CuI/L-proline catalyzed click reaction in glycerol for the synthesis of 1,2,3-triazoles

Article abstract of DOI:10.1016/j.tetlet.2018.11.078

Despite the apparent simplicity of the copper(I) iodide catalyzed CuAAC reaction, the conversion of the catalytic species, i.e. Cu(I) to thermodynamically more stable Cu(II), via aerial oxidation or disproportionation is a major issue. To stabilize the Cu

Full text of DOI:10.1016/j.tetlet.2018.11.078

Accepted Manuscript
CuI/L-proline catalyzed Click reaction in glycerol for the synthesis of 1,2,3-
triazoles
Bala Gangadhar Pasupuleti, Ghanashyam Bez
PII:
S0040-4039(18)31432-1
https://doi.org/10.1016/j.tetlet.2018.11.078
TETL 50463
DOI:
Reference:
Tetrahedron Letters
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23 November 2018
30 November 2018
Please cite this article as: Pasupuleti, B.G., Bez, G., CuI/L-proline catalyzed Click reaction in glycerol for the
synthesis of 1,2,3-triazoles, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.11.078
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Graphical Abstract
CuI/L-proline catalyzed Click reaction in glycerol
for the synthesis of 1,2,3-triazoles
Bala Gangadhar Pasupuleti and Ghanashyam Bez

Tetrahedron Letters
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Tetrahedron Letters
CuI/L-proline catalyzed Click reaction in glycerol for the synthesis of 1,2,3-triazoles
Bala Gangadhar Pasupuletia and Ghanashyam Beza*
aDepartment of Chemistry, North Eastern Hill University, Shillong-793022, Meghalaya, India
Phone: +913642722624 (O); e-mail: ghanashyambez@yahoo.com; bez@nehu.ac.in
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Despite the apparent simplicity of the copper(I) iodide catalyzed CuAAC reaction, the
conversion of the catalytic species, i.e. Cu(I) to thermodynamically more stable Cu(II), via aerial
oxidation or disproportionation is a major issue. To stabilize the Cu(I) species, the reaction is
ideally carried out under an inert atmosphere in the presence of additives such as alcohols,
amines, thiols, and aldehydes. Herein, we report the first CuI catalyzed click reaction without an
inert atmosphere by employing the CuI/L-proline system in glycerol. The method showed
remarkable stability towards sensitive functional groups such as acetonides and 1,2,4-trioxanes.
Available online
Keywords:
CuI
L-proline
2009 Elsevier Ltd. All rights reserved.
Glycerol
Click reaction
1,2,3-triazole
No inert atmosphere
Introduction
Regioselective synthesis of 1,4-disubstituted 1,2,3-triazoles
via the CuAAC reaction, also known as the click reaction, in the
presence of a copper catalyst is one of the most thoroughly
studied reactions in organic synthesis.1-4 Due to the fact that
Cu(I) is the catalytic species, the reaction generally employs
Cu(I) salts directly or Cu(II) salts in the presence of reducing
agents such as sodium ascorbate. Most methodologies have
attempted to optimize the stability of the Cu(I) catalytic species
by either complexation with appropriate ligands5-17 and/or adding
stabilizing additives such as amines.18 Since Cu(I) is
thermodynamically less stable than Cu(II), it can undergo either
oxidation to the catalytically inactive Cu(II) species or
disproportionation to a mixture of Cu(II) and Cu(0). Therefore,
maintaining an optimum concentration of the catalytic species,
i.e. Cu(I), is critical to achieving high yields. Additionally, the
formation of Cu(II) further facilitates Glaser-type alkyne
coupling processes leading to poor triazole formation.19 The use
of amines, as ligands or additives, prevents the formation of
unreactive polynuclear copper(I) acetylides and facilitates
coordination of the azide to the copper center at the ligand
exchange step (vide infra) by increasing the concentration of the
Cu(I)-species through adequate solubilization. Therefore, the
nature of the amine plays a critical role in the stability, reactivity
and concentration of the Cu(I) species. It is interesting to note
that the most commonly used Cu(I) source, i.e. CuI, gives poor
yields of 1,4-disubstituted 1,2,3-triazoles in the presence of
oxygen or air. Therefore, most reported methods4,20 employing
CuI are conducted under an inert atmosphere to avoid oxygen
mediated conversion of Cu(I) to the catalytically inactive Cu(II)
species. In this work, we proposed to screen a series of amine
additives and solvents so that the effect of oxygen can be
minimized to improve the yield in the CuAAC reaction. The
study led to a simple and highly effective CuAAC reaction
catalyzed by readily available CuI in glycerol with L-proline as
an additive in the presence of air (Scheme 1).
Scheme 1. Synthesis of 1,4-disubstituted 1,2,3-triazoles
As noted earlier, the selection of amine base is critical to the
success of the Cu(I) salt catalysed CuAAC reaction. While an
excess of amine base is necessary to facilitate deprotonation of
the alkyne to form the reactive Cu(I)-acetylide complex and to
stabilize the active Cu(I) species against oxidation or
disproportionation, it negatively effects the yield by promoting
both alkyne and triazole homocoupling.4,18,21 We presumed that if
base catalysts that can act as bidentate or multidentate ligands
were used, they could further stabilize the Cu(I) species. To test
the viability of our proposal, we examined the model reaction of
benzyl azide and phenyl acetylene in the presence of amine
additives such as L-proline, glycine, L-alanine, L-serine,
triethanolamine, N-methyldiethanolamine, and diethanolamine
that can potentially act as bidentate or tridentate ligands to
stabilize the Cu(I) species. Additionally, simpler amine additives
such as Et3N, DBU, DABCO, DIPEA, and DEA were also
chosen for screening. The model reaction was carried out at room
temperature so that our reaction conditions would be compatible
with substrates possessing sensitive functional groups. Initially, a
mixture of benzyl azide (1 mmol), phenyl acetylene (1 mmol),
CuI (0.01 mmol), and L-proline (0.01 mmol) in acetonitrile (4
mL) was stirred at room temperature for 6 h. The reaction was
conducted in acetonitrile because it is known to contribute to the
stabilization of the Cu(I) species. Initially the reaction progressed
quickly giving approximately 50% conversion in the first 2 h, but
an additional 6 h was required for the complete consumption of
phenyl acetylene and some of the benzyl azide remained

