Huisgen click cycloadditions from a copper(II)-tren precatalyst without external sacrificial reductant

Article abstract of DOI:10.1016/j.tetlet.2012.01.035

The copper(II) complex [Cu(C18₆tren)](Br)₂, 2, is an efficient precatalyst for the Huisgen 'click' cycloaddtion which can be used at low loading without the requirement of an external sacrificial reductant such as sodium ascorbate. E

Full text of DOI:10.1016/j.tetlet.2012.01.035

Tetrahedron Letters 53 (2012) 1417–1420
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Huisgen click cycloadditions from a copper(II)-tren precatalyst
without external sacrificial reductant
Lydie Harmand a, Marie-Hélène Lescure a, Nicolas Candelon a, Mathieu Duttine b,
Dominique Lastécouères a, Jean-Marc Vincent a,
⇑
a Institut des Sciences Moléculaires, CNRS-UMR 5255, Université Bordeaux 1, 351, cours de la libération, 33405 Talence Cedex, France
b Institut de Chimie de la matière Condensée, CNRS-UPR 9048, Université Bordeaux 1, 97, Avenue Dr. Schweitzer, 33608 Pessac, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The copper(II) complex [Cu(C186tren)](Br)2, 2, is an efficient precatalyst for the Huisgen ‘click’ cycloadd-
tion which can be used at low loading without the requirement of an external sacrificial reductant such as
sodium ascorbate. EPR studies support the in situ reduction of 2 by the alkyne to generate a reactive cop-
per(I) catalyst.
Received 13 October 2011
Revised 5 January 2012
Accepted 9 January 2012
Available online 15 January 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Huisgen cycloaddition
Click chemistry
Copper-tren catalyst
EPR spectroscopy
Since the discovery in 2002 by Fokin, Sharpless and co-workers,1
and Meldal and co-workers,2 that copper(I) efficiently catalyzes the
Huisgen azide–alkyne cycloaddition3 to selectively afford 1,4-tria-
zoles, this ‘click’ reaction has become a key reaction in all the fields
of chemical sciences.4 The couple CuSO4/ascorbate is still one of the
most simple and frequently used catalytic systems, particularly be-
cause reactions can be performed in aqueous or hydroalcoholic
media to afford, in general, the products in good yields with a
straightforward purification procedure. Great efforts have been
undertaken to develop more reactive catalytic systems.4d For in-
stance, the accelerating effect of nitrogenated ligands on the
CuSO4/ascorbate catalytic system was demonstrated.5 Of particular
interest are the copper(I) complexes, stabilized by more or less
sophisticated ligands, that have been shown to be very active at
low catalyst loading, typically between 0.01 mol % and 0.5 mol %,
without the requirement of an external sacrificial reductant.6
Beside the classical catalytic systems, that is, the copper(II) pre-
catalyst/ascorbate couple or the direct use of copper(I) catalysts, a
much less explored procedure is the use of copper(II) precatalysts
only. In such system, the copper(II) ions would potentially be re-
duced through the well-known oxidative homocoupling of alkynes,
the so-called Glaser reaction, to generate a significant amount of
the click-active copper(I) catalyst. Such system, particularly if the
precatalyst can be employed at low loading, would present two
interesting features from a practical point of view: (1) Handling
of air stable copper(II) complexes. Indeed, the well-known and
well-documented oxygen sensitivity of the copper(I) complexes,
particularly those bearing polyamino/polyimino ligands,7 often
complicates the preparation, handling, storage, and recyclability
of the copper(I) catalysts; (2) No need of an external sacrificial
reductant such as ascorbate which is typically added in a fivefold
excess with respect to copper.
