An efficient Cu-catalyzed azide-alkyne cycloaddition (CuAAC) reaction in aqueous medium with a zwitterionic ligand, betaine

Article abstract of DOI:10.1039/c7cy00518k

Cu-catalyzed azide-alkyne cycloaddition reaction in aqueous medium was dramatically accelerated by a simple zwitterionic additive, betaine, at ambient temperature. In the presence of betaine, 1,4-disubstituted-1,2,3-triazoles were obtained from azides and

Full text of DOI:10.1039/c7cy00518k

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An efficient Cu-catalyzed azide–alkyne
cycloaddition (CuAAC) reaction in aqueous
Cite this: DOI: 10.1039/c7cy00518k
medium with a zwitterionic ligand, betaine†
ab
b
b
Hee-Yoon Lee a and Yeong-Gweon Lim
*
*
Jung-Ah Shin,
Su-Jin Oh,
Cu-catalyzed azide–alkyne cycloaddition reaction in aqueous medium was dramatically accelerated by a
simple zwitterionic additive, betaine, at ambient temperature. In the presence of betaine, 1,4-disubstituted-
1,2,3-triazoles were obtained from azides and terminal alkynes in excellent yields under 2.5–200 ppm levels
of Cu(I) in water. This method resulted in the remarkable reduction of the Cu(I) concentration down to ppm
levels. The advantages of this protocol include the use of a conventional Cu catalytic system with commer-
cially available betaine, which is generally non-toxic for biological application. Therefore, this efficient cata-
lytic system should have broad applications in life science research and materials science.
Received 17th March 2017,
Accepted 5th April 2017
DOI: 10.1039/c7cy00518k
rsc.li/catalysis
ours led to great advances in reducing the amount of Cu cata-
lyst, they still have shortcomings.
Introduction
Azide–alkyne cycloaddition reaction, first discovered by
Huisgen,1 has received enormous attention as a powerful tool
to form 1,4-disubstituted-1,2,3-triazoles, since Sharpless and
Meldal developed the Cu(I)-catalyzed azide–alkyne 1,3-
cycloaddition (CuAAC) reaction.2 The CuAAC reaction is easy,
highly efficient, regioselective and compatible with various
functional groups. Therefore, it has been extensively utilized
in organic synthesis, biochemistry, medicinal chemistry,
chemical biology and materials science.3 For biological appli-
cation, since it is desirable for the reaction to be compatible
with living systems, especially in aqueous medium and live
cells, highly efficient Cu(I) catalysts have been developed for
the synthesis of triazoles to minimize the amount of Cu(I) cat-
alyst used. To improve the activity of the catalysts, various li-
gands such as polysaccharide-supported nanoparticles,4
polymer-embedded catalysts,5 and particularly catalysts with
nitrogen ligands such as N-heterocyclic carbenes,6 poly-
triazoles,7 and triIJaminoalkyl)amine derivatives8 have been
developed.
The major limitation of the aqueous medium of biological
systems is the mixing problem with organic materials includ-
ing the ligands of CuAAC catalysts, and thus even the reactive
ligands work less efficiently. To overcome this mixing prob-
lem in general, various surfactants and phase transfer cata-
lysts have been employed.12 Recently, Lipshutz reported a
CuAAC reaction using TPGS-750-M as a non-ionic surfactant
in water,13 and Scarso also reported that organic bromide was
reacted with sodium azide and a terminal alkyne in the pres-
ence of a surfactant to give 1,4-disubstituted-1,2,3-triazoles in
water.14 In the same context, we have successfully introduced
β-cyclodextrin as the nanoreactor and the carrier of substrates
to the aqueous phase to accelerate the CuAAC reaction.15
As a part of our continuing studies on the development of
readily applicable methods for triazole synthesis in water, we
tested the CuAAC reaction using different surfactants such as
nonionic, cationic, anionic, and zwitterionic types, with antic-
ipation of increasing the reaction efficiency through micellar
effects12a and the on-water effect.16 Herein we report a syn-
thetic method for triazoles using ppm levels of a Cu(I) catalyst
in the presence of betaine, which is a readily available and
biocompatible zwitterionic surfactant. With amounts of
0.0003 mol% (2.5 ppm) to 0.025 mol% (200 ppm) of Cu(I), the
CuAAC reaction was carried out at 30 °C, efficiently affording
excellent yields of triazoles.
To further reduce the cellular toxicity of the catalysts, a
dendritic nanoreactor containing intradendritic triazoles,9
polyIJN-isopropylacrylamide-co-N-vinylimidazole)
polymers,10
and trisIJtriazolyl)-polyethylene glycol11 promoted CuAAC,
which reduced the amount of Cu(I) catalyst for the reaction to
the part per million (ppm) level. Even though these endeav-
a Department of Chemistry, Korea Advanced Institute of Science and Technology
(KAIST), Daejeon, 34141, Korea. E-mail: leehy@kaist.ac.kr
b The 4th R&D Institute-2, Agency for Defense Development, Daejeon, 34186,
Korea. E-mail: limyg59@gmail.com
† Electronic supplementary information (ESI) available: 1H and 13C NMR spectra
for all compounds. See DOI: 10.1039/c7cy00518k
Results and discussion
Initially with anticipation of micellar effects, we carried out
CuAAC reactions with various additives such as β-cyclodextrin
(the phase transfer catalyst), SDS, aliquat 128, Triton X-100,
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and betaine (anionic, cationic, non-ionic, and zwitterionic sur-
factants, respectively) in water. The reaction of benzyl azide 1a
with phenyl acetylene 2a in the presence of 200 ppm of Cu(I)
and 5 mol% of surfactant in water at 30 °C gave the corre-
sponding triazole 3aa, and the results are listed in the Table 1.
