Tandem Knoevenagel-[3+2] cycloaddition-elimination reactions: One-pot synthesis of 4,5-disubstituted 1,2,3-(NH)-triazoles

Article abstract of DOI:10.1016/j.tetlet.2011.10.146

Sodium azide has been found to catalyse Knoevenagel condensation between aromatic aldehyde and cyano compound with active methylene hydrogens and this has led to a successful route for the one pot synthesis of 4,5-disubstituted 1,2,3-(NH)-triazoles from a

Full text of DOI:10.1016/j.tetlet.2011.10.146

Tetrahedron Letters 53 (2012) 59–63
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Tandem Knoevenagel-[3+2] cycloaddition-elimination reactions: one-pot
synthesis of 4,5-disubstituted 1,2,3-(NH)-triazoles
⇑
Thanasekaran Ponpandian, Shanmugam Muthusubramanian
Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625021, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Sodium azide has been found to catalyse Knoevenagel condensation between aromatic aldehyde and
cyano compound with active methylene hydrogens and this has led to a successful route for the one
pot synthesis of 4,5-disubstituted 1,2,3-(NH)-triazoles from aldehydes through Knoevenagel-[3+2]cyclo-
addition-elimination sequence. In the formation of 5-aryl-2H-1,2,3-triazole-4-carbonitrile derivatives,
the reaction has been found to occur efficiently in water.
Received 23 September 2011
Revised 24 October 2011
Accepted 26 October 2011
Available online 3 November 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
One-pot process
1,2,3-(NH)-Triazoles
Triethylammonium chloride
Sodium azide
Water
1,2,3-Triazole is the core moiety in several therapeutic agents,
including antifungal,1 antiallergic,2 anti-viral,3 HIV-1 inhibitors,4
antimicrobial agents5 and selective b3-adrenergic receptor
agonists.6 4,5-Disubstituted 1,2,3-(NH)-triazoles have been found
application as anti-inflammatory agents,7 neurokinin-1 receptor
antagonists8 and also the inhibitors of VIM-2 metallo-b-lacta-
mase.9 5-Aryl-2H-1,2,3-triazole-4-carbonitrile derivatives are
HER2 tyrosine kinase inhibitors10 and used for optical brighteners
for lacquers, natural or synthetic fibres and films.11 Because of
these extensive applications, new cost effective greener methods
for the preparation of this class of compounds are worth
investigating.
The recent discovery of copper and ruthenium catalysed azide-
alkyne 1,3-dipolar addition reactions is efficient protocols for the
synthesis of 1,4- and 1,5-disubstituted 1,2,3-triazoles, respec-
tively,12,13 but are inconvenient to prepare 4,5-disubstituted
1,2,3-(NH)-triazoles. Only a few methods are available for the syn-
thesis of 4,5-disubstituted 1,2,3-(NH)-triazole,14 the main one
being [3+2] cycloaddition reaction of sodium azide with electron
deficient olefin followed by elimination (Scheme 1). In such reac-
tions, the ease of elimination of the groups is found to be in the or-
der of benzenesulphonyl > nitro > cyano.15 These reactions require
harsh conditions and also lead to unsatisfactory yield,16 though
this methodology has been applied for different types of electron
deficient alkenes.14b,17
EWG
N
R2
R1
H
R2
R1
R2 EWG
R1
N
N
-HEWG
NaN3
N
NH
N
Na
EWG = SO2Ph, NO2 or CN
Scheme 1. Cycloaddition/elimination method for the synthesis of substituted (NH)-
triazoles.
group has not yet explored. In the present work, a detailed inves-
tigation has been undertaken in order to improve the scope of this
reaction under one-pot process and to find out a greener route to
this class of compounds and the interesting results obtained,
including the serendipity finding of azide as an efficient catalyst
for Knoevenagel condensation, are reported in this article.
In an attempt to prepare the target 4,5-disubstituted 1,2,3-
(NH)-triazole in a multicomponent one-pot fashion, p-tolualde-
hyde (1a) and methyl cyanoacetate (2a) was allowed to react with
sodium azide in the presence of piperidine. Only the Knoevenagel
product (3a) was obtained with a trace amount of expected tria-
zole (4a), even at 80 °C (Table 1, entries 1 and 2). L-Proline has also
been used for this reaction, but only 5–10% of the triazole (4a) was
obtained (Table 1, entries 3 and 4). Obviously, the Knoevenagel
product obtained (3a) is reluctant to undergo [3+2] cycloaddition
reaction with sodium azide under these conditions. In order to ef-
fect the cycloaddition in a single step, several catalysts were tried
to increase the reactivity of sodium azide. In one such reaction,
lithium chloride, which can form more reactive lithium azide,
In many of these reactions, the eliminating group has been
either benzenesulphonyl or nitro but the elimination of cyano
⇑
Corresponding author. Tel.: +91 452 2458246; fax: +91 452 2459845.
