Heterogeneous copper-in-charcoal-catalyzed click chemistry

Article abstract of DOI:10.1002/anie.200603726

(Chemical Equation Presented) Click here for Cu/C: Copper-in-charcoal (Cu/C) is an active catalyst for effecting click reactions between organic azides and 1-alkynes. Rates of cycloaddition are increased dramatically when carried out in the presence of Et

Full text of DOI:10.1002/anie.200603726

Angewandte
Chemie
Heterogeneous Catalysis
DOI: 10.1002/anie.200603726
Heterogeneous Copper-in-Charcoal-Catalyzed
Click Chemistry**
Bruce H. Lipshutz* and Benjamin R. Taft
Quick inspection of the 2006 literature already turns up nearly
200 papers related to “click” cycloadditions. Click chemistry
is clearly on the rise, and for good reason. It offers an almost
unlimited array of inert triazole-containing architectures
resulting from Huisgen [3+2] cycloadditions,[1] in particular
between high-energy organic azides and terminal alkynes, for
example, as shown in Equation (1) (Bn = benzyl). This
process is significantly accelerated by CuI catalysis, independ-
ently discovered and published by the groups of both
Sharpless[2] and Meldal[3] in 2002. Recently reviewed,[4]
copper(II) sulfate (ca. 1%) in an aqueous medium (e.g.
H2O/tBuOH) is typically preferred, where the presence of
sodium ascorbate (ca. 10%) serves to generate catalytically
active CuI in situ. Alternative conditions, such as in situ
oxidation of Cu0 or direct introduction of CuI salts (usually
CuI), have also been used quite successfully.[5] While both
[*] Prof. Dr. B. H. Lipshutz, B. R. Taft
Department of Chemistry and Biochemistry
University of California, Santa Barbara
Santa Barbara, CA 93106-9510 (USA)
Fax: (+1)805-893-4120
E-mail: lipshutz@chem.ucsb.edu
Homepage: http://www.chem.ucsb.edu/~lipshutzgroup/
[**] We are grateful to the NSF for financial support. Discussions with
Professor Craig Hawker and his group (UCSB) are warmly
acknowledged. ICP-AES analyses were conducted by Anthony E.
Tomaso (UCSB) and are much appreciated.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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reaction partners have been individually coupled under solid-
(Table 1). Noteworthy features of this process include a) the
regiochemistry (1,4-triazole) of addition follows that antici-
pated for such Cu-catalyzed reactions;[2] b) outstanding func-
tional group tolerance is observed under these heterogeneous
phase conditions, (e.g. on polystyrene),[3,6] examples of click
chemistry mediated by a source of heterogeneous copper(I)
are rare. One report relies on chelation to potentially labile
copper by a polystyryl-based benzylic amine.[7a] Only unhin-
dered, low-molecular-weight, and non-basic nitrogen-con-
taining examples were studied therein, without data quanti-
fying losses of copper from the solid support. Other studies
are also limited, based on suspensions of unsupported copper
clusters.[7b] Herein, we describe the virtues of copper-in-
charcoal (Cu/C) as a simple, inexpensive, and especially
general and efficient heterogeneous catalyst for use in this
emerging area.
Table 1: Click reactions catalyzed by Cu/C.[a]
Entry Alkyne
Azide
t [min] Triazole
Yield [%]
99
1
Bn-N3
10
2
3
Bn-N3
Bn-N3
20
20
97
99
Impregnation of activated wood charcoal (Aldrich, 100
mesh, $53.90/kilo)[8] with Cu(NO3)2 in water using an ultra-
sonic bath leads, after distillation of water and drying, to
nanoparticle-sized Cu/C.[9] As both CuO and Cu2O have been
proposed as the species present within a charcoal matrix,[10]
the presence of CuI suggested that a reducing agent might not
be needed. Indeed, upon mixing benzyl azide (1) with
phenylacetylene 2 (1:1) in dioxane at room temperature in
the presence of 10 mol% Cu/C, cycloaddition was complete
within 10 hours. Filtration and solvent evaporation afforded
pure triazole 3 regiospecifically and near-quantitatively.
