Supporting Information © Wiley-VCH 2006

69451 Weinheim, Germany

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Heterogeneous Copper-in-Charcoal-Catalyzed Click Chemistry

Bruce H. Lipshutz* and Benjamin R. Taft

Department of Chemistry & Biochemistry

University of California

Santa Barbara, CA 93106

Supporting Information

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General. Reactions were performed in ‘wet’ glassware under an air atmosphere containing a Teflon

coated stir bar and septum. 1,4-Dioxane, toluene, ethanol, acetonitrile, and triethylamine were purchased

(ACS grade) and used as received. All commercially available reagents were used without further

purification. Cu/C was stored on the shelf and weighed out on the bench top with no precaution taken to

exclude air or moisture. The catalyst is NOT pyrophoric or sensitive to shock. TLC analyses were

performed on commercial Kieselgel 60 F254 silica gel plates. NMR spectra were obtained on a Varian

Inova system using CDCl3, acetone-d6, or DMSO-d6 as solvent, with proton and carbon resonances at 400

MHz and 100 MHz, respectively. Mass spectral data were acquired on a VF Autospec or an analytical

VG-70-250 HF instrument. Microwave experiments were carried out in a sealed tube with a Personal

Chemistry Emrys Optimizer Reactor with variable heating from 0 to 300 W.

Preparation of Cu/C: Darco KB activated carbon (15.0 g, 100 mesh, 25 % H2O content) was added to a

300-mL round-bottom flask containing a stir bar. A solution of Cu(NO3)2 3 H2O (Acros Organics, 3.334 g,

13.80 mmol) in deionized H2O (100 mL) was added to activated carbon, and additional deionized H2O

(125 mL) was added to wash down the sides of the flask. The flask was purged under argon and stirred

vigorously for 30 min. The flask was submerged in an ultrasonic bath under a positive argon flow for 1

hour. The flask was attached to an argon-purged distillation setup and placed in a preheated 175-180 °C

sand bath with stirring plate. As the distillation ended, the flask temperature began to rise and was held

below 210 °C for an additional 15 min. Upon cooling to room temperature, toluene (75 mL) was added to

wash down the sides of the flask. The flask was again placed into a hot sand bath until the toluene/H2O

azeotrope had distilled. Once the distillation was finished, the azeotropic distillation was repeated a

second time. Upon cooling to room temperature, the black solid was washed with toluene (2×50 mL)

under argon into a predried 150-mL coarse-fritted funnel (in vacuo). The fritted funnel was turned upside

down under vacuum for 5 h until the Cu/C fell from the frit into the collection flask. The collection flask

was then heated in vacuo in a 110-115 °C sand bath for 18 h to further dry the catalyst. The impregnated

charcoal (ca. 13 grams) was transferred to and stored in an amber vial. ICP-EAS analysis of the catalyst

suggested a loading of 1.01 mmol Cu/g catalyst, or 6.4 wt. % Cu.

General Procedure for Cu/C-catalyzed ‘Click’ reaction. Cu/C (50 mg, 1.01 mmol/g, ca. 0.05 mmol)

is added to a clean 10 mL flask fitted with a stir bar and septum. Dioxane (1-2 mL) is added slowly to the

sidewalls of the flask, rinsing the catalyst down. While the heterogeneous solution is stirred,

triethylamine (1.1 mmol), alkyne (1.1 mmol), and azide (1.0 mmol) are added. The flask is stirred at rt

(or warmed to 60 °C), and the reaction progress monitored by TLC until complete consumption of azide

has occurred. The mixture is filtered through a pad of Celite® to remove the catalyst and the filter cake is

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further washed with EtOAc to ensure complete transfer. The volatiles are removed in vacuo to give pure

triazole. If needed, silica gel chromatography or crystallization is used to further purify triazole.

Notes:

Ø Reactions conducted above ambient temperature are performed in a sealed tube to prevent loss of

reagents, alternatively a condenser can be used.

