A highly active catalyst for huisgen 1, 3-dipolar cycloadditions based on the tris(triazolyl)methanol-Cu(I) structure

Article abstract of DOI:10.1021/ol9018776

A new trls(1 -benzyl-1H-1, 2, 3-triazol-4-yl)methanol ligand 3 has been prepared by a triple Cu(l)-catalyzed alkyne-azilde 1,3-dipolar cycloaddition (CuAAC). Ligand 3 forms a stable complex with CuCl, which catalyzes the Huisgen 1,3-dipolar cycloaddition

Full text of DOI:10.1021/ol9018776

ORGANIC
LETTERS
2009
Vol. 11, No. 20
4680-4683
A Highly Active Catalyst for Huisgen
1,3-Dipolar Cycloadditions Based on the
Tris(triazolyl)methanol-Cu(I) Structure
†
†
†
,†,‡
¨
Salih Ozc¸ubukc¸u, Erhan Ozkal, Ciril Jimeno, and Miquel A. Perica`s*
Institute of Chemical Research of Catalonia (ICIQ), AV. Pa¨ısos Catalans, 16. 43007
Tarragona, Spain, and Departament de Qu´ımica Orga`nica, UniVersitat de Barcelona,
08080 Barcelona, Spain
mapericas@iciq.es
Received August 25, 2009
ABSTRACT
A new tris(1-benzyl-1H-1,2,3-triazol-4-yl)methanol ligand 3 has been prepared by a triple Cu(I)-catalyzed alkyne-azide 1,3-dipolar cycloaddition (CuAAC).
Ligand 3 forms a stable complex with CuCl, which catalyzes the Huisgen 1,3-dipolar cycloaddition on water or under neat conditions. Low catalyst
loadings, short reaction times at room temperature, and compatibility with free amino groups make 3·CuCl an outstanding catalyst for CuAAC.
Following its independent discovery by Meldal1 and
Sharpless,2 the regioselective, Cu(I)-catalyzed alkyne-azide
1,3-dipolar cycloaddition (CuAAC) reaction has become
the archetypal example of “click chemistry”,3 and the
process has found application in almost every field of
chemistry.4
In CuAAC reactions, a mixture of CuSO4 and sodium
ascorbate has been traditionally used as a precatalyst
system which generates the Cu(I) species in the reaction
media.2 Later, it was discovered that polydentate nitrogen
ligands not only stabilize Cu(I) intermediates5 but also
accelerate the catalytic process,6 and this allowed the direct
use of Cu(I) salts as catalysts in CuAAC reactions. Indeed,
a tris(triazolylmethyl)amine 1 (Figure 1) was found to be
an excellent ligand for this chemistry.7 Tripodal tetraamino
ligands like 28 and N-heterocyclic carbenes9 have also
been successfully used to stabilize the catalyst in CuAAC.
† Institute of Chemical Research of Catalonia.
‡ Universitat de Barcelona.
(1) Meldal, M.; Christensen, C.; Tornoe, C. W. J. Org. Chem. 2002,
67, 3057.
(2) Sharpless, K. B.; Fokin, V. V.; Green, L. G.; Rostovtsev, V. V.
Angew. Chem., Int. Ed. 2002, 114, 2708.
(3) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed.
2001, 40, 2004.
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thematic issue. (b) QSAR Comb. Sci. 2007, 26, 1110, special thematic issue.
(c) Angell, Y. L.; Burgess, K. Chem. Soc. ReV. 2007, 36, 1674. (d) Moses,
E.; Moorhouse, A. D. Chem. Soc. ReV. 2007, 36, 1249. (e) Lutz, J.-F. Angew.
Chem., Int. Ed. 2007, 46, 1018. (f) Wu, P.; Fokin, V. V. Aldrichim. Acta
2007, 40, 7. (g) Kappe, C. O.; Van der Eicken, E. Chem. Soc. ReV. 2009
(DOI: 10.1039/b901973c).
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Lett. 2004, 6, 2853. (b) Lewis, W. G.; Magallon, F. G.; Fokin, V. V.; Finn,
M. G. J. Am. Chem. Soc. 2004, 126, 9152.
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M. G. J. Am. Chem. Soc. 2007, 129, 12696. (b) Rodionov, V. O.; Presolski,
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10.1021/ol9018776 CCC: $40.75
Published on Web 09/23/2009
 2009 American Chemical Society

