A bile acid-based pyridino-triazole ligand for Cu(I)-stabilization and its application in Cu(I) catalyzed click reactions

Article abstract of DOI:10.1016/j.tetlet.2020.152509

A bile acid based pyridino-triazole ligand to stabilize Cu(I) state has been developed. The ligand was found to catalyze click reactions of a number of alkynes and azides in presence of Cu(CH₃CN)₄.BF₄ at very low catalyst

Full text of DOI:10.1016/j.tetlet.2020.152509

Journal Pre-proofs
A bile acid-based pyridino-triazole ligand for Cu(I)-stabilization and its appli‐
cation in Cu(I) catalyzed click reactions
Aradhana Nayal, Pramod S. Pandey
PII:
S0040-4039(20)30996-5
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152509
TETL 152509
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Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
10 July 2020
25 September 2020
26 September 2020
Please cite this article as: Nayal, A., Pandey, P.S., A bile acid-based pyridino-triazole ligand for Cu(I)-
stabilization and its application in Cu(I) catalyzed click reactions, Tetrahedron Letters (2020), doi: https://
doi.org/10.1016/j.tetlet.2020.152509
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A bile acid-based pyridino-triazole ligand for Cu(I)-stabilization and
its application in Cu(I) catalyzed click reactions
Aradhana Nayal and Pramod S. Pandey*
Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New
Delhi 110016, India
Corresponding author E-mail address: pspandey49@gmail.com;
pramod@chemistry.iitd.ac.in
Keywords: Bile acid, Triazole, Click reaction.
Abstract
A bile acid based pyridino-triazole ligand to stabilize Cu(I) state has been developed.
The ligand was found to catalyze click reactions of a number of alkynes and azides in
presence of Cu(CH3CN)4.BF4 at very low catalyst loading and under milder reaction
conditions.
Introduction
The Cu(I)-catalyzed cycloaddition reaction between an azide and an alkyne yielding
1,4-disubstituted 1,2,3-triazoles developed independently by Meldal [1] and Sharpless
[2] has found its extensive applications in a wide range of fields such as polymer
chemistry, materials science, medicinal chemistry and supramolecular chemistry [3].
Due to its importance in the field of chemistry and related sciences, there has been
considerable effort to design ligands for the stabilization of Cu(I) state [4]. The
presence of ligands is not only crucial for the protection of the Cu(I) species from
oxidation and disproportionation but is also responsible for the facilitation and
acceleration of the overall cycloaddition reactions in milder reaction conditions.
A range of click polydentate ligands have been reported and their coordination and
catalytic properties with a variety of metal ions are examined [5-7]. Fokin and co-
workers synthesized tris(benzyltriazolylmethyl)amine (TBTA) using Cu(I)-catalyzed
click reaction. They discovered that TBTA acts as a stabilizing ligand for Cu(I),
which protect it from oxidation and disproportionation and acts as a powerful catalyst
for click reaction [8]. Williams and co-workers prepared and characterized two Cu(II)

