Copper(I) 1,2,3-triazol-5-ylidene complexes as efficient catalysts for click reactions of azides with alkynes

Article abstract of DOI:10.1021/ol102858u

Complexes of copper with 1,4-diphenyl, 1,4-dimesityl, and 1-(2,6-diisopropylphenyl)-4-(3,5-xylyl)-1,2,3-triazol-5-ylidene (abnormal NHC = N-heterocyclic carbene) were prepared by consecutive treatment of the corresponding azolium salts with silver oxide and copper chloride. The new CuCl(aNHC) complexes efficiently catalyzed click reactions of azides with alkynes to give 1,4-substituted 1,2,3-triazoles in excellent yields at room temperature with short reaction times. CuCl(TPh) was particularly effective for the reaction between sterically hindered azides and alkynes.

Full text of DOI:10.1021/ol102858u

ORGANIC
LETTERS
2011
Vol. 13, No. 4
620–623
Copper(I) 1,2,3-Triazol-5-ylidene
Complexes as Efficient Catalysts for
Click Reactions of Azides with Alkynes
Tatsuhito Nakamura, Takahiro Terashima, Kenichi Ogata, and Shin-ichi Fukuzawa*
Department of Applied Chemistry, Institute of Science and Engineering,
Chuo University, 1-13-27 Kasuga, Bunkyo-ku, Tokyo 112-8551, Japan
orgsynth@kc.chuo-u.ac.jp
Received November 26, 2010
ABSTRACT
Complexes of copper with 1,4-diphenyl, 1,4-dimesityl, and 1-(2,6-diisopropylphenyl)-4-(3,5-xylyl)-1,2,3-triazol-5-ylidene (abnormal NHC = N-
heterocyclic carbene) were prepared by consecutive treatment of the corresponding azolium salts with silver oxide and copper chloride. The new
CuCl(aNHC) complexes efficiently catalyzed click reactions of azides with alkynes to give 1,4-substituted 1,2,3-triazoles in excellent yields at room
temperature with short reaction times. CuCl(TPh) was particularly effective for the reaction between sterically hindered azides and alkynes.
Since the successful isolation of N-heterocyclic carbenes
(NHCs) by Arduengo and co-workers in 1991,1,2 N-het-
erocyclic carbene (NHC) ligands have been widely used
as ancillary ligands not only for transition metal complexes
but also for main group elements. Although the majority
of NHC ligands are imidazol-2-ylidenes or 1,2,4-triazol-
5-ylidenes (normal NHC), some alternative NHC ligands
(abnormal NHC) have also been reported,3 includ-
ing 1,2,3-triazol-5-ylidene, which is easily prepared by
copper-catalyzed azide-alkyne cycloaddition (click re-
action). The preparation of this class of compounds and
their application as ligands for transition metals have been
reported by various research groups.4 Although these se-
ries of abnormal NHC (aNHC) ligands and their com-
plexes have been researched, the catalytic merit of these
ligands has yet to be developed in detail. The synthesis
of 1,2,3-triazolylidene NHC complexes and its application
to transition metal catalytic reactions have scarcely been
studied.
(1) Arduengo, A. J.; Harlow, R. L.; Kline, M. J. Am. Chem. Soc.
1991, 113, 361.
(2) Recent reviews of N-heterocyclic carbenes, see: (a) Marion, N.;
Nolan, S. P. Chem. Soc. Rev. 2008, 37, 1776. (b) W€urtz, S.; Glorius, F. Acc.
Chem. Res. 2008, 41, 1523. (c) Cavell, K. Dalton Trans. 2008, 6676. (d)
Schuster, O.; Yang, L.; Raubenheimer, H. G.; Albrecht, M. Chem. Rev. 2009,
We recently reported the synthesis of a palladium com-
plex bearing a 1,4-dimesityl-1,2,3-triazol-5-ylidene ligand
(TMes) and its application in Suzuki-Miyaura coupling
reactions using aryl chlorides.5 It was found that the 1,2,
3-triazol-5-ylidene palladium complex had greater cata-
lytic activity than the corresponding palladium complex
€
109, 3445. (e) Droge, T.; Glorius, F. Angew. Chem., Int. Ed. 2010, 49, 6940.