complex (Figure 2, bottom). Thus, the Cu-N optimized
distance has average values of 2.179 Å (c) and 2.188 Å (d),
while the Cu-Cl-optimized distances are 2.317 Å (c) and
2.260 Å (d).
We accordingly envisioned that tris(triazolyl)methanol 3
(Figure 3), constructed in turn through a “click” approach,
Figure 1. Polydentate N ligands for CuAAC.
Scorpionate ligands based on tris(pyrazolyl)borate moieties
(Figure 2, top) form very stable metal complexes due to the
Figure 3. Structural features of 3·CuCl.
could be an outstanding ligand for CuAAC. In effect, besides
the presumed stability of its Cu(I) complex, the molecule
presents two well-differentiated faces with complementary
hydrophobic and hydrophilic characters that make it ideal
for work on water, a most usual condition for CuAAC.12 In
addition, due to its modular construction,13 3 could be readily
fine-tuned for specific applications by simply changing the
nature of the azido compound employed for its synthesis.
On the other hand, the hydroxyl group placed on the
hydrophilic hemisphere of the molecule can also serve as
an anchor for supporting 3 onto polymeric materials.14
The synthesis of 3 was planned through the intermediacy
of tris(alkynyl)carbinol 415 which, in turn, was readily
prepared by addition of trimethylsilylacetylide to ethyl
chloroformate (Scheme 1).
Figure 2. Top: Schematic representation of metal complexes of a
tris(pyrazolyl)borate (a) and of a tris(triazolyl)methane (b). Bottom:
DFT (B3LYP/LANL2DZ)-optimized geometries of the CuCl
complexes of a tris(pyrazolyl)borate (c) and of tris(triazolyl)methane
(d).
(11) (a) D´ıaz-Requejo, M. M.; Belderrain, T. R.; Nicasio, M. C.;
Trofimenko, S.; Pe´rez, P. J. J. Am. Chem. Soc. 2002, 124, 896. (b) D´ıaz-
Requejo, M. M.; Pe´rez, P. J. Chem. ReV. 2008, 108, 3379.
(12) (a) Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb,
H. C.; Sharpless, K. B. Angew. Chem., Int. Ed. 2005, 44, 3157. (b) Hayashi,
Y. Angew. Chem., Int. Ed. 2006, 45, 8103.
establishment of chelated, cage structures involving the
formation of six-membered rings.10 These complexes have
found ample application as catalysts in a variety of relevant
processes and, most notably, in C-H bond activation
methods.11 We wondered whether the analogous tris(triaz-
olyl)methane complexes would depict similar stability and,
in particular, if the corresponding Cu(I) complexes would
consequently perform as highly efficient catalysts in CuAAC.
In fact, DFT theoretical calculations (B3LYP/LANL2DZ)
performed on Cu(I) complexes of both types of structures
revealed essentially identical structures for both types of
(13) For modular approaches to catalytic ligands from our research, see:
(a) Vidal-Ferran, A.; Moyano, A.; Perica`s, M. A.; Riera, A. J. Org. Chem.
1997, 62, 4970. (b) Puigjaner, C.; Vidal-Ferran, A.; Moyano, A.; Perica`s,
M. A.; Riera, A. J. Org. Chem. 1999, 64, 7902. (c) Garc´ıa-Delgado, N.;
Reddy, K. S.; Sola`, L.; Riera, A.; Perica`s, M. A.; Verdaguer, X. J. Org.
Chem. 2005, 70, 7426. (d) Rodr´ıguez-Escrich, S.; Reddy, K. S.; Jimeno,
C.; Colet, G.; Rodr´ıguez-Escrich, C.; Sola`, L.; Vidal-Ferran, A.; Perica`s,
M. A. J. Org. Chem. 2008, 73, 5340. (e) Rodr´ıguez-Escrich, S.; Sola`, L.;
Jimeno, C.; Rodr´ıguez-Escrich, C.; Perica`s, M. A. AdV. Synth. Catal. 2008,
350, 2250.
(14) For examples on the use of click chemistry as a supporting strategy
for ligands and catalysts, see: (a) Font, D.; Jimeno, C.; Perica`s, M. A. Org.
Lett. 2006, 8, 3895. (b) Bastero, A.; Font, D.; Perica`s, M. A. J. Org. Chem.
2007, 72, 2460. (c) Alza, E.; Cambeiro, X. C.; Jimeno, C.; Perica`s, M. A.
Org. Lett. 2007, 9, 3717. (d) Font, D.; Bastero, A.; Sayalero, S.; Jimeno,
C.; Perica`s, M. A. Org. Lett. 2007, 9, 1943. (e) Bastero, A.; Font, D.; Perica`s,
M. A. J. Org. Chem. 2007, 72, 2460. (f) Font, D.; Sayalero, S.; Bastero,
A.; Jimeno, C.; Perica`s, M. A. Org. Lett. 2008, 10, 337. (g) Popa, D.;
Marcos, R.; Sayalero, S.; Vidal-Ferran, A.; Perica`s, M. A. AdV. Synth. Catal.
2009, 351, 1539.
(7) Donnelly, P. S.; Zanatta, S. D.; Zammit, S. C.; White, J. M.;
Williams, S. J. Chem. Commun. 2008, 2459.
(8) Candelon, N.; Laste´coue`res, D.; Diallo, A. K.; Ruiz Aranzaes, J.;
Astruc, D.; Vincent, J.-M. Chem. Commun. 2008, 741.
(9) (a) D´ıez-Gonza´lez, S.; Correa, A.; Cavallo, L.; Nolan, S. P.
Chem.sEur. J. 2006, 12, 7558. (b) D´ıez-Gonza´lez, S.; Nolan, S. P. Angew.
Chem., Int. Ed. 2008, 47, 9013.
(10) (a) Trofimenko, S.; Calabrese, J. C.; Domaille, P. J.; Thompson,
J. S. Inorg. Chem. 1989, 28, 1091. (b) Trofimenko, S. Scorpionates, The
Coordination Chemistry of Polypyrazolylborate Ligands; Imperial Chemistry
Press: London, 1999.
(15) Alberts, A. H.; Wynberg, H. J. Chem. Soc., Chem. Commun. 1988,
748.
Org. Lett., Vol. 11, No. 20, 2009
4681

