Catalyst-free, aqueous and highly diastereoselective synthesis of new 5-substituted 1H-tetrazoles via a multi-component domino Knoevenagel condensation/1,3 dipolar cycloaddition reaction

Article abstract of DOI:10.1016/j.tet.2011.12.044

An approach for the synthesis of new 5-substituted-tetrazoles via multi-component domino Knoevenagel condensation/1,3 dipolar cycloaddition reaction of carbonyl compounds, malononitrile and sodium azide in water without assistance of any catalyst has been

Full text of DOI:10.1016/j.tet.2011.12.044

Tetrahedron 68 (2012) 1769e1773
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Tetrahedron
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Catalyst-free, aqueous and highly diastereoselective synthesis of new
5-substituted 1H-tetrazoles via a multi-component domino Knoevenagel
condensation/1,3 dipolar cycloaddition reaction
*
*
Zeinab Noroozi Tisseh, Minoo Dabiri , Mohsen Nobahar, Hamid Reza Khavasi, Ayoob Bazgir
Department of Chemistry, Shahid Beheshti University, General Campus, Tehran 1983963113, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 August 2011
Received in revised form 29 November 2011
Accepted 19 December 2011
Available online 24 December 2011
An approach for the synthesis of new 5-substituted-tetrazoles via multi-component domino Knoeve-
nagel condensation/1,3 dipolar cycloaddition reaction of carbonyl compounds, malononitrile and sodium
azide in water without assistance of any catalyst has been reported. This general protocol provides a wide
variety of 5-substituted 1H-tetrazoles in good yields under mild reaction conditions.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
1H-Tetrazoles
Knoevenagel condensation
1,3 Dipolar cycloaddition
Water
1. Introduction
to synthesize substituted tetrazoles as potential medicinal agents.
5-Substituted-tetrazoles are reported to possess antibacterial,4
Nowadays, the main goals of ‘green chemistry’ are to increase
process selectivity, maximize the use of starting materials, and to
replace hazardous reagents with eco-friendly materials. Organic
reactions in water without using harmful organic solvents have
attracted a great deal of interest in both academic and industrial
research because, in addition to environmental concerns, there are
beneficial effects of aqueous solvents on rates and selectivities of
important organic transformations.1
Multi-component domino reactions (MDR), which can occur in
aqueous media have been extensively pursued in the past decade
due to their efficient atom economy and green characteristics.2
These reactions enable multi-step synthesis to be conducted in
a one-pot operation to obtain a variety of invaluable products.
These processes can avoid time-consuming and costly syntheses
involving multistep reactions, protectionedeprotection steps, te-
dious workup and purifications. In addition, these reactions often
give excellent chemo- and regioselectivities.2,3
antifungal,5 antiviral,6 analgesic,7 anti inflammatory,8 antiulcer9
and antihypertensive10 activities. Also, this functional group has
roles in coordination chemistry as a ligand, and in various materials
science applications including propellants11 and explosives.12 Fur-
thermore, tetrazole moieties are important synthons in synthetic
organic chemistry.13 Therefore, a number of methods have been
reported for the preparation of tetrazoles.14,15 One of the major
synthetic routes to tetrazole formation is the [2þ3] cycloaddition of
an organonitrile and an azide salt.16
However, many of these protocols have some disadvantages,
such as the use of toxic metals, strong Lewis acid, expensive re-
agents, low yield, drastic reaction conditions, water sensitivity and
the presence of hydrazoic acid, which is toxic and explosive. In ad-
dition, all of the known methods use organic solvents, in particular,
dipolar aprotic solvents, such as DMF.12,17,18 Recently, Sharpless et al.