E-mail address: muthumanian2001@yahoo.com (S. Muthusubramanian).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.146

60
T. Ponpandian, S. Muthusubramanian / Tetrahedron Letters 53 (2012) 59–63
Table 1
Optimisation of the conditions for the three component reaction
O
O
O
O
O
N
H
NaN3 (3 equ)
NC
O
O
NH
CN
N
1a
2a
3a
4a
Entry
Reagent (equiv)
Solvent
T (°C)
Time (h)
Yield (%)a
3a
4a
1
2
3
Piperidine (0.2)
Piperidine (0.2)
DMSO
DMSO
DMSO
30
80
30
24
24
24
95
95
92
Trace
Trace
5
L
-proline (0.2)
4
DMSO
80
24
85
10
L
-proline (0.2)
5
6
7
8
9
10
11
LiCl (3.2)
LiCl (3.2)
None
Et3N.HCl (2.5)
Et3N.HCl (2.5)
Et3N.HCl (2.5)
Et3N.HCl (1.5)
DMF
DMF
DMF
DMSO
DMF
H2O
30
70
30
70
70
100
70
24
24
2
83
70
98
0
0
80
20
10
20
Trace
55
65
8
10
24
15
Trace
DMF
50b
a
Isolated yield.
Two equivalent of NaN3 used.
b
was employed but no significant improvement in the yield of 4a
has been noticed, though a marginal rise has been observed (Table
1, entries 5 and 6). During these trials, the reaction of p-tolualde-
hyde, methyl cyanoacetate and sodium azide without any catalyst
has also been attempted and only a trace amount of 4a was
formed. But surprisingly, Knoevenagel product (3a) was formed
in 98% (Table 1, entry 7). Thus, it is realized that azide has catalysed
Knoevenagel reaction to near perfection without any base. When
the three component reaction was carried out in the presence of
triethylammonium chloride (Et3N.HCl), which was found to en-
hance the reactivity of sodium azide in a different context,18 the
reaction has gone smoothly yielding 65% of 4a (Table 1, entry 9).
It is clear that Et3NÁHCl promotes the cycloaddition reaction by
activating sodium azide. The fact that Et3NÁHCl does not catalyse
the Knoevenagel condensation has been confirmed by a separate
experiment.19 The results of the optimisation of the reaction with
different catalysts and solvents are provided in Table 1.
Though numerous reagents have been reported to catalyse
Knoevenagel condensation,20 which is the best carbon-carbon
bond making reaction, this is the first time that sodium azide has
been found to catalyse this reaction. To test the efficacy of sodium
azide in Knoevenagel condensation, numbers of active methylene
compounds were allowed to react with p-tolualdehyde in the pres-
ence of sodium azide and the results are presented in Table 2.
Interestingly, it can be seen that azide catalysed Knoevenagel con-
densation is successful only when the active methylene compound
contains at least one cyano group as the activating group (Table 2,
products 3a, 3c, 3f and 3h). This reaction has led to E-isomer alone,
which was confirmed by the comparison of their spectroscopic
properties with those available in the literature for known prod-
ucts.21 It must be mentioned that in the case of aliphatic aldehydes,
the Knoevenagel condensation is not proceeding smoothly under
the described reaction conditions.
Table 2
Sodium azide catalysed Knoevenagel condensation
O
X
H
NaN3 (20 mol %)
DMF
X
Y
Y
1a
2a-h
3a-h
Product
X
Y
T (°C)
Time (h)
Yield (%)a
3a
3a
3a
3b
3c
3d
3e
3f
COOCH3
COOCH3
COOCH3
COCH3
CN
COOCH2CH3
COOCH3
COOCH2CH3
COOCH3
CN
CN
CN
COCH3
CN
30
70
70
70
30
70
70
70
70
70
12
2
96
98
30b
0
12
16
0.5
16
16
2
90
0
0
92
0
91
C6H5CO
COOCH3
CN
3g
3h
COCH3
CN
16
5
CONH2
a
Isolated yield.