and Cu(I) complexes of tris(benzyltriazolylmethyl)amine (TBTA) ligand and studied
their application in cycloaddition reaction between phenylacetylene and
azidoacetanilide [9]. A neutral, air and moisture stable Cu(I) complex bearing a
tris(benzyltriazolyl)methanol ligand was reported by Pericàs and co-workers for
CuAAC reactions in water or under neat conditions [10]. Prez and co-workers
immobilized tris-(benzyltriazolylmethyl)amine (TBTA) to a styrenic monomer and
subsequently copolymerized with styrene to afford catalytically active and reusable
copolymers for the CuAAC reaction [11]. Pericás and co-workers synthesized a
polystyrene resin supported Cu(I) complex, which acted as catalyst in both aqueous
and organic media [12]. L-Valine-derived low-molecular-weight gelators
functionalized with triazole units were synthesized by Escuder and co-workers. The
gelator-coordinated Cu(I), building hybrid organic–inorganic gels, were utilized in
catalyzing the cycloaddition of alkynes and azides [13]. Astruc and co-workers
synthesized an amphiphilic ligand tris(triazolyl)polyethylene glycol (tris-trz-PEG) and
used it for synthesis of Cu nanoparticles as a catalyst for CuAAC reaction between
benzyl azide and phenylacetylene [14]. Cai and co-workers synthesized a library of
Cu(I) tripodal triazolyl ligands varying in chelate arm length and evaluated their
structural effects on the CuAAC reaction, air oxidation, and ligand dissociation [15].
Bile acids, natural compounds of the steroid family, with slightly curved shape
backbone possessing carboxy and hydroxyl groups of varied reactivity, have been
very attractive as building blocks for the design of molecular and ionic receptors [16].
Their special characteristics offer a unique spatial structural arrangement for building
receptors with different sized cavities and varied binding sites. Bile acid derivatives
with 1,2,3-triazole units have received special attention in ionic recognition because
of their unique geometry and coordination properties with anions and metal ions [17].
To explore the role of the inherent features of bile acid framework in generating
polydentate Cu(I)-stabilizing ligands, we have designed and synthesized a steroidal
tetradentate pyridino-triazole ligand and examined its catalytic potential for the Cu(I)-
catalyzed click reaction. Our experimental results suggest that this system is capable
of stabilizing Cu(I) state in organic solvents, which leads to low catalyst loading and
excellent catalytic activity for a wide range of substrates.

Results and Discussion
Synthesis of ligand
The bile acid based triazole ligands 3 was synthesized by the treatment of methyl
3α,12α-bis-(azidoacetyl)deoxycholate 1 [17a] with 2-ethynylpyridine (2), in the
presence of CuSO4 (10 mol %) and sodium ascorbate (20 mol %) in t-BuOH / H2O at
60 °C (Scheme 1).
O
O
O
Me
O
O
Click Reaction
O
+
O
O
N
O
Me
O
O
N
O
N
N
N
N
N
N3
N3
N
3
2
1
N
Scheme 1: Synthesis of bile acid-based pyridine-triazole ligand 3
Binding behaviour of 3 towards Cu(I) salt
The binding behaviour of ligand 3 towards Cu(I) salt {Cu(CH3CN)4.BF4}was studied
through UV-Vis titration. A clear spectral change upon the addition of aliquots of
Cu(I) solution to the solution of the compound 3 in DCM was observed (Fig 1). A
gradual increase in absorbance between 320 nm and 400 nm with appearance of a new
band at 360 nm was observed with the increasing concentration of Cu(I) due to the
formation of a metal-ligand charge transfer (MLCT) complex between ligand and
Cu(I) (Fig. 2). A similar situation was reported earlier for a pyridino-triazole ligand
with complexation with Cu(I) [18]. The Job’s plot analysis exhibited 1:1
complexation between Cu(I) and ligand 3 (Fig. S3).

Figure 1: Absorption spectra of 3 (3 × 10−5 M) upon titration with Cu(CH3CN)4.BF4
(0−2.6 equiv) in CH2Cl2
O
O
O
Me
O
O
O
N
N
N
N
N
N
CuI
N
N
Figure 2: Proposed binding model
Click reactions catalyzed in presence of ligand 3 and Cu(I) salts
The catalytic activity of Ligand 3 was examined for click reactions of various azides
and terminal alkynes in presence of Cu(I) salts. For carrying out primary
investigations on catalytic activity of 3 for the click reaction, benzyl azide was reacted
with phenyl acetylene in DCM in the presence of ligand 3 and [Cu(CH3CN)4].BF4 (1
mol %) (Scheme 2).
N3
Cu salt / ligand
N
N
+
N
Solvent, RT, 3 h
Scheme 2: Cu(I)-catalyzed click reaction in presence of 3

