Quick and highly efficient copper-catalyzed cycloaddition of organic azides with terminal alkynes

Article abstract of DOI:10.1039/c1ob06190a

Good to excellent yields of 1,4-disubstituted 1,2,3-triazoles were obtained within 2-25 min when the Cu(i)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction was carried out under solvent-free conditions, with [Cu(phen)(PPh ₃)₂]NO

Full text of DOI:10.1039/c1ob06190a

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Quick and highly efficient copper-catalyzed cycloaddition of organic azides
with terminal alkynes†
Dong Wang,a,b Mingming Zhao,a,b Xiang Liu,a,b Yongxin Chen,a,b Na Lia,b and Baohua Chen*a,b
Received 18th July 2011, Accepted 23rd September 2011
DOI: 10.1039/c1ob06190a
Good to excellent yields of 1,4-disubstituted 1,2,3-tria-
zoles were obtained within 2–25 min when the Cu(I)-
catalyzed azide–alkyne cycloaddition (CuAAC) reaction
was carried out under solvent-free conditions, with
[Cu(phen)(PPh3)2]NO3 (1mol%) as the catalyst.
room temperature (25–28 ◦C) for 5 min. The results showed that
the [Cu(phen)(PPh3)2]NO3 complex provided the best result: the
cycloaddition reached completion within 5 min. The use of amines
as additives can promote the CuAAC reaction (entries 6–10), and
the effects of phen and TBTA were especially remarkable (entries
9 and 10).
The reaction time gradually decreased when the catalyst loading
or reaction temperature increased (entries 11 and 12). Replacing
[Cu(phen)(PPh3)2]NO3 complex by copper(I) salts (such as Cu2O,
CuCl, CuBr and CuI) almost completely shut down the catalysis,
confirming the role of [Cu(phen)(PPh3)2]NO3 complex as the
catalyst. The reaction proceeded perfectly in toluene or water
(entries 17 and 18), but the yields decreased seriously when the
reaction was carried out in DMSO or THF (entries 19 and 20).
In addition, triazole 3a was isolated in excellent yields and high
purity after simple filtration or evaporation. According to the
“click laws”, no precautions to exclude oxygen or moisture were
taken in any of these reactions.
Encouraged by the efficiency of the reaction protocol described
above, the scope of the reaction was examined. Firstly, the
optimized conditions were applied to the cycloaddition of other
terminal alkynes with benzyl azide. As shown in Table 2, for liquid
aromatic terminal alkynes (including electron-rich, electron-poor
and heteroatom-containing aromatic alkynes), experiments were
carried out smoothly to completion in short reaction times (3–
5 min) at room temperature, and the corresponding triazoles were
obtained in excellent yields (entries 2, 3, 4, 6 and 7). When the solid
alkyne 1e was used, the yield and reaction rate were somewhat
lower, and increasing the reaction temperature can improve
the yield (entry 5). We successfully extended the procedure to
ferrocenyl acetylene, with the yield of the obtained product being
89% (entry 8). Besides aromatic terminal acetylenes, the reactivity
of aliphatic compounds toward azides was also tested. Although,
compared to the aromatic acetylenes, the aliphatic acetylenes
required much more time (12–25 min); the click products were
obtained in good to excellent yields at 40 ◦C (entries 9–12). It
was shown that the quick solvent-free [Cu(phen)(PPh3)2]NO3-
catalyzed Huisgen cycloaddition reaction tolerates a variety of
terminal alkynes.
