'Click' ligand for 'click' chemistry: (1-(4-methoxybenzyl)-1-H-1,2,3-triazol-4-yl)methanol (MBHTM) accelerated copper-catalyzed [3+2] azide-alkyne cycloaddition (CuAAC) at low catalyst loading

Article abstract of DOI:10.1016/j.tetlet.2015.09.010

Readily accessible, cost effective, remarkably stable and easily tunable 1,2,3-triazole based ligand, (1-(4-methoxybenzyl)-1-H-1,2,3-triazol-4-yl)methanol (MBHTM) synthesized itself by 'click' chemistry shown to promote the dramatic rate enhancement of co

Full text of DOI:10.1016/j.tetlet.2015.09.010

Accepted Manuscript
“Click” ligand for “Click” chemistry: (1-(4-Methoxybenzyl)-1-H-1, 2, 3-tria-
zol-4-yl) methanol (MBHTM) accelerated Copper-catalyzed [3+2] Azide-Al-
kyne cycloaddition (CuAAC) at low catalyst loading
Rajesh H. Tale, Venkatesh B. Gopula, Gopal K. Toradmal
PII:
S0040-4039(15)30055-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.09.010
TETL 46682
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
22 June 2015
15 August 2015
2 September 2015
Please cite this article as: Tale, R.H., Gopula, V.B., Toradmal, G.K., “Click” ligand for “Click” chemistry: (1-(4-
Methoxybenzyl)-1-H-1, 2, 3-triazol-4-yl) methanol (MBHTM) accelerated Copper-catalyzed [3+2] Azide-Alkyne
cycloaddition (CuAAC) at low catalyst loading, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.
2015.09.010
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Graphical Abstract
“Click” ligand for “click” chemistry: (1-(4-
methoxybenzyl)-1-H-1, 2, 3-triazol-4-yl)
methanol (MBHTM) accelerated Copper-
catalyzed [3+2] Azide-Alkyne cycloaddition
(CuAAC) at low catalyst loading.
Leave this area blank for abstract info.
Rajesh H. Talea*, Venkatesh B. Gopulaa Gopal K.Toradmala
,
CuSO4 (1.0 mol%),
Na ascorbate (5.0 mol %)
R
R1 N3
R
R1
N
N
Ligand (1.1 mol %) ,
DMSO:H2O (1:3), rt, 4h.
N
21 examples, upto 99%
N
N
L=
MeO
OH
N

1
Tetrahedron Letters
journal homepage: www.elsevier.com
“Click” ligand for “Click” chemistry: (1-(4-Methoxybenzyl)-1-H-1, 2, 3-triazol-4-yl)
methanol (MBHTM) accelerated Copper-catalyzed [3+2] Azide-Alkyne cycloaddition
(CuAAC) at low catalyst loading.
Rajesh H. Talea*, Venkatesh B. Gopulaa Gopal K. Toradmala
,
a Organic and Dendrimer Chemistry Research Laboratory, School of Chemical Sciences S. R. T. M. University, Nanded, Maharashtra, India. 431606.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Readily accessible, cost effective, remarkably stable and easily tunable 1,2,3- triazole based
ligand, (1-(4-Methoxybenzyl)-1-H-1,2,3-Triazol-4-yl)Methanol (MBHTM) synthesized itself by
“ click” chemistry shown to promote the dramatic rate enhancement of copper catalyze azide–
alkyne cycloaddition (CuAAC) at low catalyst loading to give diverse 1,4-disustituted 1,2,3-
triazoles in high to excellent yields under mild conditions. Using higher catalyst and ligand
loading, excellent and 49 % yield of the corresponding 1,2,3 triazole product could be obtained
within less than hour and few minutes respectively indicating the feasibility of the reaction for
the development of rapid “click” protocol.
