CuII-hydrotalcite as an efficient heterogeneous catalyst for huisgen [3+2] cycloaddition

Article abstract of DOI:10.1002/chem.200802384

A copper-aluminum hydrotalcite (Cu/Al-HT(3:1) as a new, environmentally benign, recyclable, efficient, and heterogeneous Cu^II catalyst system for the Huisgen [3+2] cycloaddition of azides and alkynes, was reported. (Cu/Al-HT(3:1) was prepared a

Full text of DOI:10.1002/chem.200802384

COMMUNICATION
DOI: 10.1002/chem.200802384
CuII–Hydrotalcite as an Efficient Heterogeneous Catalyst for Huisgen [3+2]
Cycloaddition
Kayambu Namitharan, Mayilvasagam Kumarraja, and Kasi Pitchumani*[a]
Click chemistry[1]—“a modular synthetic approach to-
wards the assembly of new molecular entities”—finds exten-
sive applications, ranging from functionalizing biological
molecules,[2] solubilizing carbon nanotubes,[3] to forming su-
pramolecules.[4] The Huisgen 1,3-dipolar cycloaddition[5] of
azides to alkynes to yield 1,2,3-triazoles[6] has emerged as a
highly useful and premier example of click chemistry
(Scheme 1).
immobilized onto various supports such as silica,[18] zeo-
lites,[19] activated charcoal,[20] and amine-functionalized poly-
mers[21] were reported recently. However, heterogeneous
catalysts immobilized with CuI species frequently suffer
from the general thermodynamic instability of CuI, which re-
sults in its easy oxidation to CuII and/or disproportionation
to Cu0 and CuII. Consequently most of the reports require
an inert atmosphere and anhydrous solvents. Fokin et al.[12d]
introduced polytriazolylamines as powerful stabilizing li-
gands for copper(I), without the need for any reducing
agent and inert atmosphere. In contrast to the copper-cata-
lyzed version, ruthenium complexes ([Cp*RuClACHTUNGTRENNUNG(PPh3)2],
[Cp*RuCl]) are found to be efficient catalysts for producing
1,5-disubstituted triazoles regioselectively.[22] Herein we
report copper–aluminum hydrotalcite (3:1) (Cu/Al–HT
(3:1) abbreviated hereafter as CuII–HT), as a novel, environ-
mentally benign, recyclable, efficient, and heterogeneous
CuII catalyst system for the Huisgen [3+2] cycloaddition of
azides and alkynes, without any sacrificial reducing agents
and ligands.
Scheme 1.
In 2002, Sharpless and co-workers[7] and Meldal and co-
workers[8] independently discovered the copper-catalyzed
version of the regiospecific azide–alkyne cycloaddition
which displayed a dramatic rate acceleration of up to 107
times.[9] This reaction seems to be catalyzed by CuI species,
which are either added directly as cuprous salts (CuI, CuBr)
with triphenylphosphine,[10] iminopyridine,[11] or mono- (or)
polydentate nitrogen ligands,[12,2b] as N-heterocyclic copper
carbene complexes,[13] or generated by the reduction of CuII
salts[14,7] or by comproportionation of a Cu0/CuII couple,[9,15]
and by copper nanoclusters.[16] Recent research in this area
has concentrated on heterogeneous catalytic systems,[17]
which can have several advantages such as faster and sim-
pler isolation of the reaction products by filtration, as well
as recovery and recycling of the catalyst systems. CuI species
Hydrotalcite-like compounds constitute a class of two-di-
mensional materials, which are represented by the general
formula [MII
[Ax/nnÀ]·mH2O, where MII is a bi-
M x(OH)2]ACTHUNTGNRUEGN
III
1Àx
valent metal cation (MgII, CuII, ZnII),[23] MIII is a trivalent
metal cation (AlIII, CrIII), and x can have values between 0.2
to 0.4. A is the interlayer anion (with a charge n), mainly
CO3 or NO3 . Recently, Angel and Burgess, in their stud-
ies on the copper-mediated Huisgen addition of azides to al-
kynes in the presence of carbonate bases, have observed oxi-
dative dimerization to give 5,5’-bistriazole.[24]
2À
À
Preliminary investigations in the reaction of benzyl azide
with phenylacetylene in the presence of CuII–HT with car-
bonate ions as interlayer stabilizing anions, revealed they
give the expected adduct as a single regioisomer. The CuII
species present in the clay framework has shown excellent
reactivity at room temperature without the need for an inert
atmosphere. Cu/Al–HT (3:1) was prepared[25] and character-
ized by powder XRD.[26] To the best of our knowledge, in
only one instance, CuII (as CuII acetate) was reported to pro-
mote the regioselective synthesis of 1,4-disubstituted 1,2,3-
[a] K. Namitharan, Dr. M. Kumarraja, Prof. K. Pitchumani
School of Chemistry, Madurai Kamaraj University
Madurai, 625021 (India)
Fax : (+91)0452-2459181
E-mail: pit12399@yahoo.com
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200802384.
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2755