Aromatic alkynes are usually among the more reactive
partners, while aliphatic alkynes oftentimes result in signifi-
cantly slower cycloadditions. Steric hindrance in either
substrate can also reduce rates, but with mild heating
(608C) reactions are driven to completion (Scheme 1).
4
5
Bn-N3
20
45
94
99
6[b]
BnN3
20
96
7
8
30
30
92
98
9
120
120
99
97
10[c]
Scheme 1. A representative click reaction under mild heating.
Surprisingly, no bases, ligands,[11] or other additives are
required for Cu/C to effectively catalyze these cycloadditions.
However, given the likely intermediacy of copper acety-
lides,[4,5,12] the impact of an amine base was examined. This
additive is assumed to aid in both anion formation as well as
CuI stabilization, thereby significantly increasing rates of
triazole formation.[13] Cycloaddition catalyzed by Cu/C in the
presence of several different bases led to the unexpected
finding, contrary to literature precedent (which encourages
use of excess Hünigꢀs base),[14] that one equivalent of Et3N
was particularly effective. Stronger (e.g. 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU)) and weaker (e.g. pyridine) amine
bases had marginal impact (< 10% conversion under other-
wise identical conditions), while lithium tert-butoxide showed
no catalytic effect whatsoever. The dramatic role of Et3N was
noted in the case of partners 1 and 4, for example, where the
reaction time leading to product 5 was reduced from 4 h to
4 min (Scheme 1).
[a] Run at 0.5m in dioxane at 608C with 5 mol% Cu/C and 1 equivalent Et3N.
[b] Direct comparison to Sharpless’ method (88% yield).[2] [c] Product was
further purified by silica gel chromatography.
conditions; c) yields are uniformly high; d) generally, reac-
tions are complete within minutes; e) sterically demanding
precursors are not precluded from participation; f) hetero-
aromatics couple smoothly; and g) high-molecular-weight
adducts, such as the triazole-containing steroidal derivative
6 (Mr = 673), and the precursor to an analogue of coen-
zyme Q10, 7 (Mr = 1029), were both readily formed and
isolated in good yields (Figure 1).
Numerous control experiments indicated not only that the
CuI dispersed within charcoal is essential for catalysis but that
Cu/C is also quite robust. Treatment of 1 and 4 with activated
charcoal alone, from the same source used to make Cu/C,[8]
gave no trace of product 5 (Table 2, entry A). Meticulous
drying of these substrates, solvent, and catalyst (including the
use of 4-Š molecular sieves) did not noticeably alter the rate
Several additional examples were carried out using the
same conditions: Cu/C (cat.), Et3N (1 equiv), dioxane, 608C
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Table 3: Microwave irradiation in the absence of base.
T [8C]
t
Yield [%]
conventional heating
23
60
48 h
4 h
65
99
microwave irradiation
120
150
10 min
3 min
3 min
99
99
0
Figure 1. Examples of higher-molecular-weight adducts. Ts=para-tol-
uenesulfonyl.
150 (no catalyst)
In addition to the simplicity and efficiency of cyclo-
additions carried out in the presence of Cu/C, product
contamination by copper is minimized if not completely
averted. Quantitative ICP-AES[15] analyses of triazole prod-
ucts from multiple reactions revealed insignificant copper;
indeed, copper concentrations observed were too low for
accurate measurement of these millimole-scale reactions.
Thus, these data further suggest that Cu/C-catalyzed click
cycloadditions take place heterogeneously with negligible
leaching of copper into solution, a characteristic that could
simplify both preparation and isolation of triazoles for many
applications.
Table 2: Assessment of catalyst (Cu/C).