Available online
Keywords:
Click chemistry
1,2,3-triazole
Cycloaddition
Click ligand
2009 Elsevier Ltd. All rights reserved.
Radiolabelling
1. Introduction
the preferred ligand even today. The other ligands include
sulphide ligands7, histidine and benzimidazole derivatives8,9,
The Huisgen1 first of all discovered the 1, 3-dipolar
cycloaddition of azides to terminal or internal alkynes to form 1,
4-disubsituted-1, 2, 3-triazoles. Following the pioneering work
by Huisgen1, Sharpless 2 defined what makes a click reaction” as
one that is wide in scope and easy to perform, uses only readily
available reagents and provide high to quantitative yields. Since
the inception of independent discovery by groups of Sharpless2
and Meldal3 in 2002 that copper(I) catalyses the 1,3-dipolar
cycloaddition of azides and alkynes (CuAAC) to form 1,4-
disubstituted triazoles regioselectivity, within a decade CuAAC
has emerged as one of the most powerful paradigms in drug
discovery, synthesis and material science4. The development of
selective, stable and tunable transition metal catalysts by
exploiting the properties of ligand such as steric bulk and
electronic effect has become crucial and demanding research area
in modern chemical research. The prominent role of a ligand in
the rate acceleration of CuAAC is now well established as it not
only stabilizes the oxidation state of Cu (I) but shown to increase
and modulate its reactivity by providing the effective
concentration throught the catalytic cycle.5 In order to advance its
scope further, recently much efforts have been focused on the
ligand acceleration of CuAAC. Recently various ligands have
been tested to promote the rate acceleration of CuAAC.
Sharpless’s group first of all reported that polytriazolylamine
(TBTA)6 facilitate reaction rate at low catalyst loadings and is
pyridine-phosphinimine10
Bisoxazolynyl-pyridine
(pybox)
ligands,11 phosphites,12 Phosphinite and Phosphonite,13 and NHC
carbenes14. Though some of these ligands proved to be highly
effective for rate acceleration, however many of them suffer from
the limitations such as high copper and ligand loading7, high
temperature15, long reaction time, high cost and lack of
tunability. Moreover, the applicability of one the most efficient
ligands in CuAAC, NHC carbene, has been limited by their
challenging synthetic routes. Recently, Feringa et.al16 reported
highly efficient BINOL based phosphoramidite accelerated
copper (I)-catalyzed [3 + 2] cycloaddition of azides and alkyne.
The 1, 2, 3–triazoles could be readily synthesized via CuAAC
reaction, they are remarkably stable, inexpensive and easily
tunable. Moreover, the 1, 2, 3-triazole with an additional co-
ordinating site provide excellent mixed bidanted ligand for
transition metal complexes. Several 1, 2, 3-triazole based ligand
systems for transition metal complexes have been extensively
studied and well documented in the literature.17 In addition the
catalytic potential of such a complexes17 or ligand has also been
tested for CuAAC reaction.
Very recently Mendoza-Espinosa et al.18 reported the N,N-, N,O-
and N,S-triazole supported ligands and Sharghi et al.19 reported
2-Phenyl -2-(4-phenyl -1H -1,2,3-triazo l -1-yl)ethanol ligand for
copper catalysed azide-alkyne cycloaddition reaction (CuAAC).
Though these methods are highly efficient, however, the main
focused of the work of Mendoza-Espinosa group seems to be on
the inorganic and physical chemistry aspect of respective metal
complexes. Furthermore, these method involved high catalyst
loading of up to 3-5 mol %, ligand 10 mol % and or longer
∗Corresponding author. Tel.: +918888000820; Fax +912462229572;
e-mail; rkht_2008@rediffmail.com

2
Tetrahedron
Table 1. Ligand screening for CuAACa
reaction time was required to have significant rate acceleration
using these triazole based catalytic system.
Ligand
none
Yield (%)b
Entry
Time (h)
Thus despite of the above methods, the efforts focused on
developing more efficient catalytic system for CuAAC still
remained challenge, particularly, from the perspective of one of
the fundamental principles of “Click” chemistry (the use of
readily available reagents and high to excellent yield) and
radiolabelling (rapid formation of 1,2,3-triazole). Therefore, an
efficient, further economical and tunable ligand for copper
catalyzed [3+2] cycloaddition of azide and alkyne (CuAAC) is
highly desired.