Interestingly, different reaction rates for triazole formation
were observed depending on the surfactant type. Among them,
in the case of using the zwitterionic surfactant betaine, the re-
action showed a remarkable improvement in the reactivity to
produce 3aa in 98% conversion in 1 h (entry 6).
Through these experiments, we decided to investigate the
betaine–Cu catalytic system in detail. To verify the effects of
betaine, reactions were performed in various amounts of
Cu(I) with 5 mol% of betaine (Table 2). No reaction occurred
in the absence of Cu(I) regardless of the presence of betaine
for 24 h (entry 1–2). Without betaine, the reaction also
proceeded sluggishly using 100 ppm of Cu(I) (entry 3). On the
other hand, in the presence of betaine, 3aa was obtained in
97% conversion even with only 10 ppm of Cu(I) in 5 h (entry
4). Reduction of the Cu(I) concentration to 1 ppm resulted in
77% conversion, leading to TONs of up to 616 000 and TOFs
of up to 123 200 h−1 (entry 5). Surprisingly, when the reaction
temperature was increased to 40 °C, 1a was converted to 3aa
in 24 h cleanly even at a 25 ppb level of Cu(I) (entry 6). Even
though the best results were obtained at 40 °C, considering a
wide range of applications including chemical biology and
bioorthogonal chemistry, all the reactions were carried out at
30 °C. These results implied that both Cu and betaine play
important roles in the CuAAC reaction in water.
tem. Sodium acetate and sodium propionate, having a car-
boxylate group in their molecules, showed 46% (entry 2) and
74% (entry 3) conversions, respectively. Remarkably, betaine,
which has both a positively charged quaternary ammonium
group and a negatively charged carboxylate group, existing in
the zwitterionic form, showed an excellent conversion under
the same reaction conditions (entry 4). These results showed
clearly that both the ammonium part and the anionic part
play important roles in this catalytic system. It is well known
that betaine coordinates easily with Cu to stabilize and/or ac-
tivate it.17 Therefore, we could speculate that betaine im-
proves the solubility of the reactants and reagents in water,
facilitates deprotonation of the terminal alkyne, and stabi-
lizes the Cu(I) generated in the catalytic cycle.18
Next, the recycling of the CuAAC reaction between 1a and
2a in the presence of 200 ppm of Cu(I) and betaine (5 mol%)
was performed; a longer reaction time was required to observe
the complete conversion with successive reuse of the betaine–
Cu system (1st cycle: 1 h, 2nd cycle: 3.5 h, 3rd cycle: 9 h). The
decrease in catalytic activity was ascribed to the well antici-
pated loss of Cu in the aqueous medium during workup.
To find the minimum concentration of Cu, we carried out
experiments to optimize the reaction conditions for the
CuAAC reaction depending on various substrates. As shown
in Table 4, 1a was reacted with various alkynes 2a–2n in the
presence of 2.5–200 ppm of Cu at 30 °C, affording the desired
triazoles 3aa–3an. Although most reactions were completed
within several hours, the reaction time was set to 24 h to
maximize the conversion and to compare the results with the
recently reported CuAAC reaction results using ppm levels of
Cu(I).9–11 In the case of phenyl acetylene (2a), the desired
triazole 3aa was obtained quantitatively with only 2.5 ppm of
Cu(I) in water at 30 °C for 24 h. Moreover, a large-scale reac-
tion (1a, 1g scale) under these conditions was also success-
fully conducted to afford an excellent isolated yield (95%)
Then, to gain insight into the role of betaine in the Cu cat-
alytic mechanism, we tested other additives, such as choline
chloride, sodium acetate, and sodium propionate, with re-
spect to their potential to accelerate triazole formation
(Table 3). In the case of choline chloride, which has only an
ammonium part in the molecule, the reaction gave a moder-
ate conversion of 66% in the presence of 200 ppm of Cu(I) for
1 h at 30 °C (entry 1). This result indicates that the ammo-
nium part of choline chloride contributes to the catalytic sys-
Table 2 CuAAC reaction between 1a and 2a using various concentra-
tions of the Cu catalysta
Table 1 Surfactant effects on the Cu-catalyzed [2 + 3] cycloaddition of
azide 1a with alkyne 2aa
Betaine Time Conv.
TOF
Entry Cu(I)
(mol%) (h)
(%)
TON
(h−1
)
1
2
3
—
—
—
5
—
24
24
5
<1
<1
48
—
—
3840
—
—
768
Entry
Surfactant
Type
Time
Conv. (%)
100 ppm
(0.0125
mol%)
10 ppm
1 ppm
25 ppb
10 ppb
1
—
β-CD
SDS
Aliquat 128
Triton X-100
Betaine
—
—
5 h
1 h
1 h
1 h
1 h
1 h
49
61
68
33
42
98
2b
3
Anionic
Cationic
Non-ionic
Zwitterionic
4
5
5
5
5
5
5
24
24
97
77
100
19
77 600
616 000
32 000 000 1 333 333
15 200 000 633 333
15 520
123 200
4
5
6
5
6b
7b
a
a
All the reactions were carried out with benzyl azide 1a (0.75 mmol),
phenyl acetylene 2a (1.05 equiv.), CuSO4·5H2O (0.025 mol%, 200 ppm
based on Cu), Na ascorbate (0.15 equiv.) and a surfactant (0.05
equiv.) in H2O (1 mL) at 30 °C. b β-CD, the phase transfer catalyst.
