Sonochemical synthesis of 1,4-disubstituted 1,2,3-triazoles in aqueous medium

Article abstract of DOI:10.1080/00397910601133599

An ultrasound-accelerated fast and efficient three-component reaction for the regioselective synthesis of l,4-disubstituted 1,2,3-triazoles using different alkyl and allyl halides, terminal alkynes, and sodium azide in water at room temperature has been developed using CuI as catalyst. Ultrasonication dramatically decreases the reaction times. Copyright Taylor & Francis Group, LLC.

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Sonochemical Synthesis of 1,4‐Disubstituted
1,2,3‐Triazoles in Aqueous Medium
B. Sreedhar a & P. Surendra Reddy a
a Inorganic and Physical Chemistry Division, Indian Institute of Chemical
Technology, Hyderabad, India
Published online: 10 Mar 2007.
To cite this article: B. Sreedhar & P. Surendra Reddy (2007) Sonochemical Synthesis of 1,4‐Disubstituted
1,2,3‐Triazoles in Aqueous Medium, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 37:5, 805-812, DOI: 10.1080/00397910601133599
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Synthetic Communicationsw, 37: 805–812, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910601133599
Sonochemical Synthesis of 1,4-Disubstituted
1,2,3-Triazoles in Aqueous Medium
B. Sreedhar and P. Surendra Reddy
Inorganic and Physical Chemistry Division, Indian Institute of Chemical
Technology, Hyderabad, India
Abstract: An ultrasound-accelerated fast and efficient three-component reaction for
the regioselective synthesis of l,4-disubstituted 1,2,3-triazoles using different alkyl
and allyl halides, terminal alkynes, and sodium azide in water at room temperature
has been developed using CuI as catalyst. Ultrasonication dramatically decreases the
reaction times.
Keywords: copper iodide, 1,4-disubstituted 1,2,3-triazoles, ultrasonication
INTRODUCTION
The search for novel medicinally active compounds and optimization of fast and
efficient approaches for their synthesis has drawn considerable attention in
recent years. Cu(I)-catalyzed ligation of organic azides and terminal alkynes
that belong to a group of reactions referred to as “click chemistry”, a term
coined by Sharpless et al. has enjoyed much use since its discovery because
these compounds are known to possess remarkable biological properties such
as anti-allergic,[1] antibacterial,[2] anti-HIV,[3] antiviral, and anti-epileptic activi-
ties and applications in drug discovery, bioconjugates, and medicinal chemistry
as well as materials chemistry.[4] Among the different methods for the synthesis
of triazoles, Huisgen’s 1,3-dipolar cycloaddition of azides and terminal alkynes
is perhaps the most remarkable example of click chemistry.[5] Some of the other
methodologies include the Cu(I)-catalyzed regioselective ligation of azides and
Received in India 28 July, 2006
Address correspondence to B. Sreedhar, Inorganic and Physical Chemistry
Division, Indian Institute of Chemical Technology, Hyderabad 500 007, India.
E-mail: sreedharb@iict.res.in
805

806
B. Sreedhar and P. S. Reddy
terminal alkynes,[6] reaction of azides with metal acetylides,[7] alkynic Grignard
reagents,[8] phosphonium salts,[9] electron-deficient terminal alkynes,[10] and
Pd(0)–Cu(I) bimetallic catalyst[11] for the synthesis of triazoles. Recently,
Prasad et al. reported the three-component reaction to synthesize 1,4-disubsti-
tuted 1,2,3-triazoles under microwave irradiation.[12] Very recently, 1,3-
cycloadditions of azides to terminal alkynes using copper nanoclusters[13] and
amine hydrochloride salts[14] have been reported for the synthesis of 1,2,3-
triazoles. Most of these methods require longer reaction times, except the
reaction under microwave conditions.
Ultrasound-accelerated chemical reactions are well known and proceed via
the formation and adiabatic collapse of the transient cavitation bubbles.[15]
Ultrasonic irradiation can be utilized as an alternative energy source for
organic reactions ordinarily accomplished by heating. It increases the reaction
rate many fold when compared with the conventional reaction conditions.
Many reports on versatile reactions carried out using ultrasonication are
reported in the literature.[16–19] Low-temperature Heck reaction with Pd/C by
Ambulgekar et al.[16] Reformatsky reactions by Ross and coworkers,[17] and
sonochemical preparation of ionic liquids by Namboodiri et al.[18] are some
few examples. In continuation of our studies on sonochemical reactions,[19]
we have developed a sonochemical synthesis of 1,4-disubstituted 1,2,3-
triazoles through 1,3-dipolar cycloadditon of alkyl/aryl azides, which are
formed in situ by the reaction of alkyl halide and sodium azide with terminal
alkynes (Scheme 1) using water as the solvent and CuI catalyst in a shorter time.
RESULTS AND DISCUSSION
Initially, different copper salts were screened for the synthesis of triazoles
using benzyl chloride, phenylacetylene, and sodium azide as model substrates
in water under sonication for 20 min. The results are as shown in Table 1. It is
evident from the table that Cu(II) salts and copper powder were effective, and
the product was obtained in lower yields in a nonregioselective manner
(entries 1–4), whereas a combination of Cu(II), Cu(0)12 salts, CuSO4, and
sodium ascorbate systems[20] afforded the product in moderate yields
(entries 5, 6). Among the copper(I) salts, CuI was found to be more
Scheme 1.