reported an improved preparation of tetrazoles by the reaction of
nitriles and NaN3 in the presence of Zn(II) salts inwater. In the case of
sterically hindered aromatic or deactivated alkyl nitriles, high
temperature (140e170 ꢀC) and long reaction times are required.19
Thus, the development of a convenient and safe process for the
preparation of new tetrazole derivatives is an interesting target for
investigation. Despite continuous research for the synthesis of
tetrazoles and development of new multi-component reactions,
only a limited number of multi-component syntheses of tetrazole
derivatives have been reported.15a,20
The chemistry of heterocycles has acquired immense impor-
tance in recent years. The tetrazole function is metabolically stable
and a close similarity between the acidic character of the tetrazole
group and carboxylic acid group have inspired medicinal chemists
* Corresponding authors. Tel.: þ98 (0) 21 22401765; fax: þ98 21 22431661;
e-mail address: a_bazgir@sbu.ac.ir (A. Bazgir).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.12.044

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Z.N. Tisseh et al. / Tetrahedron 68 (2012) 1769e1773
Table 2
Synthesis of tetrazoles 3
Herein, we would like to report a novel, facile, eco-friendly and
one-pot process for synthesis of 5-substituted 1H-tetrazoles via
a domino Knoevenagel condensation and 1,3 dipolar cycloaddition
reaction.
2. Results and discussion
The choice of an appropriate reaction medium is of crucial im-
portance for successful synthesis. Initially, the three-component
reaction of benzaldehyde 1a, malononitrile 2 and sodium azide as
a simple model substrate was investigated in different solvents
without any catalyst (Table 1). The desired product was scarcely
obtained in non-polar solvents (entries 5e7) and even methanol
and ethanol as a polar protic solvent failed to produce the desired
1H-tetrazole in good yield (entries 8,9). It was found that water is
the best solvent with respect to reaction yield (entry 4). This effect
can be attributed to the strong hydrogen bond interaction at the
organicewater interface, which stabilizes the reaction in-
termediate.21 We performed the model reaction using different
quantities of reagents in water. The best result was obtained with
a 1:1:2 ratio of benzaldehyde, malononitrile and sodium azide.
Product
Time (h)
Yield (%)
24
81
3a
24
26
80
63
3b
3c
Table 1
Model reaction, conditions and yielda
30
76
Entry
Solvent
NaN3 (mmol)
Yield (%)
3d
1
2
3
4
5
6
7
8
9
H2O
H2O
H2O
H2O
Benzene
Toluene
CHCl3
MeOH
Ethanol
1
1.5
2
2.5
2
2
2
2
2
57
75
81
82
Trace
Trace
30
48
55
24
78
3e
a
Benzaldehyde (1 mmol), malononitrile (1 mmol).
To explore the scope and limitations of the reaction, the pro-
cedure was extended to various aromatic aldehydes 1aee. As in-
dicated inTable 2, the reactions proceeded veryefficiently, and led to
the formation of the corresponding (E)-(1H-tetrazole-5-yl) acrylo-
nitrile 3aee in good yields and stereoselectivities. X-ray crystallo-
graphic analysis revealed the relative configuration of the isomer 3b
as depicted in Fig. 1. Details of the structure determination and re-
finement are described in the Experimental section.
To the best of our knowledge, this new procedure provides the
first example of the synthesis of (E)-(1H-tetrazole-5-yl) acryloni-
trile using a three-component domino reaction and this new re-
action opens an important field to the use of MCR strategy in
5-substituted 1H-tetrazoles synthesis. The reaction preceded very
cleanly under mild conditions at 50 ꢀC in the absence of any cata-
lyst. The catalyst-free reactions carried out in water are safe, non-
toxic, environmentally friendly and inexpensive. The absence of
Fig. 1. X-ray crystal structure of sodium salt of 3b.

Z.N. Tisseh et al. / Tetrahedron 68 (2012) 1769e1773
1771
Table 3
catalyst for the reaction avoids the use of moisture-sensitive heavy
metals, such as Lewis acids.
Synthesis of oxoindolin-tetrazoles 8
Mechanistically, the formation of tetrazoles 3 can be rational-
ized by initial formation of arylidenemalononitrile 4 through
a Knoevenagel condensation reaction of 1 and 2. Afterwards the
intermediate 4 undergoes [2þ3] cycloaddition reaction with the
sodium azide to afford product 3. To clarify the proposed mecha-
nism, first, 2-benzylidenemalononitrile 4a was synthesized from
the condensation of benzaldehyde and malononitrile. Subsequently
reaction of 4a with sodium azide afforded the corresponding (E)-3-
phenyl-2-(1H-tetrazole-5-yl)acrylonitrile 3a (Scheme 1). Although
the role of water as the reaction medium and its mechanism is not
clear, this one-pot reaction with regards to the observations of
Sharpless et al.,22 might take place at the interface of organic
substrates with water in a heterogeneous system.
