Copper-in-charcoal-catalyzed, tandem one-pot diazo transfer-click reactions

Article abstract of DOI:10.1002/adsc.200900604

Copper-in-charcoal (Cu/C) is an effective heterogeneous catalyst for tandem diazo transfer/click reactions. In the presence of Cu/C, various azides can be generated in situ from the corresponding amines, and subsequently undergo [3+ 2] cycloaddition with terminal alkynes to afford triazoles in good yields. The catalyst is also easily recycled.

Full text of DOI:10.1002/adsc.200900604

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DOI: 10.1002/adsc.200900604
Copper-in-Charcoal-Catalyzed, Tandem One-Pot Diazo Transfer-
Click Reactions
Ching-Tien Lee,a Shenlin Huang,a and Bruce H. Lipshutza,*
a
Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106-9510, USA
Fax : (+1) 805-893-8265; e-mail: lipshutz@chem.ucsb.edu
Received: September 3, 2009; Published online: December 2, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900604.
Abstract: Copper-in-charcoal (Cu/C) is an effective
heterogeneous catalyst for tandem diazo transfer/
click reactions. In the presence of Cu/C, various
azides can be generated in situ from the corre-
sponding amines, and subsequently undergo [3+
2]cycloaddition with terminal alkynes to afford tri-
the charcoal matrix, seemingly ideal for an initial
diazo transfer and subsequent [3+2]cycloaddition. In
this report we describe an especially convenient, one-
pot procedure employing a heterogeneous, recyclable,
and soon-to-be-commercially available reagent (Cu/
C)[11] for catalysis that sequentially converts primary
amines to 1,4-disubstituted 1,2,3-triazoles without
adding reducing reagents (Scheme 1).
ACHTUNGTRENNUNGazoles in good yields. The catalyst is also easily re-
cycled.
Keywords: click chemistry; copper-in-charcoal;
diazo transfer; heterogeneous catalysis
Both the Sharpless[1] and Meldal[2] groups are credited
with describing the remarkable acceleration induced
by Cu(I) in Huisgen [3+2]cycloadditions[3] between
azides and terminal alkynes. Such cycloaddition reac-
tions are among the most popular protocols for gener-
ating libraries of compounds in drug research,[4] mate-
Scheme 1. Cu/C-catalyzed tandem reactions.
Azides were readily prepared in situ from the cor-
rials science,[5] and bioconjugate chemistry.[6] Cu(I)- responding amines via diazo transfer mediated by tri-
catalyzed azide-alkyne cycloadditions (CuAAC) have fluoromethanesulfonyl azide 1 (TfN3; Scheme 2). Re-
been extensively investigated leading to several modi- agent 1 was made from the reaction of trifluorome-
fied procedures for purposes of simplifying both thanesulfonyl anhydride and sodium azide in a mix-
educt and reagent manipulation.[7] Recently, Witt- ture of water and dichloromethane (DCM) at 08C.[12]
mann[8] and co-workers reported a one-pot procedure For reasons of safety, azide 1 is handled in DCM,
leading to 1,4-disubstituted 1,2,3-triazoles from in which is separated from the aqueous phase and used
situ-generated azides, by-passing safety issues associ- directly. Benzylamine 2 and phenylacetylene (3) were
ated with the handling of these potentially explosive
compounds.[9] However, after Cu(II)-induced azide
formation, introduction of a reducing agent (sodium
ascorbate or copper powder) is required to convert
Cu(II) to click-active Cu(I).
The need for both oxidation states of copper sug-
gested that our previously[10] reported reagent,
copper-in-charcoal (Cu/C), might serve as an efficient
heterogeneous catalyst for these tandem processes.
XPS spectral data for Cu/C reveal the presence of
mostly CuO, along with lesser amounts of Cu2O in Scheme 2. Two steps, one-pot procedure.
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chosen as a model substrate pair to test efficacy of added. After 18 h of stirring at room temperature, the
Cu/C. The former was transformed into benzyl azide desired triazole was obtained in 95% isolated yield.
in the presence of Cu/C following Wongꢁs proce- Use of Cu/C prepared by Sigma–Aldrich led to the
dure[12] wherein sodium bicarbonate serves as base. same results under identical conditions (entry 1;
However, under these conditions, leaching of cop- Table 1).
A
The scope of this methodology has been studied
vealed by the blue coloration of the solution. Presum- using a variety of amines and alkynes, as illustrated in
ably, breakup of polymeric copper oxides to form Table 1. Aromatic and aliphatic primary amines can
copper carbonate within the charcoal pores may be be smoothly transformed to their corresponding