In 2001, Sharpless and co-workers defined the concept of “click
chemistry” and the criteria for a transformation to be consid-
ered as a “click” reaction.1 The copper-catalyzed 1,3-dipolar
cycloaddition of alkynes and azides yielding 1,2,3-triazoles is
undoubtedly the premier example of a “click” reaction to date. A
number of CuAAC procedures have been developed2 since it was
discovered by the groups of Sharpless3 and Meldal4 in 2002, and
the reaction mechanism is getting mature.3a,5 Due to its exclusive
regioselectivity, 100% atom economy, wide substrate scope, mild
conditions and high yields, CuAAC has found a myriad of
applications in chemical synthesis, biology and material science.6,1b
Less attention has been focused on decreasing the amount of
copper used,7 the development of “green” catalytic systems5a,8
and reducing reaction time.5a,8b,8c,9 These points are extremely
important for future industrial applications. We recently reported
that a low amount of Cu(PPh3)2NO3 complex can efficiently
promote the CuAAC reaction under solvent-free conditions.8a
But the Cu(PPh3)2NO3-catalyzed reaction proceeded relatively
slowly, as did most of the CuAAC catalytic systems. Substantially
increasing the reaction temperature10 and using a microwave-
assisted method11 could reduce this time, but these processes are
not favored for molecules containing polyfunctional groups. In
this paper, we report a quick, environmentally friendly, efficient
solvent-free system for the 1,3-dipolar Huisgen cycloaddition
reaction of terminal alkynes with organic azides based on low
catalyst loadings of [Cu(phen)(PPh3)2]NO3 complex.12
We used benzyl azide and phenylacetylene as the model sub-
strates to initialize the copper-catalyzed optimum cycloaddition
condition, as shown in Table 1. In this preliminary experiment, the
Huisgen cycloaddition reaction was carried out without a solvent,
catalyzed by PPh3-containing copper(I) complexes (1 mol%), at
aState Key Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou, 730000, P.R. of China. E-mail: chbh@lzu.edu.cn
The substrate scope of organic azides was further investigated
(Table 3). The results indicated that benzyl, alkyl, and aryl
azides reacted quickly with phenylacetylene and the corresponding
triazoles were obtained in high yields at room temperature or
40 ◦C within 2–25 min. The steric hindrance is a principal factor
bKey Laboratory of Nonferrous Metal Chemistry and Resources Utilization
of Gansu Province, Lanzhou, 730000, P. R. of China
† Electronic supplementary information (ESI) available: Experimental and
spectral data. See DOI: 10.1039/c1ob06190a
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Table 1 Screening of catalysts for Huisgen [3+2] cycloaddition reactiona
Entry
Catalyst
Solvent
Additive (1 mol%)
Time (min)
Yield (%)b
1
2
3
4
5
6
7
8
Cu(PPh3)2NO3
Cu(PPh3)3Br
Cu(PPh3)3Cl
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Toluene
H2O
None
None
None
None
5
5
5
5
5
5
5
5
5
5
2
3
5
5
5
5
5
5
5
5
53
45
50
97
93
89
62
65
71
[Cu(phen)(PPh3)2]NO3
Cu(PPh3)2NO3
Cu(PPh3)2NO3
Cu(PPh3)2NO3
Cu(PPh3)2NO3
Cu(PPh3)2NO3
Cu(PPh3)2NO3
[Cu(phen)(PPh3)2]NO3
[Cu(phen)(PPh3)2]NO3
Cu2O
phen
TBTAc
i-Pr2EtN
Et3N
9
2,6-Lutidine
2,2¢-Bipyridine
None
None
None
None
None
None
None
10
11
12
13
14
15
16
17
18
19
20
79
96d
97e
Trace
Trace
Trace
Trace
89
83
7
Trace
CuCl
CuBr
CuI
[Cu(phen)(PPh3)2]NO3
[Cu(phen)(PPh3)2]NO3
[Cu(phen)(PPh3)2]NO3
[Cu(phen)(PPh3)2]NO3
None
None
None
DMSO
THF
a The reaction was carried out using 1a (0.5 mmol) and 2a (0.5 mmol) in the presence of a catalyst (0.005 mmol) in air. b Isolated yields after column
chromatography or reduced pressure distillation. c TBTA = tris-(benzyltriazolylmethyl)amine. d The reaction temperature is 40 ◦C. e [Cu(phen)(PPh3)2]NO3
complex (2 mol%).