Scheme 1
.
Synthesis of the Tris(triazolyl)methanol/copper(I)
Table 1. CuAAC Using Catalyst 3·CuCl
Complex 3·CuCl
entry
R
R′
Ph
prod time (h) yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Ph
Ph
Ph
Ph
5a
5b
5c
5c
5d
5e
5f
5g
5h
5i
4
4
4
15
15
4
99b
99b
94b
99c
n-Oct
PhCH2
PhCH2
n-Oct
CO2Et
99b
95b
99b
99c
CH2NMe2
2-pyridyl
PhCH2CH2
n-Bu
Ph
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
8
4
16
16
18
12
2
98b,d
98b,d
64b,d
96b
92b
84b
97b
47e
n-Hex
4-chlorobutyl
CO2Et
p-HOCH2C6H4 PhCH2
CH2OH
CH2NMe2
CH2NH2
5j
5k
5l
PhCH2
PhCH2
PhCH2
5m
5n
5o
6
4
5
Subsequent deprotection of the TMS groups with K2CO3
in methanol followed by cycloaddition with benzyl azide
under the classical CuAAC conditions (CuSO4, sodium
ascorbate) led to the target tris(triazolyl)methanol 316 in good
overall yield. The final copper catalyst 3·CuCl was easily
prepared by treatment of 3 with 1 equiv of CuCl in dioxane.
After evaporation of the solvent, the residue was dissolved
in CH2Cl2, and hexane was added to the solution. A greenish
solid (3·CuCl) precipitated inmediately and was isolated in
almost quantitative yield.
Most gratifyingly, 3·CuCl turned out to be air and moisture
stable. Although we have been unable to grow single crystals
of 3·CuCl, the coordination environment around copper can
be inferred from the symmetry of the NMR spectra. In
addition, a CuCl2 complex of 3 presents in its crystal structure
a hexacoordinated copper atom surrounded by two molecules
of 3 acting as tridentate ligands (see the Supporting Informa-
tion for details). The new catalyst was then tested in the
CuAAC of benzyl azide and phenylacetylene under different
experimental conditions. To our satisfaction, 3·CuCl exhib-
ited very high catalytic activity under mild reaction condi-
tions, especially when water was present in excess in the
reaction media. In fact, reactions were fast at room temper-
ature under neat conditions or in the sole presence of water,
with catalyst loadings of only 0.5 mol %.
a Isolated yield. b Water. c Neat. d 0.25 mol % of catalyst at 40 °C. e 1
mol % catalyst in n-BuOH/water 2:1 and basic workup.
general, the CuAAC fails in the presence of free amino
groups due to the strong tendency of amines to form
complexes with Cu(I), thus deactivating the catalyst. With
the use of 3·CuCl, this deactivation did not occur, and the
corresponding triazole product could be isolated in 47%
yield. This result shows how the tight complexation present
in 3·CuCl can allow avoiding additional protection and
deprotection steps when free amines have to be involved in
CuAAC.
Taking into account the interest of avoiding storage and
manipulation of organyl azides, the use of 3·CuCl in a one-
pot process involving the in situ formation of a benzyl-type
or alkyl (octyl) azide from the corresponding bromides and
sodium azide was explored (Table 2).
This tandem process performed nicely in water using a 1
mol % catalyst at 40 °C (entries 1-7). A microwave-
promoted version, which allowed substantial reduction of
reaction times, was also set up. In this case, a 1:1 mixture
of acetonitrile/water was used, as well as reaction temper-
atures of 100 °C. Under these conditions, reaction times as
short as 40 min were sufficient to allow the isolation of the
cycloaddition products in good yields (entries 8-13).4g It
must be noted that, due to the lower reactivity of octyl
bromide in front of sodium azide, 2 equiv of this reagent
with respect to the alkyne was used.
Finally, 3·CuCl was also used to catalyze the cycloaddition
of 4 with benzyl azide in water leading to the tris(triazolyl)-
methanol ligand 3. In this way, the target tris(triazole) can
be routinely prepared in gram amounts in 86% isolated yield
(Scheme 2). With this improvement, 3·CuCl can be prepared
in only three steps from commercially available precursors
in 59% overall yield.
The scope of applicability of 3·CuCl was explored under
these conditions (Table 1). Catalyst loadings as low as 0.25
mol % could be used too, but at the expense of longer
reaction times. This decrease in reactivity was compensated
by carrying out these reactions at 40 °C (Table 1, entries
9-11). As the inspection of Table 1 reveals, excellent yields
are generally obtained in the CuAAC of a wide variety of
alkyne with alkyl, benzyl, or aryl azides.
The result obtained in the cycloaddition of propargylamine
with benzyl azide (entry 16) deserves special comment. In
(16) Patent pending.
4682
Org. Lett., Vol. 11, No. 20, 2009

