A Convenient One-Pot Synthesis of 1,5-Disubstituted Tetrazoles Containing an Amino or a Carboxy Group

Article abstract of DOI:10.1134/S1070428020050127

Abstract: A convenient method is proposed for constructing the tetrazole ring by a one-pot reaction of amides with phosphorus oxychloride and sodium azide. A series of 1,5-disubstituted tetrazoles containing an amino or a carboxy group, which present interest as buildings blocks for the synthesis of biologically active substances, were obtained.

Full text of DOI:10.1134/S1070428020050127

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2020, Vol. 56, No. 5, pp. 802–812. © Pleiades Publishing, Ltd., 2020.
Russian Text © The Author(s), 2020, published in Zhurnal Organicheskoi Khimii, 2020, Vol. 56, No. 5, pp. 753–765.
A Convenient One-Pot Synthesis of 1,5-Disubstituted
Tetrazoles Containing an Amino or a Carboxy Group
N. T. Pokhodyloa, O. Ya. Shyykaa, and M. D. Obushaka,*
a Ivan Franko National University of Lviv, Lviv, 79005 Ukraine
*e-mail: mykola.obushak@lnu.edu.ua
Received January 1, 2020; revised March 21, 2020; accepted March 23, 2020
Abstract—Aconvenient method is proposed for constructing the tetrazole ring by a one-pot reaction of amides with
phosphorus oxychloride and sodium azide.Aseries of 1,5-disubstituted tetrazoles containing an amino or a carboxy
group, which present interest as buildings blocks for the synthesis of biologically active substances, were obtained.
Keywords: tetrazole, imidoyl chlorides, amides, phthalimides, sodium azide, one-pot synthesis
DOI: 10.1134/S1070428020050127
The bioisosterism of the tetrazole ring and the carboxy
or amido groups makes tetrazole derivatives attractive
for medicinal chemistry applications. The replacement
of the cis-amide bond by a 1,5-disubstituted tetrazole
increases the metabolic stability of the molecule but
does not reduce its pharmacological activity. At pres-
ent, compounds containing a 1,5-disubstituted tetrazole
fragment are used as drugs [1]. For example, 5-[β-(10-
phenothiazinyl)ethyl]-1-acyltetrazoles showed high anal-
getic and anti-inflammatory activities [1]. The synthetic
analogs of N-acyl homoserine lactone (AHL), where the
amide bond is substituted by a tetrazole ring, were tested
as LuxR-dependent QS (Quorum Sensing) modulators
[2]. Some tetrazole derivatives act as antimycotic agents
[1]. A series of tetrazolebiarylpyrazoles were tested as
inhibitors of binding of the CB1 and CB2 cannabinoid
receptors, which provides evidence for the hypothesis
that the amide group in the antiobesity drug rimonabant
[3] can be replaced by its bioisosteric tetrazole moiety.
Tetrazole derivatives were tested as inhibitors of cellular
anandamide (endocannabinoid) uptake [1], cyclooxy-
genase (COX) inhibitors [4], and hard combretastatin
analogs with significant antiproliferative and antitumor
effects [5, 6].
hibitors, selective stearoyl coenzymeAdelta-9 desaturase
(SCD1) inhibitors for the prevention and treatment of
diseases associated with disorders in fat synthesis and
metabolism, including atherosclerosis [1]. Derivatives
of such acids as acetylhydrazones derived from tetrazole
act on ER +/– breast cancer cell lines [7].
Along with 1H-tetrazolylacetic acids, considerable
researcher’s interest has been focused on compounds
containing a (1H-tetrazol-5-yl)methylamine moiety.
One of the first studies this class of compounds assessed
structure–activity correlations for tetrazole-containing
retroamides. Later such compounds were studied as
CCR3 β-chemokine receptor antagonists for treatment
of inflammatory disorders and Alzheimer’s disease and
for prevention and treatment of type II diabetes mellitus
[1], as well as inhibitors of type 4 and 5 phosphodieste-
rase and MDM2-p53 interactions [8]. These compounds
were also tested for antibacterial [9–11] and antiprotozoal
activity [12].
Compounds with a (1-methyl-1H-tetrazol-5-yl)metha-
namine moiety, too, exhibit biological activity. They are
used as tachykinin antagonists, cholesterol ester transport-
er protein inhibitors (CETP), and progesterone receptor
(PR) ligands for the treatment and prevention of inflam-
matory, demyelinating diseases and tumor metastases,
HIV infection, cerebral insufficiency, including increased
receptor function in synapses in brain networks, orexin 2
receptor dysfunction, as well as diseases associated with
Of special mentioning are extensive studies on the
biological activity of isomeric 1H-tetrazolylacetic acids.
Such compounds act as thymidylate synthase inhibitors
and potential antitumor compounds, HIV protease in-
802

