Modular synthesis of mono, di, and tri-1,4-disubstituted-1,2,3-triazoles through copper-mediated alkyne-azide cycloaddition

Article abstract of DOI:10.1016/j.tetlet.2011.09.004

The synthesis of 1,2,3-triazoles was developed employing sequential copper azide-alkyne cycloaddition, tosylation, sodium azide, and copper azide-alkyne steps. This approach allowed the synthesis of two and three 1,2,3-triazole rings. A preliminary study

Full text of DOI:10.1016/j.tetlet.2011.09.004

Tetrahedron Letters 52 (2011) 6086–6090
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Modular synthesis of mono, di, and tri-1,4-disubstituted-1,2,3-triazoles
through copper-mediated alkyne–azide cycloaddition
⇑
Hélio A. Stefani , Hugo A. Canduzini, Flávia Manarin
Departamento de Farmácia, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, SP, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of 1,2,3-triazoles was developed employing sequential copper azide–alkyne cycloaddition,
tosylation, sodium azide, and copper azide–alkyne steps. This approach allowed the synthesis of two and
three 1,2,3-triazole rings. A preliminary study to gain further insight into the reaction was performed
using in situ ReactIR technology.
Received 8 August 2011
Revised 27 August 2011
Accepted 1 September 2011
Available online 10 September 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Click chemistry
1,2,3-Triazole
Cycloaddition
Propargyl alcohol
Ultrasound
Introduction
be the most popular reaction of the ‘click’ chemistry concept2 and
represents the most straightforward synthesis of 1,2,3-triazoles.
The copper(I)-mediated 1,3-dipolar cycloaddition of azides and
terminal alkynes1 (CuAAC) increases the reaction rates and governs
the regioselectivity, favoring 1,4-disubstituted 1,2,3-triazole for-
mation. This discovery by Sharpless and Meldal is considered to
Click chemistry has evolved as a powerful strategy with many
applications in modern chemistry, drug discovery, macromolecules,
radiopharmaceuticals, material sciences, synthesis of bis-bidentate
Pd(II) complexes, and biology, to cite just a few (Fig. 1).3
OH
H
O
OH
O
N
COOH
OH
O
HO
N
H
H
OH
AcHN
N
N
OCH3
N
N
N
HO
Antifungal activity against
various strains
Anti-AIV
Cl
O
O
H
N
N
N
N
N
N
N
N
S
S
N
N
CF3
CF3
Antifungal activity against
Candida albicans
Antifungal activity against
Candida albicans
Figure 1. Structures of biologically active 1,2,3-triazoles.
⇑
Corresponding author.
E-mail address: hstefani@usp.br (H.A. Stefani).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.004

H. A. Stefani et al. / Tetrahedron Letters 52 (2011) 6086–6090
6087
Table 1
yields, under mild conditions, and use copper sources that have
no impact on most of the other functional groups.
Screening of CuI equivalents for the click reaction
OH
This Cu(I)-mediated reaction has been largely successful be-
cause it provides virtually quantitative yields and because the ro-
bust reaction is not sensitive to solvents and functional groups.
The use of Cu(I) is superior to that of the other metal catalysts in
this reaction because it is cheap and easy to handle than the other
catalysts described to accomplish the same transformation. Most
of the other metal-catalyzed reactions involve the reduction of sta-
ble Cu(II) sources, such as CuSO4, and use sodium salts or the com-
proportionation of Cu(II)/Cu(0) species.
Recently, studies using terminal diynes show the synthesis of
bis-triazoles carried out by employing the sequential Cu-catalyzed
cycloaddition reactions involving triisopropylsilyl-protected diy-
nes and azides6 or a one-pot reaction.7
N
CuI equi
+
N
N
PMDTA (1.2 equi)
THF, rt
OH
N3
Entry
CuI equiv
Conventional yield (%)
Ultrasound yield (%)
1
2
3
0.1
0.5
1.0
44
53
67
53
63
76
Herein, we describe the initial efforts toward the modular syn-
thesis of asymmetrically di-and tri-1,4-disubstituted-1,2,3-tria-
zoles involving click chemistry using propargyl alcohol and
sodium azide.