Only a few examples of efficient Huisgen ‘click’ cycloadditions
using copper(II) precatalysts or catalysts without addition of sacri-
ficial external reductant were reported.8 In 2008, a catalytic system
employing as precatalyst a dicopper(II)-substituted silicotungstate
without external sacrificial reductant has been reported by
Mizuno and co-workers.8a Reactions were typically conducted at
60 °C in CH3CN under argon atmosphere at low copper loading
(0.2 mol %) affording triazoles in excellent yields. An induction per-
iod of ꢀ50 min was observed in these reactions, during which a
roughly stoichiometric amount of the diyne is formed with respect
to the copper(II) initially introduced, concomitant with its reduc-
tion to copper(I). In 2010, Heaney and co-workers employed cop-
per(II) hydroxyacetate as precatalyst (20 mol % in copper)
without additional reductants.8b A range of triazoles were prepared
in good yields under microwave conditions (100 °C, CH3CN). Along
with the triazoles, significant amounts of the diynes were isolated,
that is, 70–87% with respect to the Cu added. Moreover the effi-
cient formation of polymeric alkynecopper(I) catalytic species
was clearly evidenced. Very recently, it has been shown that
Cu(OAc)2 could be used as pre-catalyst without addition of an
external sacrificial agent,8c–f particularly when using chelating
⇑
Corresponding author. Tel.: +33 5 40 00 89 42.
E-mail address: jm.vincent@ism.u-bordeaux1.fr (J.-M. Vincent).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.035

1418
L. Harmand et al. / Tetrahedron Letters 53 (2012) 1417–1420
azides which proved to be the most reactive substrates.8e,8f Zhu
and co-workers reported an extensive mechanistic study on this
catalytic system showing that copper(I) was generated either by
solvent oxidation, for reactions conducted in methanol (oxidizable
solvent) or, through alkyne oxidative homocoupling for reactions
conducted in acetonitrile (non-oxidizable solvent).8d
In 2008 we reported that the copper(I) complex [Cu(C186-
tren)]Br (1), originally designed to catalyze atom transfer radical
polymerization (ATRP) reactions,9 was a highly reactive catalyst
for the Huisgen azide–alkyne cycloaddition.10 The ‘click’ reactions,
were typically run under aerobic conditions in n-octane or toluene
at 60 °C with a catalyst loading of 0.05–0.1 mol %. Using such apo-
lar solvents, the triazoles were conveniently isolated by filtration,
while the soluble catalyst was left in solution. Recently, the high
reactivity of 1 has been exploited for the efficient preparation of
sophisticated polytriazoles rotaxanes11a–c and the click assembly
of dye-functionalized octasilsesquioxanes.11d
(99.999%) or Cu(OTf)2 in CH2Cl2. The catalytic activity of the com-
plexes 1–3 was then compared in various conditions for a range of
substrates (Eq. 1, Table 1).14
N
R2
1 3
-
(0.1 to 2 mol%)
N
N
R2 N3
R1
+
aerobic conditions
R1
ð1Þ
solvent (n-octane, toluene) or neat
T = 25 or 60 °C
(eq.1)
Reactions were typically carried out under air-equilibrated
solutions in flasks closed by a stopper. Toluene and n-octane are
the solvents of choice affording a good reactivity while at the same
time the polar triazoles are separated from the soluble catalyst by
simple filtration, thus fulfilling an important criterion of the click
chemistry concept. As seen from entries 1–4, the copper(I) catalyst
1 is very active even at room temperature. The benchmark reaction
between phenylacetylene and benzyl azide proceeds efficiently at
0.1–0.2 mol % catalyst loading (entries 1–2). In neat conditions at
0.5 mol % loading the reaction is completed within 30 min (entry
3). It should be noted that the process is highly exothermic, the
reaction mixture temperature rising from 20 °C to 38 °C after
3 min reaction, reaching 103 °C after 6 min, the time after which
the temperature starts to decrease.15 Such exothermic process pre-
cludes these conditions on large scales. At 1 mol % loading, the less
reactive propargyl alcohol reacts with benzyl azide in n-octane to
afford the triazole in an 82% isolated yield in 2 h at 25 °C (entries
4–5). This is comparable to the results reported for the highly reac-
tive [CuCl(SIMes)] catalyst when activated by the addition of aro-
matic nitrogen donors.6i
Interestingly, we found that the reaction performed very well
when using the copper(II) complex 2 without external sacrificial
reductant. At 0.5 mol % loading of 2, the reaction between phenyl-
acetylene and benzyl azide at 25 °C afforded the triazole in, respec-
tively, 93% and 74% yields in n-octane and toluene (entries 6–7).