All the reactions were carried out with 1a (0.75 mmol), 2a (1.05
equiv.), CuSO4·5H2O (25 ppb – 100 ppm based on Cu), Na ascorbate
b
(0.15 equiv.) and betaine (0.05 equiv.) in H2O (1 mL) at 30 °C. The
reaction was carried out at 40 °C.
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Table 3 Comparative screening of other additives, similar types of beta-
tion, this method resulted in the remarkable reduction of the
Cu(I) concentration down to ppm levels during the reaction,
which demonstrates easy applicability since specially designed
ligands were not required for the activation and stabilization of
Cu(I). The advantages of this protocol include the use of a con-
ventional Cu catalytic mixture that is easily generated from
CuSO4–Na ascorbate and betaine, which is an easily obtained,
commercially available, biodegradable, and biocompatible sur-
factant. Therefore, this efficient catalytic system is believed to
have broad applications in biological and materials sciences.
ine, for the CuAAC reactionsa
Entry
1
Additive
Structure
Conv. (%)
66
Choline chloride
2
3
4
Sodium acetate
Sodium propionate
Betaine
46
74
98
Experimental section
General information
1H-NMR and 13C-NMR spectra were recorded on a Bruker
AVANCE 400 spectrometer. Chemical shifts are given with re-
spect to residual CHCl3 (7.28 ppm) in CDCl3. IR spectra of all
compounds were recorded on a Frontier FT-IR spectrometer,
a
All the reactions were carried out with benzyl azide 1a (0.75 mmol),
phenyl acetylene 2a (1.05 equiv.), CuSO4·5H2O (0.025 mol%, 200 ppm
based on Cu), Na ascorbate (0.15 equiv.) and an additive (0.05 equiv.)
in H2O (1 mL) at 30 °C for 1 h.
and HRMS analyses were carried out using
a Bruker
micrOTOF-Q instrument with electrospray ionization operat-
ing in positive mode. The melting temperature was deter-
mined with an IA 9200 melting point apparatus from Electro-
thermal Thermo Scientific. The mass fractions of residual Cu
in the products were determined by inductively coupled
plasma mass spectrometry (ICP-MS, Thermo Scientific Nep-
tune Plus) with the external calibration method.
close to the conversion yield.19 For aryl alkynes containing
electron-donating and electron-withdrawing groups, the reac-
tions were completed in 24 h, with excellent isolated yields
only at less than 25 ppm Cu(I) levels (3ab–3ag). Alkyne 3ah
bearing the sterically demanding adamantane group required
a higher amount of the catalyst (100 ppm) to form the corre-
sponding triazole. Also, for alkynes containing a hydroxyl
group, more Cu(I) was required for the completion of the re-
action (100 ppm for 3ai and 200 ppm for 3aj), probably due
to the compromised hydrophobic effect of the ligand. More-
over, aliphatic alkynes 3ak, 3al, and 3am efficiently reacted
with only 75–100 ppm of Cu(I). Interestingly, ethynylferrocene
(2n) also reacted with 2a without any difficulty, with only 25
ppm of Cu(I), to produce the desired product 3an in 94% iso-
lated yield.
Typical procedure for CuAAC
In a vial fitted with a screw cap, to a solution of benzyl azide
1a (100 mg, 0.75 mmol) and phenyl acetylene 2a (83 mg, 1.05
equiv.) was added sodium ascorbate (23 mg, 0.15 equiv.), betaine
(4.5 mg, 0.05 equiv.), and copperIJII) sulfate pentahydrate in H2O
(1 mL of stock solution, 2.5 ppm based on Cu) at 30 °C. The re-
action mixture was stirred for 24 h at 30 °C. The resulting prod-
uct was extracted with CH2Cl2 (3 mL) three times. The combined
organic layer was concentrated in vacuo. The crude compound
was washed with pentane to give 172 mg of 3aa (97%).
To further demonstrate the general applicability and ver-
satility of this catalytic system, diverse azides 1b–1h were also
allowed to react with alkynes 2a–2l in the presence of the be-
taine–Cu system (Table 5). Most aryl or aliphatic azides and
alkynes afforded good yields of the corresponding triazoles
using low Cu(I) levels of 25–75 ppm (4ba, 4bl, 4ca, 4da, 4ee,
4ea, 4el, 4fa, 4fl, and 4ga). An azide containing a carboxyl
group and alkynes containing a hydroxyl group required 125
and 150 ppm of Cu(I) to produce the desired products 4ha
and 4bi in high yields, respectively.