Table 2. One-Pot Azide Formation plus CuAAC Reaction
Mediated by 3·CuCl
Scheme 2. Improved Preparation of 3 Using Catalyst 3·CuCl
entry
R
R′
prod
yielda (%)
99b
98b
98b
93b
80b
88b
90b
57c
38c
88c
98c
89c
70c
metal center and to its particular functional groups arrange-
ment, catalyst 3·CuCl behaves as a very active promoter of
the CuAAC, as it has been demonstrated with a broad variety
of substrates (including free amines) under different reaction
conditions. Application of metal complexes of analogs of 3,
readily available by cycloaddition from the key intermediate
4, to a variety of catalytic processes is currently underway
in our laboratories.
1
2
3
4
5
6
7
8
9
10
11
12
13
Ph
Ph
Ph
Ph
Ph
Ph
PhCH2
5c
5p
5q
5r
5s
5t
5u
5b
5v
5m
5w
5x
5y
p-tBuC6H4CH2
p-NO2C6H4CH2
p-MeOC6H4CH2
o-ClC6H4CH2
m-NO2C6H4CH2
p-NO2C6H4CH2
n-Oct
p-HOCH2C6H4
Ph
CH2OH
n-Oct
PhCH2
PhCH2
n-Oct
CH2OH
CMe2OSiMe3
CH(OH)Ph
CH2SPh
Acknowledgment. This work was funded by MICINN
(Grant No. CTQ2008-00947/BQU), DIUE (Grant No.
2005SGR225), Consolider Ingenio 2010 (Grant No. CSD2006-
0003), and the ICIQ Foundation.
n-Oct
a Isolated yield. b In water at 40 °C. c In acetonitrile/water at 100 °C,
under MW irrradiation.
Supporting Information Available: Experimental pro-
cedures. Spectral and analytical data for all new compounds.
Calculated atomic coordinates. Crystallographic data (CIF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
In summary, ligand 3 turns out to be a simple yet powerful
complexing agent for Cu(I). Indirect evidence (XRD and
NMR) suggests that 3 forms a 1:1 complex with CuCl, with
all three triazole moieties interacting with the metal center.
Probably due to the tight protecting cage formed around the
OL9018776
Org. Lett., Vol. 11, No. 20, 2009
4683