(f) John, A.; Ghosh, P. Dalton Trans. 2010, 7183. (g) Melaimi, M.;
Soleilhavoup, M.; Bertrand, G. Angew. Chem., Int. Ed. 2010, 49, 8810.
(h) Kirmse, W. Angew. Chem., Int. Ed. 2010, 49, 8798. (i) N-Heterocyclic
Carbenes in Transition Metal Catalysis and Organocatalysis; Cazin,
C. S. J., Ed.; Springer: Dordrecht, 2010.
(3) (a) Aldeco-Perez, E.; Rosenthal, A. J.; Donnadieu, B.; Parameswaran,
P.; Frenking, G.; Bertrand, G. Science 2009, 326, 556. (b) Lavallo, V.; Dyker,
C. A.; Donnadieu, B.; Bertrand, G. Angew. Chem., Int. Ed. 2008, 47, 5411. For
reviews of aNHCs, see:(c) Arnold, P. L.; Pearson, S. Coord. Chem. Rev. 2007,596.
(d) Albrecht, M. Chem. Commun. 2008, 3601.
(4) (a) Mathew, P.; Neels, A.; Albrecht, M. J. Am. Chem. Soc. 2008,
130, 13534. (b) Karthikeyan, T.; Sankararaman, S. Tetrahedron Lett. 2009,
50, 5834. (c) Guisado-Barrios, G.; Bouffard, J.; Donnadieu, B.; Bertrand, G.
Angew. Chem., Int. Ed. 2010, 49, 4759. (d) Kilpin, K. J.; Paul, U. S. D.; Lee,
A.-L.; Crowley, J. D. Chem. Commun. 2011, 47, 328.
(5) Nakamura, T.; Ogata, K.; Fukuzawa, S.-i. Chem. Lett. 2010, 39,
920.
r
10.1021/ol102858u
Published on Web 01/07/2011
2011 American Chemical Society

bearing an imidazol-2-ylidene ligand. In order to establish
the utility of the 1,2,3-triazol-5-ylidene ligand, we decided
to extend its chemistry to include the synthesis of com-
plexes with other transition metals and their application
in catalytic transformation reactions. Herein, we describe
the first synthesis of a copper complex bearing a 1,2,3-
triazole carbene ligand and its application in azide-alkyne
cycloaddition reactions (Scheme 1).6,7
obtained by recrystallization in dichloromethane/diethyl
ether. An ORTEP drawing of CuCl(TPrXyl) is shown in
Figure 1. Bond distances and angles in this complex were
similar to those in the previously reported copper imidazole
carbene complex CuCl(IPr).8 The bond lengths between the
carbene carbon and copper and chlorine and copper were
1.879(5) A and 2.115 (15) A, respectively, compared with
lengths of 1.881(7) A and 2.106(2) A, respectively, in the
corresponding complex CuCl(IPr). The carbene C-Cu-Cl
bond angle was 177.8 (15)°;almost linear.
Scheme 1. Preparation of Copper-aNHC Complexesa
Figure 1. ORTEP drawing of CuCl(TPrXyl) with thermal ellip-
soids at the 50% probability level. All hydrogen atoms are
omitted for clarity. Selected bond lengths (A): Cu(1)-C(1) =
1.879(5), Cu(1)-Cl(1)=2.115(15). Selected bond angles (deg):
C(1)-Cu(1)-Cl(1)=177.8(15), C(1)-N(1)-C(12)=125.5(4),
C(1)-C(2)-C(3)=127.7(4).
ꢀ
ꢀ
Nolan and Diez-Gonzalez reportedthat(NHC)Cu com-
plexes were excellent and highly efficient catalysts in click
reactions of azides and alkynes (CuAAC reaction). It
was expected that the copper-1,2,3-triazol-5-ylidene
complexes would also be good catalysts for such reactions
because the triazolylidene NHC ligand has been revealed
to have good donor capabilities in the palladium complex
[PdCl2(TMes)2], which was used to catalyze a Suzuki-
Miyaura coupling reaction.5
a Mes=2,4,6-trimethylphenyl, Dipp=2,6-diisopropylphenyl, Xyl=
3,5-dimethylphenyl, IMes=1,3-dimesityl-imidazol-2-ylidene.