This reaction leads to the efficient formation of the correspond-
ing 1,4-disubstituted-1,2,3-triazoles as a sole regioisomer using al-
kyl, aryl, or sulfonil azides.1,4,5 The reactions take place with high
Table 2
Synthesis of 1,4-disubstituted-1,2,3-triazoles and the corresponding tosylated derivatives
OTs
OH
N
CuI (1 eq.)
N
TsCl, KOH
THF, -20 °C to r.t
1.5 to 3.0 h
R-N3
+
N
N
OH
PMDTA (1.2 eq.)
THF, r.t, )))
10 to 20 min.
N
R
N
R
4a-e
3a-e
Entry
Product
Yield (%)
Entry
TsProduct
Yield (%)
OH
OTs
N
N
N
N
1
74
6
4a
76
3a
3b
N
N
OH
N
OTs
N
N
N
4b
N
N
2
75
7
50
NO2
OH
NO2
OTs
N
N
N
N
4c
N
3c
3
4
66
70
8
9
90
86
N
Cl
Cl
OTs
N
OH
N
N
N
N
4d
N
3d
OH
OTs
N
N
N
N
N
3e
4e
N
5
90
10
74
NO2
NO2

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H. A. Stefani et al. / Tetrahedron Letters 52 (2011) 6086–6090
Table 3 (continued)
Entry
Product/yield (%)
Entry
Product/yield (%)
Table 3
Synthesis of (1H-1,2,3-triazol-4-yl)methyl-1H-1,2,3-triazol-4-yl)methanol
R1
N
N
OTs
N
N
N
N
N
i) NaN3, DMF, rt
N
N
N
N
N
1
N
N
R
ii)
N
5e
N
N
N
5
10
iii) CuI, rt, 15-90 min R
N
N
5j
N
R
Entry
Product/yield (%)
Entry
Product/yield (%)
Cl
79
OH
71
N
N
N
N
N
N
Results
N
N
N
N
1
6
5a
NO2
N
Using the conditions described earlier,8 the initial reactions
were carried out on propargylic alcohol and organic azides to form
the corresponding 1,4-disubstituted-1,2,3-triazoles using THF as
the solvent followed by the addition of PMDETA (1,1,4,7,7-penta-
methyl-diethylenetriamine) as the base in an anhydrous nitrogen
atmosphere using ultrasound as the energy source.
5f
N
69
60
In order to find an appropriate amount of CuI the reaction was
performed with three different amounts of the catalyst, having
benzyl azide and propargylic alcohol as the model reagents, using
conventional reaction condition and with ultrasound. The best re-
sult was achieved with 1.0 equiv of CuI and ultrasound (Table 1).
To further investigate the scope and limitations of this method-
ology, we carried out the reaction with various organic azides, as
summarized in Table 2.
OH
N
N
N
N
N
N
N
N
2
7
N
N
5g
N
5b
N
It was observed that the reaction changed from yellowish to
dark colors with the addition of the base, depending on the group
linked to the azide. All products were obtained as a white solid in
moderate to good yields and very short reaction times (see Table 2,
entries 1–5).9
92
63
OH
The next step was the conversion of the hydroxyl group in the
corresponding tosyl group using a procedure described in the liter-
ature.10 All the tosylated products were obtained as a white solid in
moderate to good yields as can be seen in Table 2 (entries 6–10).
In general, no significant differences in the reactivity were ob-
served for the examined aromatic azides and the aliphatic azide.
However, the aromatic azides furnished yields ranging from 90%
to 66% (entries 2–5), whereas the aliphatic azide furnished the
product in 74% yield (entry 1). Introducing an electron-withdraw-
ing substituent on the phenyl rings gave the observed products in
66–90% yield (entries 2, 3 and 5). Replacing the organic azides with
sodium azide failed to facilitate cyclization under Cu-catalyzed
conditions.
