Urea assisted copper(I)-catalyzed azide-alkyne cycloaddition reactions in water

Article abstract of DOI:10.1016/j.tetlet.2016.03.016

Urea assisting easy and greener synthesis of 1,4-disubstituted 1,2,3-triazoles has been achieved using copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction in water. The click reaction affords notable features, such as high efficiency and regio

Full text of DOI:10.1016/j.tetlet.2016.03.016

Accepted Manuscript
Urea assisted copper (I)-catalyzed azide-alkyne cycloadddition reactions in wa-
ter
Abdul Aziz Ali, Mitali Chetia, Diganta Sarma
PII:
S0040-4039(16)30239-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.03.016
TETL 47404
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
13 February 2016
2 March 2016
5 March 2016
Please cite this article as: Ali, A.A., Chetia, M., Sarma, D., Urea assisted copper (I)-catalyzed azide-alkyne
cycloadddition reactions in water, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.03.016
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Urea assisted copper (I)- catalyzed azide-
alkyne cycloaddition reactions in water
Leave this area blank for abstract info.
Abdul Aziz Ali, Mitali Chetia, and Diganta Sarma*
Department of Chemistry, Dibrugarh University, Dibrugarh-786004, Assam, INDIA.
R
N
CuSO .5H O/Na ascorbate
4
2
N
N
R N3
R'
Urea, water,r.t.
R'

1
Tetrahedron Letters
Urea assisted copper (I)-catalyzed azide-alkyne cycloadddition reactions in water
Abdul Aziz Ali, Mitali Chetia, and Diganta Sarma*
Department of Chemistry, Dibrugarh University, Dibrugarh-786004, Assam, India.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Urea assisting easy and greener synthesis of 1,4-disubstituted 1,2,3-triazoles has been achieved
using copper (I)-catalyzed azide–alkyne cycloaddition (CuAAC) reaction in water. The click
reaction affords notable features, such as high efficiency and regioselectivity, mild reaction
conditions, easy operation, and excellent yields with a broad spectrum of substrates.
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
Alkyne
Azide
Urea
1
,4-disubstituted-1,2,3 triazoles
Water
Introduction
Of all the click reactions, the copper (I)-catalyzed version of
However, these strategies have some inherent deficiencies,
including relatively sluggish synthetic routes, high copper and
ligand loading, high temperature, long reaction time and use of
organic solvents. Most of the ligands are non polar and only a
few reports are available for water soluble ligands such as
THPTA and AMTC . Consequently, there is still a need for the
development of new, efficient, highly economical, widely
applicable, commercially feasible as well as environmentally
sustainable way for the synthesis of 1,2,3-triazoles in order to
meet their growing demand in various section.
Huisgen 1,3-dipolar
azide–alkyne cycloaddition (CuAAC)
reaction independently described by the groups of Sharpless and
Meldal in 2002, is one of the most common and useful synthetic
1
-3
reactions in organic chemistry. The CuAAC has become a
prime example of click chemistry because of its reliability,
specificity, and biocompatibility and has been widely used in
different areas of science, such as organic synthesis, drug
discovery, bioconjugation, polymer and supramolecular
2
2
24
4
-8
chemistry.
Nevertheless, an increasing alertness of the need for more
sustainable approach for synthetic chemistry across academic and
industrial communities, numerous environmentally friendly
strategies have been recognized: to carry out reactions in solvent
free condition; to change the use of stoichiometric reagents with
catalysts; to use biocatalytic processes, and finally to carry out
Urea is a cheap, remarkably stable, readily accessible, water
soluble and non-toxic substance and nowadays the chemistry of
urea based organic reactions has been developed rapidly because
of interest in their geometrical structures and complexing
26
ability. We recently disclosed urea/Pd(OAc)
2
as efficient
catalyst for phosphine-free Suzuki–Miyaura cross-coupling
9
27
reactions in aqueous media. From the viewpoint of ‘click
reactions. In order to establish the utility of urea as a ligand we
chemistry’ water is used as a solvent along with other water-
decided to extend its chemistry to CuAAC reaction and to the
best of our knowledge this is one of the simplest green protocols
for ligand promoted click reactions reported so far. To contribute
t
miscible organic solvents such as DMSO, THF, and BuOH in
10
typical CuAAC reaction. In particular, water is a cheap,
11
28
nonflammable, nontoxic, and environmentally benign solvent.
our interest on click chemistry, herein we describe a simple,
Therefore, development of organic reactions in water over
traditional solvents will contribute to the cleaner green chemistry
process.
reliable and synthetically straightforward approach for the
preparation of diverse 1,2,3-triazoles under mild condition.
Results and discussion
Very surprisingly, certain Cu-binding ligands play an important
role in the rate acceleration of CuAAC over the ligand-free
process with stabilization of copper (I) ions from oxidation and
We began to explore optimal parameters for the click reaction
using benzyl azide as a coupling partner for phenyl acetylene in
water using urea as a ligand under standard cycloaddition
conditions (Table 1, entry-1). To our delight, the reaction
undergoes near completion after only 60 min and excellent yields
can be achieved. Further screening of different Cu salts indicated
12
disproportionation. In this regard, noteworthy examples include
1
3
14
15
the commonly applied TBTA, sulfide ligands, histidine and
1
6
17
19
22
benzimidazole
bisoxazoline-pyridine
derivatives,
pyridine–
phosphinimine,
18
(pybox)
ligands,
phosphites,
2
0
21
4 2
that CuSO .5H O/Na ascorbate showed superior reactivity over
phosphinite and phosphonite, NHC carbenes, THPTA,
23
24
25
others in this reaction (Table 1, entries 2-5). Interestingly, using
of thiourea or guanidine as a ligand led to slightly lower yield of
the desired product (Table 1, entries 6-7). It was worth to note
that in the absence of urea the product obtained was only 40%
oximinoalkylamines, AMTC and MBHTM.
*
Corresponding author. Tel.: +91 373-2370210
E-mail address: dsarma22@gmail.com; dsarma22@dibru.ac.in