Table 2 Substrate scope of terminal alkynesa
Table 3 Substrate scope of organic azidesa
T (◦C)
Time (min)
Yield (%)b
Entry
R2
T (◦C)
Time (min)
Yield (%)b
Entry
R1
1
2
Phenyl (2a)
RT
RT
40
RT
40
RT
RT
40
3
6
2
25
15
5
96 (4a)
97 (4b)
97 (4b)
80 (4c)
81 (4c)
97 (4d)
98 (4e)
96 (4f)
76 (4g)
91 (4h)
97 (4i)
93 (4i)
94 (4j)
93 (4j)
89 (4k)
95 (4k)
1
2
3
4
5
Phenyl (1a)
RT
RT
RT
RT
RT
40
RT
RT
40
RT
40
40
40
5
3
3
97 (3a)
93 (3b)
97 (3c)
98 (3d)
70 (3e)
82 (3e)
95 (3f)
93 (3g)
89 (3h)
45 (3i)
81 (3i)
80 (3j)
95 (3k)
90 (3l)
4-CH3OC6H4 (2b)
4-CH3OC6H4 (1b)
4-n-C5H11OC6H4(1c)
4-FC6H4 (1d)
3
2-CH3OC6H4 (2c)
4
4-NO2C6H4 (1e)
20
20
3
4
5
6
7
8
9
3,4-DiCH3C6H3 (2d)
3-ClC6H4 (2e)
2-ClC6H4 (2f)
2-IC6H4 (2g)
4-NO2C6H4CH2 (2h)
n-C5H11 (2i)
5
6
7
8
9
Pyridine-2-yl (1f)
Thiophen-3-yl (1g)
Ferrocenyl (1h)
n-C4H9 (1i)
25
25
3
25
12
8
4
16
5
3
40
25
25
25
25
20
12
RT
RT
40
RT
40
RT
40
10
11
12
t-C4H9 (1j)
n-C8H17 (1k)
HOC(CH3)2 (1l)
10
11
n-C8H17 (2j)
40
n-C12H25 (2k)
a The reaction was carried out using 1 (0.5 mmol) and 2a (0.5 mmol) in the
presence of [Cu(phen)(PPh3)2]NO3 (0.005 mmol) in air. b Isolated yields
after column chromatography or reduced pressure distillation.
a The reaction was carried out using 1a (0.5 mmol) and 2 (0.5 mmol) in the
presence of [Cu(phen)(PPh3)2]NO3 (0.005 mmol) in air. b Isolated yields
after column chromatography or reduced pressure distillation.
influencing the reaction rate. Longer reaction times were required
for organic azides containing substituents at the 2-position (entries
3, 6 and 7).
By decreasing the amount of catalyst, we were able to achieve
the click reaction with 100–250 ppm [Cu(phen)(PPh3)2]NO3, but
a significant drop in the yield and reaction rate were detected
on lowering the catalyst content (Table 4). In the presence of 100
ppm [Cu(phen)(PPh3)2]NO3, the click reaction of benzyl azide and
phenylacetylene gives yields of 65% in 14 h at room temperature. At
40 ◦C the reaction takes place faster, and we obtained the triazole
product with 85% yield after 14 h. A variety of functional groups
were suitable substrates for the low catalyst loading condition, and
the corresponding triazoles were synthesized with 52–85% yields.
In conclusion, we have developed a quick, environmentally
friendly and economical catalytic system, [Cu(phen)(PPh3)2]NO3
complex without solvent, for the [3+2] cycloaddition of azides
230 | Org. Biomol. Chem., 2012, 10, 229–231
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Table 4 [Cu(phen)(PPh3)2]NO3-catalyzed synthesis of triazoles at low
the Project of National Science Foundation of P. R. China (No.
J0730425).
catalyst loadingsa
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NO3 (ppm)
Entry Product
1
Time (h) Yield (%)b
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and alkynes under click conditions. A series of 1,4-disubstituted-
1,2,3-(NH)-triazoles were prepared readily in good to excellent
yields within 2–25 min. This system is broad in scope and highly
efficient even at very low catalyst loadings (down to 100 ppm). Low
catalyst loading, short reaction time and solvent-free conditions
make [Cu(phen)(PPh3)2]NO3 an outstanding catalyst for CuAAC.
Thus, the procedure reported in this work obeys the principles of
click chemistry and green chemistry.
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Acknowledgements
We are grateful to the project sponsored by the Scientific Research
Foundation for the State Education Ministry (No. 107108) and
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The Royal Society of Chemistry 2012
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