2
Tetrahedron Letters
unreacted. Purification of the reaction mixture by column
chromatography gave only 70% isolated yield. When the model
reaction was carried out in the presence of other amino acids such
as glycine, L-alanine, and L-serine under similar reaction
conditions, the results were less encouraging in terms of reaction
time and yield. When amine additives such as triethanolamine,
N-methyldiethanolamine, and diethanolamine were examined to
determine the effect of hydroxy group carrying amine additives,
we did not observe any improvement in comparison to the amino
acid additives (Table 1, entries 5-7). The use of readily available
amines such as Et3N, DBU, DABCO, DIPEA, and DEA in place
of L-proline resulted in reduced yields despite increasing the
reaction time to 12 h. Interestingly, the reaction gave 32%
isolated yield after 12 h without amine additives. The poor yield
might be due to the formation of unreactive polynuclear copper(I)
acetylides or the formation of unreactive Cu(II) species.
improvement, but ethylene glycol and glycerol substantially
improved the yield of the reaction. In order to determine the
effect of water in the reaction, the model reaction was carried out
in various ratios of glycerol-water (Table 2, entries 6-8). The
reactions were slow and gave low yields. Unlike acetonitrile, we
observed that the reaction was slow for the first 4 h and increased
thereafter to proceed to completion within 6 h. We presumed that
the lower solubility of L-proline and CuI in glycerol might be
involved. Therefore, the model reaction was conducted after
mixing L-proline and CuI in glycerol in a sonicator bath. To our
pleasure, the reaction was complete within 2 h to give complete
conversion and 94% isolated yield.
Table 2. Screening of solvents for the click reactiona
Table 1. Screening of amine additives for the click reactiona, b
Entry
Solvent
Time (h)
Yield
(%)b
70
67
53
1a
1
2
3
4
5
6
7
8
9
Ethanol
Isopropanol
t-Butanol
Monoethylene glycol
Glycerol
Glycerol: H2O (1:1)
Glycerol: H2O (2:1)
Glycerol: H2O (1:2)
Glycerol
12
12
12
12
Entry
Amine additive
Time (h)
Yield
(%)c
70
62
59
1a
77
6
92
39
47
28
94c
1
2
3
4
L-proline
glycine
L-alanine
L-serine
8
12
12
12
2
12
12
12
52
5
6
7
8
Triethanolamine
N-Methyldiethanolamine
Diethanolamine
Triethylamine
DBU
DABCO
DIPEA
DEA
None
12
12
12
12
12
12
12
12
12
3
51
57
52
45
39
36
47
49
32
94d
aReaction was conducted on a 1 mmol scale in 4 mL solvent
bIsolated yield after purification by column chromatography
cPremixed CuI and L-proline in glycerol by sonication
9
10
11
12
13
14
Having optimized the additives and solvent, we screened the
catalyst loading and its ratio with L-proline (Table 3). These
results suggest that an equimolar mixture of L-proline and 1
mol% CuI is optimal. Increasing the catalyst loading gave no
noticeable improvement in yield, while a decreased catalyst
loading led to incomplete reaction during the same reaction time.
At the same time, variation of the CuI to L-proline ratio showed
that the concentration of L-proline contributed to the overall yield
(Entries 4, 5).
L-proline
aReaction was conducted on a 1 mmol scale
bReaction did not give complete conversion except in the case of L-proline
cIsolated yield after purification by column chromatography
dReaction was carried out under an N2 atmosphere
The reaction under a nitrogen atmosphere proceeded more
efficiently to give the desired product in 94% isolated yield
(Entry 14). These observations confirmed that although the use of
L-proline as an additive helped stabilize the Cu(I) species to some
extent, it is not enough to completely prevent the aerial oxidation
of Cu(I) to the unreactive Cu(II) species. In 2009, Zhu and co-
workers reported a Cu(OAc)2 catalyzed CuAAc reaction between
2-picolylazide and propargyl alcohol in an alcohol media in the
absence of additives.22 From spectroscopic evidence, they
concluded that Cu(II) was reduced to the active Cu(I) species
either by alcohol oxidation or by alkyne oxidative homocoupling.
Since our aim was to enhance the efficiency of the CuI catalysed
CuAAC reaction in the presence of air, we therefore explored the
role of alcohol solvents to counter the aerial oxidation of the
catalytic species. Since iodide anions are known to act as
bridging ligands for Cu(I) ions resulting in the formation of
unproductive polymeric Cu(I)-acetylide complexes,23 we
proposed that the use of alcohol solvents may help in avoiding
such deleterious complexation. For this purpose, we screened a
series of solvents which may undergo oxidation in the presence
of the cupric ion that can itself be reduced to the catalytically
active Cu(I) species (Table 2). The use of solvents such as
ethanol, isopropanol, and t-butanol did not give any noticeable
Table 3. Optimization of catalyst loading for the click
reactiona,b
Entry
CuI (mol%)
L-proline (mol%)
Yield
(%)c
94
83
94
1a
1
2
3
4
1
1
0.5
1.5
1
0.5
1.5
0.5
85
5
1
1.5
93
aReaction was conducted on a 1 mmol scale in 4 mL glycerol
bPremixed CuI and L-proline in glycerol by sonication
cIsolated yield after purification by column chromatography
With the optimized protocol in hand, we studied its substrate
scope using the reaction of various alkyl, benzyl, and aryl azides
with phenyl acetylene (Table 4). The reaction is efficient in all
cases giving excellent yields and was not dependent on the nature
of the azide. Variation of the alkyne counterpart also did not have
a noticeable effect on the yield.
Table 4. Substrate scope for the CuI/L-proline catalyzed click reactiona,b