The reaction was carried out in the absence of NaN3.
b
strong electron donating group (like methoxy) in the phenyl ring
leads to comparatively less yield (4j and 4k), whereas other groups
such as SCH3, CH3, OPh and Cl do not affect the product yield (4d–
4h). This reaction proceeded smoothly even in the presence of free
carboxylic acid substituent in the phenyl ring without the need for
protection (4i). It can be seen that cyanoacetamide involved reac-
tion has resulted in good yield of the triazole derivatives (4n–4u)
compared to those involving methyl cyanoacetate. The reported
method by Lam and co-workers17a yielded only 37 and 51% of 4o
and 4t respectively, whereas our methodology resulted in 82 and
84% of these products by a relatively simple process. 1-(Cyanoace-
tyl)piperidine also works well in this reaction (4v).
On the basis of above results, a plausible mechanism for the for-
mation of (NH)-triazoles (4) is proposed in Scheme 2. Path I leading
to the formation of a tetrazole 5 via nitrile-azide cycloaddition has
not taken place, indicating the product selectivity associated with
this reaction.
After establishing the role of sodium azide in the Knoevenagel
reaction and that of Et3N.HCl in [3+2] cycloaddition reaction, syn-
thesis of several 4,5-disubstituted 1,2,3-(NH)-triazoles (4b–4v) has
been carried out from a range of aromatic aldehydes (1, where Ar is
substituted phenyl or heteroaryl) and cyano compounds with ac-
tive methylene (2, where R is OCH3, NH2 or N-piperidyl) under
optimized conditions (Table 3).22,23 The results demonstrate that

T. Ponpandian, S. Muthusubramanian / Tetrahedron Letters 53 (2012) 59–63
61
Table 3
Synthesis of 4,5-disubstituted (NH)-1,2,3-triazoles 4 (4a–4v)a
O
O
N
N
R
R
Et3N.HCl
DMF, 70oC
NC
NH
NaN3
Ar
H
O
Ar
1
4
2
Entry
Ar
R
Time (h)
Product
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
4-MeC6H5
Ph
4-CH(CH3)2C6H5
3-OPhC6H5
4-SMeC6H5
2-ClC6H5
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
N-piperidyl
10
7
9
8
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
65
68
70
70
72
53
78
62
76
51
50
65
61
78
82
80
87
72
90
84
81
70
8
8
4-ClC6H5
3,4-Me2C6H4
3-COOHC6H5
4-OCH3C6H5
3,4-(OMe)2C6H4
2-Thienyl
3-Thienyl
4-MeC6H5
Ph
3-(OPh)C6H5
4-SMeC6H5
2-ClC6H5
4-ClC6H5
2-Thienyl
10
6
10
12
8
4j
4k
4l
8
4m
4n
4o
4p
4q
4r
4s
4t
10
10
10
10
10
10
10
10
10
3-Thienyl
4-ClC6H5
4u
4v
a
Reactions and condition: 5 mmol of 1, 5 mmol of 2, 15 mmol of NaN3, 12.5 mmol of Et3N.HCl in 15 mL DMF, 70 °C, 6–10 h.
Isolated yield.
b
NaN3
Et3N.HCl
O
R
H
+
NC
O
+
R'
Et3NH N3
2
H2O
1
NaCl
O
O
R
R
CN
Path I
R'
N
N
NH
N
3
R'
Path II
O
5
O
NC
H
O
R
R
N
N
R
N
NH
H+
N
N
+
N
N
N
+
Et3NH
Et3NH
R'
HCN
R'
4
R'
Scheme 2. Mechanism for the formation of 4.
It can be seen that in the three-component reaction described in
out at 90 °C, it completed in 1 h (Table 4, entry 3). Interestingly this
tandem Knoevenagel-cycloaddition-elimination reaction pro-
ceeded smoothly in aqueous medium and also giving excellent yield
of the (NH) triazole 7a (Table 4, entry 4). It can be noted that water is
not a suitable medium for the formation of 4 (Table 1 entry 10).
