Alkyne-azide cycloaddition catalyzed by a dinuclear copper(I) complex

Article abstract of DOI:10.1016/j.tetlet.2014.10.029

A novel dinuclear copper complex Cu^I₂(pip)₂ was used as a catalyst for alkyne-azide cycloaddition (CuAAC) reaction. High yields (95-99%) were obtained for various substrates at a low loading of 0.2 mol %. The unique struct

Full text of DOI:10.1016/j.tetlet.2014.10.029

Accepted Manuscript
Alkyne-azide cycloaddition catalyzed by a dinuclear copper(I) complex
Hong-Bin Chen, Nawodi Abeyrathna, Yi Liao
PII:
S0040-4039(14)01712-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.10.029
TETL 45258
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Accepted Date:
26 September 2014
6 October 2014
Please cite this article as: Chen, H-B., Abeyrathna, N., Liao, Y., Alkyne-azide cycloaddition catalyzed by a dinuclear
copper(I) complex, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.10.029
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Alkyne-Azide Cycloaddition Catalyzed by a Dinuclear Copper(I) complex
Hong-Bin Chen,a Nawodi Abeyrathnab and Yi Liaob*
aDepartment of Chemistry, Xiamen University, Xiamen 361005, P. R. China
bDepartment of Chemistry, Florida Institute of Technology, Melbourne, FL 32901, USA
* Corresponding author. Tel.: +1 321 674 8043; Fax: +1 321 674 8951; Email: yliao@fit.edu.
Abstract: A novel dinculear copper complex CuI2(pip)2 was used as a catalyst for alkyne-azide
cycloaddition (CuAAC) reaction. High yields (95-99%) were obtained for various substrates at a
low loading of 0.2 mol%. The unique structure, high stability of the dinuclear structure in solution,
and easy preparation make this complex not only a high-efficiency catalyst but also a model for
understanding the mechanism of the CuAAC reaction.
Abstract graphic
N
Bn
CuI2(pip)2 (0.2 mol%)
DCM, rt, 4h
N
N
+
R
N3 Bn
R
yields: 95-99%
N
N
N
N
N
Cu Cu
N
CuI2(pip)2
=
Keywords: alkyne-azide cycloaddition; dinuclear copper complex; catalysis; click chemistry

The 1,3-dipolar cycloaddition reaction between alkynes and azides was first studied by
Huisgen.1 The copper-catalyzed version of this reaction (CuAAC) was later investigated and
popularized by Meldal2 and Sharpless3. This reaction has become one of the most popular
reactions in multidisciplinary areas owing to its high efficiency, excellent atom economy,
exclusive regioselectivity, high tolerance towards a range of functional groups, and mild reaction
condition. The products, 1,4-disubstituted 1,2,3-triazoles (also referred as ‘click triazoles’), have
found widespread applications in bioorganic chemistry, drug discovery, and material science.4
Although great progress has been made over the past decade,4,5 the mechanism of CuAAC is still
not fully elucidated because several reactive intermediates are involved in the reaction and they
are difficult to be separated and identified. Mechanistic studies, both experimental6 and
theoretical,7 showed that two copper(I) atoms are involved in the transition-states of the catalytic
mechanism. The dicopper transition states significantly reduced the activation energy of the
reaction.
Currently two methods are commonly used for CuAAC.4,5 One is in-situ reduction of
copper(II) sulfate with sodium ascorbate in aqueous solution. This method is limited to
water-tolerant substrates that are inert to reducing agents. The other method is using copper(I)
species directly, often together with organic bases. Although mechanistic studies have indicated
that dicopper intermediates are involved, only a few examples of dicopper catalysts for CuAAC
have been reported.6c-e,8 Herein we reported a study of homogenous CuAAC reaction using a
novel dinuclear copper(I) complex CuI2(pip)2 [Figure 1, pip = (2-picolyliminomethyl)pyrrole
anion] as the catalyst.
R2
N
N
N
N
N
N
N
N
N
N
N
N
CuI
CuI
CuI
CuI
[Cu]a
[Cu]b
N
R1
N
N
Figure 1. Structure of CuI2(pip)2 (left) and a dicopper transition state resulting from a DFT
calculation6.
CuI2(pip)2 were easily prepared according to a procedure reported by the author and coworkers.9
Once isolated, the compound is stable in solid state under ambient conditions. Whereas its

structure was previously reported,9 the catalytic property has never been explored before. The
unique structure possesses two different copper (I) sites. One copper is bonded to two
deprotonated pyrroles, and the other is bonded to four imino- and pyridinyl nitrogens. The
coordination numbers are relatively low and the ligand is not bulky, which allow the substrates to
access the copper centers easily. The distance between the two copper atoms is 2.61 Å, which is
close to the Cu-Cu distance of the dicopper transition states (Figure 1) predicted by DFT
calculations (2.54-2.88 Å).7 In addition, the dinuclear structure has been proofed to be stable in
dichloromethane by a temperature/concentration-dependent NMR study.9 These features make the
complex a promising candidate as a catalyst for CuAAC.
CuAAC reaction between phenylacetylene and benzyl azide was studied first in the presence of
1 mol% of CuI2(pip)2 using dichloromethane as solvent. After stirring under nitrogen for 4 hours,
the triazole product was isolated with nearly quantitative yield (99%). Further studies revealed that
even when the catalyst amount was decreased to 0.2 mol%, the reaction still proceeded well with a
99% isolated yield, which showed that this catalyst is highly active for CuAAC reaction.
Reactions of several aliphatic and aromatic alkynes bearing various electron-withdrawing and
electron-donating groups were performed to study the tolerance of the catalyst towards different
functional groups. The same loading of 0.2 mol% was used for the reactions. All the reactions
proceeded smoothly to give the corresponding triazoles in 95-99% isolated yields Scheme 2).
N
Bn
CuI2(pip)2 (0.2%)
DCM, rt, 4h
N
N
+
R
N3 Bn
R
1
2
3
N
N
Bn
Bn
N
N
N
N
N
Bn
N
N
N
N
Bn
Bn
N
N
N
N
MeO2C
F
3a 99%
3b 98%
3c 95%
3d 97%
3e 99%
N
N
N
Bn
N
N
Bn
N
Bn
Bn
N
N
N
N
N
N
I
O
O
OHC
O
MeO
OHC
3g 99%
3i 99%
3f 99%
3h 99%
Scheme 2. Structures and yields of triazole products

A relatively large scale (40.0 mmol) reaction between phenylacetylene and benzyl azide was
performed to demonstrate the practical utility of this catalyst. This scale allowed us to use only 0.1
mol% of the catalyst. The reaction proceeded well and the triazole product was obtained in 93%
yield by recrystallization from dichloromethane/hexane.
In summary, a novel dicopper complex CuI2(pip)2 showed high catalytic activity for
homogenous CuAAC reactions. The unique structure, high stability of the dinuclear structure in
solution, and easy preparation make this complex not only a high-efficiency catalyst but also a
good model for understanding the mechanism of this important reaction.
Acknowledgements
Financial support from the Air Force Office of Scientific Research (FP048956) is gratefully
acknowledged.
Supplementary data
General procedures, characterization data and spectra of the products are provided in the
supplementary information.
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