2
N
after 60 min and the reaction was completed only after 6h
highlighting the indispensable role of the ligand (Table 1, entries
N
N
N3
1
2
3
1h
1h
1h
99
96
92
8
-9). Notably, it was found that all these reactions could be
performed in air with no detectable evidence of side product
formation. Throughout this work, the optimized reaction
N
N
N
N3
conditions comprise of 1 mol% CuSO
4 2
.5H O as catalyst, 5 mol%
O2N
O2N
Na ascorbate as reducing agent and 2 mol% urea as the promoter
ligand.
N3
N
a
N
N
Table 1. Optimization of reaction conditions.
[Cu] / Na ascorbate
Ph
N
N
Ph
Bn N3
N
N3
N3
N
N
ligand, H2O, rt
1h
96
95
Cl
Cl
N
N
N
Bn
4
Cl
Entry
[Cu]
mol%
CuSO .5H
CuI
Na
Ligand
time Yield
b
1
ascorbate
5mol%
-
2 mol%
Urea
Urea
(%)
1
2
3
4
5
6
7
8
9
4
2
O
1h
1h
1h
1h
1h
1h
1h
1h
6h
24h
99
90
88
89
90
78
84
40
92
-
1h
N
5
6
CuCl
2
2
.2H O
5mol%
5mol%
-
5mol%
5mol%
5mol%
5mol%
-
Urea
Urea
Urea
Cl
2 2
Cu(OAc) .H O
F
N3
CuCl
N
CuSO
4
4
4
.5H
.5H
.5H
.5H
2
O
Thiourea
Guanidine
-
1h
1h
1h
96
95
97
N
N
CuSO
CuSO
CuSO
2
O
O
O
F
2
4
2
-
Br
N3
1
1
0
-
Urea
N
a
7
8
N
N
mmol of azide, 1.2 mmol of alkyne, 1.0 mol % of [Cu] and 5.0 mol %
sodium ascorbate in the presence of 2 mol % of ligand in H
temperature.
2
O at room
Br
MeO
b
N3
Isolated yields by column chromatography.
N
N
N
With the optimized reaction conditions established,
exploration of the scope of the catalyst system was performed
with structurally different azides and acetylenes. Phenylacetylene
could react satisfactorily with diverse azides (Table 2, Entries 1-
OMe
N3
NC
N
9
1h
3h
96
90
N
N
N
10) affording the corresponding products with high isolated
yields. It is noteworthy that both the electron-rich and the
electron deficient aryl azides showed an excellent reactivity and
furnished the products in high yields in short reaction times
CN
N
10
N
N3
7
(Table 2, entries 3-9) at room temperature. Halide substituents
such as Br, F, and Cl were all tolerated in this transformation and
resulting triazoles are primed for further functionalization. In the
case of aliphatic azide also, good yields were observed under the
standard reaction conditions (Table 2, entry -10). Obviously,
a
1
mmol of azide, 1.2 mmol of alkyne, 1.0 mol % of CuSO
4
.5H
2
O and 5.0
mol % sodium ascorbate in the presence of 2 mol % of urea in H
temperature.
2
O at room
cycloaddition with aromatic alkynes
such as
p-
methylphenylacetylene, p-methoxyphenylacetylene proceeded
smoothly to give the corresponding 1,2,3-triazoles in almost
quantitative yields (Table 3, Entries 1-3). In addition, aliphatic
alkynes were also effectively clicked with the benzyl azide to
form the desired triazole products in excellent yields (94-99%)
after 3h (Table 3, entries 4-5). Moreover the reaction appears to
be quite tolerant of common functional groups including
alcohols, esters and acids (Table 3, entries 6-8).
b
Isolated yields by column chromatography.
Table 3. Azide–alkyne cycloaddition of benzyl azide and
different alkynes in water.
a
CuSO .5H O/ Na ascorbate
R
N
4
2
N
R
Bn N3
N
urea, H O, rt
2
Table 2. Azide–alkyne cycloaddition of phenyl acetylene and
Bn
a
different azides in water.
b
Entry
1
Alkyne
Product
Time
1h
Yield
99
N
N
N
CuSO .5H O/ Na ascorbate Ph
N
4
2
N
Ph
R' N3
N
urea, H O, rt
2
R'
N
N
N
b
2
1h
94
Entry
Azide
Product
Time Yield

