Well-defined diimine copper(I) complexes as catalysts in click azide-alkyne cycloaddition reactions

Article abstract of DOI:10.3390/molecules18088919

A series of 1,4-disubstituted 1,2,3-triazoles have been prepared in high yields while respecting the stringent Click criteria. In these reactions, highly stable pre-formed complexes bearing diimine ligands were used.

Full text of DOI:10.3390/molecules18088919

Molecules 2013, 18, 8919-8928; doi:10.3390/molecules18088919
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Well-Defined Diimine Copper(I) Complexes as Catalysts in
Click Azide-Alkyne Cycloaddition Reactions
Jordi Markalain Barta † and Silvia Díez-González *
Department of Chemistry, Imperial College London, Exhibition Road, South Kensington,
SW7 2AZ London, UK; E-Mail: j_markalain@hotmail.com
†
Erasmus Student from the Universidad de Barcelona, Barcelona 08130, Spain.
* Author to whom correspondence should be addressed; E-Mail: s.diez-gonzalez@imperial.ac.uk;
Tel.: +44-207-549-699.
Received: 29 June 2013; in revised form: 21 July 2013 / Accepted: 23 July 2013 /
Published: 26 July 2013
Abstract: A series of 1,4-disubstituted 1,2,3-triazoles have been prepared in high yields
while respecting the stringent Click criteria. In these reactions, highly stable pre-formed
complexes bearing diimine ligands were used.
Keywords: ligand; diimine; copper(I); Click; dipolar cycloaddition; azide
1. Introduction
The introduction of copper(I) catalysts in the cycloaddition of azides and terminal alkynes
represents one of the latest success stories of organometallic catalysis [1–4]. Not only is this
transformation high yielding and completely regioselective, but also it exemplifies the utility and
importance of Click chemistry [5]. Whereas this cycloaddition reaction has been applied in a plethora
of fields, the efforts to develop efficient catalytic systems, respectful of the Click criteria, have been
significantly fewer. Nevertheless, the use of ligands in the cycloaddition of alkynes and azides has
been shown to stabilize the copper(I) centre, increase the catalytic activity, and even modulate it [6].
Among the different families of ligands applied in this reaction, nitrogen-based ones are arguably the
most widely used. Whereas Meldal et al. used diisopropylethylamine in their groundbreaking report [1],
N,N',N''-pentametyletylentriamine (PMDETA) and tris-triazoles are also very popular choices [6].
However, examples of well-defined catalysts containing nitrogen based remain scarce [7–11]. Most

Molecules 2013, 18
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reported examples employ polydentate ligands such as polytriazoles or tren ligands (Figure 1). Particularly
relevant to this work are complexes bearing bis(aryl)acenaphthenenquinonediimine (Ar-BIAN) ligands C.
These have been shown to lead to the formation of triazoles in conversion ranging from modest to
good in THF at 50 °C [11].
Figure 1. Reported preformed copper(I) catalysts with N-ligands.
OH
Bn
N
Bn
N
N
N
N
N
Cu
N
Cl
N
N
N
N
PPh3
PPh3
Bn
A
Cu
BF4
N
N
N
C18H37
C18H37
Cu
Br
C18H37
C18H37
C18H37
N
C18H37
B
C
Herein, we report the catalytic activity of pre-formed copper(I) complexes bearing one or two
α-diimine ligands in the preparation of 1,2,3-triazoles from azides and terminal alkynes. The structures
of the screened complexes are shown in Figure 2. These complexes are all highly stable and easy to
prepare from simple diazabutadiene compounds [12].
Figure 2. Copper(I) catalysts used in this study.
OMe
OMe
OMe
N
N
N
N
N
N
N
N
N
N
N
N
NCMe
Cu
Cu
Cu Cl
Cu
BF4
NCMe BF4
BF4
OMe
OMe
OMe
2
1
3
4
N
N
N
N
N
N
N
N
N
N
N
Cu
Cu Cl
Cu
Cu Cl
N
BF4
BF4
5
7
6
8

