[(NHC)2Cu]X complexes as efficient catalysts for azide-alkyne click chemistry at low catalyst loadings

Article abstract of DOI:10.1002/anie.200803289

(Chemical Equation Presented) La click, c'est chic! A catalytic system based on an [(NHC)₂Cu]X complex (NHC=N-heterocyclic carbene) was developed for the [3+2] cycloaddition of azides with alkynes under click conditions (see scheme). This syste

Full text of DOI:10.1002/anie.200803289

Angewandte
Chemie
DOI: 10.1002/anie.200803289
1,3-Dipolar Cycloaddition
[(NHC)2Cu]X Complexes as Efficient Catalysts for Azide–Alkyne
Click Chemistry at Low Catalyst Loadings**
Silvia Díez-Gonzµlez* and Steven P. Nolan*
Dedicated to Professor Carl D. Hoff on the occasion of his 60th birthday
In 2001, Sharpless and co-workers defined the concept of
“click chemistry” and the criteria for a transformation to be
considered a “click” reaction.[1] Since then, the copper-
catalyzed reaction of azides with alkynes to produce 1,2,3-
triazoles regioselectively[2] (the 1,3-dipolar Huisgen cyclo-
addition[3]) has become the most widely used click reaction.
As a result of its mild conditions and high efficiency, this
reaction has found a myriad of applications in biology and
materials science.[4] Less attention has been focused on the
development of novel copper(I)-based well-defined catalytic
systems[5–7] and on decreasing the amount of copper used.[5b,8]
This last point is extremely important for future industrial
applications and might be one of the last challenges to
overcome for this transformation.
We recently reported the remarkable activity of
[(NHC)CuX] complexes (NHC = N-heterocyclic carbene;
X = Cl, Br) in the Huisgen cycloaddition.[9] Such catalytic
systems have already been applied to the preparation of
triazole-containing carbanucleosides,[10] porphyrins,[11] and
platinum-based anticancer drugs,[12] as well as to the develop-
ment of a latent catalyst for this transformation.[13]
We also studied a family of cationic NHC-containing
Scheme 1. Catalyst design.
complexes of the general formula [(NHC)2Cu]X (X = PF6,
BF4).[14] During the examination of their activity in the
hydrosilylation of ketones, we observed enhanced reactivity
of these complexes relative to that of their neutral analogues
[(NHC)CuCl].[15] This improved activity was rationalized in
terms of a more efficient pathway for the activation of the
cationic precatalyst. Specifically, the second NHC ligand was
postulated to have an active role in the catalytic cycle. Under
hydrosilylation conditions, one NHC ligand is displaced by
the base in the reaction mixture. We wondered if an alkyne
could play a similar role to produce an active copper acetylide
from [(NHC)2Cu]X species (Scheme 1).
We investigated the activity of [(NHC)2Cu]X complexes
1–7 in the Huisgen cycloaddition with benzyl azide and
phenylacetylene as model substrates (Table 1). The reactions
were conducted on water with 2 mol% of the copper catalyst.
The SIMes-containing complexes 4a and 4b displayed poor
activity under these conditions, in contrast to the results of our
previous studies with [(NHC)CuX] complexes.[9] This lack of
reactivity can not simply be correlated with the medium steric
bulk of the SIMes ligand, as complexes 7a and 7b with very
bulky ItBu ligands were also ineffective.[16] [(ICy)2Cu]PF6
(5a) provided the best result: The cycloaddition reached
completion within 90 min. No general trend in reactivity was
found for this reaction with respect to the counterion of the
metal complex. Further optimization with complex 5a
showed that acetonitrile, instead of water, was the most
suitable solvent for this transformation.[17] Moreover, the
reaction was found to proceed smoothly under neat con-
ditions with a significantly decreased catalytic loading.
The scope of the reaction was examined with 5a
(0.5 mol%) under neat conditions at room temperature
(Scheme 2). All reactions proceeded smoothly to completion
[*] Dr. S. Díez-Gonzµlez, Prof. Dr. S. P. Nolan
Institute of Chemical Research of Catalonia (ICIQ)
Av. Països Catalans 16, 43007 Tarragona (Spain)
Fax: (+34)977-920-244
E-mail: sdiez@iciq.es
snolan@iciq.es
Homepage: http://www.iciq.es/english/research/grups_eng/
nolan/entrada.htm
[**] The ICIQ Foundation and the Spanish Ministerio de Educación y
Ciencia are gratefully acknowledged for financial support. S.D.G.
thanks the MEC for financial support through the Torres Quevedo
program. S.P.N. is an ICREA Research Professor. We thank Dr.
Nicolas “La Click, c’est chic” Marion for insightful reading of this