Under neat conditions (entry 8) the reaction is completed within
1 h, the temperature rising to a maximum of 65 °C after 12 min
reaction, which is significantly lower compared to 1 (103 °C). As re-
vealed by the results obtained from propargyl alcohol at 1 mol %
catalyst loading (compare entries 9–11 with 4–5), the reaction
kinetics using 2 are slower than with 1. Nonetheless, increasing
the temperature to 60 °C afforded the triazole in a satisfactory
82% yield (entry 12). As shown from the other results reported in
Table 1 (entries 13–22), a range of triazoles were prepared effi-
ciently in smooth conditions using 2 as precatalyst at 0.5–
2 mol % loading. Catalyst recycling experiments were conducted
under the reaction conditions of entry 6 (Table 1). After isolation
of the product by filtration, the filtrate is recovered and loaded
with aliquots of the reactants. A satisfactory 88% yield was ob-
tained for the first recycling while, for the second recycling, a sig-
nificant decrease in the catalytic activity was noticed, the yield
dropping to 47%. Surprisingly, the complex 3 with the triflate coun-
ter-anions is a poor pre-catalyst affording only 5% of the triazole
after 24 h (entry 23) compared to 93% with 2. This shows that
the observed reactivity, that is, from a copper(II) complex without
external sacrificial reductant, is very sensitive to the copper envi-
ronment and that the bromide counter-anions might play a role
in the activation process of the pre-catalyst.
(X)n
N
Cu
N
1, X = Br, n = 1
N
C18H37
C18H37
C18H37
2
, X = Br, n = 2
3, X = OTf, n = 2
C18H37
C18H37
N
C18H37
During the course of our research aiming to study the stability of
1 toward oxygen under the reaction conditions we performed the
following experiment. Complex 1 (10 lmol) in n-octane (2 mL)
was left under air-equilibrated conditions and its oxidation fol-
lowed by UV–vis. As shown in Figure 1, the oxidation of 1 is fast,
the solution turning rapidly to green in accordance with the appear-
ance of copper(II) species. The maximum absorbance at 757 nm
was reached after 48 h, indicating that 1 was fully oxidized. Then
benzyl azide (2 mmol) and phenylacetylene (2 mmol) were added
to the solution (copper loading 0.5 mol %) and the mixture strirred
for 24 h at room temperature. To our surprise the cycloaddtion pro-
ceeded very efficiently, the triazole being isolated by filtration in a
93% yield. We thus wondered whether the copper(II)-tren complex
2 could be employed as precatalyst without sacrificial external
reductant.
The copper(II) complexes 2 and 3, isolated as green powders,12
were prepared by reacting the C186tren ligand13 with Cu(Br)2
0.65
0.6
0.55
0
0
0
0
0
0
0
.
.
.
.
.
.
.
7
6
5
4
3
2
1
0.5
0.45
0.4
0.35
0.3
500
600
700
800
0.25
0.2
Wavelenght (nm)
0
10
20
30
40
50
Based on these results and previous work,8a–f we hypothesized
that the observed catalytic activity could be due to the in situ
reduction of 2 by the alkyne. Strong evidence of reduction of 2
by the alkynes came from EPR studies. For instance, when 1-dode-
cyne is added to a solution of 2 (1 mol %) in n-octane, the area of
the characteristic copper(II) signal, obtained by double integration
after baseline correction, decreased by 31% after 1 h (Fig. 2). The
Time (h)
Figure 1. Evolution with time of the absorbance at 757 nm of an air-equilibrated n-
octane solution (2 mL) containing (10 mol). The inset shows the visible
1
l
absorption spectra recorded between 500 nm and 800 nm. The lower spectrum
(t = 0) was recorded from a strictly anaerobic solution. Then, the flask was opened
to air and the spectra recorded after 5 min, 15 min, 30 min, 45 min, 1 h, 1.5 h, 2 h,
3 h, 26 h and 48 h of stirring.

