Solvent-free synthesis of 1,4-disubstituted 1,2,3-triazoles using a low amount of Cu(PPh3)2NO3 complex

Article abstract of DOI:10.1039/c0gc00381f

We have developed an environmentally friendly and highly efficient method for copper-catalyzed cycloaddition of organic azides and terminal alkynes under solvent-free conditions. The protocol uses the cheap and easy-to-prepare Cu(PPh₃)₂

Full text of DOI:10.1039/c0gc00381f

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/greenchem | Green Chemistry
Solvent-free synthesis of 1,4-disubstituted 1,2,3-triazoles using a low
amount of Cu(PPh3)2NO3 complex†
Dong Wang,a,b Na Li,a,b Mingming Zhao,a,b Weilin Shi,a,b Chaowei Maa,b and Baohua Chen*a,b
Received 1st August 2010, Accepted 24th September 2010
DOI: 10.1039/c0gc00381f
We have developed an environmentally friendly and highly
efficient method for copper-catalyzed cycloaddition of or-
ganic azides and terminal alkynes under solvent-free con-
ditions. The protocol uses the cheap and easy-to-prepare
Cu(PPh3)2NO3 complex as the catalyst.
and other additives were also required and substrate scope was
limited. In this paper, we report an environmentally friendly,
efficient solvent-free system that allows the 1,3-dipolar Huisgen
cycloaddition reaction of terminal alkynes with organic azides
based on low catalyst loadings of Cu(PPh3)2NO3 complex16 at
room temperature.
Introduction
Results and discussion
1,2,3-Triazoles are basically five-membered nitrogen hetero-
cyclic compounds. They have tremendous applications in var-
ious research fields, including biological science,1 synthetic or-
ganic chemistry,2 medicinal chemistry3 and material chemistry.4
Numerous synthetic methods for the preparation of 1,2,3-
triazole derivatives have been developed. Among them, Cu(I)-
catalyzed azide-alkyne cycloaddition (CuAAC) reaction is the
most efficient way to assemble the 1,2,3-triazole ring because
of its 100% atom economy, exclusive regioselectivity, wide
substrate scope and mild reaction conditions. CuAAC was
discovered by the groups of Sharpless5 and Meldal6 in 2002.
Until now, a number of CuAAC procedures have been developed
including the use of (1) Cu(II) salts/reductants,5 (2) Cu(I) salts
directly,6 (3) Cu(II) salts,7 (4) Cu(I) complexes,8 (5) copper-
containing nanoparticles9 and (6) oxidation of copper metal
turning to give Cu(I) species.10 These CuAAC procedures are
efficient methods for the synthesis of 1,4-disubstituted 1,2,3-
triazoles, and the reaction mechanism is getting mature.5,8a,10,11
However, their corresponding catalytic systems have some
drawbacks. They required reductants, a significant amount of
expensive and difficult-to-prepare catalyst and organic solvent
(such as methanol, acetone, toluene, dioxane, tert-butyl alcohol,
dichloromethane and mixed solvents). Perica`s et al. described
such reaction in the presence of tris(triazolyl)methanol-CuCl
complexes.12 This system has been shown to be broad in
scope and highly efficient under mild conditions, but the
catalyst was not easy-to-prepare. Lipshutz et al. reported the
efficient Cu/C-promoted click chemistry between organic azides
and terminal alkynes,13 but solvents are required. Recently,
the groups of Kiser14 and Fokin15 developed the transition-
metal-free methods for promoting the Huisgen cycloaddition