The reaction proceeded smoothly in the presence of 3 (1 mol %). After carrying out
reaction for 3 h at room temprature, the product was obtained in 100 % yield (Table 1;
Entry 1). In the absence of 3, the product yield was found to be only 4% under similar
reaction conditions (Table 1; Entry 2). On replacing DCM with solvents THF,
acetonitrile, aqueous t-butanol, ethanol and acetone, yield was significantly reduced
(Table 1; Entries 3-8). For the optimization process, various Cu(I) salts such as CuI,
CuBr, CuCl, and Cu2O have been used for the model reaction in presence of 3 (Table
1; Entries 9-12). However, the best result was obtained when [Cu(CH3CN)4]BF4 was
used as Cu(I) salt and DCM was used as solvent (Table 1; Entry 1).
Table 1. Standardization of reaction conditionsa
Entry
1.
Cu (I) Source
Cu(CH3CN)4.BF4
Cu(CH3CN)4.BF4
Cu(CH3CN)4.BF4
Cu(CH3CN)4.BF4
Cu(CH3CN)4.BF4
Cu(CH3CN)4.BF4
Cu(CH3CN)4.BF4
Cu(CH3CN)4.BF4
Cu2O
Ligand
Solvent
DCM
NMR Yieldb (%)
3
-
100 (96)
2.
DCM
4
40
3.
3
3
3
3
3
3
3
3
3
3
THF
4.
t-BuOH-H2O
CH3CN
C2H5OH
CH3COCH3
No Solvent
DCM
75
5.
36
6.
63
7.
42
8.
95 (89)
trace
27
9.
10.
11.
12.
CuI
DCM
CuBr
DCM
0
CuCl
DCM
56
aReaction conditions: 1.0 mmol benzyl azide, 1.1 mmol phenyl acetylene, RT, Reaction time 3 h, Cu(I)
salt (1 mol %), Solvent 5 mL, 3 (1 mol %). bIn parentheses are shown the isolated yields after column
chromatography.
The click reaction of benzyl azide with phenyl acetylene also proceeded smoothly
when no solvent was used (neat reaction) and the product was obtained in 95% yield.
Subsequently, click reactions of a variety of terminal alkynes including aliphatic and
aromatic systems were carried out using 3 as a catalyst. The results are presented in
Table 2.

The 1,4-disubstituted 1,3-cycloaddition products are formed following the reaction
mechanism proposed by Fokin and co-workers [6] (Scheme 3).
N
R1
N
N
R
H
[CuL]
R
H
H+
Step 5
Step 1
H+
N
R1
A
N
N
R
CuL
D
R1
Step 2
R
CuL
N
N
N
Step 4
N
R1
R1
N
N
N
N
N
B
CuL
Step 3
CuL
R
R
C
O
O
O
Me
O
O
O
L=
N
N
N
N
N
N
N
N
Scheme 3: Mechanism for Cu(I)-catalyzed azide–alkyne cycloaddition reaction using
bile acid-based pyridine triazole ligand
Table 2 Click reactions catalyzed in presence of ligand 3a
Entry
1
Azide
Alkyne
t (h)
3
Product
Yieldb
96
N
N3
N3
N
N
(4a)
2
10
92
OH
N
N
OH
N
(4b)
3d,e
4d,e
5d,e
12
12
12
83
94
83
N
N
S
S
N
(4c)
(4d)
N3
N3
N3
N
N
O
O
O
N
N
N
N
O
O2N
(4e)
NO2