3
N
9
1
.
(a) Blackmond, D. G.; Armstrong, A.; Coombe, V.; Wells, A.
N
N
3
1h
95
Angew. Chem. Int. Ed. 2007, 46, 3798. (b) Jessop, P. G. Green
Chem. 2011, 13, 1391.
0. (a) Wu, P.; Feldman, A. K.; Nugent, A. K.; Hawker, C. J.; Scheel,
ꢁꢂ ꢃoitꢄ ꢅꢁꢂ ꢆyunꢄ ꢇꢁꢂ Frꢈchet, J. M. J.; Sharpless, K. B.; Fokin, V.
MeO
ꢀ
OMe
N
V. Angew. Chem., Int. Ed. 2004, 43, 3928. (b) Helms, B.; Mynar,
J.; ꢉawkerꢄ ꢊꢁ ꢇꢁꢂ Frꢈchet, J. M. J. J. Am. Chem. Soc. 2004, 126,
5020. (c) Rodionov, V.; Fokin, V. V.; Finn, M. G. Angew.
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N
4
5
3h
3h
90
92
1
Chem., Int. Ed. 2005, 44, 2210.
N
N
N
1
1
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3. Chan, T. R.; Hilgraf, R.; Sharpless, K. B.; Fokin, V. V. Org. Lett.
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004, 6, 2853.
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52.
N
O
N
N
6
7
8
2h
2h
3h
90
94
4
HO
HO
OH
1
5. Tanaka, K.; Kageyama, C.; Fukase, K. Tetrahedron Lett. 2007, 48,
6475.
6. Rodionov, V. O.; Presolski, S. I.; Gardinier, S.; Lim, Y.-H.; Finn,
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O
N
N
N
O
1
O
O
O
N
N
N
92
OH
a
1
mmol of benzyl azide, 1.2 mmol of alkyne, 1.0 mol % of CuSO
4
.5H
2
O
19. Perez-Balderas, F.; Ortega-Munoz, M.; Morales-Sanfrutos, J.;
Hemandez-Mateo, F.; Calvo-Flores, F. G.; Calvo-Asin, J. A.; Isac-
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2
of H O at room temperature.
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Ed. 2009, 48, 9879.
b
Isolated yields by column chromatography.
Conclusion
In summary, we have developed a simple and highly efficient
methodology for copper-catalyzed azide alkyne cycloaddition
reactions at room temperature. With the ease of procedure, mild
reaction conditions, use of inexpensive reagents, and high
generality of substrates, we believe that this greener and cost
effective process creates a new avenue for scientific community.
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Acknowledgement
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013, 11, 5793. (c) Roberts, J. M.; Fini, B. M.; Sarjeant, A. A.;
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We are grateful to CSIR, New Delhi for a research grant [No.
0
2(0154)/13/EMR-II] and A. A. A is thankful to CSIR, New
1
Delhi for SRF. DST and UGC, New Delhi is favorably
acknowledged for financial assistance to the Department of
Chemistry, Dibrugarh University. The authors thank Dr. Prakash
J. Saikia, Analytical Chemistry Division, CSIR-North East
Institute of Science and Technology, Jorhat-785006, Assam,
India for recording the NMR spectra. We acknowledge Dr.
Arvind Kumar, Central Salt and Marine Chemicals Research
Institute, Council of Scientific and Industrial Research, Gijubhai
Badheka Marg, Bhavnagar 364002, Gujarat, India for helping us
in the mass spectrometric analysis of the compounds.
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2
9. In a typical experiment, a solution of CuSO
4
·5H
2
O (2.49 mg, 0.01
O (2.0
mmol), and sodium ascorbate (9.9 mg, 0.05 mmol) in H
2
mL) was added a mixture of azide (1 mmol, 1 equiv.) and
acetylene (1.2 mmol 1.2 equiv.) at room temperature. The
resultant mixture was stirred continuously and after completion
References and notes:
(
monitored by TLC); the reaction mixture was extracted with ethyl
acetate (10 mL x 3) and the combined organic layer was washed
with brine (20 mL), dried over Na SO . Removal of the solvent
yielded a residue, which was purified by a short chromatography
silica gel, EtOAc:n-Hexane = 1:3) to give the desired product.
1
2
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(
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4
HIGHLIGHTS




The method exploits commercially available
and inexpensive urea as a ligand
Economical and environmentally friendly
water as the medium
One of the simplest protocols for ligand
promoted click reactions reported so far
CuAAC reaction can be performed in water
at room temperature