1-Benzyl-4-phenyl-1H-1,2,3-triazole (3aa)
Ivory needles (97%); mp = 131 °C; 1H NMR (400 MHz, CDCl3) δ
7.82 (d, J = 7.1 Hz, 2H), 7.67 (s, 1H), 7.44–7.33 (m, 7H), 5.60 (s,
2H); 13C-NMR (100 MHz, CDCl3) δ 148.1, 134.6, 130.5 (2C), 129.0
(2C), 128.7, 128.6, 128.0, 127.9 (2C), 125.6 (2C), 119.5, 54.1.
1-Benzyl-4-(p-tolyl)-1H-1,2,3-triazole (3ab)
White needles (91%); mp = 154–155 °C; 1H-NMR (400 MHz,
CDCl3) δ 7.71 (d, J = 7.4 Hz, 2H), 7.64 (s, 1H), 7.42–7.38 (m,
3H), 7.35–7.31 (m, 2H), 7.23 (d, J = 7.6 Hz, 2H), 5.58 (s, 2H),
2.38 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ 148.3, 138.0, 134.7,
129.4 (2C), 129.1 (2C), 128.7, 128.0, 127.7 (2C), 125.6 (2C),
119.1, 54.2, 21.2.
Conclusions
A simple betaine–Cu catalytic system with remarkably small
amounts of Cu, which provided facile and convenient access to
triazoles, was developed. The use of this catalytic system in wa-
ter at 30 °C efficiently produced a wide range of triazoles in
good to excellent yields. Furthermore, workup was easy, requir-
ing only simple suction filtration or solvent extraction. In addi-
1-Benzyl-4-(3-fluorophenyl)-1H-1,2,3-triazole (3ac)
Ivory needles (100%); mp = 109–111 °C; 1H-NMR (400 MHz,
CDCl3) δ 7.72 (s, 1H), 7.57–7.53 (m, 2H), 7.38–7.30 (m, 6H),
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Table 4 Results of the CuAAC reaction between 1a and various alkynes
2a–2n using betaine in watera
1-Benzyl-4-(3-(trifluoromethyl)phenyl)-1H-1,2,3-triazole (3ae)
White amorphous solid (97%); mp = 70 °C; 1H-NMR (400
MHz, CDCl3) δ 8.07 (s, 1H), 8.00 (d, J = 7.6 Hz, 1H), 7.79 (s,
1H), 7.57–7.48 (m, 2H), 7.42–7.31 (m, 5H), 5.59 (s, 2H); 13C-
NMR (100 MHz, CDCl3) δ 146.8, 134.4, 131.4, 131.4 (q, J =
32.4 Hz), 129.3, 129.2 (2C), 128.9, 128.8, 128.1 (2C), 124.7 (q,
J = 3.7 Hz), 124.0 (d, J = 272.3 Hz), 122.4 (q, J = 3.9 Hz),
120.0, 54.3.
Entry
Alkyne
Product
3aa
Cu(I)
(ppm)
2.5
Isolated
yield (%)
97
1
2
3
2a
2b
2c
3ab
25
25
97
88
1-Benzyl-4-(3,5-dimethoxyphenyl)-1H-1,2,3-triazole (3af)
3ac
Tan needles (95%); mp = 119–121 °C; 1H-NMR (400 MHz,
CDCl3) δ 7.67 (s, 1H), 7.37–7.29 (m, 5H), 6.99 (s, 2H), 6.44 (s,
1H), 5.55 (s, 2H), 3.82 (s, 6H); 13C-NMR (100 MHz, CDCl3) δ
161.1 (2C), 147.9, 134.6, 132.3, 129.0 (2C), 128.6, 127.9 (2C),
119.8, 103.5 (2C), 100.5, 55.3 (2C), 54.1; FT-IR (KBr, cm−1)
3119 (m), 3089 (w), 2998 (w), 2961 (w), 2936 (w), 2837 (w),
1595 (vs), 1551 (w), 1497 (w), 1474 (m), 1453 (m), 1417 (m),
1359 (m), 1274 (w), 1229 (m), 1153 (s), 1179 (m), 1200 (vs),
1092 (m), 1065 (m), 1044 (m), 1001 (m), 925 (m), 849 (m),
833 (s), 716 (s); HRMS [M + Na]+ calcd. For C17H17N3O2Na
318.1218, found 318.1226.
4
5
7
3adb
3ae
3af
25
25
25
98
97
95
2d
2e
2f
8
3ag
3ah
3ai
25
96
83
98
2g
9
100
100
2h
3-(1-Benzyl-1H-1,2,3-triazol-4-yl)aniline (3ag)
10
2i
1
Brown needles (96%); mp = 135–137 °C; H-NMR (400 MHz,
CDCl3) δ 7.63 (s, 1H), 7.41–7.38 (m, 3H), 7.38–7.31 (m, 6H),
7.30–7.28 (m, 2H),7.25 (s, 1H), 7.18 (t, J = 7.7 Hz, 1H), 7,12–
7.11 (m, 1H), 6.66–6.64 (m, 1H), 5.57 (s, 2H); 13C-NMR (100
MHz, CDCl3) δ 148.3, 146.9, 134.7, 131.4, 129.7 (2C), 129.1,
128.7, 128.0 (2C), 119.5, 115.9, 114.9, 112.2, 54.1.