Product
Time (h)
Yield (%)
24
88
8a
8b
8c
8d
24
24
67
78
Scheme 1. Reaction of 2-benzylidenemalononitrile and sodium azide.
Encouraged by these results, ninhydrin 5 was selected as an
active carbonyl compound and the desired 2-(1,3-dioxo-1H-inden-
2(3H)-ylidene)-2-(1H-tetrazole-5-yl)acetonitrile 6 was obtained in
79% yield under the same reaction conditions (Scheme 2).
30
80
Scheme 2. Synthesis of 2-(1,3-dioxo-1H-inden-ylidene)-2-tetrazole-5-yl.
Due to the importance of oxindole derivatives23,24 and to further
explore the potential of this protocol for three-component tetra-
zoles synthesis, we investigated reaction of isatins 7 instead of al-
dehyde 1 and obtained the corresponding (Z)-oxoindolin-(1H-
tetrazole-5-yl) acetonitrile 8 in good yields under the same reaction
conditions (Table 3). The best evidence for the formation of (Z)-
configuration is its less steric hindrance and the appearance of
20
79
8e
3
a deshielded singlet for 4-H (9.07 ppm, d, JHH¼7.8 Hz,) in the 1H
NMR spectrum of 8a resulting probably from the anisotropic effect
of the nitrile group25 (Supplementary data).
75.47 MHz, respectively. 1H and 13C NMR spectra were obtained on
solutions in DMSO-d6. IR spectra were recorded using a BOMEM
MB-Series. Elemental analyses were performed using a Heracus
CHN-O-Rapid analyzer.
The chemicals used in this work were obtained from Fluka and
Merck and were used without purification.
3. Conclusion
In conclusion, an efficient, green and convenient method for the
preparation of new 5-substituted-tetrazoles in water is reported.
This new process provides an opportunity to use water and avoid
environmentally harmful conventional organic solvents, easy
work-up and reduced waste production by the lack of catalyst or
additive agent.
4.2. General procedure for the synthesis of tetrazoles 3,
6 and 8
4. Experimental
4.1. General
A mixture of carbonyl compound (1 mmol), malononitrile
(1 mmol) and sodium azide (2 mmol) in H2O (5 mL) was stirred at
50 ꢀC for appropriate time, after completion of the reaction, as in-
dicated by TLC, the reaction mixture was filtered. To the filtrate was
added 30 mL of 2 N HCl with vigorous stirring causing the tetrazole
to precipitate. The precipitate was filtered and dried in a drying
oven to furnish the tetrazole.
Melting points were measured on an Electrothermal 9100 ap-
paratus and are uncorrected. 1H and 13C NMR spectra were recor-
ded on a BRUKER DRX-300 AVANCE spectrometer at 300.13 and

1772
Z.N. Tisseh et al. / Tetrahedron 68 (2012) 1769e1773
4.2.1. (E)-3-Phenyl-2-(1H-tetrazole-5-yl) acrylonitrile (3a). Cream
powder (0.16 g, yield 81%), mp 168e170 ꢀC. IR (KBr) (nmax/cmꢁ1): 3583,
2130, 1644, 1612,1498. MS, m/z: 197 (Mþ). 1H NMR (300 MHz, DMSO-
d6): dH (ppm) 3.67 (br s, NH, overlap with solvent), 7.59 (3H, s, CHeAr),
8.00 (2H, s, CHeAr), 8.39 (1H, s, CH). 13C NMR (75 MHz, DMSO-d6): dC
(ppm) 97.3, 115.9, 129.7, 130.3, 132.6, 132.8,148.8, 155.8. Anal. Calcd for
C10H7N5: C, 60.91; H, 3.58; N, 35.51. Found: C, 60.82; H, 3.95; N, 35.44.