Entry
Conditions
Yield [%]
A
B
C
D
E
F
G
H
I
charcoal, (no Cu), 608C, 1 h
dry dioxane with 4-Š mol. sieves
wet, 2:1 dioxane/H2O
0
99
99
99
99
99
98
98
97
recycled catalyst in air
repeat (D), third use in air
dioxane, room temperature, 6 h
toluene, room temperature, 2 h
95% EtOH, 608C, 10 min
H2O, 608C, 10 min
Most recently, we have further streamlined the prepara-
tion of Cu/C (see Experimental Section) by bypassing the
distillation step. To demonstrate utility, a batch of catalyst
(> 40 gram) was quickly prepared (Scheme 2) and tested
or yield of reaction (Table 2, entry B). At the other extreme,
using water as co-solvent, likewise, had no impact (Table 2,
entry C). Upon formation of triazole 5, generated without
exclusion of moisture or air, the Cu/C was filtered (in air) and
reused in at least two additional cycles without loss of activity
(Table 2, entries D and E). In addition to unprocessed
dioxane as the medium, other solvents appear to be of
equal or even greater potential in these reactions. Toluene led
to triazole 5 at room temperature at three times the rate seen
in dioxane (entry F vs G, Table 2). Both 95% EtOH(Table 2,
entry H) and even pure water (entry I) are perfectly ame-
nable to heterogeneous Cu/C-catalyzed click reactions, with
these cycloadditions reaching completion at 608C in less than
10 min.
To further examine the possibility of Cu/C catalysis in the
absence of additives (e.g. Et3N), reactions were exposed to
controlled microwave irradiation (Table 3). As expected, the
time needed for cycloaddition resulting in triazole 5 was
reduced from 4 h to less than 10 min with the reaction
temperature being increased from 608C to 1208C. More
remarkably, Cu/C quantitatively catalyzed formation of 5 in
less than 3 min at 1508C with no loss of regioselectivity. This
flawless 1,4-selectivity suggests that the process is discrim-
inatory towards catalysis by copper (and not driven ther-
mally), which is made all the more apparent when the same
reaction in the absence of catalyst afforded no trace of
triazole.
Scheme 2. Simplified, scaled-up preparation of Cu/C.
successfully in the conversion of 1 and 4 into 5. No noticeable
difference in reaction rate or extent of leaching (by ICP-AES)
was observed, notwithstanding impregnation of copper(II)
nitrate.[16] Assuming catalysis by CuI, partial reduction by
charcoal could account for the observed activity.
In conclusion, highly efficient click chemistry between
organic azides and terminal alkynes can be heterogeneously
catalyzed by copper nanoparticles mounted within the pores
of activated charcoal.[9] Reactions can be accelerated with
stoichiometric Et3N or by simply increasing the reaction
temperature. Under microwave irradiation, triazoles can be
formed in minutes at 1508C. Cycloadditions can be carried
out in a purely organic medium, in aqueous solvent mixtures,
or in pure water. Solubility issues, copper contamination, and
modest yields usually associated with the choice of copper salt
are completely averted. External ligands known to accelerate
click reactions are not needed. The catalyst appears to be
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Communications
[3] M. Meldal, C. Christensen, C. W. Tornoe, J. Org. Chem. 2002, 67,
3057.
[4] J. H. Maarseveen, H. Hiemstra, V. D. Bock, Eur. J. Org. Chem.
2006, 51.
[5] a) K. B. Sharpless, V. V. Fokin, V. V. Rostovtsev, L. Noodleman,
R. Hilgraf, T. Lovell, F. Himo, J. Am. Chem. Soc. 2005, 127, 210;
b) C. J. Hawker, T. P. Russell, P. Wu, V. V. Fokin, E. Drock-
enmuller, K. Schleicher, M. Malkoch, Macromolecules 2005, 38,
3663.
unaffected by exposure to air, suggesting a substantial shelf-
life. Steric congestion in one or both partners is well-
tolerated, and product isolation is notably facile.[17] Further
studies that take advantage of Cu/C in several contexts (e.g.
kinetic resolutions, mechanistic questions, formation of new
triazole-containing ligands, etc.) are ongoing, the results from
which will be reported in due course.
[6] a) P. Gmeiner, H. Hubner, S. Lober, P.-R. Loaiza, J. Comb.
Chem. 2006, 8, 252; b) M. G. Finn, Q. Wang, J. Kuzelka, S. Punna,
Angew. Chem. 2005, 117, 2255; Angew. Chem. Int. Ed. 2005, 44,
2215.