reaction. The transition-metal-free systems are efficient and
economic, but they also present some imperfections. Solvents
We initialized the copper-catalyzed optimum cycloaddition
conditions using benzyl azide with phenylacetylene as the
model substrates, as shown in Table 1. In this preliminary
experiment, the Huisgen cycloaddition reaction was carried out
in various solvents, with Cu(PPh3)2NO3 complex (0.5 mol%)
as a catalyst, in air at room temperature for 40 min. The
reaction proceeded perfectly in toluene or water (Table 1, entries
1 and 2), but the yields decreased when the reaction was
carried out in other solvents (Table 1, entries 3–7). It was very
surprising that the reaction proceeded in excellent yields (96%)
under solvent-free conditions (Table 1, entry 8). Considering
Table 1 Screening of solvents and catalysts for Huisgen [3+2] cycload-
dition reactiona
Entry
Catalyst
Solvent
Time/min
Yield (%)b
1
2
3
4
5
6
7
8
Cu(PPh3)2NO3
Cu(PPh3)2NO3
Cu(PPh3)2NO3
Cu(PPh3)2NO3
Cu(PPh3)2NO3
Cu(PPh3)2NO3
Cu(PPh3)2NO3
Cu(PPh3)2NO3
Cu(PPh3)2NO3
Cu(PPh3)2NO3
Cu(PPh3)2NO3
CuI
CuBr
CuCl
Cu2O
Cu(PPh3)3Br
Cu(PPh3)3Cl
Toluene
H2O
DMSO
CH2Cl2
C2H5OH
CH3COCH3
THF
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
40
40
40
40
40
40
40
40
35
25
15
60
60
60
60
40
40
96
92
64
14
32
21
19
96
9
96c
97d
92e
Trace
61
42
30
90
91
10
11
12
13
14
15
16
17
aState Key Laboratory of Applied Organic Chemistry, Lanzhou
a The reaction was carried out using 1a (1 mmol) and 2a (1 mmol) in
the presence of catalyst (0.005 mmol) in the solvent (2 ml) at room
temperature in air. b Isolated yields after column chromatography or re-
duced pressure distillation. c Cu(PPh3)2NO3 (1 mol%). d Cu(PPh3)2NO3
(2.5 mol%). e The reaction temperature is 45 ◦C.
University, Lanzhou, 730000, P. R. of China. E-mail: chbh@lzu.edu.cn
bKey Laboratory of Nonferrous Metal Chemistry and Resources
Utilization of Gansu Province, Lanzhou, 730000, P. R. of China
† Electronic supplementary information (ESI) available: Additional
experimental information. See DOI: 10.1039/c0gc00381f
2120 | Green Chem., 2010, 12, 2120–2123
This journal is
The Royal Society of Chemistry 2010
©

View Article Online
Table 2 Substrate scope of terminal alkynesa
Table 3 Substrate scope of organic azidesa
Entry
R2
Time
Product
Yield (%)b
Entry
R1
Time
Product
Yield (%)b
1
2
3
4
5
6
7
8
4-NO2C6H4CH2 (2a)
n-C5H11 (2b)
2 h
3 h
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
98
94
99
90
98
98
98
57
45
81
97
81
99
99
85
98
1
2
3
4
5
6
7
8
Phenyl (1a)
40 min
5 h
10 h
15 h
4 h
40 min
10 h
20 h
15 h
1 h
3a
3b
3c
3d
3e
3f
3g
3h
3i
96
80
81
81
86
99
70
94
95
98
95
4-FC6H4 (1b)
n-C8H17 (2c)
40 min
3 h
20 min
16 h
30 min
4 h
24 h
5 h
5 h
24 h
24 h
2 h
24 h
1 h
4-NO2C6H4 (1c)
4-n-C5H11OC6H4 (1d)
Pyridine-2-yl (1e)
Thiophen-3-yl (1f)
Ferrocenyl (1g)
n-C4H9 (1h)
t-C 4H9 (1i)
n-C8H17 (1j)
HOC(CH2)2 (1k)
n-C12H25 (2d)
Phenyl (2e)
2-ClC6H4 (2f)
3-ClC6H4 (2g)
4-ClC6H4 (2h)
2-NO2C6H4 (2i)
3-NO2C6H4 (2j)
2-BrC6H4 (2k)
2-IC6H4 (2l)
2-CH3OC6H4 (2m)
4-CH3OC6H4 (2n)
2-CH3C6H4 (2o)
3,4-CH3C6H3 (2p)
9
9
10
11
10
11
12
13
14
15
16
3j
3k
7 h
a The reaction was carried out using 1 (1 mmol) and 2a (1 mmol) in
the presence of Cu(PPh3)2NO3 (0.005 mmol) at room temperature in
air. b Isolated yields after column chromatography or reduced pressure
distillation.