(Mþ). 1H NMR (300 MHz, DMSO-d6): dH (ppm) 3.50 (br s, NH, overlap
with solvent), 7.62e7.72 (3H, m, HeAr), 7.92 (1H, s, HeAr). 13C NMR
(75 MHz, DMSO-d6): dC (ppm) 114.7, 124, 125.3, 133.4, 134.5, 136.2,
137.8, 138.2, 152.1, 162.7, 186.4 (CeAr and CN). Anal. Calcd for
C12H5N5O2:C,57.38;H, 2.01; N, 27.88. Found: C, 57.31;H,1.97;N,27.94.
4.2.7. (Z)-2-(2-Oxoindolin-3-ylidene)-2-(1H-tetrazole-5-yl) acetoni-
trile (8a). Red powder (0.21 g, yield 88%). Mp 210e212 ꢀC. IR (KBr)
4.2.2. (E)-3-(4-Hydroxyphenyl)-2-(1H-tetrazole-5-yl) acrylonitrile
(3b). White powder (0.17 g, yield 80%). Mp 159e161 ꢀC. IR (KBr)
(
nmax/cmꢁ1): 3406, 3305, 2206, 1720, 1612, 1563, 1467. MS, m/z: 238
(Mþ). 1H NMR (300 MHz, DMSO-d6): dH (ppm) 3.38 (br s, NH,
3
(
nmax/cmꢁ1): 3425, 3141, 2225, 1600, 1581, 1498. MS, m/z: 213 (Mþ).
overlap with solvent), 6.84 (1H, d, JHH¼7.6 Hz, HeAr), 6.95 (1H, t,
1H NMR (300 MHz, DMSO-d6): dH (ppm) 6.94 (2H, d, JHH¼8.4 Hz,
HeAr), 7.91 (2H, d, 3JHH¼8.4 Hz, HeAr), 8.18 (1H, s, CH),10.63 (1H, br
s, OH). 13C NMR (75 MHz, DMSO-d6): dC (ppm) 91.8, 116.6, 116.7,
123.7, 133, 148.8, 155.6, 162.2. Anal. Calcd C10H7N5O: C, 56.34; H,
3.31; N, 32.85. Found: C, 56.28; H, 3.25; N, 32.76. X-ray data for
sodium salt of 3b (suitable crystals for X-ray diffraction analysis
were obtained from slow evaporation in MeOH solvent):
3JHH¼7.8 Hz, HeAr), 7.34 (1H, t, JHH¼7.6 Hz, HeAr), 9.07 (1H, d,
3
3
3JHH¼7.8 Hz, HeAr), 10.86 (1H, s, NH). 13C NMR (75 MHz, DMSO-d6):
dC (ppm) 110.1, 121.2, 121.7, 128.1, 128.7, 133.1, 133.2, 134.8, 143.4,
151.7, 166.9. Anal. Calcd for C11H6N6O: 55.46; H, 2.54; N, 35.28.
Found: C, 55.55; H, 2.59; N, 35.17.
4.2.8. (Z)-2-(5-Bromo-2-oxoindolin-3-ylidene)-2-(1H-tetrazole-5-yl)
acetonitrile (8b). Brown powder (0.21 g, yield 67%). Mp 218e220 ꢀC.
IR (KBr) (nmax/cmꢁ1): 3425, 3147, 2218,1701, 1574,1486. MS, m/z: 317
(Mþ), 315 (Mþ). 1H NMR (300 MHz, DMSO-d6): dH (ppm) 3.37 (br s,
NH, overlap with solvent), 6.70e6.72 (1H, m, HeAr), 7.12e7.19 (1H,
m, HeAr), 7.31 (1H, s, HeAr), 10.47 (1H, s, NH). 13C NMR (75 MHz,
DMSO-d6): dC (ppm) 117.6, 121.4, 124.9, 128.5, 129.1, 130.3, 134.5,
139.3, 149.0, 151.2, 170.5. Anal. Calcd for C11H5BrN6O: C, 41.66; H,
1.59; N, 26.50. Found: C, 41.58; H, 1.54; N, 26.45.