To illustrate the generality of this reaction, a diverse set of 7
(Table 5 compounds 7b–7q) was prepared (where Ar is substituted
phenyl or heteroaryl).25
Table 3, XCH2CN has been employed as one of the components and
ultimately cyano group gets eliminated retaining X as the substitu-
ent in the triazole ring. We wanted the cyano group to be retained
in the triazole ring in a multicomponent reaction of the above type
and the identified component for such a reaction is phenylsulfonyl
acetonitrile (6).24
The three-component reaction of p-tolualdehyde (1a) and phen-
ylsulfonyl acetonitrile (6) with sodium azide in DMF at 30 °C, re-
sulted in 75% of 7a after 15 h, but 90% of 7a was obtained after 3 h
at 70 °C (Table 4, entries 1 and 2). When the reaction was carried
In summary, it is shown that a diverse set of 4,5-disubstituted
(NH)-1,2,3-triazole can be prepared efficiently by a Knoevenagel-
cycloaddition-elimination reaction sequence from aromatic alde-

62
T. Ponpandian, S. Muthusubramanian / Tetrahedron Letters 53 (2012) 59–63
Table 4
References and notes
Optimization of reaction condition for the formation of 7a
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NC
O
N
N
O
S
O
NH
NaN3 (1.5 equ)
CN
H
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1a
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Entry
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1
2
3
DMF
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3
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75
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93
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Table 5
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O
O
O
NC
Ar
N
N
S
CN
Water
Reflux
NH
NaN3
Ar
H
1
7b-7q
6
Product
1
Time (h)
Yield (%)
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
7q
Ar = Phenyl
1
1
4
3
1
1
1
1
1
2
4
3
0.5
1
0.5
1
91
99
65
99
96
95
90
88
93
75
60
70
93
84
88
76
Ar = 4-Chlorophenyl
Ar = 4-Methylthiophenyl
Ar = 3-Phenoxyphenyl
Ar = 3-Carboxyphenyl
Ar = 2-Fluorophenyl
Ar = 4-Methoxyphenyl
Ar = 3-Methoxy-4-flourophenyl
Ar = 3,4,5-Trimethoxyphenyl
Ar = 5-Acetoxymethyl-2-furyl
Ar = 2-Thienyl
Ar = 3-Thienyl
Ar = 2-Thiazolyl
Ar = 3-Pyridyl
Ar = 4-Pyridyl
Ar = 4-Quinolinyl
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hyde and active methylene compound where sodium azide not
only acts as the reactant but also serves as the catalyst for Knoeve-
nagel condensation. The generation of electron deficient alkene in a
separate step is avoided in this protocol. It has also demonstrated
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Bhuyan, P. J. Tetrahedron Lett. 2005, 46, 6453–6456; (f) Sabitha, G.; Reddy, B. V.
S.; Babu, R. S.; Yadav, J. S. Chem. Lett. 1998, 773–774; (g) Kumbhare, R. M.;
Sridhar, M. Catal. commun. 2008, 9, 403–405.
21. General procedure for the synthesis of Knoevenagel product 3a, 3c, 3f and 3h: A
mixture of p-tolualdehyde (1a) (5 mmol), active methylene compound (2)
(5 mmol) and sodium azide (20 mol %) was mixed with DMF (10 mL) in a
round-bottomed flask. The reaction mixture was heated in an oil bath at given
temperature for the desired time (Table 2). After cooling to room temperature,
the reaction mixture was poured into cold water (100 mL), the solid obtained
was collected by filtration and washed with water to afford pure 3 as a white
solid. See Supplementary data for spectral data of all compounds.
22. General procedure as exemplified for Methyl 5-p-tolyl-2H-1,2,3-triazole-4-
carboxylate (4a): To a mixture of p-tolualdehyde (0.5 g, 4.2 mmol), methyl
Acknowledgments
The authors thank the DST, New Delhi for assistance under the
IRHPA program for the NMR facility, Orchid Research Laboratory
Ltd for providing the chemicals, laboratory facility and Mr. R. Vig-
nesh for his support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.10.146.

T. Ponpandian, S. Muthusubramanian / Tetrahedron Letters 53 (2012) 59–63
63
cyanoacetate (0.41 g, 4.2 mmol) and Et3NÁHCl (1.43 g, 10.4 mmol) in DMF
(12 mL) was added sodium azide (0.81 g, 12.5 mmol). The mixture was then
stirred at 70 °C for 10 h. Following, to the reaction mixture was added water
(50 mL), 10% HCl solution (2 mL) at room temperature and extracted with ethyl
acetate (2 Â 75 mL). The combined organic phases were washed with water
(3 Â 100 mL), brine solution (1 Â 100 mL), dried over anhydrous Na2SO4 and
concentrated in vacuo. The residue was subjected to column chromatography
with dichloromethane/methanol (99.5/0.5) as eluent to obtain the desired 4a
(0.585 g, 65% yield) as a white solid; mp 106–108 °C; Rf 0.45 (DCM/MeOH,
95:5); IR (KBr) 3138, 1721, 1528, 1483, 1451, 1204, 1149, 1119, 1055,
987 cmÀ1; dH (400 MHz, CDCl3) 2.36 (s, 3H), 3.84 (s, 3H), 7.19 (d, J = 8.0 Hz, 2H),
7.66 (d, J = 8.0 Hz, 2H), 9.85 (br s, 1H); dC (100 MHz, CDCl3) 21.5, 52.4, 124.3,
129.1, 129.2, 133.7, 140.1, 145.7, 161.8; Anal. Calcd for C11H11N3O2: C, 60.82;
H, 5.10; N, 19.34%. Found: C, 60.77; H, 5.08; N, 19.31; ESI-m/z calcd for
[C11H11N3O2 – H]+ 216.1, found 216.1.