A CONVENIENT ONE-POT SYNTHESIS OF 1,5-DISUBSTITUTED TETRAZOLES
803
Scheme 1.
N
R
O
N
N
O
O
H
NH2CH2COOC2H5·HCl
K2CO3
NaN3, POCl3
MeCN
N
O
N
OEt
OEt
R
Cl
R
1a–1e
2a–2e
3a–3e
N
N
N
O
NaOH
H2O, EtOH
N
OH
R
4a–4e
R = PhCH2CH2 (a), trans-PhCH=CH (b), PhOCH2 (c), 2-ClC6H4OCH2 (d), 4-ClC6H4OCH2 (e).
lipoprotein metabolism, monoamine neurotransmitter
reuptake, and purinergic receptor P2X7 inhibitors [1].
treatment of amides with PCl5 or PCl3 followed by heating
of imidoyl chloride with HN3 [24, 25]. Phosgene and tet-
ramethylguanidinium azide [26] ammonium cerium(IV)
nitrate, trimethylsilyl azide, triphenylphosphine, and
diethyl azodicarboxylate are also used [27]. The most
common reagents for transforming the thioamide bond
into a tetrazole ring include trimethylsilyl azide, diiso-
propyl azodicarboxylate, and triphenylphosphine in THF
[28], as well as hydrogen azide [29].
Tetrazole derivatives are also of interest as chelating
agents for metals [13–15] and candidates for the design
of functional materials, in particular, those with nonlinear
optical properties [16, 17].
Thus, the development of convenient methods of
synthesis of tetrazole derivatives is a relevant task. There
are a few main synthetic approaches to 1,5-disubstituted
tetrazoles: 1,3-dipolar cycloaddition of azides to nitriles;
synthesis of imidoyl chlorides and imidoyl azides from
amides and thioamides followed by the reaction of the
products with azide anion; reactions of trimethylsilyl
azide with ketones in the presence of a Lewis acid, involv-
ing the Schmidt rearrangement; reactions of 1-substituted
tetrazoles; and synthesis from heterocumulenes (isocya-
nates, isothiocyanates, carbodiimides). These approaches
have been described in detail in the literature, in particular,
in a recent review [18].
In the present work we developed a facile and con-
venient one-pot synthesis of 1,5-disubstituted tetrazoles
containing an amino or a carboxy group, based on the
conversion of the amide under the action of POCl3 into
imidoyl chloride and its in situ reaction with sodium
azide.
Starting from commercially available acids, we pre-
pared chlorides 1 and used them to acylate ethyl glyci-
nate hydrochloride to prepare amides 2. The latter were
almost quantitatively converted into tetrazoles 3 in the
POCl3/NaN3 system (Scheme 1). Hydrolysis of esters 3
gave acids 4.
It should be noted that the conversion of readily
available amides to the corresponding imidoyl chlorides
and subsequent reaction of the latter with sodium azide
remains one of the most convenient approaches to con-
structing the tetrazole ring, which involves no by-product
formation, unlike some of the other methods mentioned
above. Thus, the alkylation of 5-substituted tetrazoles
forms a mixture of products [19, 20], and only a few
examples of the introduction of substituents to position
5 of the tetrazole ring, on account of the instability of the
latter in basic media [21–23].
Tetrazole derivatives 7 and 8 were prepared in a simi-
lar way starting from chloride 5 via amide 6 (Scheme 2).
Note that, alternatively 1H-tetrazol-5-ylacetic acids
can be prepared by the lithiation of 5-methyltetrazoles
followed by carbonylation [30].
To prepare 5-tetrazolylmethylamines, we used ac-
cessible acids containing a phthalimide fragment. By
treatment with SOCl2 the acids were converted into
chlorides 9a and 9b, which were reacted with amines
10a–10c to obtain amides 11a–11e (Scheme 3). Amides
11 were reacted with POCl3 and sodium azide in aceto-
nitrile to find that they, like compounds 2, form a tetrazole
Amides or thioamides are converted to imidoyl chlo-
rides by means of PCl5, PCl3, POCl3, SOCl2, and oxalyl
chloride. With amides, a two-stage scheme is often used:
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 5 2020