a The reaction was carried out using 1a (1 mmol) and 2 (1 mmol) in
the presence of Cu(PPh3)2NO3 (0.005 mmol) at room temperature in
air. b Isolated yields after column chromatography or reduced pressure
distillation.
to develop an economic and environmentally friendly reaction,
these solvent-free conditions are clearly the most favorable.
We then investigated the activity of copper catalysts (including
Cu(I) salts and Cu(I) complexes) in the Huisgen cycloaddition.
The results show that Cu(I) salts displayed poor activity under
these conditions (entries 12–15), in contrast to those with Cu(I)
complexes. Cu(PPh3)2NO3 complex provided the best result
among Cu(I) complexes: the cycloaddition reached completion
within 40 min (entry 8). Reaction time decreased gradually with
increasing the catalyst loadings or reaction temperature (entries
9–11).
Encouraged by the efficiency of the reaction protocol de-
scribed above, the scope of the reaction was examined with
Cu(PPh3)2NO3 (0.5 mol%) under solvent-free conditions at
room temperature. Firstly, various terminal alkynes were in-
vestigated to be reacted with benzyl azide. As shown in Table 2,
electron-rich and electron-poor alkynes were suitable cycload-
dition partners (entries 2–4). The reaction of the heteroatom-
containing alkynes 1e, 1f also proceeded efficiently (entries 5,
6). Several aliphatic alkynes were suitable substrates to produce
1,4-disubstituted 1,2,3-triazoles in excellent yields (94–98%), as
shown in entries 8–11. When ferrocenylacetylene was used, the
yield was somewhat lower (entry 7). In addition, the crude
products of 1,4-disubstituted 1,2,3-triazoles could be purified by
reduced pressure distillation (except 3c and 3g). Reduced pres-
sure distillation is simpler and more environmentally friendly
than column chromatography. It was shown that the solvent-
free Cu(PPh3)2NO3-catalyzed Huisgen cycloaddition reaction
tolerates a variety of terminal alkynes. Notably, no direct
correlation could be drawn between the electronic nature of the
terminal alkynes and the outcome of the reaction. The longer
chain aliphatic terminal alkynes can accelerate the process.
The substrate scope of organic azides was further investigated
(Table 3). The results indicated that benzyl, alkyl, and aryl azides
were successfully employed. The electronic properties of organic
azides did not affect the yields. The steric hindrance and physical
state of organic azides are critical. Longer reaction times were
required for organic azides containing substituents at the 2-
position (entries 6, 9, 11, 12, 13, 15), and solid organic azides
gave poorer results because they easily precipitated from alkyne
(entries 8, 9, 10).
Encouraged by the high activity of this catalytic system,
we further examined the possibility of decreasing the amount
of metal used in this transformation (Table 4). Several 1,4-
disubstituted 1,2,3-triazoles were synthesized at low catalyst
loadings at reasonable reaction times. A variety of functional
groups were suitable substrates for the conditions. The synthesis
of 3a showed the best results (entry 1): When the loading of
catalyst was reduced to 50 ppm, 3a was obtained in 81% yield at
the reaction time of 24 h.
Taking into account the interest of avoiding storage and
manipulation of organic azides, a one-pot process was explored
through the reactions of alkyne, sodium azide and bromides
(Table 5). When the bromides with benzyl were used, this
tandem process performed nicely without other additive in
water for 14 h at room temperature. Unfortunately, due to the
inability of phenyl bromide to undergo SN2 reactions, only
trace product was obtained when the bromide was employed.