38
80
4
1
2
3
none
none
24
24
93c
N
71
82
4
5
4
4
N
OH
N
L1
N
N
OH
MeO
O2N
N
L2
Herein, we report that the readily accessible, cost effective,
easily tunable and simple but powerful “Click” [(1H-1, 2, 3-
triazolyl) methanol)] ligand dramatically accelerates the copper
catalyze [3+2] cycloaddition of azide and alkyne at low copper
catalyst loading at ambient conditions.
N
N
4
4
6
7
61
46
OH
N
L3
N
N
O
N
N
L4
N
OMe
Results and Discussion
N
8
42
4
N
L5
In order to search for the most effective 1,2,3-triazole based
ligands for the rate acceleration of CuAAC reaction, several
1,2,3–triazole ligands synthesized themselves by “Click”
chemistry were investigated. The model reaction between the
benzyl azide and phenyl acetylene using CuSO4 as copper source
and sodium ascorbate as reductant in DMSO-water (1:3) at room
temperature was initially considered for ligand screening,
scheme-1.
N
N
O
MeO
N
L6
N
9
66
55
4
4
O
N
N
N
N
10
N
Ph
L7
CuSO4 1 mol %, Na-ascorbate 5.0 mol %
Ligand 1.1 mol %, DMSO:H2O 1:3, rt
N3
Ph
N
N
N
1.2 equiv.
1.0 equiv.
a 0.2 mmol of azide, 0.24 mmol of alkyne (1.2 equiv.), 1.0 mol % of CuSO4
and 5.0 mol % Sodium Ascorbate in the presence of 1.1 mol % of ligand in
DMSO-H2O (1:3) at room temperature. b Isolated yields by column
chromatography. c Using 2.0 equiv. of alkyne
Scheme 1.
The DMSO-water system was chosen deliberately as it was
previously proved to be most effective solvent system for rate
acceleration study of CuAAC15. The results of this study are
summarised in table-1
Thus within the (1, 2, 3-triazol-4-yl)-methanol series, the
electronic effect of substituent played a vital role on the rate
acceleration of present CuAAC. The ligand possessing electron
donating substituent on terminal benzene ring shown highest rate
acceleration, (p-OMe- >H >p-NO2) (table-1, compare entries 4,5
and 6). The ligand L4 , resulted by replacing -CH2OH group in
L2 by CHO group, found to be less effective as compared to
ligand L1, L2 and L3 but still exhibited significant rate
acceleration compared to the ligandless reaction (Table 1, entry-
4 vs. 7). The 1,2,3-triazole ligand bearing imine moiety such as
L5 shown the marginal rate enhancement and thus proved to be
ineffective ligand (table-1, compare entries 1 and 8). Notably,
replacing -OH group in L1 by electron rich group, for example,
the ligand L6, found to have detrimental effect on the rate
acceleration as the considerable decrease in the yield was
observed, (table-1, entry-4 vs 9 and 5 Vs 9). We hypothesized
that appending the additional triazole moiety to the 1,2,3-triazle
core could provide the ligand capable of ligation to multiple
copper centers and could prove itself to be the most effective
ligand in “Click” ligand series. Accordingly, the triazole ligand
possessing additional triazole unit , ligand L7 was investigated in
the model reaction. Unfortunately, L7 though found to promote
the rate enhancement but it could not surpass the rate accelerating
power of any of the other ligands except L4 and L5 (table-1,
compare entry 10 with entries 4-6 and 9). It’s worth mentioning
here that the presence of hydroxymethyl (-CH2OH) moiety at C-4
along with electron releasing substituent on the terminal benzene
ring of 1, 2, 3-triazole found to have favourable effect on the rate
enhancement of the CuAAC. Overall, all the triazoles based
As shown in our results, in the absence of ligand the reaction
was very sluggish and it took longer reaction time (up to 24h ) to
achieve the good yield of the 1,2,3-traiazole product(table-1,
entry-2). To our pleasure, the addition of “Click” ligand,
however, promoted the dramatic rate enhancement of the
reaction. Among different triazole ligands screened, the 1-(4-
Methoxybenzyl-1H)-1,2,3-triazol-4-yl)-methanol (MBHTM) L2
shown highest rate acceleration to give 82 % yield within 4h (
table 1, entry-5)and low yield was obtained under same reaction
conditions but without ligand (table-1 entry-1). The unsubstituted
analogue of L2, (1-benzyl-1H-1, 2, 3-triazol-4-yl)-methanol
(BHTM), ligand L1 also shown the similar ligand accelerating
effect but to give lower yield than L2 (table-1, entry-4). The 4-
nitrocounterpart of L2, the ligand L3, however, found to be the
least effective ligand for rate acceleration in the (1, 2, 3-triazol-4-
yl)-methanol series but still giving good yield of 1, 2, 3-triazol
product (table-1, entry-6)

3
ligands screened here found to promote the rate enhancement of
the reaction, but the ligand L2 proved to be the most effective
one.