C10H6N5NaO(2CH3OH), M¼299.27 g/mol, triclinic system, space
ꢀ
group P1, a¼8.5926(7), b¼ꢀ 9.2683(7), c¼9.2161(7) A,
a
¼77.105(6),
3
ꢀ
ꢁ3
b¼82.720(6),
g
¼80.648(6) , V¼702.81(9) A , Z¼2, Dc¼1.414 g cm
,
m
(Mo K
a
)¼0.130 mmꢁ1, crystal dimension of 0.45ꢂ0.30ꢂ0.15 mm.
The structure was solved by using SHELXS. The structure refinement
and data reduction was carried out with SHELXL of the X-Step32
suite of programs. The non-hydrogen atoms were refined aniso-
tropically by full matrix least-squares on F2 values to final
R1¼0.0599, wR2¼0.1853 and S¼1.004 with 202 parameters using
3766 independent reflection (
q
range¼2.28e29.15ꢀ). Hydrogen
4.2.9. (Z)-2-(5-Nitro-2-oxoindolin-3-ylidene)-2-(1H-tetrazole-5-yl)
acetonitrile (8c). Dark powder (0.22 g, yield 78%). Mp 225e227 ꢀC.
IR (KBr) (nmax/cmꢁ1): 3430, 3171, 2221, 1706, 1566, 1483. MS, m/z:
283 (Mþ). 1H NMR (300 MHz, DMSO-d6): dH (ppm) 3.45 (br s, NH,
atoms were located from expected geometry and were not refined.
Crystallographic data for 3b have been deposited with the Cam-
bridge Crystallographic Data Centre. Copies of the data can be ob-
tained, free of charge, on application to The Director, CCDC 837494,
Union Road, Cambridge CB2 1EZ, UK. Fax: þ44 1223 336033 or e-
mail: deposit@ccdc.cam.ac.uk.
3
overlap with solvent), 7.16 (1H, d, JHH¼8.6 Hz, HeAr), 8.10 (1H, d,
3JHH¼8.6 Hz, HeAr), 8.76 (1H, s, HeAr), 10.66 (1H, s, NH). 13C NMR
(75 MHz, DMSO-d6): dC (ppm) 118.1, 123.8, 124.1, 124.7, 127.6, 128.3,
129.6, 138.3, 149.6, 152.3, 170.1. Anal. Calcd for C11H5N7O3: C, 46.65;
H, 1.78; N, 34.62. Found: C, 46.73; H, 1.70; N, 34.55.
4.2.3. (E)-3-(4-Bromophenyl)-2-(1H-tetrazole-5-yl)
(3c). Cream powder (0.17 g, yield 63%). Mp 165e167 ꢀC. IR (KBr)
nmax/cmꢁ1): 3431, 2117, 1530, 1473. MS, m/z: 274 (Mþ). 1H NMR
acrylonitrile
(
4.2.10. (Z)-2-(1-Methyl-2-oxoindolin-3-ylidene)-2-(1H-tetrazole-5-
yl) acetonitrile (8d). Brown powder (0.17 g, yield 67%). Mp
214e216 ꢀC. IR (KBr) (nmax/cmꢁ1): 3380, 2212, 1725, 1605, 1466, 1416.
MS, m/z: 252 (Mþ). 1H NMR (300 MHz, DMSO-d6): dH (ppm) 3.43 (br s,
NH, overlap with solvent), 3.20 (3H, s, CH3). 7.03 (2H, d, 3JHH¼7.7 Hz,
HeAr), 7.43 (1H, t, 3JHH¼7.7 Hz, HeAr), 9.16 (1H, d, 3JHH¼7.8Hz, HeAr).
13C NMR (75 MHz, DMSO-d6): dC (ppm) 26.5, 107.8,109.1, 116.5, 120.4,
122.3,128.3,133.2,133.8,144.5,156.7,165.4. Anal. Calcd for C12H8N6O:
C, 57.14; H, 3.20; N, 33.32. Found: C, 57.22; H, 3.29; N, 33.25.
(300 MHz, DMSO-d6): dH (ppm) 3.52 (br s, NH, overlap with solvent),
7.68 (2H, d, 3JHH¼6.3 Hz, HeAr), 7.81 (2H, d, 3JHH¼6.3 Hz, HeAr), 8.02
(1H, s, CH). 13C NMR (75 MHz, DMSO-d6): dC (ppm) 99.6, 117.7, 124,
127.8, 130, 131.4, 132.1, 132.3, 157. Anal. Calcd C10H6BrN5: C, 43.50; H,
2.19; N, 25.37. Found: C, 43.58; H, 2.14; N, 25.31.