Tetrahedron Letters
3
Entry
1
R1N3
Product
Time (h)
2
Yield (%)c
94
2
3
2
3
91
93
4
5
6
3
2
89
90
3
2
92
90
7
8
3
2
86
91
9
10
3
86
aReaction was conducted on a 1 mmol scale in 4 mL glycerol
bPremixed CuI and L-proline in glycerol by sonication
cIsolated yield after purification by column chromatography
Since 1,2,3-triazole containing compounds are known to
possess interesting pharmacological activities such as
antimicrobial, antiretroviral, anti-inflammatory, antiproliferative,
anticonvulsant properties,24,25 and are excellent H-bond acceptors
of biomolecular targets, they have found applications in various
drugs.26-31 In recent years, 1,2,3-trizoles have found immense
importance as a linker in the synthesis of bioconjugates due to
their stability under a wide pH range and also redox conditions
under physiological conditions.32 Nevertheless, they are stable
against metabolic degradation.33 We tested the viability of our
protocol using propargylated dihydroartemisinin possessing a
highly sensitive 1,2,4-trioxane unit (Scheme 2). The reaction was
complete within 4 h to give 75% isolated yield.
reaction conditions are compatible with the sensitive acetonide
group (Table 5, compound 3f).
Scheme 2. CuI/L-proline catalysed CuAAC reaction using a
dihydroartemisinin derivative
The method was extended to synthesize a 1,2,4-trioxane dimer
(73%) by reacting a 1,2,4-trioxane tethered azide with 1,4-
diethynylbenzene (0.5 equiv.) under the optimized reaction
conditions (Scheme 3) and it is interesting to compare with the
reported methods.34
Encouraged by the success of our method using propargylated
dihydroartemisinin, we extended the reaction for synthetic 1,2,4-
trioxane tethered azides with four different alkynes (Table 5).
High yields of 1,2,3-triazole tethered 1,2,4-trioxanes were
obtained which we are planning to test for antimalarial and
antitumor efficacy. These observations also suggest that the

