The first multicomponent synthesis of propargyl-1,2,3-triazoles

Article abstract of DOI:10.1055/s-0030-1260105

The three-component reaction of benzotriazoles, aldehydes, and alkynes has been carried out for the first time using zinc bromide as a catalyst. The corresponding propargylbenzotriazoles are formed in high yields (79-97%) within 6-10 hours. Georg Thieme V

Full text of DOI:10.1055/s-0030-1260105

PAPER
2625
The First Multicomponent Synthesis of Propargyl-1,2,3-triazoles1
Multicomponent
i
Synthe
s
sis of
P
rop
w
argyl-1,2, 3-triazo
a
les nath Das,* Nisith Bhunia, Maram Lingaiah, Parigi Raghavendar Reddy
Organic Chemistry Division-1, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax +91(40)27193198; E-mail: biswanathdas@yahoo.com
Received 15 April 2011
zinc bromide in toluene under reflux. The reaction was
complete in six hours and the yield of the product, 1-(1,3-
diphenylprop-2-ynyl)-1H-benzo[d][1,2,3]triazole, was
98% (Table 1, entry 11).
Abstract: The three-component reaction of benzotriazoles, alde-
hydes, and alkynes has been carried out for the first time using zinc
bromide as a catalyst. The corresponding propargylbenzotriazoles
are formed in high yields (79–97%) within 6–10 hours.
Key words: propargyl-1,2,3-triazole, benzotriazole, aldehyde,
alkyne, zinc bromide
Table 1 Optimization of Reaction Parameters for the Synthesis of
1-(1,3-Diphenylprop-2-ynyl)-1H-benzo[d][1,2,3]triazolea
N
N
1,2,3-Triazoles are highly important on account of their
medical uses.2 They are occasionally found in various
orally administrated drugs.3 They behave as light activat-
able DNA cleaving agents4a and potassium channel acti-
vators.4b They are also applicable in material science.5
Some of these compounds are used as building blocks for
the preparation of bioactive molecules.6 Additionally,
they are employed as ligands in transition metal catalysis.7
Acetylenic compounds, on the other hand, are valuable in
biochemistry and material system.8 Thus, the preparation
of triazoles having alkynyl moiety is a useful task in or-
ganic synthesis. Here, we report a simple synthesis of pro-
pargyl-1,2,3- triazoles involving the coupling of three
substrates in one pot. To the best of our knowledge, there
is no report of the multicomponent synthesis of these
compounds.
N
N
catalyst (10 mol%)
N
+
PhCHO
H
solvent, reflux
6–10 h
N
Ph
H
+
Ph
Ph
Entry
Catalyst
Solvent
Temp (°C)/ Yield(%)b
time (h)
1
2
Zn dust
Zn dust/I2
ZnO
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
toluene
THF
80/10
80/10
80/10
80/10
80/10
80/10
80/10
110/10
80/10
100/10
110/6
56
65
47
52
83
85
84
93
61
57
97
3
4
ZnO nano
ZnCl2
5
6
ZnBr2
In continuation of our work9 on the development of useful
synthetic methodologies, we have now discovered that the
treatment of benzotriazoles 1 with aldehydes 2 and
alkynes 3 in the presence of a catalytic amount of zinc bro-
mide in toluene afforded the corresponding propargyl-
1,2,3-triazoles 4 under reflux conditions (Scheme 1).
7
Zn(OTf)2
ZnBr2
8
9
ZnBr2
10
ZnBr2
1,4-dioxane
toluene
Initially, the parent benzotriazole was treated with benzal- 11
dehyde and phenylacetylene using zinc dust and several
other zinc salts as catalysts in various solvents at different
ZnBr2
a Reaction conditions: benzotriazole (1 mmol), benzaldehyde (1
mmol), phenylacetylene (1.2 mmol), and catalyst (10 mol%) in sol-
vent under reflux.
temperatures (Table 1). The conversion was found to be
most effective when it was carried out in the presence of b Isolated yield after purification.