L. Harmand et al. / Tetrahedron Letters 53 (2012) 1417–1420
1419
Table 1
Results of 1,3-dipolar cycloadditions between alkynes and azides catalyzed by 1–3
Entry
R1
R2
Solventa
Cat.
mol %
T (°C)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Ph
Ph
Ph
CH2OH
CH2OH
Ph
Ph
Ph
CH2OH
CH2OH
CH2OH
CH2OH
(CH2)4OH
(CH2)4OH
Si(CH3)3
CO2Et
n-Bu
p-MeOC6H4
p-CHOC6H4
n-Dec
(CH2)2Br
Ph
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
n-octane
Toluene
Neatc
n-octane
n-octane
n-octane
Toluene
Neatc
n-octane
n-octane
n-octane
n-octane
n-octane
Toluene
n-octane
n-octane
n-octane
n-octane
n-octane
n-octane
Toluene
Toluene
n-octane
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
3
0.2
0.1
0.5
1
25
25
25e
25
25
25
25
25f
25
25
25
60
25
25
60
25
60
25
25
25
25
60
25
24
24
0.5
1
84
76
99
56
82
93
74
97
18
38
64
82
91
79
68
96
71
90
85
80
80d
75
5
1
2
0.5
0.5
0.5
1
1
1
1
2
2
0.5
0.5
0.5
0.5
0.5
0.5
2
24
24
1
1
6
24
24
24
24
24
24
24
24
24
24
24
24
24
Bn
Bn
Bn
Bn
Bn
p-BrC6H4O(CH2)2O(CH2)2
Bn
1
0.5
Ph
a
b
c
d
e
f
Reactions run under air-equilibrated conditions on 1 mmol of each reactant in 1 mL of solvent.
Isolated yields after filtration unless otherwise noted.
Reactions run under air-equilibrated conditions on 4 mmol of each reactant.
Isolated yield after column chromatography on silica.
The reaction temperature rose up to 103 °C within 6 min.
The reaction temperature rose up to 65 °C within 12 min.
15000
10000
5000
0
In summary, we have shown that the copper(II) pre-catalyst 2
can be employed at low loading to efficiently promote the Huisgen
click cycloaddition without the addition of an external sacrificial
reductant. Such a catalytic system is of potential interest from a
practical point of view as the copper(II) complex 2 is obviously sta-
ble undefinitely under ambient conditions. Moreover, this system
is particularly well-adapted for substrates soluble in apolar sol-
vents such as toluene or n-octane, the resulting triazoles being iso-
lated in most cases by a straightforward filtration.
2000
2500
3000
3500
4000
4500
-5000
-10000
-15000
Acknowledgments
Magnetic field (G)
The University of Bordeaux 1, the CNRS and la Région Aquitaine
(Salary Grant to L.H.) are gratefully acknowledged for their finan-
cial support. We thank Dr. E. Amigues from the ISM for providing
us the 1-(2-(2-azidoethoxy)ethoxy)-4-bromobenzene (entry 22 in
Table 1).
Figure 2. EPR spectra at 77 K of a solution of 2 (10 mM) in n-octane (black), and
after 5 min (red) and 1 h (blue) after the addition of 1-dodecyne (100 equiv).
same trend was observed for the two other tested alkynes, for
example, a 24% and 22% decrease for phenyacetylene and propar-
gyl alcohol, respectively. When benzyl azide is tested in the same
conditions, the intensity of the copper(II) signal is retained with
time. These results would suggest that the alkyne could be, to some
extent, oxidized by 2 to afford significant amounts of the catalyti-
cally active copper(I) complex along with the diyne oxidation
product.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2012.01.035.
References and notes
We thus followed by GC–MS a reaction performed in the condi-
tions of entry 7 of Table 1 to try to detect and titrate such side-
product. Our study revealed that the 1,4-diphenyl-1,3-butadiyne
could be detected after 24 h reaction, but in extremely small
amounts, that is, ꢀ50 nmoles,16 representing approximately 0.5%
of the total amount of copper. This obviously means that extremely
small amounts of copper(I) are generated through the Glaser-type
coupling pathway. To determine whether this tiny amount of
in situ generated copper(I) complex is reactive enough to account
for the observed reactivity or, whether an unknown additional
activation pathway is occurring, will require further studies.