N
N
N
N
N
N
N
N
N
N
5c
N
3
8
5h
NO2
N
51
72
OH
With the tosylate 1,2,3-triazole compounds in hand, the second
one-pot cyclization reaction was carried out to achieve a new bis-
1,2,3-triazole ring.11 The reaction was performed in DMF as the sol-
vent and with propargyl alcohol, phenylacetylene, octyl-, and hex-
yl-acetylene, leading to the bis-1,2,3-triazoles in moderate to high
yields and with short reaction times (Table 3).
The flexibility of the developed methodology using tosylated
propargyl acetylene can be extended to prepare a sequence of
tri-1,2,3-triazole rings in a one-step reaction starting from the
bis-1,2,3-triazole as shown in Scheme 1. The products were ob-
tained in moderate yields.
N
N
N
N
N
N
N
N
N
N
5d
4
9
N
5i
NO2
N
Cl
69
64

H. A. Stefani et al. / Tetrahedron Letters 52 (2011) 6086–6090
6089
R1
N
OTs
N
N
N
N
N
N
TsO
N
N
N
N
N
N
N
N
N
N
6a- 45%
NaN3, DMF, 80 o
C
N
i)
N
N
ii)
R1
, CuI, rt
N
N
N
N
N
N
N
R
N
N
N
N
N
N
5
R
6
R1= CH2OTs, Ph
6b- 50%
Scheme 1. Synthesis of tri-1,2,3-triazole rings in a one-step reaction starting from the bis-1,2,3-triazole.
Figure 2. In situ IR spectroscopy monitoring of starting material consumption.
Figure 3. In situ IR spectroscopy monitoring: (A) triazole azide formation and consumption. (B) product formation.
The low yield observed was probably due the bis-triazole reac-
tant is chelating to the catalyst and deactivating it, hence the low
yields due to unreacted starting materials.3k
As part of the optimization study, each stage of the substitu-
tion–cycloaddition process was studied using in situ ReactIR spec-
troscopy, which is a useful tool for monitoring and optimizing the
reaction process.12,13 During the experiment, it was found that the
After the addition of phenyl acetylene and copper iodide, the
peak of triazolic azide disappeared and an interesting peak at
765 cmÀ1 was visible in the IR spectrum (Fig. 3). This band re-
mained constant for few minutes. In this context, the real-time
infrared technique is very suitable for a precise interpretation of
some parameters concerning the reaction, such as its duration
and product formation. Through this analysis, we could determine
that the substitution occurs instantly at room temperature, and
also that the one-pot procedure lasts for only 15 min.
mSO2 of the tosyl group could be observed easily. As soon as sodium
azide was added, the peak at 1178 cmÀ1 which was assigned to the
vibrational stretching of the sulfone in the tosyl group disappeared.
This information indicates that the substitution occurs quite rap-
idly at room temperature (Fig. 2). Moreover, there was a rapid in-
crease in the band at 2102 cmÀ1, indicating the formation of a
triazolic azide. This peak was assigned to the vibrational stretching
of N3, which is related to azides.14
Summary
In summary, a modular method for the generation of function-
alized one, bis-, and tri-1,4-disubstituted 1,2,3-triazoles has been

6090
H. A. Stefani et al. / Tetrahedron Letters 52 (2011) 6086–6090
9. General procedure: Synthesis of 1,4-disubstituted-1,2,3-triazoles. In a 50 mL
two-neck flask under a nitrogen atmosphere, a propargyl alcohol solution
(0.28 g, 0.3 mL, 5 mmol) was added with a dissolved organic azide (1.2 equiv,
6 mmol) in THF (8 mL) and the copper catalyst (1 equiv, 5 mmol). The reaction
developed employing a sequence of Cu(I)-catalyzed 1,3-cycloaddi-
tion of organic azides with terminal alkynes, the CuAAC ‘click’ reac-
tion, in good to excellent yields. The execution of this strategy is
simple and suitable for the rapid assembly of molecular complex-
ity, with new bonds being formed. The new 1,2,3-triazoles were
fully characterized by HRMS, IR, 1H, and 13C NMR. A preliminary
study to gain further insight into the reaction was performed using
in situ ReactIR technology. Further studies on this methodology,
applications, and the mechanism of the reaction are currently
ongoing in our laboratory and will be reported in due course.