R1
N
N
N
N
ZnBr2 (10 mol%)
R2CHO
R1
H
R3
N
+
+
toluene, reflux
6–10 h
R2
N
H
R3
1
2
3
4
R1 = H, aryl
R
R
79–97%
2 = aryl
3 = aryl, alkyl
Scheme 1 Synthesis of propargylbenzotriazoles
SYNTHESIS 2011, No. 16, pp 2625–2628
x
x.
x
x
.
2
0
1
1
Advanced online publication: 14.07.2011
DOI: 10.1055/s-0030-1260105; Art ID: Z40411SS
© Georg Thieme Verlag Stuttgart · New York

2626
B. Das et al.
PAPER
Following the above screening result, a series of propar- tion of triazolium imines. The aromatic aldehydes con-
gyl-1,2,3-triazoles were prepared by zinc bromide cata- tained electron-donating as well as electron-withdrawing
lyzed three-component reaction of benzotriazoles 1, groups. Both the aromatic and aliphatic alkynes under-
aldehydes 2, and alkynes 3 in toluene under reflux went the conversion smoothly. Even a naphthylacetylene
(Table 2). Aromatic and heteroaromatic aldehydes were derivative afforded the desire product in high yield
used to prepare the triazole derivatives. However, aliphat- (Table 2, entry 9). The structures of all the products were
ic aldehydes could not yield any products, probably due to established from their spectral (NMR and MS) and analyt-
less reactivity of aliphatic aldehydes towards the forma- ical data.
Table 2 Zinc Bromide Catalyzed Three-Component Coupling of Aldehyde, Alkyne, and Triazolesa
R1
N
N
N
N
ZnBr2 (10 mol%)
R1
R2CHO
R3
H
N
+
+
toluene, reflux
6–10 h
R2
N
H
R3
1
2
3
4
Entry
1
R1
H
R2
Ph
R3
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Time (h)
Productb
4a
Yield (%)c
97
6
6
2
H
4-FC6H4
4b
4c
96
3
H
4-MeC6H4
7
90
4
H
4-MeOC6H4
6.5
6
4d
4e
86
5
H
2-NO2C6H4
84
6
H
furyl
7
4f
88
7
H
thienyl
8
4g
95
8
H
Me(CH2)3CH2
10
6
4h
4i
n.r.
93
9
H
Ph
Ph
Ph
Ph
Ph
Pr
7-methoxy-2-naphthyl
10
11
12
13
14
15
H
CH2(CH2)3Me
9
4j
91
H
SiMe3
Ph
7
4k
4l
89
4-Ph
H
6
82
Pr
10
10
10
4m
4n
4o
79
H
Ph
n.r.
n.r.
H
Bn
Ph
a Reaction conditions: benzotriazole (1 mmol), aldehyde (1 mmol), alkyne (1.2 mmol), ZnBr2 (10 mol%), and toluene (2 mL) under reflux.
b The structures of the products were established from their spectral (1H, 13C NMR, and ESI-MS) and analytical data.
c Isolated yields after purification.
ZnBr2
N
N
N
R2
H
+ R1CHO
N
N
N
H
R2
R1
HBr
N
N
Br
N
R1
R2
ZnBr
Scheme 2 Plausible mechanism for the zinc bromide catalyzed synthesis of propargyl-1,2,3-triazoles
Synthesis 2011, No. 16, 2625–2628 © Thieme Stuttgart · New York

PAPER
Multicomponent Synthesis of Propargyl-1,2,3-triazoles
2627
The multicomponent synthesis,10 which produces the
product directly without requiring the purification of any
intermediates, has gained much importance in recent
years. The yields are also increased and the reaction times
decreased. Additionally, the other advantages are atom-
economy and selectivity. Here the propargyltriazoles have
been prepared by a three-component reaction in one pot.