As can be seen from our results, among all the solvent
tested, the DMOS-water, as rightly chosen previously was found
to be the most effective solvent system for the present reaction.
The Ethanol-Water and t-BuOH-Water were also found to
equally effective solvents but they gave much lower yield than
DMSO-Water. On the other hand, DMF-Water and Acetone-
Water found to be less effective solvents as they furnished
inferior results as compared to DMSO-water.
Though the sufficient rate enhancement was observed using
ligand L2, however, the reaction was still falling short of yield as
required by “click” chemistry criteria (generally high to excellent
yields). In order to improve the yield further without lengthening
the reaction time, we decided to check the effect of azide–alkyne
ratio on the CuAAC using ligand L2 (MBHTM). We decided to
use twofold excess of alkyne assuming that this would provide
the effective concentration of alkyne to facilitate the reaction
further. Thus the model reaction was repeated again but this time
using twofold excess of phenyl acetylene and to our pleasure the
yield raised to 95% under these conditions. (table-2, entry-4).
Thus the use of two fold excess of alkyne found to be sufficient
to reach reaction to completion with excellent yield without
altering the catalyst/ ligand loading and reaction time.
As the optimal rate acceleration at low catalyst loading and
within short reaction time using ligand L2 was achieved without
relying unnecessarily on higher catalyst loading, we considered
1.0 equiv. of azide, 2.0 equiv. of alkyne, 1.0 mol % of CuSO4, 5
mol % of Na-ascorbate in the presence of ligand L2 (1.1 mol %)
in DMSO-H2O (1:3) at room temperature for 4h as optimized
reaction conditions. With optimized conditions at hand, next the
scope of the reaction was explored with structurally diverse
alkynes, scheme 2. The results are collected in table-4.
The rapid “click” protocol is highly desired in the field of
radiolabelling1, 20. Many of reported ligands for CuAAC reaction
found to be falling short of rate acceleration as required by
radiolabelling study. Towards this objective, we thought it is
worthwhile to explore the possibility of developing rapid “click”
protocol using present catalytic system. Accordingly, the model
reaction was repeated again but this time using higher (but within
the acceptable limit) catalyst and ligand loading. Thus increasing
the catalyst loading from 1 to 10 mol % and in the presence of 11
mol % of ligand L2, the reaction reached to completion within 50
minutes to give 95% yield (table-2, entry-4). Notably, 49% yield
of the 1, 2, 3-triazole could be obtained within few minutes under
same reaction conditions (table-2, entry-5). Thus, the present
method could be readily adapted for rapid generation of
radiolabelled 1, 2, 3-triazoles with short lived radioisotopes
though we did not check its practical feasibility with
radiolabelled substrate.
R
CuSO4 1 mol %, Na-ascorbate 5.0 mol %
N3
R
N
N
Ligand 1.1 mol %, DMSO:H2O 1:3,
rt, 4h
N
2 equiv.
1.0 equiv.
Scheme 2.
As can be seen from results, a wide range of alkynes such as
aryl acetylenes, aliphatic alkynes and alicyclic alkynes reacted
rapidly with high to near quantitative yields21. As compared to
the parent phenyl acetylene, electron rich, p-(t-butyl) phenyl
acetylene gave little lower yield. Several 1-(prop-2-ynyloxy)
benzene derivatives such as 1-(prop-2-ynyloxy)-, 1-ethyl-4-
(prop-2-ynyloxy)-, 1-bromo-4-(prop-2-ynyloxy)-, 1-nitro-4-
(prop-2-ynyloxy) benzene participated successfully in present
CuAAC reaction to give excellent yields (table-4, entries 3-6).