4.2.4. (E)-3-(4-Nitrophenyl)-2-(1H-tetrazole-5-yl)
(3d). Cream powder (0.18 g, yield 76%). Mp 166e168 ꢀC. IR (KBr)
nmax/cmꢁ1): 3330, 2233, 1602, 1566. MS, m/z: 242 (Mþ). 1H NMR
(300 MHz, DMSO-d6): dH (ppm) 3.44 (br s, NH, overlap with sol-
acrylonitrile
(
4.2.11. (Z)-2-(1-Methyl-5-nitro-2-oxoindolin-3-ylidene)-2-(1H-tet-
razole-5-yl) acetonitrile (8e). Brown powder (0.24 g, yield 79%). Mp
228e230 ꢀC. IR (KBr) (nmax/cmꢁ1): 3153, 2218, 1701, 1581, 1498. MS,
m/z: 297 (Mþ). 1H NMR (300 MHz, DMSO-d6): dH (ppm) 3.36 (br s,
NH, overlap with solvent), 3.26 (3H, s, CH3), 7.13 (2H, d, 3JHH¼8.6Hz,
HeAr), 8.07 (1H, d, 3JHH¼8.6 Hz, HeAr), 8.56 (1H, s, HeAr). 13C NMR
(75 MHz, DMSO-d6): dC (ppm) 26.5, 114.7, 124.1, 125.5, 132.4, 134.5,
135.2, 136.2, 137.8, 138.5, 150.8, 169.7. Anal. Calcd for C12H7N7O3: C,
48.49; H, 2.37; N, 32.99. Found: C, 48.42; H, 2.33; N, 32.90.
3
3
vent), 8.12 (2H, d, JHH¼7.4 Hz, HeAr), 8.29 (2H, d, JHH¼7.4 Hz,
HeAr), 8.32 (1H, s, CH). 13C NMR (75 MHz, DMSO-d6): dC (ppm) 90,
114, 118.4, 124.8, 126.3, 139.1, 146, 146.3. Anal. Calcd C10H6N6O2: C,
49.59; H, 2.50; N, 34.70. Found: C, 49.66; H, 2.45; N, 34.78.
4.2.5. (E)-3-(1H-Indol-3-yl)-2-(1H-tetrazole-5-yl)
(3e). Brown powder (0.18 g, yield 78%). Mp 218e220 ꢀC. IR (KBr)
nmax/cmꢁ1): 3513, 3400, 2218, 1593, 1498. MS, m/z: 236 (Mþ). 1H
acrylonitrile
(
NMR (300 MHz, DMSO-d6): dH (ppm) 3.56 (br s, NH, overlap with
solvent), 7.25e7.27 (2H, m, HeAr), 7.54e7.56 (1H, m, HeAr),
7.81e7.91 (1H, m, HeAr), 8.26e8.77 (2H, m, CH), 12.41 (1H, s, NH).
13C NMR (75 MHz, DMSO-d6): dC (ppm) 87, 118.6, 122.1, 123.8, 127.4,
130.5, 136.4, 141.3, 154.4, 154. Anal. Calcd C12H8N6: C, 61.01; H, 3.41;
N, 35.58. Found: C, 61.10; H, 3.449; N, 35.47.
Acknowledgements
We gratefully acknowledge financial support from the Research
Council of Shahid Beheshti University.
Supplementary data
4.2.6. 2-(1,3-Dioxo-1H-inden-2(3H)-ylidene)-2-(1H-tetrazole-5-yl)
acetonitrile (6). Cream powder (0.21 g, yield 81%). Mp 156e158 ꢀC. IR
(KBr) (nmax/cmꢁ1): 3311, 2193, 1713, 1612, 1568, 1486. MS, m/z: 251
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.12.044.

Z.N. Tisseh et al. / Tetrahedron 68 (2012) 1769e1773
1773
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