Earlier the synthesis of these compounds was achieved in-
volving the reaction of 1,2,3-triazoles with substituted
propargyl alcohols by ‘C–O’ bond activation of the lat-
ter.11
1-[1-(4-Methoxyphenyl)-3-phenylprop-2-ynyl]-1H-ben-
zo[d][1,2,3]triazole (4d)
1H NMR (200 MHz, CDCl3): d = 8.05 (d, J = 8.0 Hz, 1 H), 7.58 (d,
J = 8.0 Hz, 1 H), 7.52–7.46 (m, 4 H), 7.39–7.26 (m, 6 H), 6.84 (d,
J = 8.0 Hz, 2 H), 3.78 (s, 3 H).
13C NMR (50 MHz, CDCl3): d = 160.3, 147.0, 131.9, 131.4, 129.1,
128.5, 128.4, 127.2, 124.1, 121.5, 120.0, 114.1, 111.0, 89.1, 82.6,
55.3, 55.2.
ESIMS: m/z = 362 [M + Na]+.
Anal. Calcd for C22H17N3O: C, 77.86; H, 5.05; N, 12.38. Found: C,
77.92; H, 5.09; N, 12.43.
A plausible mechanism of the present conversion is
shown in Scheme 2. The catalyst zinc bromide activates
the alkyne ‘C–H’ bond to form a zinc acetylide.12 The lat-
ter reacts with the triazolium salt generated by the reaction
of a triazole and an aldehyde to furnish the propargyl-
1,2,3-triazole derivative.
1-[1-(2-Nitrophenyl)-3-phenylprop-2-ynyl]-1H-ben-
zo[d][1,2,3]triazole (4e)
1H NMR (200 MHz, CDCl3): d = 8.12–8.03 (m, 2 H), 8.01 (s, 1 H),
7.78 (d, J = 8.0 Hz, 1 H), 7.70–7.61 (m, 2 H), 7.59–7.50 (m, 2 H),
7.48–7.34 (m, 3 H), 7.32–7.24 (m, 3 H).
13C NMR (50 MHz, CDCl3): d = 147.4, 141.9, 135.5, 134.0, 133.1,
132.0, 131.2, 130.1, 129.3, 128.4, 128.0, 125.9, 124.4, 110.2, 88.1,
82.2, 51.2.
In conclusion, we have developed for the first time a sim-
ple multicomponent synthesis of propargyltriazoles in-
volving the coupling of benzotriazoles, aldehydes, and
alkynes in one pot using zinc bromide as a catalyst.
ESIMS: m/z = 355 [M + H]+.
Anal Calcd for C21H14N4O2: C, 71.19; H, 3.96; N, 15.82. Found: C,
71.28; H, 3.92; N, 15.76.
1-[1-(Fur-2-yl)-3-phenylprop-2-ynyl]-1H-benzo[d][1,2,3]tria-
zole (4f)
The silica gel F254 plates were used for TLC; the spots were exam-
ined under UV light and then developed by I2 vapor. Column chro-
matography was performed with silica gel (BDH 100–200 mesh).
Solvents were purified according to standard procedures. The spec-
tra were recorded with the following instruments; IR: Perkin-Elmer
RX FT-IR spectrophotometer; NMR: Varian Gemini 200 MHz (1H)
and 50 MHz (13C) spectrometer; ESIMS: VG-Autospec micromass.
1H NMR (200 MHz, CDCl3): d = 8.06 (d, J = 8.0 Hz, 1 H), 7.72 (d,
J = 8.0 Hz, 1 H), 7.50–7.31 (m, 9 H), 6.72 (m, 1 H), 6.38 (m, 1 H).
13C NMR (50 MHz, CDCl3): d = 151.6, 147.8, 142.8, 132.0, 131.7,
129.3, 128.5, 127.6, 127.1, 124.0, 120.0, 110.5, 110.2, 108.3, 87.9,
80.6, 50.0.
ESIMS: m/z = 300 [M + H]+.