Ø The concentration of substrates is important with regard to rate of cycloaddition; reactions are run

at (0.5 M) or higher.

Ø Order of addition of reagents does not appear to be important.

Ø The catalyst does not appear to be air or moisture sensitive.

Ø The catalyst is reusable, simply use a medium or fine glass fritted filter without Celite® so the

catalyst can be easily recovered and dried under vacuum.

Ø Some substrates ‘click’ quite rapidly at room temperature, but mild heating will more than likely

be ideal.

Compound Characterization Data. Triazoles (Table 1, entry 1, 2, 3, 6, and 7) are known; spectral data

correspond to that in the literature.[1]

N

NNCl

1-Benzyl-4-(4-chlorobutyl)-1H-1,2,3-triazole (Table 1, entry 4). Yellow solid. 1H NMR (400 MHz, CO(CD3)2) d 7.72 (s,

1H), 7.33-7.35 (m, 5H), 5.57 (s, 2H), 3.62 (t, J = 12.0 Hz, 2H), 2.69 (t, J = 12.0 Hz, 2H), 1.84-1.75 (m, 4H). 13C NMR (100

MHz, CDCl3) d148.2, 134.9, 129.0, 128.6, 127.9, 120.8, 54.0, 44.8, 31.9, 26.5, 24.9. HREIMS calcd for C13H16ClN3Na

[M+Na] = 272.0924, found 272.0917.

N

NN

OH

1-(1-Phenethyl-1H-1,2,3-triazol-4-yl)hexan-1-ol (Table 1, entry 5). Light tan/yellow solid. 1H NMR (400 MHz, CO(CD3)2)

d 7.64 (s, 1H), 7.29-7.18 (m, 5H), 4.75, (m, 1H), 4.61 (dt, J = 7.6, 2.0 Hz, 2H), 4.14 (d, J = 5.2 Hz, 1H), 3.21 (t, J = 7.6 Hz,

2H), 1.82-1.68 (m, 2H), 1.44-1.26 (m, 6H), 0.87 (t, J = 3.6 Hz, 3H). 13C NMR (100 MHz, CDCl3) d 168.0, 137.0, 128.8, 128.7,

127.0, 121.0, 66.8, 51.7, 37.3, 36.7, 31.7, 25.1, 22.6, 14.1. HREIMS calcd for C16H23N3ONa [M+Na] = 296.1733, found

296.1726.

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N

NN N

2-(1-Phenethyl-1H-1,2,3-triazol-4-yl)pyridine (Table 1, entry 8). Light brown solid. 1H NMR (400 MHz, SO(CD3)2) d

8.57 (d, J = 4.8 Hz, 1H), 8.55 (s, 1H), 8.01 (d, J = 7.6 Hz, 1H), 7.87 (dt, J = 7.6, 1.6 Hz, 1H), 7.27 (m, 6H), 4.69 (t, J = 7.2 Hz,

2H), 3.23 (t, J = 7.2 Hz, 2H). 13C NMR (100 MHz, CDCl3) d 150.2, 149.4, 148.2, 136.9, 136.8, 128.8, 128.6, 127.1, 122.8,

122.2, 120.2, 51.7, 36.7. HREIMS calcd for C15H15N4 [M+H] = 251.1291, found 251.1300.

NNN

OH

4-Cyclohexanol-1-(adamant-1-yl)-1H-1,2,3-triazole (Table 1, entry 9). White Solid. 1H NMR (400 MHz, CDCl3) d 7.53 (s,

1H), 2.23 (s, 9H), 2.01-1.50 (m, 16H), 1.36 (m, 1H). 13C NMR (100 MHz, CDCl3) d 154.4, 115.7, 69.4, 59.2, 42.8, 38.0, 35.8,

29.3, 25.3, 21.9. HREIMS calcd for C18H27N3ONa [M+Na] = 324.2046, found 324.2038.