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5.17 (t, JHH = 5.7 Hz, 1H, OH), 4.49 (d, JHH = 5.7 Hz, 2H, CH2OH); 13C RMN
(DMSO, 75 MHz) d 148.3 (1C, triazole), 136.2 (1C, triazole), 128.7 (2C, CAr),
128.1 (1C, CAr), 127.9 (2C, CAr), 122.8 (1C, CAr), 55.0 (1C, CH2OH), 52.7 (1C,
CH2Ph); LRMS (ESI) 212.8 [(M+Na)+]; HRMS (ESI) Calcd for C10H11N3ONa,
212.0794; Found, 212.0795; mp 76–77 °C (Lit. 76–77 °C).6g 4-(1-Benzyl-1H-
1,2,3-triazol-4-yl)butan-1-ol (entry 13). White powder; 1H NMR (DMSO,
200 MHz) d 7.90 (s, 1H, triazole), 7.25–7.41 (m, 5H, HAr), 5.53 (s, 2H, CH2Ph),
3
3
4.39 (t, JHH = 5.3 Hz, 1H, OH), 3.40 (q, JHH = 5.8 Hz, 2H, CH2OH), 2.60 (t,
3JHH = 7.5 Hz, 2H, CH2-triazole), 1.39–1.64 (m, 4H, CH2–CH2); 13C RMN (DMSO,
75 MHz) d 136.3 (1C, triazole), 129.5 (1C, triazole), 128.7 (2C, CAr), 128.0 (1C,
CAr), 127.8 (2C, CAr), 121.9 (1C, CAr), 60.4 (1C, CH2OH), 52.6 (1C, CH2Ph), 32.0
(1C, CH2triazole), 25.54(1C, CH2), 24.9 (1C, CH2); LRMS (ESI) 254.1 [(M+Na)+];
HRMS (ESI) Calcd for C13H17N3ONa, 254.1263; Found, 254.1264; mp 79–80 °C
(Lit. 80 °C).6h 1-Benzyl-4-(trimethylsilyl)-1H-1,2,3-triazole (entry 15). White
powder; 1H NMR (DMSO, 300 MHz) d 8.21 (s, 1H, triazole), 7.33–7.35 (m, 5H,
HAr), 5.60 (s, 2H, CH2), 0.24 (s, 9H, 3CH3); 13C RMN (DMSO, 100 MHz) d 145.1
(1C, triazole), 136.2 (1C, triazole), 130.5 (1C, CAr), 128.7 (2C, CAr), 128.0 (1C,
CAr), 127.9 (2C, CAr), 52.2 (1C, CH2), -1.04 (3C, CH3); LRMS (ESI) 232.1 [(M+H)+];
HRMS (ESI) Calcd for C12H18N3Si, 232.1264; Found, 232.1271; mp 59–60 °C
(Lit. 60–61 °C).10 1-Benzyl-4-ethanoate -1H-1,2,3-triazole (entry 16). White
powder; 1H NMR (CDCl3, 300 MHz) d 7.96 (s, 1H, triazole), 7.38–7.41 (m, 3H,
HAr), 7.26-7.30 (m, 2H, HAr), 5.58 (s, 2H, CH2Ph), 4.41 (q, JHH = 7.1 Hz, 2H,
3
CH2CH3), 1.39 (t, 3JHH = 7.1, 3H, CH2CH3); 13C NMR (DMSO, 75 MHz) d 160.7 (1C,
CO); 139.5 (1C, triazole), 136.0 (1C, triazole), 129.7 (1C, CAr), 129.3 (2C, CAr),
128.8 (1C, CAr), 128.5 (2C, CAr), 61.0 (1C, CH2CH3), 53.6 (1C, CH2Ph), 14.6 (1C,
CH2CH3); LRMS (ESI) 254.1 [(M+Na)+]; HRMS (ESI) Calcd for C12H13N3O2Na,
254.0899; found, 254.0888; mp 88–89 °C (Lit. 88–90 °C).10 1-Benzyl-4-(n-
butyl)-1H-1,2,3-triazole (entry 17). White powder; 1H NMR (DMSO, 300 MHz)
d 7.89 (s, 1H, triazole), 7.26–7.40 (m, 5H, HAr), 5.53 (s, 2H, CH2), 2.59 (t,
3JHH = 7.6 Hz, 2H, CH2), 1.55 (q, 3JHH = 7.4 Hz, 2H, CH2), 1.30 (s, 3JHH = 7.4 Hz, 2H,