entry 22) White solid; mp 210–211 °C; Rf 0.46 (DCM/MeOH, 95:5); IR (KBr)
3073, 1592, 1529, 1501, 1446, 1368, 1284 cmÀ1; dH (400 MHz, DMSO-d6) 1.30–
1.31 (m, 2H), 1.56–1.57 (m, 4H), 3.19–3.20 (m, 2H), 3.65–3.66 (m, 2H), 7.56 (d,
J = 8.4 Hz, 2H), 7.72 (d, J = 8.4 Hz, 2H), 15.47 (br s, 1H); dC (75 MHz, DMSO-d6)
24.7, 26.1, 26.9, 43.1, 48.3, 128.9, 129.3, 129.9, 134.3, 162.4; Anal. Calcd for
C
14H15ClN4O: C, 57.83; H, 5.20; N, 19.27. Found: C, 57.79; H, 5.19; N, 19.24;
ESI-m/z calcd for [C14H15ClN4O – H]+ 289.1, found 289.1. See Supplementary
data for spectral data of all other compounds.
24. (a) Rahimizadeh, M.; Rajabzadeh, G.; Khatami, S. M.; Eshghi, H.; Shiri, A. J. Mol.
Catal. A: Chem 2010, 323, 59–64; (b) Surya Prakash, G. K.; Zhao, X.; Chacko, S.;
Wang, F.; Vaghoo, H.; Olah, G. A. Beilstein J. Org. Chem. 2008, 4, 1–7; (c) Zhou,
W.; Xu, L. Z. X.; Zhang, Z.; Xuebao, W. H. Wuji Huaxue Xuebao 1992, 8, 88–90.
25. General procedure as exemplified for 5-p-Tolyl-2H-1,2,3-triazole-4-carbonitrile
(7a). A mixture of p-tolualdehyde (0.5 g, 4.2 mmol), phenylsulfonyl acetonitrile
6 (0.75 g, 4.2 mmol) and sodium azide (0.4 g, 6.25 mmol) in water (15 mL) was
stirred under reflux for 1 h. The resulting mixture was then cooled to 5 °C, the
solid obtained was filtered and washed with water (50 mL) to afford pure 7a
(0.73 g, 95% yield) as a white crystals; mp 175–177 °C; Rf 0.38 (DCM/MeOH,
95:5); IR (KBr) 2873, 2240, 1613, 1510, 1275 cmÀ1; dH (400 MHz, DMSO-d6)
2.39 (s, 3H), 7.43 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 8.0 Hz, 2H), 16.47 (br s, 1H); dC
(100 MHz, CDCl3) d 21.0, 112.9, 116.3, 122.7, 126.4, 129.8, 140.8; Anal. Calcd
for C10H8N4: C, 65.21; H, 4.38; N, 30.42. Found: C, 65.16; H, 4.30; N, 30.39; ESI-
m/z calcd for [C10H8N4 – H]+ 183.1, found 183.1. See Supplementary data for
spectral data of all other compounds.
23. Spectroscopic data for representative example: 5-p-Tolyl-2H-1,2,3-triazole-4-
carboxamide (4n, Table 3, entry 14) White solid; mp 244–245 °C; Rf 0.37
(DCM/MeOH, 95:5); IR (KBr) 3388, 3338, 3282, 3225, 1676, 1600, 1578, 1491,
1413, 1352, 1281, 1273, 1236, 1191 cmÀ1; dH (400 MHz, DMSO-d6) 2.35 (s, 3H),
7.27 (d, J = 7.6 Hz, 2H), 7.50 (s, 1H), 7.80 (d, J = 7.6 Hz, 2H), 7.86 (s, 1H), 15.5 (br
s, 1H); dC (75 MHz, DMSO-d6) 21.7, 129.5, 129.7, 138.2, 139.4, 163.8; Anal.
Calcd for C10H10N4O: C, 59.40; H, 4.98; N, 27.71. Found: C, 59.36; H, 4.97; N,
27.68; ESI-m/z calcd for [C10H10N4O
Chlorophenyl)-2H-1,2,3-triazol-4-yl)(piperidin-1-yl)methanone (4v, Table 3,
–
H]+ 201.1, found 201.1. (5-(4-