 4 h and the products were isolated by
simple purification using flash column chromatography (silica gel). All the
spectroscopic data of the reaction CuAAC products were compared with
those reported in the literature.[9]
HIGHLIGHTS
CuSO4/KI as an effective catalyst in the Huisgen [3 + 2] cycloaddition of
organic azides and terminal alkynes.
It is
a
convenient procedure to obtain 1,4-disubstituted 1,2,3-
triazolonucleoside analogous.
CuSO4/KI serves as a novel and efficient catalyst without any additives under
aerobic conditions.

440
H. Elayadi and H. B. Lazrek
FUNDING
This project was supported by the Centre National de Recherche Scien-
tifique et Technique (CNRST, Rabat, Morocco): Research programme RS
2011/01.
ACKNOWLEDGMENTS
We would like to thank Professor J. L. M. Abboud (Fukuoka University,
Japan) for his help and encouragement. We express our thanks to Profes-
sor A. Lachgar (Department of Chemistry Wake Forest University, Winston
Salem, NC, United States) for his helpful discussion.
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