6c
7c
6
8
91
86
O2N
O2N
N3
O2N
N
N
N
N
N
(4f)
N3
N
N
O2N
O2N
O2N
N
N
(4g)
8c
9c
3
8
89
93
S
O2N
O2N
N3
S
N
N
(4h)
O
N
N3
N
O
N
O2N
(4i)
NO2
10c
11
3
3
89
90
OH
OH
OH
O2N
O2N
N3
N
N
N
(4j)
N3
N3
N3
N
N
4
4
4
4
N
(4k)
12
15
15
88
84
N
N
4
OH
S
N
(4l)
13d
N
N
S
4
N
(4m)
14c,f
6
86
92
N
N
N
N
N3
N3
N
N
N
N
N
N
N3
N
(4n)
N3
15d,e,g
10
O
N
N
N
N
NO2
N3
N
N
O
O
NO2
O2N
(4o)
aReaction conditions: 1.0 mmol benzyl azide, 1.1 mmol phenyl acetylene, RT, DCM 5 mL, Cu(I) salt
(1 mol %), 3 (1 mol %). bIsolated yield after column chromatography. cColumn not required. dReaction
temperature was 40 °C. eCu(I) salt (2 mol%) and 3 (2 mol %). f4 mmol of alkyne was used. g2.0 mmol
of alkyne was used.

All reactions proceeded smoothly to completion in 3–15 h and triazoles were isolated
in excellent yields in high purity by simple filtration through short silica column.
Benzylic, alkyl and aryl azides all reacted very well in the presence of 3. Electron-
rich, electron-poor and / or hindered alkynes all gave good yields. However, alkynes
with adjacent heteroatoms (O, S) seem to require longer reaction time (10−15 h) and
slightly higher temperature (Entries 2−5, 13 and 15). When 4-nitrobenzene azide was
reacted with various alkynes, the corresponding click products precipitated out due to
their lower solubility in DCM and could be easily separated by filtration (Entries
6−10 and 14). No column chromatography was required in such cases.
Conclusion
We have designed and synthesized a bile acid based 1,2,3-triazole ligand containing
pyridine moiety for stabilization of Cu(I) ion. This ligand has been found to show
excellent catalytic activity for cycloaddition reactions of a number of alkynes and
azides in the presence of Cu(CH3CN)4.BF4. Very low catalyst loading (1 mol % of
Cu(I) and 1 mol % of ligand) and milder reaction conditions are required for the click
reaction of a wide range of substrates. Reactions are very clean and, in many cases,
column chromatography in not required.
Acknowledgement
AN thanks the Council of Scientific and Industrial Research, New Delhi, for the
research fellowship.
Supplementary data
The experimental procedure for the synthesis of the ligand and click products, and
their 1H and 13C NMR spectra are available in supporting information.
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Declaration of Interest statement
10-07-2020
Professor Vinod Singh
Associate Editor
Tetrahedron Letters
Subject: Declaration of Interest statement
Dear Professor Singh,
Please find the manuscript entitled “A bile acid-based pyridino-triazole ligand
for Cu(I)-stabilization and its application in Cu(I) catalyzed click reactions” for
publication in Tetrahedron Letters.
The article demonstrates the synthesis and catalytic properties of a bile acid-
based tetradentate pyridino-triazole ligand for the Cu(I)-catalyzed click reaction. The
ligand was found to catalyze click reactions of a number of alkynes and azides in
presence of Cu(CH3CN)4.BF4 at very low catalyst loading and under milder reaction
conditions. Over past years, there has been considerable interest on design of ligands
and their application in copper catalyzed azide–alkyne cycloaddition (CuAAC)
reactions. Hence, the steroidal tetradentate pyridino-triazole ligand, being reported for
the first time, will be of a particular interest as an efficient catalyst for the CuAAC
reactions.
The work presented in the manuscript have not been submitted or published in
any other journal. We hope that the manuscript would be reviewed and considered for
publication in Tetrahedron Letters.

Best regards,
Yours Sincerely,
Pramod S Pandey
Former Professor
Department of Chemistry
Indian Institute of Technology Delhi
New Delhi 110016
India
Highlights
 Synthesis of a pyridino-triazole ligand based on bile acid framework.
 The bile acid-based pyridino-triazole ligand stabilizes Cu(I) state.
 The ligand catalyzes click reactions in presence of Cu(CH3CN)4.BF4.