manuscript. NHC=N-heterocyclic carbene.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200803289.
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Table 1: Catalyst screening.
electronic nature of the reactants
and the outcome of the reaction. As
we had observed previously,[9] the
physical state of the reaction prod-
uct is critical: Longer reaction times
were required for the formation of
oily or low-melting-point triazoles.
In these cases, the results were
improved simply by increasing the
reaction temperature to 408C.[19]
The high activity of this catalytic
system naturally led us to examine
the possibility of further decreasing
the amount of metal used in this
transformation. Again with benzyl
azide and phenylacetylene as model
[(NHC)2Cu]PF6
t [h]
Conv. [%][a]
[(NHC)2Cu]BF4
[(IPr)2Cu]BF4
[(SIPr)2Cu]BF4
[(IMes)2Cu]BF4
[(SIMes)2Cu]BF4
[(ICy)2Cu]BF4
[(IAd)2Cu]BF4
[(ItBu)2Cu]BF4
t [h]
Conv. [%][a]
[(IPr)2Cu]PF6
1a
2a
3a
4a
5a
6a
7a
18
5
6
18
1.5
5
71
100
100
5
99
100
76
1b
2b
3b
4b
5b
6b
7b
8
5
6
18
5
3
100
100
100
13
95
100
35
[(SIPr)2Cu]PF6
[(IMes)2Cu]PF6
[(SIMes)2Cu]PF6
[(ICy)2Cu]PF6
[(IAd)2Cu]PF6
[(ItBu)2Cu]PF6
18
18
1
[a] The conversion (determined by H NMR spectroscopy) is an average of the values for at least two
independent experiments.
in short reaction times (from minutes to 9 h), and triazoles 8
were isolated in excellent yields and high purity after simple
filtration or evaporation. According to the “click laws”, no
precautions to exclude oxygen or moisture were taken in any
of these reactions. Neither copper disproportionation with the
precipitation of metallic copper nor copper oxidation was
observed under the optimized reaction conditions, which
shows, once more, the high ability of NHCs to stabilize
copper(I) species.[18]
Electron-rich, electron-poor, and hindered alkynes were
found to be suitable cycloaddition partners, as well as enynes.
Benzyl, alkyl, and aryl azides were successfully employed. A
number of functional groups were tolerated, such as alcohol,
ketone, ester, amine, pyridine, nitrile, and halogen function-
alities. No direct correlation can be drawn between the
substrates, we tested different catalyst loadings at various
temperatures under neat conditions. In this particular case,
reactions at 40 or 508C were faster than those at room
temperature and could be carried out with the lowest catalyst
loadings.[20] However, minor formation of the 1,5-disubsti-
tuted triazole regioisomeric to 8a was observed consistently
1
by GC and H NMR spectroscopy after prolonged reaction
times (8 h at 408C and 5 h at 508C). Thus, extreme caution is
required to avoid undesired thermal processes. Results for the
formation of a number of triazoles are presented in Table 2.
In all cases, the loading of 5a could be lowered at least to
300 ppm at room temperature or 100 ppm at 408C. Under
these conditions, good conversion was still attained after short
to reasonable reaction times. The best results were observed
for the synthesis of triazole 8a: A copper loading as low as
40 ppm led to a remarkable turnover number (TON) above
20000 and a turnover frequency above 5000 hÀ1.[21] It is
important to note that, under these reaction conditions, the
Table 2: [(ICy)2Cu]PF6-catalyzed synthesis of triazoles at low catalyst
loadings.
8
T
[8C]
[Cu]
[ppm]
t
[h]
Conv.
[%][a]
TON
RT
40
50
50
50
40
48
8
4
80
89
81
16000
17800
20250
RT
RT
75
6
91
72
12133
3600
200
20
RT
40
300
100
43
18
85
70
2833
7000
RT
40
300
100
40
18
45
71
1500
7100
[a] The conversion (determined by GC) is an average of the values for at
least two independent experiments.
Scheme 2. [(ICy)2Cu]PF6-catalyzed formation of triazoles.
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use of our previous catalyst [(SIMes)CuBr] led to no
conversion after 24 h.
To gain some insight into the activation pathway of the
precatalyst, we next carried out a number of stoichiometric
experiments. Whereas no interaction was observed between
benzyl azide and 5a in CD3CN, the same copper complex was
completely consumed in minutes in the presence of phenyl-
acetylene. The equimolar formation of two new species was
evidenced by 1H NMR spectroscopy (Figure 1). One of them
Scheme 3. Postulated mechanism. Bn=benzyl.
of C in the absence of a proton source. In contrast, when a
mixture of A and B was treated with the azide, clean
formation of triazole 8a was observed, along with the
regeneration of [(ICy)2Cu]PF6.
Figure 1. 1H NMR spectrum for the reaction of 5a with phenylacety-
lene. Cy=cyclohexyl.
Further experiments to isolate the triazolide intermediate
C met with limited success. The treatment of 5a with an