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2. Results and Discussion
We started our optimization studies with the screening of different solvents. We chose cationic
complex 1 and benzyl azide (9a) and phenylacetylene as the model reaction. Using 5 mol% of the
copper catalyst, virtually no conversion of the starting materials was observed with MeCN,
cyclohexane, or ethyl acetate, whereas poor results were obtained in MeOH or under neat conditions
(Table 1). Satisfyingly, complete conversions into triazole 10a were obtained on water and in acetone
(Table 1, entries 8 and 9). Similar results were observed in THF or in a mixture water/t-BuOH,
however, reactions in these solvents were not always reproducible and they were not studied further
(Table 1, entries 6 and 7).
In order to determine the best reaction medium for this reaction, the copper loading was next
reduced to 2 mol% with acetone and water (Table 1, entries 10 and 11). A higher conversion of 86%
was observed in acetone and hence it was kept as solvent for the rest of the study. It is important to
note that all tested solvents were technical grade, and in particular, the acetone employed here was the
one normally used for cleaning the glassware in the laboratory.
Table 1. Solvent screening.
N
1
N
N
NCMe
+
N
N
Ph
Ph
N3
Ph
Cu
RT, 20 h, air
NCMe BF4
9a
10a
Ph
1
Entry
Solvent
MeCN
[Cu] (mol%)
Conv. (%) a
1
2
5
5
5
5
5
5
5
5
5
2
2
<5
<5
Cyclohexane
Ethyl Acetate
MeOH
3
<5
4
52
5
Neat
13
6
THF
84 to <5
>95 to 9
>95
>95
52
7
Water/t-BuOH
Water
8
9
Acetone
Water
10
11
Acetone
86
a 1H-NMR conversions are the average of at least two independent reactions.
We next performed a catalyst screening in acetone at room temperature using 2 mol% of different
diimine copper complexes (Scheme 1). All the tested complexes performed well in the model reactions
with conversion ranging from 42% to complete. For complexes bearing aromatic groups on the
ligands, steric hindrance proved to be more beneficial to the reaction outcome than the presence of
electron donating groups. In general, cationic complexes performed better than their neutral analogues,
except for complexes bearing adamantyl imine ligands 5 and 6. Additionally, the best performing

Molecules 2013, 18
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complexes had aliphatic substituents on the diimine ligand(s). Hence, complexes 5, 7 and 8 led to total
conversions and further experiments were run with these in order to determine the best performing one.
Scheme 1. Catalyst screening a.
[Cu] (2 mol %)
RT, 20 h, air
N
+
N
N
Ph
Ph
N3
Ph
9a
10a
Ph
OMe
OMe
N
OMe
N
N
N
N
N
N
N
N
NCMe
Cu
Cu
Cu Cl
Cu
BF4
N
NCMe BF4
BF4
N
N
OMe
OMe
3, 42%
OMe
2, 82%
1, 86%
4, 68%
N
N
N
N
N
N
N
N
N
N
Cu
Cu Cl
Cu
Cu Cl
N
BF4
BF4
N
5, <95%
6, 57%
7, <95%
8, <95%
a 1H-NMR conversions are the average of at least two independent reactions.
First, the metal loading was further reduced (Table 2). Similar results were obtained with 1 mol%
[Cu], but at 0.5 mol% [Cu] it became apparent that complexes bearing either one or two cyclohexyl
diimine ligands 7 and 8 displayed a better activity than complex 5, with adamantyl substituents.
Gratifyingly, complex 8 could still achieve total conversion in a more concentrated reaction (1 M
rather than 0.5 M), and it was chosen as the optimal catalyst within the tested series.
With an optimized catalytic system in hand, the scope of the reaction was then explored. All
reactions were carried out in technical grade acetone, in air and in no cases oxidation to copper(II) or
disproportionation to copper(0) and copper(II) were observed. Also, no other by-products were formed
and the prepared triazoles could be easily isolated as pure products in high yields after a simple
extraction (Scheme 2).
A number of functional groups were well tolerated, such as alcohols, amines, alkenes and nitriles.
Benzyl, alkyl and aryl azides well suitable cycloaddition partners, as well as electron rich or electron
poor alkynes. In some cases, total conversions were not reached under the optimized conditions.
However, a slight increase in the reaction temperature (from RT to 40 °C) or the metal loading was
enough to ensure a high isolated yield.