CH2), 0.88 (t, 3JHH = 7.6 Hz, 3H, CH3); 13C NMR (DMSO, 100 MHz) d 147.2 (1C, Cq
triazole), 136.3 (1C, triazole), 128.7 (2C, CAr), 127.8 (1C, CAr), 127.7 (2C, CAr),
121.9 (1C, CAr), 52.6 (1C, CH2Ph), 31.1 (1C, CH2), 24.6 (1C, CH2), 21.6 (1C, CH2),
13.6 (1C, CH2); LRMS (ESI) 216.1 [(M+H)+]; HRMS (ESI)) Calcd for C13H18N3,
216.1495; found, 216.1496; mp 61–62 °C (Lit. 62–63 °C).18 1-Benzyl-4-(4-
methoxyphenyl)-1H-1,2,3-triazole (entry 18). White powder; 1H RMN (DMSO,
300 MHz) d 8.52 (s, 1H, triazole), 7.75–7.78 (m, 2H, HAr), 7.33–7.39 (m, 5H,
HAr), 6.98–7.01 (m, 2H, HAr), 5.62 (s, 2H, CH2), 3.78 (s, 3H, CH3); 13C NMR
(DMSO, 75 MHz) d 159.0 (1C, CAr), 146.6 (1C, triazole), 136.1 (1C, triazole),
128.8 (2C, CAr), 128.1 (1C, CAr), 127.9 (2C, CAr), 126.5 (2C, CAr), 123.2 (1C, CAr),
120.6 (1C, CAr), 114.3 (2C, CAr), 55.1 (1C, CH2), 52.9 (1C, CH3); LRMS (ESI) 288.1
[(M+Na)+]; HRMS (ESI) Calcd for C16H15N3ONa, 288.1107; found, 288.1120; mp
144–146 °C (Lit. 145 °C).6h 4-(1-Benzyl-1H-1,2,3-triazol-4-yl)benzaldehyde
(entry 19). Yellowish powder; 1H NMR (DMSO, 300 MHz) d 10.00 (s, 1H,
COH), 8.84 (s, 1H, triazole), 7.96-8.10 (m, 4H, HAr), 7.35–7.41 (m, 5H, HAr), 5.68
(s, 2H, CH2); 13C NMR (DMSO, 75 MHz): 192.5 (1C, CO), 145.6 (1C, triazole),
136.3 (1C, triazole), 135.8 (1C, CAr), 135.4 (1C, CAr), 130.3 (2C, CAr), 128.8 (2C,
CAr), 128.2 (1C, CAr), 128.0 (2C, CAr), 125.5 (2C, CAr), 123.1 (1C, CAr), 53.1 (1C,
CH2); LRMS (ESI) 286.1 [(M+Na)+]; HRMS (ESI) Calcd for C16H13N3ONa,
286.0950; found, 286.0959; mp 138–140 °C. 1-Benzyl-4-(n-decyl)-1H-1,2,3-
triazole (entry 20). White powder; 1H NMR (DMSO, 300 MHz) d 7.88 (s, 1H,
9. Barré, G.; Taton, D.; Lastécouères, D.; Vincent, J.-M. J. Am. Chem. Soc. 2004, 126,
7725–7764.
10. Candelon, N.; Lastécouères, D.; KhadriDiallo, A.; RuizAranzaes, J.; Astruc, D.;
Vincent, J.-M. Chem. Commun. 2008, 741–743.
11. (a) Collin, J.-P.; Durot, S.; Keller, M.; Sauvage, J.-P.; Trolez, Y.; Cetina, M.;
Rissanen, K. Chem. Eur. J. 2011, 17, 947–957; (b) Durola, F.; Durot, S.; Heitz, V.;
Joosten, A.; Sauvage, J.-P.; Trolez, Y. J. Inclusion Phenom. 2011, 71, 507–515; (c)
Xiao, S.; Fu, N.; Peckham, K.; Smith, B. D. Org. Lett. 2010, 12, 140–143; (d) Pérez-
Ojeda, M. E.; Trastoy, B.; Lõpez-Arbeloa, I.; Bañuelos, J.; Costela, U.; García-
Moreno, I.; Chiara, J. L. Chem. Eur. J. 2011, 17, 13258–13268.