equimolar amount of phenylacetylene and a slight excess of
benzyl azide in acetonitrile led either to the decomposition of
the reaction mixture or to the direct formation of triazole 8a.
was identified unequivocally as ICy·HPF6 (B) by comparison
with a pure sample.[22] The second species was also isolated
cleanly and identified as the mononuclear copper(I) acetylide
A by NMR spectroscopy. To determine the identity of A
unambiguously, we carried out the same reaction with the IPr-
containing complex 1a. In this case, no reaction was observed
at room temperature. However, when the reaction mixture
was heated overnight at 808C, the formation of two new
species was observed, as well as remaining starting material.
1
Nevertheless, we were able to observe by H NMR spectros-
copy the consumption of the starting materials and the
formation of a new compound. The spectrum of the new
species was attributed to C;[20] however, the formation of this
intermediate as a minor component of the mixture and its
high instability precluded its full characterization. Moreover,
upon acidic hydrolysis this crude mixture rapidly evolved to
triazole 8a and ICy·HPF6. These findings are in line with a
report by Straub and co-workers, who recently isolated a
NHC triazolide complex in which the environment around
the copper center was highly encumbered, probably stabiliz-
ing the complex.[26]
In conclusion, we have developed a new catalytic system,
[(ICy)2Cu]PF6 (5a) without a solvent, for the [3+2] cyclo-
addition of azides and alkynes under click conditions. This
system has been shown to be broad in scope and highly
efficient (TOFs up to 5000 hÀ1) even at very low catalyst
loadings (down to 40 ppm). Furthermore, preliminary mech-
anistic studies have shown the ability of the NHC ligand on
the copper center to act as a base and deprotonate the starting
alkyne to initiate the catalytic cycle. Further applications of
this catalyst system, especially with a low catalyst loading, are
currently under investigation in our laboratory.
The new products were separated and identified as the known
[23]
À
complex [(IPr)Cu C ꢀ CPh]
and IPr·HPF6. The lower
reactivity of 1a relative to that of 5a can be correlated
directly to its moderate catalytic activity (Table 1). Thus, it
appears that one of the NHC ligands on the copper center can
act as a base, deprotonating the alkyne, to initiate the catalytic
cycle.
A proposed mechanism for this transformation is depicted
in Scheme 3. The bis(NHC) complex 5a would be trans-
formed into an acetylide A and an azolium salt B by reaction
with the alkyne. Upon the interaction of A with the azide, the
reaction would follow the pathway commonly accepted for
this transformation[24] to form a triazolide intermediate C, the
reaction of which with the azolium salt B would lead to the
formation of the expected triazole 8a and the regeneration of
the catalyst. However, a binuclear mechanism can not be
ruled out at this time.[25] We are currently carrying out
theoretical calculations to clarify this point.
In an attempt to isolate intermediate C, we treated
isolated complex Awith benzyl azide in CD3CN. However, we
observed the formation of a complex mixture of unknown
products as well as considerable precipitation, presumably of
copper salts. We attribute this result to the extreme instability
Received: July 7, 2008
Revised: August 14, 2008
Published online: October 10, 2008
Angew. Chem. Int. Ed. 2008, 47, 8881 –8884
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www.angewandte.org
8883

Communications
[15] a) H. Kaur, F. K. Zinn, E. D. Stevens, S. P. Nolan, Organo-
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4784 – 4796.
Keywords: alkynes · azides · click chemistry · copper ·
N-heterocyclic carbenes
.
[16] For discussion on the stereoelectronic parameters of NHC
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[17] During the optimization studies, complete conversion was
observed in dimethyl sulfoxide (2 h), water (1.5 h), N,N-dime-
thylformamide (1.5 h), THF (1 h), acetone (0.5 h), and MeCN
(0.2 h) in the presence of 5a (2 mol%). Sluggish reactions were
observed when alcohols were used as solvents.
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[19] For example, triazole 8g was produced quantitatively at 408C in
3 h instead of 9 h. For triazoles 8n and 8o, a reaction time of only
1.5 h was required at 408C.
[20] For further details, see the Supporting Information.
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508C after only 5 h.
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