Molecules 2013, 18
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Table 2. Final optimization reactions.
[Cu]
N
+
N
N
Ph
Ph
N3
Ph
RT, 20 h, air
9a
10a
Ph
Entry
[Cu]
Concentration (M)
Conv. (%) a
1
2
3
4
5
6
7
8
5, 1 mol%
7, 1 mol%
8, 1 mol%
0.5
0.5
0.5
0.5
0.5
0.5
1.0
1.0
<95
<95
<95
63
5, 0.5 mol%
7, 0.5 mol%
8, 0.5 mol%
7, 0.5 mol%
8, 0.5 mol%
92
<95
93
<95
a 1H-NMR conversions are the average of at least two independent reactions.
Scheme 2. Preparation of 1,2,3-triazoles catalyzed by complex 8 a.
N
N
N
R1
N
8 (0.5 mol %)
BF4
R1 N3
R2
+
N
N
Cu
RT, 20 h, air
10
9
N
R2
8
N
N
N
N
N
N
N
N
N
N
N
N
N
Ph
Ph
Ph
Ph
Bu
Ph
10b, 92%b,c
10c, 84%c,d
OH
10a, 95%
10d, 85%
O
O
N
N
N
N
Ph
N
N
O
N
N
N
Ph
OEt
NMe2
Ph
10e, 84%d
10f, 88%d
10g, 96%
N
N
N
Ph
N
N
N
N
N
N
5
NC
Ph
NMe2
Ph
10h, 97%
10i, 94%
10j, 85%c,d
a Isolated yields are the average of at least two independent reactions; b 2 mol% 8; c 40 °C; d 1 mol% 8.
3. Experimental Section
3.1. General
All reagents were commercially available and used as received. 1H-NMR (400 MHz) and 13C-NMR
(100 MHz) spectra were recorded in CDCl3 on a Bruker AVANCE400 spectrometer at room