The triazolium salts 2 were obtained as stable solids in
quantitative yield by treatment of 1,2,3-triazoles 1 with
Me3OBF4, according to Crowley’s method.4d Consecutive
treatment of 2 with Ag2O/ammonium chloride and then
CuCl at room temperature successfully afforded the air-
stable 1,2,3-triazol-5-ylidene-copper(I) complexes CuCl-
(TPh), CuCl(TPrXyl), and CuCl(TMes), which were char-
acterized by 1H, 13C NMR, and HRMS analysis. A signal
attributable to a metal-bonded carbon was observed
around160 ppm in the 13C NMR spectrum, demonstrating
the formation of a copper carbene complex. A single
crystal of CuCl(TPrXyl) suitable for X-ray analysis was
We first evaluated the activity of CuCl(TPh), CuCl-
(TMes), and CuCl(TPrXyl) in the benchmark click reac-
tion of benzyl azide with phenylacetylene. The imidazol-
2-ylidene-copper complex CuCl(IMes) was also tested for
comparison. The products were the expected 1,4-substi-
tuted 1,2,3-triazoles, and the results of the reactions are
summarized in Table 1. Conversion vs time graphs for
CuCl(TPh), CuCl(TMes), and CuCl(IMes) are shown in
Figure 2. The reaction was carried out at room tempera-
ture for 1 h under air in the absence of solvent with a cata-
lyst loading of 1.0 mol %. The percentage conversion was
1
determined by H NMR integration of the two benzyl
(6) Recent reviews for the CuAAC reaction: (a) Bock, V. D.; Hiemstra,
H.; Maarseveen, J. H. Eur. J. Org. Chem. 2006, 51. (b) Meldal, M.; Tornøe,
C. W. Chem. Rev. 2008, 108, 2952. (c) Kappe, C. O.; Eycken, E. V. Chem. Soc.
Rev. 2010, 39, 1280. (d) Hein, J. E.; Fokin, V. V. Chem. Soc. Rev. 2010, 39, 1302.
(e) Struthers, H.; Mindt, T. L.; Schibli, R. Dalton Trans. 2010, 675.
protons of the starting benzyl azide (4.31 ppm) and the
product 1,2,3-triazole (5.55 ppm). No decomposition of the
catalysts or precipitation of metallic copper was observed
during these reactions. The product was isolated as a solid
simply by washing with pentane after an aqueous workup.
As can be seen from the graph, the fastest reaction was
achievedusingCuCl(TPh), withaconversionof 100%after
30 min. When CuCl(TMes) was used as a catalyst, the
(7) Recent examples for copper-NHC complex catalyzed azide-
ꢀ
alkyne cycloaddition reaction. (a) Dıez-Gonzalez, S.; Correa, A.; Cavallo,
ꢀ
L.; Nolan, S. P. Chem.;Eur. J. 2006, 12, 7558. (b) Díez-Gonzalez, S.;
ꢀ
Stevens, E. D.; Nolan, S. P. Chem. Commun. 2008, 4747. (c) Díez-Gonzalez, S.;
Nolan, S. P. Angew. Chem., Int. Ed. 2008, 47, 8881. (d) Teyssot, M.-L.; Chevry,
A.; Traïkia, M.; El-Ghozzi, M.; Avignant, D.; Gautier, A. Chem.;Eur. J. 2009,
15, 6322. (e) Teyssot, M.-L.; Nauton, L.; Canet, J.-L.; Cisnetti, F.; Chevrey, A.;
ꢀ
Gautier, A. Eur. J. Org. Chem. 2010, 3507. (f) Díez-Gonzalez, S.; Escudero-
ꢀ
Adan, E. C.; Benet-Buchholz, J.; Stevens, E. D.; Slawin, A. M. Z.; Nolan, S. P.
(8) Mankad, N. P.; Gray, T. G.; Laitar, D. S.; Sadighi, J. P. Orga-
nometallics 2004, 23, 1191.
Dalton Trans. 2010, 7595.