804
POKHODYLO et al.
Scheme 2.
N
N
N
N
O
O
O
O
PhCH2CH2NH2
Et3N, dioxane
NaN3, POCl3
MeCN
O
Ph
N
H
OEt
EtO
Cl
Ph
OEt
5
6
7
N
N
N
N
NaOH
H2O, EtOH
O
OH
Ph
8
ring in these conditions; therewith, compounds 12 were
obtained in nearly quantitative yields. The cleavage of
the phthalimide fragment with hydrazine hydrate gave
amines 13a–13e in high yields.
scheme was applied to obtain 4-(5-methyl-1H-tetrazol-
1-yl)benzoic acid (24) (Scheme 6).
Some problems with realization of the proposed proce-
dure arise in the case of amides containing active halogen
which can react with azide ion. For example, amides 25a
and 25b were converted into the corresponding tetrazoles
with medium yields (Scheme 7), while this reaction with
amide 27 formed a mixture of products, comprising the
target bromide 28a, chloride 28b, and vinyltetrazole 28c
(Scheme 8).
5-Tetrazolylethylamines can be prepared in the same
way, which was demonstrated by the synthesis of com-
pound 17. Starting from substituted alanine chloride 14
we prepared amide 15 and further tetrazoles 16 and 17
(Scheme 4).
Anilines with a tetrazole fragment can be synthesized
starting from nitrobenzoic acids. It was shown that ni-
trobenzoic acid chlorides 18a and 18b can be converted
by the developed scheme to tetrazoles 20a and 20b and
further to amines 21a and 21b (Scheme 5). The same
Thus, the one-pot synthesis of 1,5-disubstituted tetra-
zoles by the reaction of amides with POCl3 and sodium
azide is a convenient method for constructing structural
blocks with a tetrazole ring.
Scheme 3.
N
N
O
O
N
O
O
O
R2 NH2
10a–10c
N
Cl
NH
R2
NaN3, POCl3
MeCN
R2
N
N
N
R1
R1
R1
O
O
O
9a, 9b
11a–11e
12a–12e
N N
N2H4·H2O
EtOH
NH2
R1
N
N
R2
13a–13e
9, R1 = H (a), Me (b); 10, R2 = Me (a), 3-BrC6H4 (b), 4-BrC6H4 (c); 11, 12, 13, R1 = H, R2 = Me (a);
R1 = H, R2 = 3-BrC6H4 (b); R1 = H, R2 = 4-BrC6H4 (c), R1 = Me, R2 = 3-BrC6H4 (d), R1 = Me, R2 = 4-BrC6H4 (e).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 5 2020

A CONVENIENT ONE-POT SYNTHESIS OF 1,5-DISUBSTITUTED TETRAZOLES
805
Scheme 4.
i-Pr–NH2
NaN3, POCl3
MeCN
N2H4ÂH2O
EtOH
Scheme 5.
N
O
O
N
N
R
NH2
NaN3, POCl3
O
O
O
O
O
Cl
NH
N
MeCN
N+
N+
N+
_
_
_
R
R
O
18a, 18b
19a, 19b
20a, 20b
N
N
N
[H]
N
H2N
R
21a, 21b
18, 3-NO2 (a), 4-NO2 (b); 19, 20, 21, 3-NO2, R = i-Bu (a); 4-NO2, R = Me (b). [H] = SnCl2, HCl or H2, Pd/C, 5%.
Scheme 6.
N
N
N
N
N
N
H
N
N
O
N
NaN3, POCl3
MeCN
NaOH
EtO
Me
H2O, EtOH
Me
Me
EtO
O
O
O
OH
22
23
24
Scheme 7.
N
N
N
Cl
O
NaN3, POCl3
MeCN
N
Cl
R
N
R
H
25a, 25b
26a, 26b
R = Me (a), Ph (b).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 5 2020