1-Bromooctane also led a poor result, probably because of the
insolubility of 1-bromooctane in water. Then, we attempted to
add some quaternary ammonium salts as phase transfer catalyst
to promote the heterogeneous reaction. The results showed that
quaternary ammonium salts produced the desired product in
21–82% yield. The cetyl trimethyl ammonium bromide provided
the best result at 60 ◦C (entry 6). When 1-bromopentane and
1-bromododecane were employed, the corresponding yields of
1,4-disubstituted 1,2,3-triazoles obtained were in 78% and 83%,
respectively.
This journal is
The Royal Society of Chemistry 2010
Green Chem., 2010, 12, 2120–2123 | 2121
©

View Article Online
Table 4 Cu(PPh3)2NO3-catalyzed synthesis of triazoles at low catalyst loadingsa
Entry
1
Product
Cu(PPh3)2NO3/ppm
Time/h
Yield (%)b
1000
100
50
1
11
24
92
91
81
2
3
200
24
80
200
48
62
4
5
200
200
72
40
35
68
6
7
200
200
48
48
81
80
a The reaction was carried out using 1 and 2 in the presence of Cu(PPh3)2NO3 (50–1000 ppm) at room temperature in air. The reaction scale is about
5 mmol. b Isolated yields after column chromatography or reduced pressure distillation.
a
Table 5 One-pot azide formation plus CuAAC reaction mediated by Cu(PPh3)2NO3
Entry
R2
PTCb
T/◦C
Yield (%)c
1
2
3
4
5
6
7
8
C6H4CH2
4-NO2C6H4CH2
Ph
None
None
None
None
RT
RT
RT
RT
RT
60
60
60
60
60
97
96
Trace
Trace
30 57d
82
41
35
42
21
n-C8H17
n-C8H17
n-C8H17
n-C8H17
n-C8H17
n-C8H17
n-C8H17
n-C5H11
n-C12H25
Cetyl trimethyl ammonium bromide
Cetyl trimethyl ammonium bromide
Tetrabutyl ammonium bromide
Tetrabutyl ammonium iodide
Tetraethyl ammonium Bromide
Benzyl triethyl ammonium chloride
Cetyl trimethyl ammonium bromide
Cetyl trimethyl ammonium bromide
9
10
11
12
60
60
78
83
a The reaction was carried out using bromide (1 mmol), sodium azide (1 mmol), phenylacetylene (1 mmol) and PTC (0.1 mmol) in the presence of
Cu(PPh3)2NO3 (0.005 mmol) in water. b PTC (phase transfer catalyst). c Isolated yields after column chromatography. d PTC (25 mol%).
2122 | Green Chem., 2010, 12, 2120–2123
This journal is
The Royal Society of Chemistry 2010
©

View Article Online
J. B. Hester, D. K. Hutchinson, J. Morris, R. J. Reischer, C. W. Ford,
Conclusion
G. E. Zurenko, J. C. Hamel, R. D. Schaadt, D. Stapert and B. H.
Yagi, J. Med. Chem., 2000, 43, 953; (c) R. Alvarez, S. Velazquez,
A. San-Felix, S. Aquaro, E. D. Clercq, C. F. Perno, A. Karlsson, J.
Balzarini and M. J. Camarasa, J. Med. Chem., 1994, 37, 4185.
2 (a) S. Wacharasindhu, S. Bardhan, Z.-K. Wan, K. Tabei and T. S.
Mansour, J. Am. Chem. Soc., 2009, 131, 4174; (b) Y. X. Liu, W. M.
Yan, Y. F. Chen, J. L. Petersen and X. D. Shi, Org. Lett., 2008, 10,
5389; (c) A. R. Katritzky, S. Bobrov, Kirichenko Kostyantyn, Y. Ji
and P. J. Steel, J. Org. Chem., 2003, 68, 5713; (d) A. K. Reid, C. J.