1,4-Disubstituted 1,2,3-Triazoles
807
Table 1. Screening of copper salts for the synthesis of 1,4-disub-
stituted 1,2,3-triazolesa
Entry
Copper salt
Isolated yieldb (%)
1
2
Cu (acac)2
Cu(OAc)2
26
35
40
30
65
56
50
70
92
16
30c
92d
3
CuCl2
Cu powder
4
5
Cu powder þ CuSO4
6
CuSO4 þ Sodium ascorbate
7
CuCl
CuOTf
CuI
8
9
10
11
12
—
CuI
CuI
aReaction conditions as exemplified in the typical experimental
procedure.
bIsolated yields.
cReaction at room temperature.
effective catalyst when compared to CuCl and CuOTf (entries 7–9). However,
in the absence of catalyst, the product was obtained in a trace quantity (entry
10). To establish the generality of the reaction, a sonochemical protocol has
been compared with the conventional method of synthesis using the model
substrates in the presence of CuI as catalyst in an aqueous medium. The
reaction at room temperature gave the product in low yield, whereas the
reaction at high temperature afforded the product in good yield but required
a longer reaction time (entries 11, 12).
Under the optimized reaction conditions using CuI as the catalyst,
different 1,4-disubstituted triazoles were synthesized in good to excellent
yields with high regioselectivity under ultrasonic irradiation, and the results
are tabulated in Table 2. Benzylic halides were subjected to reaction with
different terminal alkynes and sodium azide, and the corresponding
products were obtained in high yields (Table 1, entries 1–6). When ethyl bro-
moacetate was used as the alkyl halide, the reaction proceeded smoothly and
the product was isolated in quantitative yield (Table 1, entry 7). Allyl halides
such as allyl bromide, allyl iodide, and cinnamyl chloride afforded the
products in excellent yield (Table 1, entries 8, 9, and 10). As can be seen
from Table 2, the scope of reaction using different terminal alkynes such as
phenyl acetylene, p-methyl phenyl acetylene, and propargyl and homopropar-
gyl alcohols were also found to be excellent. When methyl iodide was used as
the halide source, the product was obtained in good yield (Table 2, entry 11),
and this methodology serves as a powerful tool for the synthesis of l-methyl-4-
phenyl-1H-1,2,3-triazole because the hazardous methyl azide is formed in situ

808
B. Sreedhar and P. S. Reddy
Table 2. Synthesis of 1,4-disubstituted 1,2,3-triazoles with different alkyl halides,
terminal alkynes, and sodium azidea
Terminal
alkyne
Time Yieldb
(h) (%)
Entry
1
Alkyl halide
Product
20 92 68c
2
20
95
3
4
5
6
7
8
9
30
30
30
30
15
30
30
89
84
92
86
95
89
86
10
11
12
30
30
30
82
80
52
13
30
68
aReaction conditions as exemplified in the typical experimental procedure.
bIsolated yields.
cYield with 5 mol% of CuI catalyst.

