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Scheme 3 Large-scale synthesis of 3a.
not only sulfonyl triazoles,18 but also N-acylsulfonamides19 or
azetidimines20 can be prepared. In our case, 3l was the only
product formed, but no further optimization for this specific
example was carried out.
6 R. Huisgen, Pure Appl. Chem., 1989, 61, 613–628; R. Huisgen, G.
Szeimies and L. Moebius, Chem. Ber., 1967, 100, 2494–2507.
7 A. Padwa, in Comprehensive Organic Synthesis, ed. B. M. Trost,
Pergamon, Oxford, 1991, vol. 4, pp. 1069–1109; R. Huisgen,
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New York, 1984, pp. 1–176.
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Ed., 2001, 40, 2004–2021.
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Rev., 2007, 526–539; A. Dondoni, Chem.–Asian J., 2007, 2,
700–708; J.-F. Lutz, Angew. Chem., Int. Ed., 2007, 46,
1018–1025. Special issue on Click chemistry: J.-F. Lutz, QSAR
Comb. Sci., 2007, 26, 1110–1323.
11 S. Dıez-Gonzalez, A. Correa, L. Cavallo and S. P. Nolan,
Chem.–Eur. J., 2006, 12, 7558–7564; J. Broggi, S. Dıez-Gonzalez,
J. L. Petersen, S. Berteina-Raboin, S. P. Nolan and L. A.
Agrofoglio, Synthesis, 2008, 141–148.
For the sake of comparison, some of the entries in Table 2
were also performed without passing through the latent
period. Similar or slightly shorter reaction times were required
in those cases, and comparable yields were reached. These
results clearly illustrate the stability of the catalyst in solution.
All the preceding reactions were carried out on a 1 mmol
scale and required 1 mL of each solvent. In view of the
potential application of this catalytic system to large-scale
synthesis, we took a closer look at the quantity of water
required to efficiently activate the catalyst. A DMSO/water
ratio of 1 : 0.6 was found optimal (see ESIw for details) in the
reaction of benzyl azide and phenylacetylene, and it was
successfully applied to a 15 mmol scale synthesis (Scheme 3),
allowing for the isolation of 3.4 g of 3a.
In conclusion, a robust and highly effective [(NHC)CuI]-
based catalytic system for latent Huisgen cycloaddition reac-
tions has been developed. While no reaction was observed
under ambient conditions, triazoles were efficiently prepared
by gentle heating upon addition of water. This novel approach
to this reaction should open new and exciting applications,
notably in material science, where for instance, a mixture of
polymer precursors and the catalyst could be stored for a long
time (or even be commercially available) under ambient con-
ditions but transformed when desired upon heating.
12 L. A. Goj, E. D. Blue, S. A. Delp, T. B. Gunnoe, T. R. Cundari, A.
W. Pierpont, J. L. Petersen and P. D. Boyle, Inorg. Chem., 2006,
45, 9032–9045.
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Nolan, J. Org. Chem., 2005, 70, 4784–4796; N. P. Mankad, T. G.
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Commun., 2001, 2340–2341. See also ref. 12.
The ICIQ Foundation, the Ministerio de Educacion y
Ciencia (MEC, Spain) and the ACS/PRF are gratefully ac-
knowledged for financial support of this work. SDG thanks
the MEC through the Torres Quevedo program for support of
young researchers. SPN is an ICREA Research Professor. We
thank E. Escudero for crystallography support.
14 For reviews, see: C.-J. Li, Chem. Rev., 2005, 105, 3095–3166; R.
Breslow, Acc. Chem. Res., 2004, 37, 471–478; F. Fringuelli,
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15 When the reaction mixture was heated for 5 min after the addition
of water and stirred at room temperature for 1 h, a similar
conversion was obtained.
16 GC results after 7 days of reaction: 1a (9%), 3a (66%),
1,5-regioisomer of 3a (25%).
Notes and references
17 General procedure for the latent [3+2] cycloaddition of azides and
terminal alkynes: In a vial fitted with a screw cap, azide 1
(1.0 mmol), alkyne 2 (1.0 mmol), [(SIPr)CuCl] (10 mg, 2 mol%)
and technical grade DMSO (1 mL) were loaded. The solution was
stirred at room temperature for at least one week and controlled by
GC to ensure the absence of reaction. Then, water (1 mL) was
added and the reaction mixture was heated at 60 1C. After total
consumption of the starting azide or no further conversion, the
corresponding triazole was collected by filtration and washed with
water and pentane. Alternatively, 3 could be also recovered after
extraction with EtOAc. In all examples, the crude products were
z Crystal structure data for [(SIPr)CuCl], details can be found in the
Supporting information.
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1
estimated to be greater than 95% pure by H NMR.
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This journal is The Royal Society of Chemistry 2008
Chem. Commun., 2008, 4747–4749 | 4749