McHugh, G. Richie and D. Graham, Tetrahedron Lett., 2006, 47,
4201; (e) A. K. Verma, J. Singh and R. Chaudhary, Tetrahedron
Lett., 2007, 48, 7199; (f) Q. Dai, W. Gao, D. Liu, L. M. Kapzes and
X. Zhang, J. Org. Chem., 2006, 71, 3928.
3 (a) R. Manetsch, A. Krasiski, Z. Radi, J. Raushel, P. Taylor, K. B.
Sharpless and H. C. Kolb, J. Am. Chem. Soc., 2004, 126, 12809; (b) M.
Whiting, J. Muldoon, Y. C. Lin, S. M. Silverman, W. Lindstrom, A. J.
Olson, H. C. Kolb, M. G. Finn, K. B. Sharpless, J. H. Elder and V. V.
Fokin, Angew. Chem., Int. Ed., 2006, 45, 1435; (c) J. Wang, G. Sui,
V. P. Mocharla, R. J. Lin, M. E. Phelps, H. C. Kolb and H.-R. Tseng,
Angew. Chem., Int. Ed., 2006, 45, 5276; (d) G. C. Tron, T. Pirali, R. A.
Billington, P. L Canonico, G. Sorba and A. A. Genazzani, Med. Res.
Rev., 2008, 28, 278.
4 (a) H. Nandivada, X. W. Jiang and J. Lahann, Adv. Mater., 2007,
19, 2197; (b) C. F. Ye, G. L. Gard, R. W. Winter, R. G. Syvret, B.
Twamley and J. M. Shreeve, Org. Lett., 2007, 9, 3841; (c) P. Wu, A. K.
Feldman, A. K. Nugent, C. J. Hawker, A. Scheel, B. Voit, J. Pyun,
J. M. J. Fre’chet, K. B. Sharpless and V. V. Fokin, Angew. Chem., Int.
Ed., 2004, 43, 3928; (d) V. Aucagne, K. D. Ha”nni, D. A. Leigh, P. J.
Lusby and D. B. Walker, J. Am. Chem. Soc., 2006, 128, 2186.
5 (a) K. B. Sharpless, V. V. Fokin, L. G. Green and V. V. Rostovtsev,
Angew. Chem., Int. Ed., 2002, 114, 2708; (b) V. V. Rostovtsev, L. G.
Green, V. V. Fokin and K. B. Sharpless, Angew. Chem., Int. Ed., 2002,
41, 2596.
In summary, an environmentally friendly, economical and
efficient method was successfully developed for synthesizing
1,4-disubstituted 1,2,3-triazoles based on low catalyst loadings
of Cu(PPh3)2NO3 complex under solvent-free conditions at
room temperature. This system is broad in scope and highly
efficient even at very low catalyst loadings (down to 50 ppm). In
addition, the catalyst could be applied to the one-pot synthesis
of triazoles from aliphatic bromides, alkyne and sodium azide.
The catalyst Cu(PPh3)2NO3 is cheap and easy-to-prepare. Thus,
the procedure reported in this work is in accordance with the
principles of click chemistry and green chemistry.
Experimental
All reagents were commercially available without further pu-
rification. Flash column chromatography was performed on
silica gel (200–300 mesh) and thin layer chromatography (TLC)
analyses were performed on commercial silica gel plates (60
F254).
General procedures for copper-catalyzed cycloaddition of
organic azides with alkynes to triazoles
Alkyne (1 mmol), azide (1 mmol) and Cu(PPh3)2NO3
(0.005 mmol, 3.28 mg) were added to a flask with a ◦stir bar, and
the mixture was stirred at room temperature (~25 C) without
exclusion of air under solvent-free conditions. When the starting
materials became solid, the reaction time was recorded and the
product was purified. Two methods were used to purify the
product. For the first method, the mixture was diluted with ethyl
acetate and filtered. The filtrate was removed under reduced
pressure to get the crude product, which was further purified
by silica gel chromatography (petroleum ether/ethyl acetate as
eluent) to yield corresponding triazole. For another purification
method, the mixture was diluted with ethyl acetate and filtered.