1,4-Disubstituted 1,2,3-Triazoles
809
in this reaction. However, when the reaction was conducted with disubstituted
benzyl chloride as alkyl halide, moderate yields were obtained (Table 2,
entries 12, 13). When the mole percent of the catalyst was reduced to
5 mol%, the reaction proceeded equally well, but moderate yields were
obtained within the reaction time. (Table 2, entry 1).
In conclusion, a ultrasound-accelerated fast and efficient three-component
reaction for the synthesis of l,4-disubstituted 1,2,3-triazoles in a completely
regioselective manner directly using different alkyl, allyl halides, sodium
azide, and terminal alkynes in water has been developed using CuI as
catalyst. The operational simplicity of this protocol using water as the
solvent and the purity of the recovered products makes it attractive not only
for large-scale synthesis of this class of biologically active molecules but
for the synthesis of screening libraries for drug discovery as well.
EXPERIMENTAL
1H NMR spectra were recorded in CDCl3 on Varian FT-200 (200-MHz)
machine using TMS as internal standard. Mass spectra were taken on a
Finnigan Mat-1210 double focusing spectrometer.
General Procedure for the Synthesis of Triazoles
A mixture of halide (1.0 mmol), terminal alkyne (1.1 mmol), sodium azide
(0.0064 g, 1.0 mmol), and CuI (0.010 g, 0.001 mol) in water (5 ml) was
sonicated for 20 min in a laboratory ultrasonic cleaning bath. After completion
of the reaction, as indicated by TLC, the reaction mixture was diluted with
water (20 mL), and the precipitated product was collected by filtration and
washed with cold water (20 mL), 0.25 M HCl (10 mL), and petroleum ether
(50 mL) to furnish pure product. All other products were characterized
similarly and were found to be comparable with the literature reports.[12]
Spectral Data
1
Table 2, entry 2: H NMR (200 MHz, CDCl3) d 2.37 (s, 3H), 5.55 (s, 2H),
7.14–7.18 (d, J ¼ 8.018, 2H), 7.26–7.37 (m, 5H), 7.55 (s, 1H), 7.63–7.67
(d, J ¼ 8.018, 2H) ppm. EIMS: m/z (%): 249 (Mþ, 90); HRMS (ES):
calcd. for C15HI3N3: 249.2105, found: 249.166. Anal. calcd. for C15H13N3:
C, 77.08; H, 6.06; N, 16.85. Found: C, 77.45; H, 6.31; N, 16.14.
1
Table 2, entry 7: H NMR (200 MHz, CDCl3): d 1.30–1.41 (q, J ¼ 7.623,
3H), 4.24–4.35 (q, J ¼ 6.776, 2H), 5.17 (s, 2H), 7.26–7.43 (m, 5H), 7.80
(s, 1H). EIMS: m/z (%): 231 (Mþ, 30); HRMS (ES): calcd. for

810
B. Sreedhar and P. S. Reddy
C12H13N3O2: 231.2506, found: 231.2008. Anal. calcd. for C12H13N3O2: C,
62.33; H, 5.67; N, 18.17. Found: C, 62.30; H, 5.71; N, 18.61.
Table 2, entries 8 and 9: 1H NMR (200 MHz, CDCl3): d 4.97–5.01
(d, J ¼ 6.250, 2H), 5.28–5.39 (t, J ¼ 10.156, 2H), 5.9–6.21 (ddd, J ¼ 5.45,
6.25, 10.156, IH), 7.26–7.43 (m, 5H), 7.76 (s, 1H) ppm. EIMS: m/z (%):
185 (Mþ, 45); HRMS (ES): calcd. for C11H11N3: 185.2253, found:
182.2213. Anal, calcd. for C11H11N3: C, 71.33; H, 5.99; N, 22.69. Found:
C, 61.31; H, 6.17; N, 22.54.
Table 2, entry 11: 1H NMR (300 MHz, CDCl3): d 5.25–5.31 (t, J ¼ 7.13, 2H),
6.24–6.36 (dt, J ¼ 15.75, 6.20, 1H), 6.45–6.50 (d, J ¼ 15.75), 7.31–7.49
(m, 5H), 7.80 (s, 1H) ppm. EIMS: m/z (%): 261 (Mþ, 90); HRMS (ES):
calcd. for C17H15N3: 261.3212, found: 261.1263. Anal. calcd. for C17H15N3:
C, 78.13; H, 5.79; N, 16.08. Found: C, 78.15; H, 5.92; N, 15.98.
Table 2, entry 12: 1H NMR (300 MHz, CDCl3): d 3.78 (s, 6H), 5.24 (s, 1H),
7.12–7.19 (d, J ¼ 8.40, 1H), 7.28–7.31 (d, J ¼ 8.40, 1H), 7.43–7.6 (m, 5H)
ppm. EIMS: m/z (%): 295 (Mþ, 100); HRMS (ES): calcd. for C17H15N3:
295.3159, found: 295.3359. Anal. calcd. for C16H15N3O2: C, 69.14; H,
5.80; N, 14.23. Found: C, 69.11; H, 5.92; N, 14.15.
Table 2, entry 13: 1H NMR (300 MHz, CDCl3): d 3.74 (s, 6H), 5.32 (s, 2H),
6.72 (s, 1H), 7.43–7.52 (m, 5H), 7.68 (s, 1H) ppm. EIMS: m/z (%): 295 (M:þ
100); HRMS (ES): calcd. for C]7H15N3: 295.3159, found, 295.3132. Anal.
calcd. for C16H15N3O2: C, 69.14; H, 5.80; N, 14.23. Found: C, 69.11; H,
5.89; N, 14.18.
ACKNOWLEDGMENTS
PSR thanks the director, Indian Institute of Chemical Technology, Hyderabad,
for providing facilities for carrying out his M. Tech. dissertation work. PSR also
thanks the Council of Scientific and Industrial Research, New Delhi, for the
award of Senior Research Fellowship.
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