The aliphatic alkynes such as 1-pentyne and 3-methyl non-1-yn -
3-ol reacted quickly and cleanly with very high yields of
corresponding 1,2,3-triazoles (table-4, entry 8 and 10). Notably,
the cyclic alkynes, for example, ethynylcyclopropane reacted
quickly with excellent yield under these conditions without
giving any side products (table-4, entry-9). Interestingly, the
alkyne derived from 1-H- indoline- 2, 3-dione, 1-(prop-2-ynyl)-
indoline-2, 3-dione, could be readily converted to the
corresponding (1-triazolylmethyl) indoline-2, 3-dione hybrid
scaffold in high yield. In general no significant difference in the
reactivity of theses alkynes towards CuAAC was observed as
they furnished the 1, 2, 3-triazole products ranging over 92-99 %
yields. Unfortunately, the propargyl alcohol, which happened to
be the precursor for present “Click” ligand did not react all under
these conditions (table-4, entry11).
Table-2. Effect of copper, ligand loading and azide-alkyne
ratio on CuAAC
Ligand Azide-
Copper(II)
(mol%)
Yield
(%)a
Entry
(mol
%)
alkyne Time(h)
Ratio
1
2
3
4
5
1.0
1.0
1.0
10
none
1.1
1.1
11
1:1.2
1:1.2
1:2
1:2
1:2
4
4
4
0.8
0.16
38
82
94
95b
49c
10
11
a Isolated yields. b,c 20 mol % of Na-ascorbate was used.
With good results being obtained in DMSO-water system,
next, the effect of other solvent systems such DMF-water, and
Acetone-water, Ethanol-Water and t-BuOH-Water etc. was
investigated. The results are summaries in table-3.
Having tested different alkynes, next, the scope of different
azides in CuAAC was explored, scheme-3.
Ph
Table-3. Effect of solvent in [3+2] azide-alkyne
Cycloaddition (CuAAC)a
CuSO4 1 mol %, Na-ascorbate 5.0 mol %
R1 N3
Ph
N
N
Solvent system
Ligand 1.1 mol %, DMSO:H2O 1:3,
rt, 4h
R1
Entry
Time(h)
Yield (%)b
N
(1:3)
1.0 equiv.
2 equiv.
1
2
3
4
5
DMSO:H2O
DMF: H2O
Acetone: H2O
EtOH:H2O
4
4
4
4
4
94
50
58
77
80
Scheme 3.
The results are collected in table-5.
t-BuOH:H2O
a 0.2 mmol of azide, 0.4 mmol of alkyne (2.0 equiv.), 1.0 mol % of CuSO4,
5.0 mol % Na-ascorbate in the presence of 1.1 mol % of ligand L2 at room
temperature. b Isolated yields by column chromatography.

4
Tetrahedron
Table-5.Scope of azides in [3+2] azide-alkyne Cycloaddition
Table-4 Scope of alkynes in [3+2] azide-alkyne
(CuAAC)a
Cycloaddition (CuAAC)a
Product
Yield (%)b
94
Entry
Alkyne
Azide
N
N
1
2
Product
Alkyne
Yield (%)b
94
N3
N3
Entry
N
N
N
1
N
N
76
N
N
Br
I
Br
I
N
2
89
N
N
N3
N
N
3
45
91
83
N
O
O
N
3
4
5
N3
N3
N
N
97
96
N
4
5
N
NC
NC
N
N
O
O
O
O
N
N
N
N
O2N
O2N
N
N
Br
N
92
99
76
N3
N
N
N
6
7
40
31
19
Br
N
O
NO2
O
O
N
6
N3
N
N
N
N
O2N
N
O
O
N
O
O
N
N
7
O
N3
O
O
8
9
N
N
N
N
N
N
N
N
57
N
8
N
N3
92
97
N
N
N
N
N
N
N
N
N
I
I
9
N
OH
O
O
10
50c
N
10
11
93
0
N
OH
N
N
N3
N
N
O
O
N
N
I
I
OH
OH
OH
C5H12
N3
N3
N
N
N
11
12
94
OH
OH
N
a
0.2 mmol of azide, 0.4 mmol of alkyne (2.0 equiv.), 1.0 mol % of CuSO4,
OH
C5H12
5.0 mol % Na-ascorbate in the presence of 1.1 mol % of ligand in DMSO-
H2O (1:3) at room temperature for 4 h. bIsolated yields. Reaction was
c
92d
N
N
N
performed on 0.15 mmol scale.