12. Synthesis of [Cu(C186tren)](Br)2 (2). The ligand (200 mg, 0.12 mmol) is added
to a solution of Cu(Br)2 (0.12 mmol, 99.999% purity) in CH2Cl2 (20 mL). After
30 min of stirring, the green solution is concentrated and put at ꢁ18 °C
overnight, leading to the precipitation of 2. After filtration and washing with
cold ethanol, 2 is obtained as a green powder in 95% yield (215.1 mg). LRMS
(MALDI-TOF) 1723.8 [(Mꢁ2Br)+], 1683.9 [(MꢁCuBr2+Na)+], 1661.9
[MꢁCuBr2+H)+]; elemental anal. calcd (%) for C114H234Br2CuN4,CH2Cl2: C,
70.13; H, 12.08; N, 2.84. Found: C, 69.46; H, 12.07; N, 2.81. UV–visible (n-
triazole) 7.25–7.39 (m, 5H, HAr), 5.53 (s, 2H, CH2Ph), 2.58 (t, JHH = 7.5 Hz, 2H,
3
CCH2), 1.53–1.58 (m, 2H, CCH2CH2) 1.23–1.29 (m, 14H, 7CH2, (CH2)7CH3) 0.85
(t, JHH = 6.7, 3H, CH3); 13C RMN (DMSO, 75 MHz) d 147.2 (1C, triazole), 136.3
3
octane) [kmax
,
nm
(
e,
Mꢁ1 cmꢁ1)]: 344 (4965), 771 (135). Synthesis of
(1C, triazole), 128.7 (2C, CAr), 128.0 (1C, CAr), 127.7 (2C, CAr), 121.9 (1C, CAr),
52.6 (1C, CH2Ph), 31.3 (1C, CH2), 29.0 (3C, 3CH2), 28.7 (2C, 2CH2), 28.5 (1C,
CH2), 25.0 (1C, CH2), 22.1 (1C, CH2), 13.9 (1C, CH3); LRMS (ESI) 322.2 (100)
[(M+Na)+]; HRMS (ESI) Calcd for C19H29N3Na, 322.2253; Found, 322.2263; mp
81–82 °C (Lit. 80–81 °C).18 1-Benzyl-4-(2-bromoethyl)-1H-1,2,3-triazole (entry
21). White powder; 1H NMR (DMSO, 200 MHz) d 8.03 (s, 1H, triazole), 7.26–
[Cu(C186tren)](OTf)2 (3). The ligand (200 mg, 0.12 mmol) is added to
a
solution of Cu(CF3SO3)2 (0.12 mmol) in CH2Cl2 (20 mL). After 30 min of
stirring, the green solution is concentrated and put at ꢁ18 °C overnight,
leading to the precipitation of 3. After filtration and washing with cold ethanol,
3 is obtained as a greenish powder in 82% yield (201.8 mg). LRMS (MALDI-TOF)
1723.8 [(Mꢁ2CF3SO3)+]; elemental anal. calcd (%) for C116H234F6CuN4O6S2,
CH2Cl2: C, 66.67; H, 11.29; N, 2.66; S, 3.04. Found: C, 66.90; H, 11.46; N, 2.68; S,
2.90.
7.38 (m, 5H, HAr), 5.58 (s, 2H CH2Ph), 3.73 (t, JHH = 7.1 Hz, 2H, CH2), 3.18 (t,
3
3JHH = 7.1 Hz, 2H, CH2); 13C NMR (DMSO, 100 MHz) d 144.4 (1C, triazole), 136.1
(1C, triazole), 128.7 (2C, CAr), 128.0 (1C, CAr), 127.8 (2C, CAr), 122.9 (1C, CAr),
52.7 (1C, CH2Ph), 32.7 (1C, CH2Br), 28.9 (1C, CH2triazole); LRMS (ESI) 280.0
(100) [(M+Na)+]; HRMS (ESI) Calcd for C11H12N3BrNa, 288.0106; found,
288.0106; mp 73–74 °C. 1-(2-(2-(4-bromophenoxy)ethoxy)ethyl)-4-phenyl-
1H-1,2,3-triazole (entry 22). White powder; 1H NMR (DMSO, 200 MHz) d 8.51
(s, 1H, triazole), 7.78–7.82 (m, 2H, HAr), 7.29–7.47 (m, 5H, HAr), 6.83–6.91 (m,
13. In an optimized synthetic procedure for the C186tren ligand, the protocol of
Ref.9 was employed, except that the reaction was carried out at 40 °C instead of
refluxing acetonitrile to limit the over-alkylation of the amino groups.