11
12
13
14
15
3aj
200
100
75
87
93
97
76
94
2j
2k
3ak
3al
2l
2m
3am
3an
100
25
2n
a
4-((Adamantan-1-ylmethoxy)methyl)-1-benzyl-1H-1,2,3-triazole
(3ah)
All reactions were performed with azide 1a (0.75 mmol), alkynes
2a–2n (1.05 equiv.), CuSO4·5H2O (2.5–200 ppm based on Cu), Na
ascorbate (0.15 equiv.), and betaine (0.05 equiv.) in water (1 mL) for
24 h at 30 °C. The yields shown represent those obtained for isolated
Yellow solid (94%); mp =125–127 °C; 1H-NMR (400
MHz, CDCl3) δ 7.44 (s, 1H), 7.40–7.37 (m, 2H), 7.30–
7.28 (m, 3H), 5.55 (s, 2H), 4.60 (s, 2H), 3.07 (s, 2H),
1.95 (s, 3H), 1.66 (dd, J = 32.0, 12.2 Hz, 6H), 1.51–
b
products. The concentration of residual Cu in the product was 14
ppm.
1.50 (m, 6H); 13C-NMR (100 MHz, CDCl3)
δ 146.5,
7.00 (t, J = 8.4 Hz, 1H), 5.56 (s, 2H); 13C-NMR (100 MHz,
CDCl3) δ 163.0 (d, J = 245.6 Hz), 147.0, 134.4, 132.6 (d, J = 8.6
Hz), 130.3 (d, J = 8.4 Hz), 129.1 (2C), 128.7, 127.9 (2C), 121.2
(d, J = 2.8 Hz), 119.9, 114.7 (d, J = 21.2 Hz), 112.4 (d, J = 23.0
Hz), 54.1.
134.7, 129.0 (2C), 128.7, 128.0 (2C), 122.1, 81.5, 65.1,
54.1, 39.7 (3C), 37.1 (3C), 34.0, 28.2 (3C); FT-IR (KBr,
cm−1) 3141 (w), 2901 (vs), 2847 (s), 1722 (w), 1638
(w), 1497 (w), 1454 (m), 1362 (w), 1344 (w), 1224
(m), 1156 (w), 1089 (m), 1048 (m), 812 (w), 723 (m),
695 (w); HRMS [M
360.2052, found 360.2038.
+
Na]+ calcd. For C21H27N3ONa
1-Benzyl-4-(2,4-difluorophenyl)-1H-1,2,3-triazole (3ad)
Tan needles (98%); mp = 124–126 °C; 1H-NMR (400 MHz,
CDCl3) δ 8.29 (dd, J = 15.3, 7.2 Hz, 1H), 7.84 (d, J = 3.0 Hz,
1H), 7.42–7.31 (m, 5H), 7.00 (t, J = 8.4 Hz, 1H), 6.87 (t, J =
10.8 Hz, 1H), 5.60 (s, 2H); 13C-NMR (100 MHz, CDCl3) δ 163.7
(d, J = 12.2 Hz), 160.8 (dd, J = 83.9, 11.9 Hz), 157.9 (d, J = 11.7
Hz), 140.9, 134.6, 129.1 (2C), 128.9–128.6 (m), 127.9 (2C),
122.1 (d, J = 12.2 Hz), 115.0 (dd, J = 13.2, 3.8 Hz), 111.9 (dd, J
= 21.3, 3.4 Hz), 104.0 (t, J = 25.7 Hz), 54.2.
1-(1-Benzyl-1H-1,2,3-triazol-4-yl)cyclohexan-1-ol (3ai)
Ivory needles (98%); mp = 123–125 °C; 1H NMR (400 MHz,
CDCl3) δ 7.40–7.32 (m, 4H), 7.27–7.25 (m, 2H), 5.47 (s, 2H),
2.92 (brs, 1H, OH), 1.93–1.25 (m, 10H); 13C-NMR (100 MHz,
CDCl3) δ 156.0, 134.6, 128.9 (2C), 128.7, 128.1 (2C), 119.6,
69.4, 54.0, 37.9 (2C), 25.2, 21.8 (2C).
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Table 5 Results of the CuAAC reaction of different azides 1b–1h with al-
kynes 2a–2l using betaine in watera
(100 MHz, CDCl3) δ 149.0, 135.0, 129.0 (2C), 128.6, 127.9
(2C), 120.4, 54.0, 31.5, 25.4, 22.3, 13.8.
1-Benzyl-4-hexyl-1H-1,2,3-triazole (3al)
1
Ivory amorphous solid (97%); mp = 52–54 °C; H NMR (400
MHz, CDCl3) δ 7.50–7.45 (m, 3H), 7.37–7.35 (m, 3H), 5.60 (s,
2H), 2.79 (t, J = 7.7 Hz, 2H), 1.77–1.71 (m, 2H), 1.46–1.39 (m,
6H), 0.98–0.95 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 149.0,
135.0, 129.0 (2C), 128.6, 127.9 (2C), 120.4, 54.0, 31.5, 29.3,
28.9, 25.7, 22.5, 14.0.