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Tetrahedron Letters
Table 5. CuI/L-proline catalyzed click reaction in the 1,2,4-trioxane systema,b,c
aReaction was conducted on a 0.25 mmol scale in 1 mL glycerol
bPremixed CuI and L-proline in glycerol by sonication
cIsolated yield after purification by column chromatography
12. Wang, D.; Zhao, M.; Liu, X.; Chen, Y.; Li, N.; Chen, B. Org. Biomol.
Chem. 2012, 10, 229.
13. Gonda, Z.; Novák, Z. Dalton Trans. 2010, 39, 726.
14. Liang, L.; Ruiz, J.; Astruc, D. Adv. Synth. Catal. 2011, 353, 3434.
15. Özçubukçu, S.; Ozkal, E.; Jimeno, C.; Pericàs, M. A. Org. Lett. 2009,
11, 4680.
16. Díez-González, S.; Nolan, S. P. Angew. Chem. Int. Ed. 2008, 47, 8881.
17. Teyssot, M. L.; Chevry, A.; Traïkia, M.; El-Ghozzi, M.; Avignant, D.;
Gautier, A. Chem.-Eur. J. 2009, 15, 6322.
18. Gerard, B.; Ryan, J.; Beeler, A. B.; Porco, J. A. Tetrahedron 2006, 62,
6405.
Scheme 3. Synthesis of a 1,2,3-triazole tethered 1,2,4-trioxane
19. Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem. Int. Ed.
2000, 39, 2632.
dimer
20. (a) Rostovtsev, V.V.; Green, L. G.; Fokin, V.V.; Sharpless, K. B.
Angew. Chem. Int. Ed. 2002, 41, 2596. (b) Dehaen, W.; Bakulev, V. A.
Chemistry of 1,2,3-Triazoles, 1st ed.; Springer, New York, 2014.
21. Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew.
Chem. Int. Ed. 2002, 41, 2596.
In conclusion, we have developed an efficient method for the
CuI catalyzed CuAAC reaction in glycerol medium, using L-
proline as an additive without employing an inert atmosphere.
The protocol was also tested for its compatibility with the
sensitive acetonide group and 1,2,4-trioxane systems.
22. Brotherton, W. S.; Michaels, H. A.; Simmons, J. T.; Clark, R. J.; Dalal,
N. S.; Zhu, L. Org. Lett. 2009, 11, 4954.
23. Liang, L.; Astruc, D. Coord. Chem. Rev. 2011, 255, 2933.
24. Kharb, R.; Sharma, P. C.; Yar, M. S. J. Enzyme Inhib. Med. Chem.
2011, 26, 1.
Acknowledgments
25. Ferreira, V. F.; da Rocha, D. R.; da Silva, F. C.; Ferreira, P. G.;
Boechat, N. A.; Magalhães, J. L. Expert Opin. Ther. Pat. 2013, 23, 319.
26. Whiting, M.; Muldoon, J.; Lin, Y.-C.; Silverman, S. M.; Lindstrom, W.;
Olson, A. J.; Kolb, H. C.; Finn, M. G.; Sharpless, K. B.; Elder, J. H.;
Fokin, V. V. Angew. Chem. Int. Ed. 2006, 45, 1435.
27. Horne, W. S.; Yadav, M. K.; Stout, C. D.; Ghadiri, M. R. J. Am. Chem.
Soc. 2004, 126, 15366.
28. Agalave, S. G.; Maujan, S. R.; Pore, V. S. Chem - Asian J. 2011, 6,
2696.
Sophisticated Analytical Instruments Facility, NEHU is
acknowledged for analytical support.
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Supplementary Material

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1
Supplementary materials (procedures, data and HNMR and
13CNMR spectra for selected compounds) can be found in the
website www….

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Highlights
. First CuI catalysed Click reaction without inert atmosphere
. Study on the role of glycerol in increasing the catalytic efficiency of CuI
. Use of L-proline as an amine additive
. Short reaction time and excellent yields
. Highly compatible to sensitive 1,2,4-trioxane system