Table 2 Catalyst loading studiesa
41%, Entry 7). The results of reactions with different bases showed
that the cation of the base has not significantly determined the
catalytic activity, and increasing the length of the carbon chain of
the carboxylate anion showed slightly enhanced reactivity (Entries
16–20).
Conv.
After finding the importance of the carboxylates, we tested
copper(I)-acetate14 as copper source in CuAAC. Although the
click reaction of benzyl-azide and phenylacetylene in toluene,
performed with 1 mol% CuOAc without ligand showed better
activity than other copper(I) salts (Entry 21),15 repeating the
experiment in the presence of PPh3 the reaction was complete
in 1 h at 25 ◦C (Entry 22). Reducing the copper catalyst
loading to 0.05 mol% and the phosphane to 0.1 mol% the
full conversion was reached in 3 h (Entry 23). We suppose
that the presence of the ligand not only makes the copper
catalyst more soluble in organic media by complexation, but also
stabilizes the copper(I) carboxylate, and prevents the catalyst from
oxidation.
Entry Product
1
Solv. T/◦C t/h Cu (ppm) (%)b
DCM 25
2
500
100
2
3
4
5
6
7
8
9
3aa
3aa
3aa
3aa
3aa
3aa
3aa
3aa
3aa
DCM 25
DCM 25
DCM 25
DCM 25
Neat 25
Neat 50
Neat 50
Neat 50
Neat 50
Neat 50
2
2
2
2
6
6
6
6
6
2
400
300
200
100
50
50
30
10
0
50
88
78c
67c
19c
44d
86d
7e
2e
10
11
2f
50c
As an optimal choice,16 we used triphenylphosphane as ligand
for further examination and we prepared three copper phosphane
12
Neat 50
2
50
33c
complexes. Catalytic activity of CuNO3(PPh3)2,17 CuOAc(PPh3)2
18
and C3H7COOCu(PPh3)2 were compared in different organic
solvents.19 A general trend in the catalytic activity of the complexes
has been found in the cycloaddition with respect to the choice
of solvent. In all tested solvents the copper(I)-butyrate complex
showed superior activity in the reaction of benzyl azide and
phenylacetylene, and dichloromethane proved to be the most
suitable solvent for the reaction.
a Reaction conditions: 0.25 mmol benzyl azide, 0.25 mmol phenyl-
acetylene, 25 ◦C. b Conversions were determined by GC. c Reaction stopped
after the indicated time. d Formation of a negligible amount of 1,5-
regioisomer was observed. e Larger amount of 1,5-regioisomer was formed.
f 1 : 1 mixture of regioisomers was obtained.
Decreasing the amount of catalyst, we were able to achieve the
click reaction with 0.01% C3H7COOCu(PPh3)2, but a significant
drop in the conversion was detected on lowering the catalyst
content (Table 2, Entries 1–5). Under solvent free conditions a
further decrease of the catalyst loading was found to be possible.
The click reaction of benzyl azide and phenylacetylene in the
presence of 50 ppm copper catalyst reached 44% conversion
after 6 h at rt. At 50 ◦C the reaction takes place faster, and we
obtained the triazole product with 86% conversion after 6 h. In
the presence of 10–30 ppm copper the reaction was found to be
very sluggish. In the absence of copper catalyst at 50 ◦C we have
observed only the slow formation of a 1 : 1 mixture of triazole
regioisomers.
After the optimization studies, exploration of the scope
of the catalyst system was performed with 0.05–0.15 mol%
C3H7COOCu(PPh3)2 in DCM at room temperature without
the exclusion of air with structurally different azides and
acetylenes. Cycloaddition of phenylacetylene 2a with function-
alized benzyl azides (1b–d) (Table 3, Entries 2–4) also gave
the appropriate products (3ba, 3ca, 3da) with high isolated
yields. Reaction of benzyl azide and other aromatic acetylenes,
such as tolyl acetylene (2b) (Entry 5) and 2-pyridylacetylene
(2c) (Entry 6) also afforded the triazoles (3ab, 3ac) with high
yields.
For the reaction of azidomethyl phenylsulfide (1e) and pheny-
lacetylene (2a) 0.1 mol% catalyst was used and the reaction was
complete in 5 h at 28 ◦C. The efficiency of the catalyst system was
demonstrated with the reaction of bulky 1-azidoadamantane (1f)
and phenylacetylene (2a) and the triazol 3fa was isolated in 92%
yield.
Aliphatic azides were also effectively clicked with the terminal
acetylenes in the presence of 0.05 mol% bis-triphenylphosphano-
copper(I)-butyrate (Entries 12–16). The catalyst also proved
to be applicable for the transformation of azido and ethynyl
substituted sugar and amino acid derivatives. We were able to
prepare straightforwardly different triazoles (3ke, 3ig, 3le,
3ih) bearing these important molecular architectures
(Entries
17–20).
Summarizing our results, we have demonstrated that
copper catalyzed azide-alkyne cycloaddition can be achieved very
efficiently with stable phosphane based complexes of copper(I)
carboxylates. The presence of phosphane ligands and carboxylate
ions makes the copper(I) ion more soluble in organic media, and
ensures better accessibility of the transition metal for the reactant.
In dichloromethane the cycloaddition takes place in the presence
of 0.05 mol% copper catalyst at room temperature in short
reaction time. We have found that under solvent free conditions
the reaction proceeded in the presence of 50 ppm copper catalyst.
The developed conditions proved to be very effective for the azide-
alkyne click reaction, and the methodology offers good alternative
for the straightforward synthesis of versatile triazole compounds
in high yield.
Besides aromatic terminal acetylenes, the reactivity of aliphatic
compounds toward azides was also tested. Although, the reaction
of benzyl azide (1a) with 5-cyanopent-1-yne (2d), propargyl
acetate (2e) and hex-1-yne (2f) required longer reaction times
compared to the aromatic acetylenes, the click product (3ad,
3ae, 3af) was obtained almost quantitatively in all three cases
(Entries 7–9).
This journal is
The Royal Society of Chemistry 2010
Dalton Trans., 2010, 39, 726–729 | 727
©
Gonda, Zsombor