was then put in
a ultrasound bath for homogenization, followed by the
addition of PMDETA (1.03 g, 1.25 mL, 6 mmol) drop by drop until the starting
material was consumed, followed by TLC. The resulting aqueous phase was
washed with ethyl acetate, the organic phase was dried with MgSO4, filtered
and the solvent was evaporated under vacuum. The crude product was purified
by column chromatography using as the eluent a mixture of hexane/ethyl
acetate (2/8) (see Supplementary data for reaction time). (1-Benzyl-1H-1,2,3-
triazol-4-yl)methanol (3a): The product was obtained as a with solid, MP. 78–
79 °C, in 74% yield: 1H NMR (300 MHz, CDCl3) d (ppm): 7.43 (s, 1H), 7.39–7.34
(m, 3H), 7.27–7.25 (m, 2H), 5.51 (s, 1H), 4.76 (s, 2H). 13C NMR (75.5 MHz,
CDCl3) d (ppm): 54.17, 56.08, 121.93, 128.13, 128.77, 129.12, 134.58, 148.35. IR
cmÀ1 (ethyl acetate solution): 3600, 2989, 1759, 1241, 1055, 927. HRMS calcd
for C10H11N3O 189.0902. Found: [M+Na] = 212.0794.
Acknowledgments
10. Hastings, C. J.; Fiedler, D.; Bergman, R. G.; Raymond, K. N. J. Am. Chem. Soc.
2008, 130, 10977.
We gratefully acknowledge financial support from FAPESP (07/
59404-2) and CNPq for fellowships (HAS - 300.613/2007-5 and
HAC - 130736/2011-2).
General procedure: Synthesis of Tosyl triazoles. In a two neck flask of 50 mL
under nitrogen atmosphere was added KOH (0.64 g, 5 mmol) and tosyl chloride
(0.45 g, 2.2 mmol) dissolved in THF (8 mL). The suspension was cooled to 0 °C
and the required triazole (2 mmol) was added in one portion. The mixture was
stirred for 2 h at room temperature. In the end of reaction the aqueous phase
was washed with ethyl acetate, the organic phase obtained was dried with
MgSO4, filtered and the solvent evaporated under vacuum. The crude product
was purified by column chromatography using as eluent a mixture of hexane/
ethyl acetate (7/3). (1-(3-Chlorophenyl)-1H-1,2,3-triazol-4-yl)methyl-4-
methylbenzenesulfonate (4c): The product was obtained as a white solid in
90% yield: 1H NMR (300 MHz, CDCl3) d (ppm): 7.91 (s, 1H); 7.74 (d, J = 8.4 Hz,
1H), 7.65 (d, J = 1.9 Hz, 1H), 7.52 (tt, J = 2.0/7.30 Hz, 2H), 7.42–7.34 (m, 2H), 7.27
(d, J = 8.4 Hz, 2H), 5.22 (s, 2H), 2.36 (s, 3H). 13C NMR (75 MHz, CDCl3) d (ppm):
145.2, 142.0, 141.2, 140.5, 137.5, 135.7, 135.5, 133.0, 131.5, 130.9, 130.8, 130.2,
129.9, 129.2, 128.9, 128.2, 128.0, 125.8, 124.3, 122.2, 121.7, 120.8, 118.5, 62.9,
Supplementary data
Supplementary data (experimental procedures and spectral
data) associated with this article can be found, in the online ver-
sion, at doi:10.1016/j.tetlet.2011.09.004.
References and notes
1. (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int.
Ed. 2002, 41, 2596; (b) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem.
2002, 67, 3057.
21.6. IR (neat)
m: 4433, 3509, 2988, 2349, 2088, 1759, 1460, 1241, 1055, 848,
624 cmÀ1
.
2. Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40, 2004.