Molecules 2013, 18
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temperature. Chemical shifts (δ) are reported in ppm and referenced to tetramethylsilane (1H) and
deuterated chloroform (13C), respectively. All reactions were carried out in air and using technical
solvents with no particular precautions to exclude oxygen or moisture. All reported yields are isolated
yields and are the average of at least two independent reactions. Benzyl azide (9a) [13] 2-azidoethyl-
diisopropylamine (9b) [14], 2-(2-azidoethyl)-1,3-dioxolane (9c) [15], (2-azidoethyl)benzene (9d) [13],
3-(azidoprop-1-en-yl)benzene (9e) [16], phenyl azide (9f) [17], 6-azidohexanenitrile (9g) [18] and
(1-azidoethy)benzene (9h) [13] are known in the literature and the corresponding spectroscopic data
for all these compounds were in good agreement with the reported data.
3.2. Catalytic Results
General Procedure for the [3+2] Cycloaddition of Azides and Terminal Alkynes
In a vial fitted with a screw cap, azide 9 (1 mmol), alkyne (1 mmol), acetone (1 mL) and 8 (3 mg,
0.5 mol%) were loaded. The reaction was allowed to proceed at room temperature overnight (20 h).
The reaction mixture was then hydrolyzed with a saturated aqueous solution of NH4Cl (1 h) and
extracted with EtOAc. In all examples, the crude products were estimated to be greater than 95% pure
by 1H-NMRs.
1-Benzyl-4-phenyl-1H-1,2,3-triazole (10a). Using the general procedure 223 mg (95%) of the title
compound were prepared from benzyl azide (9a, 125 μL) and phenylacetylene (112 μL). Spectroscopic
1
data for 10a were consistent with previously reported data for this compound [19]. H-NMR
(CDCl3): δ 7.80 (d, J = 7.0 Hz, 2H, HAr), 7.66 (s, 1H, NCH = C), 7.42–7.37 (m, 5H, HAr), 7.34–7.31
13
(m, 3H, HAr), 5.59 (s, 2H, PhCH2). C-NMR (CDCl3): δ 148.2 (C, =C–Ph), 134.7 (C, CAr), 130.5 (C,
CAr), 129.1 (CH, CHAr), 128.8 (CH, CHAr), 128.8 (CH, CHAr), 128.1 (CH, CHAr), 128.0 (CH, CHAr),
125.7 (CH, CHAr), 119.5 (CH, NCH=), 54.2 (CH2).
1-Benzyl-4-butyl-1H-1,2,3-triazole (10b). Using the general procedure 199 mg (92%) of the title
compound were prepared from benzyl azide (9a, 125 μL), 1-hexyne (115 μL), and 8 (12 mg, 2 mol%)
at 40 °C, Spectroscopic data for 10b were consistent with previously reported data for this compound [10].
1H-NMR (CDCl3): δ 7.40–7.34 (m, 3H, HAr), 7.26–7.24 (m, 2H, HAr), 7.18 (s, 1H, NCH=C), 5.50 (s,
2H, PhCH2N), 2.69 (t, J = 7.5 Hz, 2H, C=CNCH2), 1.62 (quintet, J = 7.5 Hz, 2H, CH2CH2CH2), 1.37
(sextet, J = 7.3 Hz, 2H, CH2CH3), 0.91 (t, J = 7.3 Hz, 3H, CH3). 13C-NMR (CDCl3): δ 149.8 (C,
NC=C-butyl), 135.0 (C, CAr), 129.0 (CH, CHAr), 128.6 (CH, CHAr), 127.9 (CH, CHAr), 120.9 (CH,
NCH=), 54.0 (CH2, PhCH2), 31.4 (CH2), 25.4 (CH2), 22.3 (CH2), 13.8 (CH3).
1-Benzyl-4-(2-hydroxypropan-2-yl)-1H-1,2,3-triazole (10c). Using the general procedure 183 mg
(84%) of the title compound were prepared from benzyl azide (9a, 125 μL), 2-methylbut-3-yn-2-ol
(100 μL), and 8 (6 mg, 1 mol%) at 40 °C. Spectroscopic data for 10c were consistent with previously
1
reported data for this compound [19]. H-NMR (CDCl3): 7.39–7.35 (m, 3H, HAr), 7.34 (s, 1H,
NCH=C), 7.31–7.27 (m, 2H, HAr), 5.51 (s, 2H, CH2), 2.34 (br s, 1H, OH), 1.61 (s, 6H, CH3). 13C-NMR
(CDCl3): δ 156.0 (C, NC=C–), 134.6 (C, CAr), 129.2 (CH, CHAr), 128.6, (CH, CHAr), 128.2 (CH,
CHAr), 119.1 (CH, NCH=), 68.3 (C, C(OH)Me2), 54.2 (CH2, PhCH2), 30.5 (CH3).