ZnBr2-Catalyzed Three-Component Coupling Reaction; Gen-
eral Procedure
Anal. Calcd for C19H13N3O: C, 76.25; H, 4.35; N, 14.05. Found: C,
76.33; H, 4.31; N, 14.10.
Under an N2 atmosphere, a sealed reaction tube with a Teflon-coat-
ed screw-cap equipped with a magnetic stir bar was charged with
alkyne 3 (1.2 mmol), aldehyde 2 (1.0 mmol), benzotriazole 1 (1.0
mmol), ZnBr2 (0.10 mmol), and toluene (2 mL). The reaction vessel
was placed in an oil bath at 110 °C and the mixture was stirred for
10 h. After completion of the reaction as monitored by TLC (hex-
ane–EtOAc, 9:1), the reaction mixture was cooled to r.t., concen-
trated under reduced pressure, and extracted with EtOAc (3 × 10
mL). The combined extracts were dried (Na2SO4) and concentrated
under reduced pressure. The residue was purified by flash column
chromatography (eluent: hexane–EtOAc, 20:1) to give the expected
product 4 (Table 2).
1-[3-Phenyl-1-(thien-2-yl)prop-2-ynyl]-1H-benzo[d][1,2,3]tria-
zole (4g)
1H NMR (200 MHz, CDCl3): d = 8.03 (d, J = 8.0 Hz, 1 H), 7.71 (d,
J = 8.0 Hz, 1 H), 7.52–7.48 (m, 3 H), 7.41–7.20 (m, 7 H), 6.92 (m,
1 H).
13C NMR (50 MHz, CDCl3): d = 139.0, 131.9, 131.2, 129.8, 128.2,
127.4, 127.2, 126.9, 124.1, 121.1, 120.1, 110.0, 88.2, 82.1, 51.4.
ESIMS: m/z = 316 [M + H]+.
Anal. Calcd for C19H13N3S: C, 72.36; H, 4.15; N, 13.32. Found: C,
72.42; H, 4.17; N, 13.24.
The spectral data of some representative products are given below.
1-[3-(7-Methoxynaphthalen-2-yl)-1-(thiophen-2-yl)prop-2-
ynyl]-1H-benzo[d][1,2,3]triazole (4i)
1-[1-(4-Fluorophenyl)-3-phenylprop-2-ynyl]-1H-ben-
zo[d][1,2,3]triazole (4b)
1H NMR (200 MHz, CDCl3): d = 8.08 (d, J = 8.0 Hz, 1 H), 7.92 (s,
1 H), 7.69–7.55 (m, 5 H), 7.44 (d, J = 8.0 Hz, 1 H), 7.40–7.29 (m, 4
H), 7.15–7.02 (m, 4 H), 3.90 (s, 3 H).
1H NMR (200 MHz, CDCl3): d = 8.05 (d, J = 8.0 Hz, 1 H), 7.60–
7.48 (m, 5 H), 7.39–7.28 (m, 6 H), 7.10–7.02 (m, 2 H).
13C NMR (50 MHz, CDCl3): d = 162.8 (d, J = 280.0 Hz), 146.9,
132.0, 131.7, 129.1, 129.0, 128.9, 128.3, 127.2, 127.0, 123.9, 119.9,
115.8 (d, J = 10.0 Hz), 110.6, 89.1, 82.2, 55.0.
13C NMR (50 MHz, CDCl3): d = 158.8, 147.1, 134.6, 131.8, 131.2,
129.1, 129.0, 128.9, 128.7, 127.4, 127.0, 124.1, 119.1, 118.8, 116.0,
115.8, 110.5, 105.8, 90.2, 81.5, 55.1.
ESIMS: m/z = 328 [M + H]+.
ESIMS: m/z = 390 [M + H]+.
Anal Calcd for C21H14FN3: C, 77.06; H, 4.28; N, 12.84. Found: C,
77.14; H, 4.23; N, 12.93.
Anal. Calcd for C26H19N3O: C, 80.21; H, 4.88; N, 10.80. Found: C,
80.32; H, 4.94; N, 10.85.