triazoles in water,[27] a result consistent with experimental
findings of the rate acceleration in water, since formation of
copper acetylide is exothermic by 11.7 kcalmolÀ1 in aqueous
medium. However, the chemistry of the click reaction in the
present study is largely different as it is carried out in a non-
aqueous medium, in which (in the absence of a decreased
HOMO–LUMO gap and a consequent rate acceleration in
water) this Huisgen [3+2] cycloaddition requires external
nitrogen ligands or reducing agents to activate the acetylide
or to stabilize the CuI species to obtain regioselectivity.
Table 2. Synthesis of 1,4-disubstituted-1,2,3-triazoles with different azides
and alkynes.[a]
Entry
1
Azide R
C6H4CH2
Alkyne R1
C6H5
Time [h]
6
Yield[b] [%]
86, 84[c]
,
85[d],83[e]
2
3
4
5
6
7
8
9
10
11
12
13
14
15
p-ClC6H4CH2
p-CH3C6H4CH2
p-OCH3C6H4CH2
p-NO2C6H4CH2
C6H5
3-NH2C6H4
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5
C6H5
C6H5
C6H5
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
p-OCH3C6H4
p-FC6H4
3-NH2C6H4
CH3OOC
C2H5OOC
HOCH2
8
12
10
12
11
12
10
10
10
9
88
84
80
In sharp contrast to the use of CuACTHNUTRGNEUNG(NO3)2 alone as a cata-
lyst, CuII–HT affords the corresponding 1,4-disubstituted-
1,2,3-triazoles at room temperature as a single regioisomer
in good to excellent yields (the remainder (10–15%) corre-
sponds to recovered starting materials as evident from GC).
Control experiments (Table 1) with Mg/Al–HT (Table 1,
75 + others[f]
86
82
83
78
82
86
89
88
89
86
7
8
7
8
Table 1. Synthesis of 1,4-disubstituted-1,2,3-triazoles with different cata-
lysts and solvents.[a]
C6H5CH2
C6H5CH2
cyclopropyl
[a] Reaction conditions: azide (0.37 mmol), alkyne (0.44 mmol), catalyst
(10 mg), ACN (1.5 mL), room temperature. [b] Yield of isolated pure
product. [c,d,e] Yield of successive reused runs. [f] Unidentified by-prod-
ucts.
Entry
Catalyst
Solvent
Time [h]
Yield [%][b]
1
2
none
Cu/Al–HT
ACN
ACN
48
6
0
86
yields of a single regioisomer, namely 1,4-disubstituted
1,2,3-triazoles, are obtained. Only in the case of an azide
with an electron-withdrawing nitro group (Table 2, entry 5)
was the yield lower.
3
4
5
6
7
8
9
10
Cu
(NO3)2·3H2O
ACN
ACN
ACN
ACN
PhCH3
CH2Cl2
MeOH
THF
48
48
48
48
6
6
6
6
0
0
0
0
74
72
77
Al(NO3)2·9H2O
A
Mg/Al–HT
Zn/Al–HT
Cu/Al–HT
Cu/Al–HT
Cu/Al–HT
Cu/Al–HT
We have also developed an experimentally convenient
one-pot, regioselective synthesis of 1,2,3-triazole from
benzyl bromide, sodium azide, and phenylacetylene. Here
too, the corresponding 1,2,3-triazole is obtained (in 78%
yield) as a single regioisomer. Since the formation of copper
acetylide is exothermic by 11.7 kcalmolÀ1 in aqueous solu-
tion,[1f] CuII species can catalyze this click reaction in aque-
ous medium. However, in acetonitrile, the same reaction is
endothermic by 0.6 kcalmolÀ1. Recently, Fokin et al.,[29]
demonstrated that dinuclear alkynyl copper complexes ex-
hibit superior reactivity toward organic azides compared to
their monomeric analogues. The barrier to the addition is
calculated to be 10.5 kcalmolÀ1, compared to the value of
17 kcalmolÀ1 calulated for the mononuclear copper acety-
lides.
53+ others[c]
[a] Reaction conditions: benzyl azide (0.37 mmol), phenylacetylene
(0.44 mmol), catalyst (10 mg), solvent (1.5 mL), room temperature.
[b] Yield of isolated product. [c] Unidentified by-products.
entry 5) and Zn/Al–HT (Table 1, entry 6), clearly highlight
the specific role of CuII in hydrotalcite layers.[28] We have
also investigated the effect of the solvent on the “click” re-
action (Table 1), and a marginal decrease in yield is ob-
served when the reaction is performed in toluene, dichloro-
methane, and methanol (Table 1, entries 7–9). Only in case
of THF does the reaction lead to lower conversion. Thus,
when the reactions are conducted in acetonitrile, pure prod-
ucts are isolated in good to excellent yields, and a simple
workup procedure is sufficient without the need for chroma-
tographic separations. The reusability of the CuII–HT cata-
lyst was also investigated. It was recovered and reused five
times without any significant loss in yield (Table 2, entry 1).
To evaluate the scope of this new CuII-catalyzed process
further, reactions of benzyl azide with several aliphatic and
aromatic terminal alkynes substituted by electron-donating
as well as electron-withdrawing groups were carried out.
Likewise, the reactivity of alkynes with various alkyl and
aryl azides was also studied. In all the cases, very good
By analogy with previous reports,[1f,15] a stepwise mecha-
nism involving an initial CuII–acetylide complex 2 is pro-
posed. The role of the second copper atom seems to be the
activation of the azide functionality as in 3 and 4/4a
(Scheme 2) towards nucleophilic attack by reducing the
electron density of the alkyne. A six-membered-ring inter-
mediate 4a, as previously proposed,[15] is also likely, in
which the neighboring Cu can accelerate the rate by coordi-
nation of the Cu to the alkynyl moiety of the reaction
center. Since, the chance of having adjacent CuII ions in the
HT framework is very high, the energy barrier for the addi-
tion decreases considerably and this thereby accelerates the
2756
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Chem. Eur. J. 2009, 15, 2755 – 2758

CuII–Hydrotalcite Catalyzed [3+2] Cycloaddition
COMMUNICATION
Keywords: copper
· click chemistry · cycloaddition ·
heterogeneous catalysis · regioselectivity · triazoles
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Acknowledgements
We are grateful to the Department of Biotechnology (DBT), New Delhi
for financial support to this work.
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Received: November 17, 2008
Published online: February 5, 2009
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