Molecules 2013, 18
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1-(2-Diisopropylaminoethyl)-4-phenyl-1H-1,2,3-triazole (10d). Using the general procedure 232 mg
(85%) of the title compound were prepared from azide 9b (170 mg) and phenylacetylene (112 μL).
1H-NMR (CDCl3): δ 7.84–7.81 (m, 3H, HAr), 7.45 (t, J = 6.4 Hz, 2H, HAr), 7.35 (t, J = 6.4 Hz, 1H, HAr),
4.38 (t, J = 6.5 Hz, 2H, CH2), 3.04 (septet, J = 6.5 Hz, 2H, CH(CH3)2), 2.95 (t, J = 6.5 Hz, 2H, CH2),
13
0.99 (d, J = 6.5 Hz, 12H, CH3); C-NMR (CDCl3): δ 147.1 (NCH=C), 130.9 (C, CAr), 128.8 (CH,
CHAr), 127.9 (CH, CHAr), 125.7 (CH, CHAr), 120.8 (CH, NCH=), 51.2 (CH2, CH2N), 48.7 (CH, CHN),
45.7 (CH2, CH2N), 20.8 (CH3). HRMS calculated for C16H25N4: 273.2079; found 273.2086 [(M+H)+].
Ethyl 1-(2-(1,3-dioxolan-2-yl)ethyl)-1H-1,2,3-triazole-4-carboxylate (10e). Using the general
procedure 203 mg (84%) of the title compound were prepared from azide 9c (143 mg), ethyl propiolate
(102 μL), and 8 (6 mg, 1 mol%). Spectroscopic data for 10e were consistent with previously reported
1
data for this compound [20]. H-NMR (CDCl3): δ 8.12 (s, 1H, NCH=C), 4.93 (t, J = 4.0 Hz, 1H,
OCHO), 4.58 (t, J = 7.0 Hz, 2H, CH2CH2N), 4.43 (q, J = 7.0 Hz, OCH2CH3), 4.03–3.93 (m, 2H,
OCH2CH2O), 3.93–3.83 (m, 2H, OCH2CH2O), 2.33 (dt, J = 4.0; 7.0 Hz, CHCH2CH2), 1.41 (t,
J = 7.0 Hz, 3H, OCH2CH3). 13C-NMR (CDCl3): δ 160.2 (C, C=O), 139.3 (C, =C–CO2Et), 127.5 (CH,
CH=C), 127.5 (CH, O–CH–O), 64.55 (CH2, O–CH2–CH2–O), 64.48 (CH2, O–CH2–CH2–O), 60.6
(CH2, OCH2–CH3), 45.0 (CH2, CH2–CH2–N), 33.2 (CH2, CH2–CH2–N), 13.7 (CH3).
N,N-Dimethyl-1-(1-phenethyl-1H-1,2,3-triazol-4-yl)methanamine (10f). Using the general procedure
202 mg (88%) of the title compound were prepared from (2-azidoethyl)benzene (9d, 147 mg),
dimethylprop-2-ynylamine (111 μL) and 8 (6 mg, 1 mol%). Spectroscopic data for 10f were consistent
1
with previously reported data for this compound [20]. H-NMR (CDCl3): δ 7.31–7.21 (m, 4H,
HAr + NCH=C), 7.09 (d, J = 7.0 Hz, 2H, HAr), 4.58 (t, J = 7.0 Hz, 2H, PhCH2CH2), 3.57 (s, 2H,
13
CH2NMe2), 3.21 (t, J = 7.0 Hz, 2H, PhCH2CH2), 2.23 (s, 6H, NMe2). C-NMR (CDCl3): δ 144.7 (C,
NCH=C), 137.0 (C, CAr), 128.7 (CH, CHAr), 128.6 (CH, CHAr), 126.9 (CH, CHAr), 122.6 (CH, NCH=),
54.2 (CH2, PhCH2CH2N), 51.4 (CH2, CH2NMe2), 44.9 (CH2, PhCH2), 36.6 (CH3).
4-Phenyl-1-(3-phenyl-2-propenyl)-1H-1,2,3-triazole (10g). Using the general procedure 250 mg (96%)
of the title compound were prepared from azide 9e (159 mg) and phenylacetylene (112 μL).
Spectroscopic data for 10g were consistent with previously reported data for this compound [21].
1H-NMR (CDCl3): δ 7.84–7.82 (m, 3H, HAr + NCH=C), 7.43–7.39 (m, 4H, HAr), 7.36–7.32 (m, 4H,
HAr), 6.72 (d, J = 16.0 Hz, 1H, PhCH=CH), 6.40 (dt, J = 16.0, 6.5 Hz, 1H, PhCH=CH), 5.20 (d, J = 6.5 Hz,
13
2H, CH2N). C-NMR (CDCl3): δ 148.0 (C, NCH=C), 135.4 (C, CAr), 135.2 (CH, CHAr), 130.5 (C,
CAr), 128.7 (CH, CHAr), 128.6 (CH, CHAr), 128.4 (CH, CHAr), 128.0 (CH, CHAr), 126.6 (CH, PhCH=),
125.6 (CH, PhCH=CH), 121.8 (CH, CHAr), 119.3 (CH, NCH=), 52.3 (CH2, CH2N).
Dimethyl(1-phenyl-1H-1,2,3-triazol-4-ylmethyl)amine (10h). Using the general procedure 196 mg
(97%) of the title compound were prepared from phenyl azide (9f, 107 μL) and dimethylprop-2-
ynylamine (111 μL). Spectroscopic data for 10h were consistent with previously reported data for this
1
compound [22]. H-NMR (CDCl3): δ 7.95 (s, 1H, NCH=C), 7.74 (d, J = 8.0 Hz, 2H, HAr), 7.53 (t,
J = 8.0, 2H, HAr), 7.43 (t, J = 8.0 Hz, 1H, HAr), 3.71 (s, 2H, CH2NMe2), 2.34 (s, 6H, NMe2). 13C-NMR
(CDCl3): δ 146.0 (C, NCH=C), 137.0 (C, CAr), 129.6 (CH, CHAr), 128.5 (CH, CHAr), 120.4 (CH,
NCH=), 120.3 (CH, CHAr), 54.3 (CH2, CH2N), 45.2 (CH3).