Org. Lett., Vol. 13, No. 4, 2011
621

Table 1. Results of the Benchmark Reaction of Benzyl Azide
with Phenylacetylene Using Copper(I)-aNHC Complexes as
Catalystsa
entry
catalyst
[Cu] (mol %)
time (min)
yield (%)b
1
CuCl(TPh)
CuCl(TPh)
CuCl(TPh)
CuCl(TPh)
CuCl(TPh)
CuCl(TMes)
CuCl(IMes)
CuCl(TPrXyl)
CuCl(TPrXyl)
CuCl
1
30
20
97
2
3
95
3
0.5
3
90
87
4c
5d
6
1440
40
62
3
80
1
60
35
7
1
60
25
8
1
60
95
9
1
30
11
10
1
60
trace
a Benzyl azide (0.50 mmol), phenylacetylene (0.55 mmol). b Isolated
yield. c The reaction was carried out in 1:1 tert-BuOH/H2O. d The
reaction was carried out in H2O.
Figure 2. Time vs conversion plot for the Cu(I)-aNHC-catalyzed
reaction of benzyl azide with phenylacetylene. ([) CuCl(TPh),
(b) CuCl(TMes), (2) CuCl(IMes).
product yield was 35% after 60 min, with a conversion of
100% after 90 min. The use of CuCl(IMes) resulted in a
25% yield after 60 min, and even after 180 min a conver-
sionof 100% was not achieved; 300 min were required to
achieve 100% conversion. Based on these results, the
1,2,3-triazol-5-ylidene ligand was concluded to be superior
to the imidazol-2-ylidene ligand in catalyzing the reaction.
Although the initial reaction rates were nearly identical, the
reaction rate was considerably accelerated with CuCl(TPh).
However, the acceleration effect was not observed by
the addition of a slight amount of 3a (1 mol %), suggest-
ing that autocatalysis may be ruled out.9 CuCl(TPrXyl)
also seemed to be an effective catalyst, giving a good
yield (95%) after 60 min; however, the yield was con-
siderably smaller after a shorter (30 min) reaction time.
The use of CuCl(TPh) gave a high product yield even when
the reaction was stopped after 30 min (entry 1). Moreover,
the reaction was nearly completed in an even shorter time
(20 min) with a catalyst loading of 3 mol % (entry 2). With
a reduced catalyst loading of 0.5 mol %, a longer reaction
time (100 min) was required to complete the reaction (entry 3).
The finding that CuCl(TPh) was the most efficient
catalyst suggested that sterically hindered ligands are not
suitable for the reaction; the steric factor of the ligand
is more critical thanthe electronic factor. The reaction with
ligand-free CuCl (catalyst loading 1 mol %) under neat
conditions for 60 min gave a trace of 3a (entry 10), which
showed that 1,2,3-triazole-5-ylidene acted as a good
σ-donor ligand in activating the Cu(I) center. It was con-
cluded that Cu(I)-aNHC complexes are highly efficient
catalysts for click reactions.
Since the click reaction is exothermic, carrying out such
reactions under neat conditions has some drawbacks even
with short reaction times. In order to address this problem,
we examined the catalytic activity of CuCl(TPh) (3 mol %)
in a 1:1 mixture of tert-BuOH/water and in water only at
room temperature. The reaction was very slow in tert-
BuOH/water(entry 4), with a conversionof only 62% after
24 h of stirring. The reaction in water gave a conversion
of 80% after 40 min, showing the efficiency of the catalyst
even in water (entry 5).
Next, we investigated the scope of the reaction with
respect to alkynes by carrying out reactions of benzyl azide
with a variety of alkynes using 3 mol % CuCl(TPh) as a
catalyst under neat conditions. The results are summarized
in Table 2. Cycloaddition with electron-poor (p-CF3, o-F)
phenylacetylenes proceeded smoothly to give the corre-
sponding 1,2,3-triazoles in almost quantitative yield in
20 min (entries 4-5). The reaction tended to be slow for
electron-rich alkynes such as 3,5-dimethylphenylacetylene,
alkyl alkynes, and trimethylsilylacetylene (entries 3, 10-
12). The exception to this was p-methylphenylacetylene,
for which the reaction was completed in 10 min (entry 2).
Functional groups such as alcohol, amine, ester, and
pyridine were tolerated (entries 9, 13-15), while pri-
mary amine was not; the reaction of propargyl amine
(entry 15) produced a complex mixture. For sterically
hindered alkynes such as o-substituted (o-Me, o-MeO,
o-AcNH) phenylacetylenes, the reaction time was long-
er, but it still took less than 60 min to complete the
reaction (entries 6-8). In summary, aromatic, electron-
rich, electron-poor, sterically hindered, and functiona-
lized alkynes were tolerated, and the reactions were fast
(from 20 min to 2.5 h).