As can be seen from our results, in contrast to the alkynes, the
azides shown very striking trend in their reactivity. While the
parent benzyl azide reacted efficiently, both the electron rich as
well as electron deficient benzyl azides such as 4-I, 4-Br-, 4-CN-,
and 4-NO2benzyl azide shown lower reactivity but still they
quickly reacted to give good to very high yields of the
corresponding 1,2,3-triazole products, (table-5, compare entry 1
with entries 2-5). The p-iodobenzyl azide gave lowest yield in the
benzylic azide series under these conditions. In contrast to
benzylic azides, the reaction of arylazides, for example, p-toulyl
azide, was much sluggish and gave moderate yield (table-5,
entry-6). To our surprise same azide shown exceptionally high
reactivity in the reaction with sterically hindered, 3-methyl-non-
1-yn-3-ol giving the corresponding 2-(1-p-tolyl-1H-1, 2, 3-
triazol-4-yl) octan-2-ol in excellent yield (table 5, entry-11). This
surprising result prompted us to find out the exact cause behind
it. As the ligand L2 bears the CH2OH at C-4 of 1,2,3-triazole
core and since the resulting triazole product in the above reaction
is analogous to ligand L2, we believe that above 1,2,3-triazole
must be acting as insitu ligand concomitantly with L2 thereby
exhibiting such unexpected high rate acceleration.
a
b
c
Reaction conditions: as for table-3. Isolated yields. Reaction was
d
performed on 0.03 mmol scale. Yield in the bracket is that obtained
without using L2.
To check whether this was indeed the case, the independent
controlled experiment involving benzyl azide and phenyl
acetylene but in the absence of ligand L2 was carried out. As
anticipated, the reaction gave more or less similar result to that
with L2 (table-5, entry-11 vs. 12) which confirmed that the
observed dramatic rate enhancement was mainly due to the large
excess of 2-(1-p-tolyl-1H-1,2,3-triazol-4-yl)octan-2-ol (insitu
ligand) with respect to copper(I)-catalyst formed progressively
during course of reaction. Unfortunately, the other azides such as
cinnamyl azide and the esters functionalized azide, however,
found to be most reluctant substrates under these conditions and
gave low yield of the corresponding 1,2,3-triazole, (table-5,
entry-7 and 8).
Of particular importance, the novel azides such as 4-
(azidomethyl)-1-benzyl-1H-1, 2, 3-triazole and [3, 5-bis (p-
iodobenzyloxy)] benzyl azide were also found to be suitable
substrates under present reaction condition. It is to be noted that
the dendritic azide such as [3,5-bis(p-iodobenzyloxy)]benzyl
azide can be smoothly converted to the corresponding Freche’t
type G1 dendron grafted 1,2,3–triazole in moderate yield (table
5, entry 10). Thus the method is compatible with many complex
azides leading to the highly functionalized 1,2,3-triazole
derivatives at great ease.

5
3. References
Reagrding mechanistic aspect of reaction, we believe that the
present 1,2,3-triazole ligand accelerated CuAAC might have
catalysed by the five membered copper complex formed by
mixed bidented ligand L2 with insitu formed Cu(I). How the
present ligand accelerates the reaction has been illustrated by the
plausible mechanism as outlined in scheme-4.The copper (II) is
initially reduced to Cu (I) by Na-ascorbate. The copper (I)
complex of the type Cu (I) L2 formed insitu by coordinating of
bidented N, O-1, 2, 3,-triazole ligand might be acting as a true
catalyst. The copper (I) complex first coordinate to the terminal
alkyne π electron to form the π-complex 1 and then copper
acetylide 2. The ligation of azide to 2 at the expense of 1, 2, 3-
triazole ligand results into azido complex 3 which then rearranges
to the cyclic six membered metallocycle 4 and further into copper
metalated triazole 5. Finally the copper metalated triazole
releases the 1, 2, 3-triazole 6 by protonation and the copper
catalyst is regenerated and reused again. However, the possibility
of involvement of multinuclear copper complex5d in the
cycloaddition reaction cannot be ruled out at this stage.