Molecules 2013, 18
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6-(4-Phenyl-1,2,3-triazol-1-yl)hexanenitrile (10i). Using the general procedure 227 mg (94%) of the title
compound were prepared from 6-azidohexanenitrile (9g, 138 mg) and phenylacetylene (112 μL).
Spectroscopic data for 10i were consistent with previously reported data for this compound [23].
1H-NMR (CDCl3): δ 7.85–7.82 (m, 2H, HAr), 7.76 (s, 1H, NCH=), 7.45–7.42 (m, 2H, HAr), 7.36–7.31
(m, 1H, HAr), 4.44 (t, J = 7.0 Hz, 2H, CH2N), 2.36 (t, J = 7.0 Hz, 2H, CH2CN), 2.08–1.97 (m,
2H,CH2), 1.77–1.67 (m, 2H,CH2), 1.59–1.48 (m, 2H, CH2). 13C-NMR (CDCl
): δ 147.8 (C, C=C–Ph),
3
130.5 (C, CAr), 128.8 (CH, CAr), 128.1 (CH, CAr), 125.6 (CH, CAr), 119.5 (CH, CH=C–Ph), 119.3 (C,
CN), 49.8 (CH2, CH2–N), 29.5 (CH2), 25.5 (CH2), 24.7 (CH2), 17.0 (CH2).
4-Cyclopropyl-1-(1-phenylethyl)-1H-1,2,3-triazole (10j). Using the general procedure 183 mg (85%)
of the title compound were prepared from azide 9h (147 mg), ethynylcyclopropane (87 μL) and 8
(6 mg, 1 mol%) at 40 °C. Spectroscopic data for 10j were consistent with previously reported data for
this compound [23]. 1H-NMR (CDCl3): δ 7.40–7.28 (m, 3H, HAr), 7.27–7.24 (m, 2H, HAr), 7.11 (s, 1H,
NCH=C), 5.76 (q, 1H, J = 7.0 Hz, PhCH), 1.95 (d, 3H, J = 7.0 Hz, CH3), 1.93–1.87 (m, 1H,
CHcyclopropyl), 0.94–0.87 (m, 2H, CH2), 0.84–0.79 (m, 2H, CH2). 13C-NMR (CDCl3): δ 150.2
(C=Ccyclopropyl), 140.1 (C, CAr), 128.9 (CH, CHAr), 128.3 (CH, CHAr), 126.4 (CH, CHAr), 118.3 (CH,
N–CH=C), 58.9 (CH, PhCH), 21.2 (CH3), 7.6 (CH, CHcyclopropyl), 6.7 (CH2, CH2).
4. Conclusions
Diimine copper(I) complexes are highly efficient catalysts for the [3+2] cycloaddition of azides and
terminal alkynes. Low copper loadings were enough to ensure high isolated yields of 1,2,3-triazoles at
room temperature, in air and in technical grade acetone. Furthermore, purification by column
chromatography was not necessary, and a simple extraction was enough to isolate pure triazoles. The
reported catalysts are noticeably more active than related Ar-BIAN complexes. This might be
attributed to two factors: (1) the presence of alkyl groups on the diimine ligands; which in these series
systematically outperformed aryl diimines; or (2) the increased chemical stability of simple diimine
scaffolds, in particular towards oxidation and reduction reactions.
Acknowledgments
Imperial College London is acknowledged for financial support. J.M.B. thanks the Universidad de
Barcelona for an Erasmus Scholarship.
Conflict of Interest
The authors declare no conflict of interest.
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Sample Availability: Not available.
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