Entry
1
Azide
Alkyne
Product
Cu(I)
(ppm)
25
Isolated
yield (%)
95
4ba
2a
2l
2b
2b
2
3
4blb
4bi
75
96
96
1,5-BisIJ1-benzyl-1H-1,2,3-triazol-4-yl)pentane (3am)
2b
150
Ivory amorphous solid (98%); mp = 125–127 °C; 1H-NMR
(400 MHz, CDCl3) δ 7.42–7.36 (m, 6H), 7.30–7.28 (m, 4H),
7.21 (s, 2H), 5.52 (s, 4H), 2.71 (t, J = 7.4 Hz, 4H), 1.74–1.67
(m, 4H), 1.46–1.40 (m, 2H); 13C-NMR (100 MHz, CDCl3) δ
148.6 (2C), 135.0 (2C), 129.0 (4C), 128.6 (2C), 127.9 (4C),
120.5 (2C), 54.0 (2C), 29.0 (2C), 28.6 (2C), 25.5.
2i
4
5
2a
4ca
4da
25
25
100
94
2c
2a
2d
2e
1-Benzyl-4-ferrocenyl-1H-1,2,3-triazole (3an)
6
4ee
25
94
Red needles (94%); mp = 153–155 °C; 1H-NMR (400 MHz,
CDCl3) δ 7.40–7.36 (m, 4H), 7.29–7.28 (m, 2H), 5.54 (s, 2H),
4.71 (s, 2H), 4.23 (s, 2H), 4.07 (s, 5H); 13C-NMR (100 MHz,
CDCl3) δ 147.1, 134.8, 129.0 (2C), 128.6, 127.8 (2C), 118.7,
75.3, 69.4 (5C), 68.5 (2C), 66.5 (2C), 53.9.
2e
7
8
9
2e
2e
2a
2l
2a
4ea
4el
4fa
75
75
25
92
97
92
1-Phenethyl-4-phenyl-1H-1,2,3-triazole (4ba)
2f
2f
White amorphous solid (95%); mp = 140 °C; 1H-NMR (400
MHz, CDCl3) δ 7.79 (d, J = 7.8 Hz, 2H), 7.49 (s, 1H), 7.43 (t, J
= 7.6 Hz, 2H), 7.36–7.26 (m, 2H), 7.17–7.15 (m, 4H), 4.66 (t, J
= 7.0 Hz, 2H), 3.28 (t, J = 7.2 Hz, 2H); 13C-NMR (100 MHz,
CDCl3) δ 147.5, 137.1, 130.7, 128.8 (2C), 128.8 (2C) 128.7 (2C),
128.1, 127.1, 125.7 (2C), 119.9, 51.7, 36.8.
10
11
2l
2a
4fl
4ga
75
50
92
94
2g
2h
12
2a
4ha
125
90
a
All reactions were performed with azides 1b–1h (0.75 mmol),
alkynes 2a–2l (1.05 equiv.), CuSO4·5H2O (25–150 ppm based on Cu),
Na ascorbate (0.15 equiv.), and betaine (0.05 equiv.) in water (1 mL)
for 24 h at 30 °C. The yields shown represent those obtained for
isolated products. The concentration of residual Cu in the product
was 16 ppm.
4-Hexyl-1-phenethyl-1H-1,2,3-triazole (4bl)
1
Yellow oil (96%); H-NMR (400 MHz, CDCl3) δ 7.33–7.25 (m,
b
3H), 7.11 (d, J = 7.2 Hz, 2H), 7.00 (s, 1H), 4.55 (t, J = 7.2 Hz,
2H), 3.20 (t, J = 7.2 Hz, 2H), 2.67 (t, J = 7.5 Hz, 2H), 1.64–1.59
(m, 2H), 1.33–1.29 (m, 6H), 0.91–0.88 (m, 3H); 13C-NMR (100
MHz, CDCl3) δ 148.1, 137.2, 128.7 (2C), 128.6 (2C), 126.9,
120.9, 51.4, 36.8, 31.5, 29.4, 28.8, 25.5, 22.5, 14.0.
3-(1-Benzyl-1H-1,2,3-triazol-4-yl)propan-1-ol (3aj)
1
Yellow oil (87%); H-NMR (400 MHz, CDCl3) δ 7.40–7.35 (m,
1-(1-Phenethyl-1H-1,2,3-triazol-4-yl)cyclohexan-1-ol (4bi)
3H), 7.28–7.25 (m, 3H), 5.50 (s, 2H), 3.70 (t, J = 5.8 Hz, 2H),
2.82 (t, J = 7.2 Hz, 2H), 2.70–2.60 (brs, 1H, OH), 1.92 (quintet,
J = 6.6 Hz, 2H); 13C-NMR (100 MHz, CDCl3) δ 148.0, 134.6,
128.8 (2C), 128.4, 127.7 (2C), 121.0, 61.1, 53.8, 31.8, 21.7.
1
Ivory needles (96%); mp = 109 °C; H-NMR (400 MHz, CDCl3)
δ 7.29–7.17 (m, 4H), 7.09 (d, J = 7.0 Hz, 2H), 4.55 (t, J = 7.0
Hz, 2H), 3.19 (t, J = 7.0 Hz, 2H), 2.77 (brs, 1H, OH), 1.96–1.70
(m, 6H), 1.59–1.32 (m, 4H); 13C-NMR (100 MHz, CDCl3) δ
155.1, 137.0, 128.7 (2C), 128.6 (2C), 127.0, 120.1, 69.3, 51.5,
38.0, 36.7, 25.3, 22.0.