The filtrate was removed under reduced pressure to get the pure
product. The second method was only applied to the triazoles
whose starting materials are liquid.
6 M. Meldal, C. Christensen and C. W. Tornoe, J. Org. Chem., 2002,
67, 3057.
7 (a) W. S. Brotherton, H. A. Michaels, J. T. Simmons, R. J. Clark,
N. S. Dalal and L. Zhu, Org. Lett., 2009, 11, 4954; (b) K. Kamata, Y.
Nakagawa, K. Yamaguchi and N. Mizuno, J. Am. Chem. Soc., 2008,
130, 15304.
8 (a) S. Die´z-Gonza´lez and S. P. Nolan, Angew. Chem., Int. Ed., 2008,
47, 8881; (b) S. Dıez-Gonzalez, E. D. Stevens and S. P. Nolan, Chem.
Commun., 2008, 4747; (c) B. W. T. Gruijters, M. A. C. Broeren, F. L.
Delft, R. P. Sijbesma, P. H. H. Hermkens and F. P. J. T. Rutjes, Org.
Lett., 2006, 8, 3163.
9 (a) L. D. Pacho´n, J. H. Maarseveen and G. Rothenberg, Adv. Synth.
Catal., 2005, 347, 811; (b) G. Molteni, C. L. Bianchi, G. Marinoni,
N. Santo and A. Ponti, New J. Chem., 2006, 30, 1137; (c) I. S. Park,
M. S. Kwon, Y. Kim, J. S. Lee and J. Park, Org. Lett., 2008, 10, 497.
10 F. Himo, T. Lovell, R. Hilgraf, V. V. Rostovtsev, L. Noodleman, K. B.
Sharpless and V. V. Fokin, J. Am. Chem. Soc., 2005, 127, 210.
11 (a) A. Sarkar, T. Mukherjee and S. Kapoor, J. Phys. Chem. C, 2008,
112, 3334; (b) M-L. Teyssot, A. Chevry, M. Tra¨ıkia, M. El-Ghozzi,
D. Avignant and A. Gautier, Chem.–Eur. J., 2009, 15, 6322; (c) S.
Chassaing, A. S. S. Sido, A. Alix, M. Kumarraja, P. Pale and J.
Sommer, Chem.–Eur. J., 2008, 14, 6713.
Acknowledgements
We are grateful to the project sponsored by the Scientific
Research Foundation for the State Education Ministry (No.
107108) and the Project of National Science Foundation of
P. R. China (No. J0730425).
12 S. o¨zc¸ubukc¸u, E. Ozkal, C. Jimeno and M. A. Perica`s, Org. Lett,
2009, 11, 4860.
13 B. H. Lipshutz and B. R. Taft, Angew. Chem., Int. Ed., 2006, 45,
8235.
14 M. Clark and P. Kiser, Polym. Int., 2009, 58, 1190.
15 S. W. Kwok, J. R. Fotsing, R. J. Fraser, V. O. Rodionov and V. V.
Fokin, Org. Lett., 2010, 12, 4217.
16 C. G. Bates, P. Saejueng, J. M. Murphy and D. Venkataraman, Org.
Lett., 2002, 4, 4727.
Notes and references
1 (a) D. R. Buckle and C. J. M. Rockell, J. Chem. Soc., Perkin Trans.
1, 1982, 627; (b) M. J. Genin, D. A. Allwine, D. J. Anderson, M. R.
Barbachyn, D. E. Emmert, S. A. Garmon, D. R. Graber, K. C. Grega,
This journal is
The Royal Society of Chemistry 2010
Green Chem., 2010, 12, 2120–2123 | 2123
©