1-(1-Phenyloct-2-ynyl)-1H-benzo[d][1,2,3]triazole (4j)
1H NMR (200 MHz, CDCl3): d = 7.51 (d, J = 8.0 Hz, 1 H), 7.33–
7.23 (m, 8 H), 5.39 (s, 1 H), 2.24 (t, J = 7.0 Hz, 2 H), 1.60–1.49 (m,
2 H), 1.43–1.39 (m, 4 H), 0.91 (t, J = 7.0 Hz, 3 H).
Synthesis 2011, No. 16, 2625–2628 © Thieme Stuttgart · New York

2628
B. Das et al.
PAPER
13C NMR (50 MHz, CDCl3): d = 149.9, 136.0, 129.8, 129.1, 128.8,
127.1, 124.0, 120.1, 113.8, 111.2, 90.2, 81.8, 55.3, 31.2, 27.9, 22.3,
18.8, 14.0.
(5) (a) Rozkiewicz, D. I.; Janezewski, D.; Verboom, W.; Ravoo,
B. J.; Reinhoudt, D. N. Angew. Chem. Int. Ed. 2006, 45,
5293. (b) Golas, P. L.; Matyjaszewski, K. Chem. Soc. Rev.
2010, 39, 1338.
(6) (a) Fazio, M. A.; Lee, O. P.; Schuster, D. I. Org. Lett. 2008,
10, 4979. (b) Hua, Y. R.; Flood, A. H. Chem. Soc. Rev. 2010,
39, 1262.
ESIMS: m/z = 304 [M + H]+.
Anal. Calcd for C20H21N3: C, 79.17; H, 6.98; N, 13.85. Found: C,
29.29; H, 6.89; N, 13.82.
(7) Duan, H.; Sengupta, S.; Petersen, J. L.; Akhmedov, N. G.;
Shi, X. J. Am. Chem. Soc. 2009, 131, 12100.
(8) Stang, P. J.; Diederich, F. Modern Acetylene Chemistry;
VCH: Weinheim, 1995.
Acknowledgment
The authors thank CSIR, New Delhi for financial assistance.
(9) (a) Das, B.; Reddy, G. C.; Balasubramanyum, P.; Salvanna,
N. Synthesis 2011, 816. (b) Das, B.; Reddy, Ch. R.; Sindhu,
Ch.; Kumar, D. N.; Krishnaiah, M. Helv. Chim. Acta 2011,
94, 289.
(10) (a) Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown,
S. D.; Keating, T. A. Acc. Chem. Res. 1996, 29, 123.
(b) Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39,
3168. (c) Estevez, V.; Villacampa, M.; Menendez, J. C.
Chem. Soc. Rev. 2010, 39, 4402.
References
(1) Part 209 in the series ‘Studies on Novel Synthetic
Methodologies.’
(2) (a) Chabre, Y. M.; Roy, R. Curr. Top. Med. Chem. 2008, 8,
1237. (b) Moumne, R.; Larue, V.; Seijo, B.; Lecourt, T.;
Micouin, L.; Tisne, C. Org. Biomol. Chem. 2010, 8, 1154.
(3) Meldal, M.; Tornoe, C. W. Chem. Rev. 2008, 108, 2952.
(4) (a) Wender, P. A.; Touami, S. M.; Alayrac, C.; Philipp, U.
C. J. Am. Chem. Soc. 1996, 118, 6522. (b) Baragatte, B.;
Biagi, G.; Calderone, V.; Giorgi, I.; Livi, O.; Martinotti, E.;
Scartoni, V. Eur. J. Med. Chem. 2000, 35, 949.
(11) Yan, W.; Wang, Q.; Chen, Y.; Peterson, J. L.; Shi, X. Org.
Lett. 2010, 12, 3308.
(12) Fischer, C.; Carreira, E. M. Org. Lett. 2004, 6, 1497.
Synthesis 2011, No. 16, 2625–2628 © Thieme Stuttgart · New York