1-Benzyl-4-butyl-1H-1,2,3-triazole (3ak)
Ivory amorphous solid (93%); mp = 60–62 °C; 1H-NMR (400
MHz, CDCl3) δ 7.42–7.36 (m, 3H), 7.28–7.26 (m, 2H), 7.19 (s,
1H), 5.51 (s, 2H), 2.71 (t, J = 7.6 Hz, 2H), 1.68–1.61 (m, 3H),
1.38 (sextet, J = 7.5 Hz, 2H), 0.93 (t, J = 7.6 Hz, 2H); 13C-NMR
4-Phenyl-1-(3-phenylpropyl)-1H-1,2,3-triazole (4ca)
1
Ivory amorphous solid (100%); mp = 81–82 °C; H-NMR (400
MHz, CDCl3) δ 7.85 (d, J = 7.8 Hz, 2H), 7.74 (s, 1H), 7.45 (t, J
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= 7.6 Hz, 2H), 7.38–7.32 (m, 3H), 7.27–7.21 (m, 3H), 4.43 (t, J
= 7.0 Hz, 2H), 2.72 (t, J = 7.3 Hz, 2H), 2.33 (quintet, J = 7.3
Hz, 2H); 13C-NMR (100 MHz, CDCl3) δ 147.8, 140.1, 130.7,
128.8, 128.6, 128.5, 128.1, 126.4, 125.7, 119.5, 49.6, 32.5, 31.7.
129.9, 128.8 (2C), 128.1, 125.7 (2C), 121.0, 119.9, 114.3, 112.6,
55.2, 51.6, 36.8; FT-IR (KBr, cm−1) 3120 (w), 3005 (w), 2951
(w), 2841 (w), 1602 (s), 1593 (w), 1494 (m), 1480 (m), 1466 (s),
1435 (w), 1358 (w), 1319 (m), 1276 (m), 1262 (s), 1225 (m),
1193 (w), 1169 (s), 1081 (m), 1041 (s), 1015 (m), 972 (w), 926
(w), 913 (w), 857 (m), 820 (m), 785 (m), 765 (vs), 721 (m), 691
4-Phenyl-1-(8-phenyloctyl)-1H-1,2,3-triazole (4da)
(vs), 559 (w), 510 (w); HRMS [M
C17H17N3ONa 302.1269, found 302.1260.
+
Na]+ calcd. For
1
White amorphous solid (94%); mp = 70–73 °C; H-NMR (400
MHz, CDCl3) δ 7.86 (d, J = 7.8 Hz, 2H), 7.75 (s, 1H), 7.45 (t, J
= 7.6 Hz, 2H), 7.38–7.34 (m, 1H), 7.32–7.26 (m, 2H), 7.20–7.18
(m, 3H), 4.41 (t, J = 7.1 Hz, 2H), 2.61 (t, J = 7.4 Hz, 2H), 2.00–
1.93 (m, 2H), 1.63–1.60 (m, 2H), 1.38–1.34 (m, 8H); 13C-NMR
(100 MHz, CDCl3) δ 147.7, 142.7, 130.7, 128.8 (2C), 128.4
(2C), 128.2 (2C), 128.1, 125.7(2C), 125.6, 119.3, 50.4, 35.9,
31.4, 30.3, 29.2, 29.1, 28.9, 26.5; FT-IR (KBr, cm−1) 3081 (m),
3031 (w), 2917 (vs), 2849 (vs), 1609 (w), 1462 (m), 1384 (w),
1352 (w), 1222 (w), 1202 (w), 1180 (w), 1085 (w), 1051 (w),
1027 (w), 912 (w), 861 (w), 766 (s), 697 (s), 517 (w); HRMS [M
+ Na]+ calcd. For C22H27N3Na 356.2103, found 356.2088.
4-Hexyl-1-(3-methoxyphenethyl)-1H-1,2,3-triazole (4fl)
1
Yellow oil (92%); H-NMR (400 MHz, CDCl3) δ 7.18 (t, J = 7.8
Hz, 1H), 7.02 (s, 1H), 6.77 (d, J = 8.1 Hz, 1H), 6.67 (d, J = 7.4
Hz, 1H), 6.61 (s, 1H), 4.52 (t, J = 7.2 Hz, 2H), 3.74 (s, 3H), 3.14
(t, J = 7.1 Hz, 2H), 2.65 (t, J = 7.4 Hz, 2H), 1.62–1.56 (m, 2H),
1.28 (s, 6H), 0.88–0.84 (m, 3H); 13C-NMR (100 MHz, CDCl3) δ
159.7, 148.0, 138.7, 129.6, 120.9, 114.2, 112.3, 55.0, 51.3, 36.7,
31.4, 29.3, 28.7, 25.4, 22.4, 13.9; FT-IR (KBr, cm−1) 3134 (w),
2930 (vs), 2857 (s), 1603 (s), 1586 (s), 1551 (w), 1492 (s), 1456
(s), 1437 (s), 1293 (m), 1263 (C–O, vs), 1216 (m), 1154 (m),
1127 (w), 1050 (C–O, s), 874 (m), 782 (m), 697 (m); HRMS [M +
Na]+ calcd. For C17H25N3ONa 310.1895, found 310.1879.