14. General procedure for the copper-catalyzed click reactions. In a 2 mL flask, the
catalyst (0.1–2 mol %), the azide (1 mmol) and the alkyne (1 mmol) are stirred
in the desired solvent (1 mL) for 24 h. The flask is then put at ꢁ18 °C for 2 h
leading to the precipitation of the product which is recovered by filtration,
washed two times with cold reaction solvent and dried under vacuum. For the
reactions conducted under neat conditions, the resulting solid is washed with
n-octane to remove the catalyst, affording the triazole as a white powder. The
triazole derivative obtained from the conditions of entry 21 (Table 1 in the
text) was purified by silica gel column chromatography (CH2Cl2/MeOH: 99/1)
as this compound does not precipitate efficiently from the toluene solution at
low temperature. 1-Benzyl-4-phenyl-1H-1,2,3-triazole (entry 1). White
powder; 1H NMR (DMSO, 200 MHz) d 8.65 (s, 1H, triazole), 7.82–7.87 (m, 2H,
HAr), 7.28–7.48 (m, 8H, HAr), 5.65 (s, 2H, CH2); 13C NMR (DMSO, 151 MHz) d
146.6 (1C, triazole), 136,0 (1C, CAr), 130.6 (1C, CAr), 128.9 (2C, CAr), 128.8 (1C,
triazole), 128.1 (2C, CAr), 127.9 (2C, CAr), 125.1 (2C, CAr), 121.5 (2C, CAr), 53.0
(1C, CH2); LRMS (ESI) 258.1 [(M+Na)+]; HRMS (ESI) Calcd for C15H13N3Na,
258.1007; Found, 258.1001; mp 131–133 °C (Lit. 126–130 °C).17 (1-Benzyl-1H-
1,2,3-triazol-4-yl)methanol (entry 4). White powder; 1H NMR (DMSO,
200 MHz) d 8.02 (s, 1H, triazole), 7.28–7.41 (m, 5H, HAr), 5.57 (s, 2H, CH2Ph),
2H, HAr), 4.60 (t, JHH = 5.0 Hz, 2H, CH2triazole), 4.05 (td, JHH = 4.5 Hz, 2H,
CH2OPh), 3.93 (t, 3JHH = 5.0 Hz, 2H, CH2CH2triazole), 3.75 (td, 3JHH = 4.5 Hz, 2H,
CH2CH2OPh); 13C NMR (DMSO, 101 MHz) d 157.7 (1C, CAr), 146.2 (1C, triazole),
132.0 (2C, CAr), 130.8 (1C, CAr), 128.8 (2C, CAr), 127.7 (1C, triazole), 125.1 (2C,
CAr), 121.7 (1C, CAr), 116.8 (2C, CAr), 112.0 (1C, CAr), 68.7 (1C, CH2O), 68.6 (1C,
CH2O), 67.3 (1C, CH2OPh), 49.5 (1C, CH2-triazole); LRMS (ESI) 410.0 [(M+Na)+];
HRMS (ESI) Calcd for C18H18N3O2BrNa, 410.0474; Found, 410.0479; mp 72–
73 °C.
3
3
15. We carefully checked (1H NMR) that under these particular conditions the final
product was not contaminated by the 1,5-triazole isomer which could form
through the uncatalyzed thermal cycloaddition.
16. Diphenylacetylene was employed as an internal standard.
A typical
chromatogram of the reaction supernatant is given in the supporting
information.
17. Kacprzak, K. Synlett 2005, 943–946.
18. Alonso, F.; Moglie, Y.; Radivoy, G.; Yus, M. Eur. J. Org. Chem. 2010, 1875–1884.