NNNOH

4-Fluorenol-1-(adamant-1-yl)-1H-1,2,3-triazole (Table 1, entry 10). White Solid. 1H NMR (400 MHz, CO(CD3)2) d 7.82

(s, 1H), 7.73 (d, J = 7.6 Hz, 2H), 7.61 (d, J = 7.6 Hz, 2H), 7.37 (dt, J = 7.6, 1.2 Hz, 2H), 7.28 (dt, J = 7.6, 1.2 Hz, 2H), 5.16 (s,

1H), 2.21 (s, 9H), 1.78 (s, 6H). 13C NMR (100 MHz, CDCl3) d 149.0, 147.9, 139.3, 129.0, 128.0, 124.8, 119.8, 116.6, 78.3,

59.3, 42.5, 35.5, 29.1. HREIMS calcd for C25H25N3ONa [M+Na] = 406.1889, found 406.1894.

OH

HONNN

OO

O

SO

OH H

H

Triazole 6. White Solid. 1H NMR (400 MHz, CO(CD3)2) d 7.96 (d, J = 8.44 Hz, 2H), 7.92 (s, 1H), 7.55 (s, 1H), 7.51 (d, J =

8.44 Hz, 2H), 6.99 (s, 1H), 6.96 (d, J = 6.0 Hz, 1H) 6.55 (dd, J = 8.4, 2.4 Hz, 1H), 6.50 (s, 1H), 5.62 (s, 1H), 5.58 (s, 2H), 3.87

(s, 3H), 3.49 (s, 3H), 2.75 (m, 1H), 2.47 (s, 3H), 2.39 (m, 3H), 2.33 (s, 3H), 1.95-1.70 (m, 4H), 1.52-1.22 (m, 6H), 1.09 (s, 3H),

0.65 (m, 1H). 13C NMR (100 MHz, SO(CD3)2) d 154.8, 154.0, 153.0, 145.5, 142.0, 139.4, 137.1, 134.2, 133.2, 130.2, 130.0,

127.7, 125.9, 122.0, 119.5, 114.8, 113.6, 112.6, 80.9, 60.0, 55.9, 54.8, 47.4, 46.6, 45.2, 43.1, 37.0, 32.4, 29.2, 27.1, 26.0, 23.5,

21.1, 18.9, 14.3. HREIMS calcd for C37H44N3O7S [M+H] = 674.2900, found 674.2878.

N

TsO

O O

N N Triazole 7. Colorless oil. 1H NMR (400 MHz, acetone-d6) d 7.96 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.38 (s, 1H),

6.93 (s, 1H), 5.52 (s, 2H), 5.12 (m, 9H), 3.87 (s, 3H), 3.51 (s, 3H), 2.64 (t, J = 6.8 Hz, 2H), 2.50 (s, 3H), 2.28 (m, 5H), 2.20-

1.93 (m, 32H), 1.72-1.48 (m, 30H). 13C NMR (100 MHz, acetone-d6) d 155.3, 148.8, 147.4, 144.3, 141.9, 137.3, 136.4, 136.3,

136.2, 136.1, 132.5, 131.6, 129.9, 126.1, 126.0, 126.0, 125.2, 122.5, 121.9, 115.2, 61.5, 57.3, 47.3, 41.4, 41.3, 29.5, 28.4, 28.2,

27.5, 26.8, 22.6, 20.4, 18.7, 17.1. ESI-TOF-MS calcd for C65H96N3O5S [M+H] = 1030.71, found 1030.71.

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1H and 13C NMR spectra.

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7

8

9

10

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References

[1] (a) K. B. Sharpless, G. Jia, V. V. Fokin, I. D. Williams, H. Y. Sun, P. Xue, X. Chen, L. Zhang, J. Am. Chem. Soc.

2005, 127, 15998. (b) V. V. Fokin, E. Eycken, W. Dehaen, P. Appukkuttan, Org. Lett. 2004, 6, 4223. (c) K. B.

Sharpless, V. V. Fokin, L. G. Green, V. V. Rostovtsev, Angew. Chem. Int. Ed. 2002, 41, 2596.