1. Huisgen, R. 1, 3-Dipolar Cycloaddition Chemistry, ed. Padwa,
A. Wiley NewYork, 1984, pp.1-176.
2. Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem. Int. Ed., 2002, 41, 2596.
3. Throne, C. W.; Meldal, C. M. J. Org. Chem. 2002, 67, 3057.
4. a) Kolb, H. C.; Sharpless, K. B. Drug Discovery Today, 2003, 8,
1128; b) Breinbauer, R.; Kohn, M. Chem. Bio. Chem, 2003, 4,
1174; c) Xi, W.; Scott, T. F.; Kloxin, C. J.; Bowman, C. N. Adv.
Funct. Mater., 2014, 24, 2572; d) Wu, P.; Malkoch, M.; Hunt, J.
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The scope of alkynes and azides (table-4 and 5) of the present
reaction is much broader. Several alkynes and azides investigated
here have no literature precedent and thus many new 1, 2; 3-
triazoles could be entered in the list of “click” products using this
protocol. The very low catalyst/ligand loading, mild condition
and quick formation of triazoles with to near quantitative yields
are some of the noteworthy feature of the method.
6. a) Chan, T. R.; Hilgraf, R.; Sharpless, K. B.; Fokin, V. V. Org.
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R
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N
Ln Cu(I)
N
1/2 H2
N
PMO
O
R
M. G. J. Am. Chem. Soc., 2007, 129, 12696.
1
10. Donnelloy, P. S.; Zanatta, S. D.; Zammit, S. C.; White, J. M.;
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46, 4543.
N
N
Cu(I)
N
PMO
N
N
N
N
PMO
O
O
2
+
R1
N
N
H
R
12. Perez-Balderas, F.; Ortega-Munoz, M.; Morales-Sanfrutos, J.;
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Organometallics, 2011, 30, 6225-6232.
R1
N
N
N
6
H+
PMO
N
O
N
O
N
N
R
PBM
N
R1
3
R
N
R
N
N
N
14. Silvia, D. –G.; Correa, A.; Cavallo, L.; Nolan, S. P. Chem. –Eur.
5
N
N
N
N
J., 2006, 12, 7559.
R1
O
N
R1
N
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Astruc, D.; Vincent, J. –M. Chem. Commun., 2008, 741.
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N
N
N
4
OMP
PMO = p-methoxybenzyl
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Scheme 4.
2. Conclusion
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In conclusion, we have demonstrated that the cheap, readily
accessible and highly efficient “click” ligand dramatically
accelerate the copper catalysed [3+2] cycloaddition of azide and
alkyne with high to excellent yields. Thus the mild, simple,
efficient and economical protocol for rapid triazoles synthesis
developed here would attract the attention of chemical
community.
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3398–3401.
21. To a 10 mL vial charged with copper sulfate (0.5 mg, 0.01 mmol)
and sodium ascorbate (2 mg, 0.05 mmol) was added 0.5 mL of
DMSO-H2O mixture (1:3) and resulting mixture was stirred at
room temperature for 10 min. Then the appropriate azide (0.2
mmol) and alkyne (0.4 mmol, 2.0 equiv.) was added to it and the
reaction mixture was stirred vigorously at room temperature for
4h. After completion of reaction (TLC), the reaction mixture was
quenched with water (10 mL) and extracted with ethyl acetate
(3x10 mL) and combined organic extract was further washed with
water and brine. Evaporation of organic extract after drying over
Acknowledgements
RHT thanks department of Science and Technology (DST)
Ministry of Science, India for financial support of this project
(SR/FT/CS-85/2011), GVB and TGK thank UGC India, for Rajiv
Gandhi National Fellowships.

6
Tetrahedron
anh. Na2SO4 followed by column chromatography afforded
analytically pure 1, 2, 3-triazole derivatives.