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Synlett 2010(12): 1873-1877  
DOI: 10.1055/s-0030-1258120
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Direct Copper(I)-Catalyzed Cycloaddition of Organic Azides with TMS-Protected Alkynes

Félix Cuevasa, Ana I. Olivaa, Miquel A. Pericàs*a,b
a Institute of Chemical Research of Catalonia (ICIQ), Av. Països Catalans 16, 43007 Tarragona, Spain
Fax: +34(977)920222; e-Mail: mapericas@iciq.es;
b Departament de Química Orgànica, Universitat de Barcelona (UB), 08028 Barcelona, Spain
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Publication History

Received 4 May 2010
Publication Date:
30 June 2010 (online)

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Abstract

A methodology for the direct use of trimethylsilyl-protected alkynes in the copper(I)-mediated alkyne-azide cycloaddition reaction without the need of a previous deprotection step is reported. This methodology is selective for the trimethylsilyl in front of other silicon-based C(sp)-H protecting groups.

Key words

alkynes - azides - cycloaddition - tandem reaction - click chemistry

11

A precipitate forms upon mixture of 1 with CuBr in DMF. In the presence of NMM, precipitation is much less intense.

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General Procedure for the Tandem Desilylation-CuAAC Reaction of 1-Trimethylsilyl-1-alkynes
Method A
A mixture of the alkyne (0.24 mmol), CuBr (0.04 mmol, 15 mol%), benzylazide (0.26 mmol), and Et3N (0.24 mmol) in DMF (0.5 mL) was stirred at 100 ˚C for the time indicated in Tables  [¹] and  [²] . The reaction mixture was cooled at r.t., a sat. solution of NH4Cl was added and extracted with EtOAc. The organic layer was washed with H2O, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by flash chromatography, silica gel, gradient hexane to EtOAc.
Method B
As described in method A, but additional H2O (2 equiv) was added.
1-Benzyl-4-phenyl-1 H -1,2,3-trizole (3a) From 1-phenyl-2-trimethylsilylacetylene (1a, 27 mg, 30 µL, 0.15 mmol), CuBr (3.3 mg, 0.02 mmol), benzylazide (22 mg, 21 µL, 0.17 mmol), and Et3N (16 mg, 22 µL, 0.16 mmol) in DMF (0.5 mL), afforded the titled compound (method A: 34 mg, 94% yield; method B: 97%) as a white solid; mp 134-136 ˚C. ¹H NMR (400 MHz, CDCl3): δ = 7.82 (d, J = 7.2 Hz, 2 H), 7.69 (s, 1 H), 7.37 (m, 5 H), 7.33 (m, 2 H) ppm. ¹³C NMR (100 MHz, CDCl3): δ = 148.35, 134.95, 130.78, 129.31, 129.01, 128.93, 128.34, 128.22, 125.88, 119.86, 54.34 ppm. HRMS (ESI+): m/z calcd for [M + Na]+: 258.1007; found: 258.1001.