(9) Since the heat of the reaction could accelerate the reaction though
its participation may be small, the curves might lack accuracy. However,
we may figure out the tendency of the activity of catalyst from the plots.
622
Org. Lett., Vol. 13, No. 4, 2011

Table 2. Scope of the Reaction Using Alkynesa
entry
R
prod.
time (min)
yield (%)b
1
C6H5
3a
3b
3c
3d
3e
3f
20
10
40
15
10
45
45
60
15
40
40
80
25
150
60
95
99
92
95
95
90
96
93
99
80
90
82
91
90
-
2
p-MeC6H4
3,5-xylyl
p-CF3C6H4
o-FC6H4
o-MeC6H4
o-MeOC6H4
o-AcNHC6H4
2-pyridyl
c-C6H11
3
4
5
6
7
3g
3h
3i
8
9
10
11
12c
13
14
15
3j
n-C6H13
3k
3l
Me3Si
Figure 3. CuAAC reactions of sterically hindered azides with
sterically hindered alkynes.
CH2OH
3m
3n
3o
CO2Me
CH2NH2
of the TPr ligand, using Sharpless or even Meldal’s condi-
tions (CuI/DIPEA).11
a Benzyl azide (0.5 mmol), alkyne (0.55 mmol). b Isolated yield.
c Desilylated products were included.
We succeeded in preparing the triazole 3s in 63% yield
by the reaction of 2,6-diisopropylphenylazide with 2,6-
diisopropylphenylacetylene using CuCl(TPh).
We then investigated the possibility of recycling the cata-
lyst. The activity of the catalyst was found to decrease in the
second cycle, with a slightly longer reaction time (30 min)
required to obtain a high yield (86%). In the third and fourth
cycle, the catalyst was still active but required even longer
reaction times (60 min, 80%; 120 min, 86%) (see Supporting
Information).
In conclusion, 1,2,3-triazol-5-ylidene was found to be a
good alternative NHC ligand for copper complexes, and
Cu(I)-aNHC complexes efficiently catalyzed many click
reactions of azides and alkynes. Furthermore, for the first
time, CuCl(TPh) successfully catalyzed the reaction between
sterically hindered azides and sterically hindered alkynes.
Encouraged by these results, we attempted reactions of
more sterically hindered alkynes with sterically hindered
azides. The results are shown in Figure 3. We usually
employ Sharpless conditions10 to prepare the precursor
triazole of TMes (3p) by the reaction of mesitylacetylene
with mesitylazide, with reaction conditions as follows: rt,
36 h, tert-BuOH/water, and 100 mol % CuSO4/sodium
ascorbate. However, the reaction using 3 mol % CuCl-
(TPh) for 30min at100 °C under neat conditions gave 3pin
71% yield, contaminated with a slight amount (<4%)
of 1,5-substituted 1,2,3-triazole. The 1,5-isomer was con-
cluded to result from a thermal Huisgen reaction. Catalyst-
free conditions gave a mixture of 1,4- and 1,5-isomers in a
ratio of 1:3 with 16% conversion after 60 min. This result
suggests that an uncatalyzed reaction might be involved
but is of negligible effect in the catalyzed reaction. The use
of CuCl(TPh) gave 3q, the precursor of TPrXyl, and the
more sterically hindered 3r in good yield from the reaction
of 2,6-diisopropylphenylazide with 3,5-dimethylphenyl-
acetylene and mesitylacetylene, respectively, under the same
conditions. So far, we have not been able to obtain 1,4-
bis(2,6-diisopropylphenyl)-1,2,3-triazole (3s), a precursor
Acknowledgment. We thank Dr. Yoshiaki Tanabe
(Tokyo University) for X-ray diffraction analysis. This
study was financially supported by a Grant-in-Aid, No.
22550044, for Scientific Research from the Japan Society
for the Promotion of Science (JSPS).
Supporting Information Available. Full experimental
procedures, characterization data, and 1H and 13C NMR
spectra (PDF) for new compounds; crystallographic data
for CuCl(TPrXyl) in a CIF file. This material is available
free of charge via the Internet at http://pubs.acs.org.
(10) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int.
Ed. 2001, 40, 2004.
(11) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002,
67, 3057.
Org. Lett., Vol. 13, No. 4, 2011
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