the release mechanism. By simply switching to azides. In all cases, triazole products were isolated in
barium hydroxide, active copper remains on the solid good-to-excellent yields. It appeared that sterically
support. Once diazo transfer is complete (monitored hindered alkynes (entries 2 and 4), and an alkyne
by GC; diazo transfer stopped at 80% conversion with a long carbon chain (entry 6), displayed lower re-
after 3 h), phenylacetylene and triethylamine[10] were activity and thereby prolonged reaction times were
Table 1. Representative examples of Cu/C-catalyzed tandem azide formation/click reaction.[a]
[a]
Standard conditions: Cu/C (12 mol%), Ba(OH)2 (1.5 mmol), TfN3 (1.5 mmol), amine (1.5 mmol), alkyne
(0.75 mmol), TEA (1.4 mmol).
TfN3 was prepared prior to use.
Isolated yields.
Sigma–Aldrich Cu/C was used.
[b]
[c]
[d]
[e]
Recovered Cu/C was used.
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Copper-in-Charcoal-Catalyzed, Tandem One-Pot Diazo Transfer-Click Reactions
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required. It is worthy of note that high-molecular- is serving as a reservoir of copper in solution that re-
weight adduct 4 could also be formed and isolated in turns to the solid support, the lack of any coloration
good yield (Figure 1).
(as previously seen; vide supra) and the mildness of
reaction conditions (room temperature to 408C)
argue against such a role for this catalyst.
In conclusion, a heterogeneous, one-pot procedure
for sequential Cu(II)-catalyzed diazo transfer of
amines to azides followed by Cu(I)-catalyzed click cy-
cloaddition between resulting azides and alkynes has
been developed. Both the isolation of azide inter-
mediates and introduction of reducing agents are ob-
viated using readily available, heterogeneous Cu/C.
Figure 1.
A significant advantage of this heterogeneous cata- Experimental Section
lyst is its recyclability without loss of activity (Table 1,
entry 5). The recovered Cu/C gave the desired prod- General Procedure for Cu/C-Catalyzed, One-Pot
uct in 86% yield under identical conditions as com- “Click” Reaction
pared to 91% yield using fresh reagent.
The influence of microwave irradiation was exam-
ined in an effort to enhance the rate of the click step;
A solution of NaN3 (200 mg, 3.0 mmol) in a mixture of H2O
(1 mL) and CH2Cl2 (1 mL) was cooled at 08C and treated
with Tf2O (250 mL, 1.5 mmol) while stirring. The reaction
cycloaddition of phenylacetylene (3) with in situ-gen-
erated benzyl azide was complete in 10 min at 1208C,
giving the product in 92% isolated yield (Scheme 3).
mixture was stirred in an ice-bath for 2 h. The organic phase
was then separated and the aqueous phase was extracted
twice with CH2Cl2. The organic layers were combined and
washed (~3 mL) with saturated Na2CO3 (5 mL) and used
without further purification. A 25-mL round-bottomed flask
was charged with Cu/C (50 mg, 1.83 mmolgÀ1, 0.09 mmol),
Ba(OH)2 (256 mg, 1.5 mmol), amine (1.5 mmol), and
CH2Cl2 (2 mL). While the mixture was stirred at room tem-
perature, a fresh solution of TfN3 in CH2Cl2 was added
slowly. After 3 h stirring at room temperature, triethylamine
(200 mL, 1.4 mmol) and alkyne (0.75 mmol) were added. The
resulting mixture was heated to the temperature indicated
in Table 1. Upon complete consumption of alkyne as moni-
tored by TLC, Cu/C was removed by filtration on a Buchner
funnel charged with a short pad of Celite and the filter cake
was washed with 10 mL of DCM. The filtrate was collected
and concentrated via rotary evaporator and purified via
flash chromatography. Compound characterization data are
available in the Supporting Information.
Scheme 3. Microwave-assisted click reaction.
To confirm that this one-pot procedure catalyzed
by Cu/C is unambiguously heterogeneous in nature,
azide 5 was generated in situ followed by addition of
Cu/C, alkyne 6, and triethylamine (Scheme 4). The
mixture was stirred for four hours at 408C and then
analyzed by GC: the ratio of educt 6 to product was
79:21. The incomplete reaction mixture was then fil-
tered to remove Cu/C and the filtrate subjected to the
same 408C for another 16 h. That the ratio did not
change strongly suggests that no copper was present
in solution. Introduction of fresh Cu/C to the filtrate
led to full conversion of the reaction. Although these
observations do not rule out the possibility that Cu/C
Acknowledgements
Financial support provided by the NSF is warmly acknowl-
edged with thanks.
Scheme 4. Experiments testing catalyst leaching.
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