[7] a) C. Girard, E. Onen, M. Aufort, S. Beauviere, E. Samson, J.
Herscovici, Org. Lett. 2006, 8, 1689; b) G. Rothenberg, J.-V.
Maarseveen, L. D. Pachon, Adv. Synth. Catal. 2005, 347, 811; see
also: A. Ponti, N. Santo, G. Marinoni, C. L. Bianchi, G. Molteni,
New J. Chem. 2006, 30, 1137.
Experimental Section
Simplified preparation of Cu/C:[18] Darco KB activated carbon
(50.0 g, 100 mesh, 25% H2O content) was added to a 500-mL
round-bottomed flask containing a stir bar. A solution of Cu-
(NO3)2·3H2O (Acros Organics, 11.114 g, 46.0 mmol) in deionized
water (100 mL) was added to the flask, and further deionized H2O
(100 mL) was added to wash down the sides of the flask. The flask was
loosely capped and stirred under air for 30 min and then submerged in
an ultrasonic bath for 7 h. Subsequent washing (toluene) and air
drying (3 h) by vacuum filtration yielded about 85 grams of “wet” Cu/
C. The catalyst could be used at this stage or further dried in vacuo at
1208C overnight (41 g yield of “dry” Cu/C).
[8] Aldrich Catalogue, #278092. Darko KB, Wet Powder, 100 mesh,
contains less than 30% water.
[9] B. H. Lipshutz, B. A. Frieman, A. E. Tomaso, Angew. Chem.
2006, 118, 1281; Angew. Chem. Int. Ed. 2006, 45, 1259.
[10] T. Tsoncheva, S. Vankova, D. Mehandjiev, Fuel 2003, 82, 755.
[11] V. V. Fokin, K. B. Sharpless, R. Hilgraf, T. R. Chan, Org. Lett.
2004, 6, 2853.
[12] M. G. Finn, V. V. Fokin, V. O. Rodionov, Angew. Chem. 2005,
117, 2250; Angew. Chem. Int. Ed. 2005, 44, 2210.
[13] M. R. Ghadiri, C. D. Stout, W. S. Horne, J. Am. Chem. Soc. 2003,
125, 9372.
[14] C-H. Wong, J. C. Paulson, O. Blixt, M. C. Bryan, F. Fazio, J. Am.
Chem. Soc. 2002, 124, 14397.
[15] ICP-AES: inductively coupled plasma–atomic emission spec-
troscopy. A. W. Varnes, Handbook of Instrumental Techniques
for Analytical Chemistry (Ed.: F. Settle), Prentice Hall, Upper
Saddle River, NJ, 1997, p. 395.
[16] For a recent article that describes use of copper(II) salts to
catalyze click cycloadditions in water, see: M. L. Kantam, K.
Rajgopal, K. R. Reddy, Synlett 2006, 957 – 959.
[17] Removal of catalyst by filtration followed by evaporation of
volatiles gives pure triazole products with little to no copper
contamination. See Experimental Section.
[18] Some Cu(NO3)2·3H2O remained in the filtrate and was recov-
ered by evaporation of the water. Further optimization of this
preparation is ongoing.
General procedure for Cu/C-catalyzed “click” reaction: Cu/C
(50 mg, 1.01 mmolgÀ1, 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 to rinse 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
room temperature (or warmed to 608C), and the reaction progress is
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 further washed with EtOAc to ensure complete
transfer. The volatiles are removed in vacuo to give pure triazole.
Received: September 12, 2006
Published online: November 17, 2006
Keywords: click chemistry · copper · cycloaddition ·
.
heterogeneous catalysis · microwave irradiation
[1] R. Huisgen, 1,3-Dipolar Cycloaddition Chemistry (Ed.: A.
Padwa), Wiley, New York, 1984.
[2] K. B. Sharpless, V. V. Fokin, L. G. Green, V. V. Rostovtsev,
Angew. Chem. 2002, 114, 2708; Angew. Chem. Int. Ed. 2002, 41,
2596.
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