3. (a) Mamat, C.; Ramenda, T.; Wuest, F. R. Mini-Rev. Org. Chem. 2009, 6, 21; (b)
Prescher, J. A.; Bertozzi, C. R. Nat. Chem. Biol. 2005, 1, 13; (c) Wangler, C.;
Schirrmacher, R.; Bartenstein, P.; Wangler, B. Curr. Med. Chem. 2010, 17, 1092;
(d) Walsh, J. C.; Kolb, H. C. Chimia Aarau 2010, 64, 29; (e) Binder, W. H.;
Sachsenhofer, R. Macromol. Rapid Commun. 2007, 28, 15; (f) Kou, L.; He, H.; Gao,
C. Nano-Micro Lett. 2010, 2, 177; (g) Kou, L.; He, H.; Gao, C. Macromol. Rapid
Commun. 2008, 29, 1073; (h) Kolb, H. C.; Sharpless, K. B. Drug Discovery Today
2003, 8, 1128; (i) Vatmurge, N. S.; Hazra, B. G.; Pore, V. S.; Shirazi, F.; Chavan, P.
S.; Deshpande, M. V. Bioorg. Med. Chem. Lett. 2008, 18, 2043; (j) Holla, B. S.;
Mahalinga, M.; Karthikeyan, M. S.; Poojary, B.; Akberali, P. M.; Kumari, N. S. Eur.
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Anderson, C. B.; Lind, S. J.; Keep, C. C.; Gordon, K. C.; Crowley, J. D. Inorg. Chem.
2011, 50, 6334.
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York, 1984; p 1.
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11. General procedure: Synthesis of bis- and tris-1,2,3-triazoles. In a 50 mL two-
neck flask under a nitrogen atmosphere, the starting material (0.5 mmol) was
added with sodium azide (1.1 equiv, 0.55 mmol) dissolved in DMF. The
mixture was stirred until the starting material was consumed, followed by
TLC. After the conversion of the starting material, acetylene (1.2 equiv,
0.6 mmol) and the copper catalyst (1.0 equiv, 0.5 mmol) were added under
vigorous stirring. At the end of reaction, the aqueous phase was washed with
ethyl acetate, the organic phase was dried with MgSO4, filtered and the solvent
was evaporated under vacuum. 1-Phenyl-4-(4-phenyl-1H-1,2,3-triazol-1-yl)-
1H-1,2,3-triazole (5e): The product was obtained as a white solid in 79% yield:
1H NMR (300 MHz, CDCl3) d (ppm); 7.99 (s, 1H); 7.92 (s, 1H); 7.75 (d, J = 7.0 Hz,
2H); 7.63 (d, J = 7.1 Hz, 2H), 7.48–7.25 (m, 6H); 5.74 (s, 2H); 13C NMR (75 MHz,,
CDCl3) d (ppm): 148.4, 136.7, 130.4, 129.9, 129.2, 128.9, 128.3, 125.8, 121.4,
120.7, 119.9, 45.5. IR (neat) m: 4435, 3509, 2988, 2088, 1759, 1460, 1241, 1055,
926, 623 cmÀ1. HRMS calcd for C17H14N6 302.1280. Found [M+Na] = 325.1172.
1-Phenyl-4-((4-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)-1H-1,2,3-triazol-
1-yl)methyl)-1H-1,2,3-triazole (6b): The product was obtained as a white
solid in 50% yield: 1H NMR (300 MHz, CDCl3) d (ppm): 8.08 (s, 1H), 8.00 (s, 1H),
7.81 (d, J = 7.2 Hz, 2H), 7.70 (d, J = 7.9 Hz, 2H), 7.54–7.32 (m, 7H), 5.80 (s, 4H).
13C NMR (75 MHz, CDCl3) d (ppm): 148.4, 142.6, 136.7, 130.4, 129.9, 129.2,
128.9, 128.3, 125.8, 121.4, 120.7, 119.9, 45.5. IR cmÀ1 (ethyl acetate solution):
3511, 2988, 2088, 1759, 1461, 1244, 1058, 849.
7. Angell, Y.; Burgess, K. Angew. Chem., Int. Ed. 2007, 46, 3649.
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