1-Octyl-4-(3-(trifluoromethyl)phenyl)-1H-1,2,3-triazole (4ee)
Yellow oil (94%); 1H-NMR (400 MHz, CDCl3) δ 8.09 (s, 1H),
8.03 (d, J = 7.2 Hz, 1H), 7.87 (s, 1H), 7.58–7.50 (m, 2H), 4.40
(t, J = 7.1 Hz, 2H), 1.95 (s, 2H), 1.36–1.23 (m, 10H), 0.87 (s,
3H); 13C-NMR (100 MHz, CDCl3) δ 146.3, 131.6, 131.4 (q, J =
32.4 Hz), 129.2, 128.0, 124.5 (q, J = 3.7 Hz), 124.0 (q, J = 272.3
Hz), 122.3 (q, J = 3.9 Hz), 119.9, 50.5, 31.6, 30.2, 28.9, 28,8,
26.4, 22.5, 13.9; FT-IR (KBr, cm−1) 3132 (w), 3096 (w), 2930
(vs), 2858 (s), 1622 (w), 1596 (w), 1557 (w), 1490 (w), 1457
(m), 1420 (m), 1353 (m), 1323 (vs), 1228 (s), 1167 (vs), 1128
(s), 1096 (s), 988 (w), 911 (m), 804 (s), 710 (m), 698 (s); HRMS
[M + Na]+ calcd. For C17H22F3N3Na 348.1664, found 348.1642.
1-(Naphthalene-2-yl)-2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethan-1-
one (4ga)
Yellow amorphous solid (94%); mp = 183–185 °C; 1H-NMR
(400 MHz, CDCl3); 8.60 (s, 1H), 8.08–7.90 (m, 7H), 7.72–7.64
(m, 2H), 7.46 (t, J = 7.4 Hz, 2H), 7.28 (t, J = 7.5 Hz, 1H), 6.05
(s, 2H); 13C-NMR (100 MHz, CDCl3) δ 190.2, 148.3, 136.2,
132.4, 131.3, 130.5, 130.3, 129.8, 129.4, 129.3, 128.8, 128.2,
128.0, 127.4, 125.8, 123.3, 121.4, 55.5.
5-(4-Phenyl-1H-1,2,3-triazol-1-yl)pentanoic acid (4ha)
1-Octyl-4-phenyl-1H-1,2,3-triazole (4ea)
Ivory amorphous solid (90%); mp = 130–131 °C; 1H-NMR
(400 MHz, DMSO-d6) δ 8.58 (s, 1H), 7.84 (d, J = 7.4 Hz, 2H),
7.44 (t, J = 7.3 Hz, 2H), 7.33 (t, J = 7.3 Hz, 1H), 4.40 (t, J = 6.7
Hz, 2H), 2.27 (t, J = 7.0 Hz, 2H), 1.93–1.83 (m, 2H), 1.52–1.45
(m, 2H); 13C-NMR (100 MHz, DMSO-d6) δ 174.6, 146.7, 131.3,
129.3 (2C), 128.2, 125.6 (2C), 121.8, 49.7, 33.4, 29.5, 21.9; FT-
IR (KBr, cm−1) 3121 (m), 2952 (w), 2869 (w), 2815 (w), 1709
(vs), 1694 (CO, vs), 1464 (m), 1441 (w), 1332 (w), 1273 (w),
1215 (m), 1190 (w), 1132 (w), 1080 (m), 1052 (w), 977 (w), 839
(w), 763 (s), 696 (s), 629 (w), 526 (w); HRMS [M + Na]+ calcd.
For C13H15N3O2Na 268.1062, found 268.1055.
1
White amorphous solid (92%); mp = 74–76 °C; H-NMR (400
MHz, CDCl3) δ 7.85 (d, J = 7.7 Hz, 2H), 7.75 (s, 1H), 7.44 (t, J
= 7.5 Hz, 2H), 7.36–7.33 (m, 1H), 4.41 (t, J = 7.2 Hz, 2H),
1.99–1.94 (m, 2H), 1.38–1.28 (m, 10H), 0.91–0.88 (m, 3H);
13C-NMR (100 MHz, CDCl3) δ 147.7, 130.8, 128.8 (2C), 128.0,
125.7 (2C), 119.3, 50.4, 31.7, 30.3, 29.0, 28.9, 26.5, 22.6, 14.0.
4-Hexyl-1-octyl-1H-1,2,3-triazole (4el)
White oil (97%); 1H-NMR (400 MHz, CDCl3) δ 7.28 (s, 1H),
4.30 (t, J = 7.1 Hz, 2H), 2.70 (t, J = 7.5 Hz, 2H), 1.89–1.85 (m,
2H), 1.68–1.64 (m, 2H), 1.35–1.25 (m, 16H), 0.87 (s, 6H); 13C-
NMR (100 MHz, CDCl3) δ 148.1, 120.2, 49.9, 31.5, 31.4, 30.1,
29.3, 28.8, 28.8, 28.7, 26.3, 25.5, 22.4, 22.3, 13.8 (2C).
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19 Procedure for a gram-scale synthesis of 3aa: In a round bot-
tom flask, to a solution of benzyl azide 1a (1 g, 7.5 mmol)
and 2a (1.05 equiv.) was added sodium ascorbate (0.15
equiv.), betaine (0.05 equiv.), and copper(II) sulfate penta-
hydrate in H2O (10 mL of stock solution, 2.5 ppm based on
Cu). The reaction mixture was stirred for 24 h at 30 °C. The
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solid in 95% isolated yields.
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