806
POKHODYLO et al.
Scheme 8.
N
N
N
N
N
N
O
Me
N
N
N
NaN3, POCl3
MeCN
N
N
N
Br
N
Me
H
Cl
Br
Me
Me
Me
Me
Me
Me
27
28a
28b
28c
EXPERIMENTAL
The 1H NMR spectra were recorded on Varian Unity
Found, %: C 66.99; H 6.43; N 5.94. C13H15NO3. Calcu-
lated, %: C 66.94; H 6.48; N 6.00.
Ethyl 2-(2-phenoxyacetamido)acetate (2c). Yield
4.6 g (96%), mp 54–56°C. 1H NMR spectrum (400 MHz,
DMSO-d6), δ, ppm: 1.27 t (3H, CH3, J 6.8 Hz), 3.89 d
(2H, CH2N, J 5.3 Hz), 4.14 q (2H, CH2O, J 6.9 Hz),
+400 and Bruker Avance 500 spectrometers at 400 and
100 MHz, respectively; internal reference TMS. The
APCI mass spectra were obtained on an Agilent 1100
LC/MSD instrument. Elemental analysis was performed
on a Carlo Erba 1106 analyzer. The melting points were
measured on a Boёtius hot stage.
4.49 s (2H, OCH2), 6.83–7.02 m (3Harom), 7.29 t (2H,
3,5
H
, J 7.5 Hz), 8.34 t (1H, NH, J 5.8 Hz). Mass spec-
arom
trum (CI), m/z: 238 [M + H]+. Found, %: C 60.70; H 6.43;
N 5.97. C12H15NO4. Calculated, %: C 60.75; H 6.37;
N 5.90. The characteristics of the product are consistent
with published data [32].
Acid chlorides 1a–1e, 5, 9a, 9b, 14, 18a, and 18b
were prepared by refluxing commercially available acids
with an excess (1.6 equiv) of thionyl chloride for 2 h
and subsequent vacuum distillation of unreacted thionyl
chloride.
Ethyl 2-[2-(2-chlorophenoxy)acetamido]acetate
1
(2d). Yield 5.0 g (92%), mp 44–45°C. H NMR spec-
Amides 2a–2e (general procedure). Chloride 1
(20 mmol) was added under vigorous stirring to a sus-
pension of 3 g of potash and 3.1 g (22 mmol) of ethyl
glycinate hydrochloride in 50 mL of methylene chloride,
and the mixture was stirred for 12 h, washed with water,
and methylene chloride was evaporated in a vacuum to
leave a pure amide.
trum (400 MHz, DMSO-d6), δ, ppm: 1.27 t (3H, CH3,
J 7.1 Hz), 3.92 d (2H, CH2N, J 5.8 Hz), 4.15 q (2H,
CH2O, J 7.1 Hz), 4.60 s (2H, OCH2), 6.96 t (1H, H4arom, J
7.9 Hz), 7.05 d (1H, H6arom, J 8.2 Hz), 7.25 t (1H, H5arom
,
J 7.7 Hz), 7.37 d (1H, H3arom, J 7.5 Hz), 8.14 t (1H,
NH, J 5.8 Hz). Mass spectrum (CI), m/z: 272 [M + H]+.
Found, %: C 53.11; H 5.23; N 5.03. C12H14ClNO4. Cal-
culated, %: C 53.05; H 5.19; N 5.16.
Ethyl 2-(3-phenylpropanamido)acetate (2a). Yield
4.6 g (97%), mp 49–50°C. 1H NMR spectrum (400 MHz,
DMSO-d6), δ, ppm: 1.23 t (3H, CH3, J 7.1 Hz), 2.51 t
(2H, CH2, J 7.7 Hz), 2.84 t (2H, CH2, J 7.7 Hz), 3.80 d
(2H, CH2N, J 5.2 Hz), 4.11 q (2H, CH2O, J 7.1 Hz),
7.17–7.33 m (5H, Ph), 8.23 t (1H, NH, J 5.2 Hz). Mass
spectrum (CI), m/z: 236 [M + H]+. Found, %: C 66.21;
H 7.30; N 5.90. C13H17NO3. Calculated, %: C 66.36;
H 7.28; N 5.95. The characteristics of the product are
consisten with published data [31].
Ethyl 2-[2-(4-chlorophenoxy)acetamido]acetate
(2e). Yield 5.2 g (95%), mp 88–90°C. 1H NMR spectrum
(400 MHz, DMSO-d6), δ, ppm: 1.26 t (3H, CH3, J 7.1 Hz),
3.87 d (2H, CH2N, J 5.9 Hz), 4.15 q (2H, CH2O, J
2,6
7.1 Hz), 4.49 s (2H, OCH2), 6.97 d (2H, H
, J 8.9 Hz),
arom
7.26 d (2H, Ha3,r5om, J 8.9 Hz), 8.35 t (1H, NH, J 5.9 Hz).
Mass spectrum (CI), m/z: 272 [M + H]+. Found, %:
C 53.19; H 5.11; N 5.21. C12H14ClNO4. Calculated, %:
C 53.05; H 5.19; N 5.16.
Ethyl {[(2E)-3-phenylprop-2-enoyl]amino}acetate
(2b). Yield 4.4 g (94%), mp 88–89°C. 1H NMR spectrum
(400 MHz, DMSO-d6), δ, ppm: 1.24 t (3H, J 7.1 Hz, CH3),
3.94 d (2H, CH2N, J 6.0 Hz), 4.13 q (2H, CH2O, J 7.1 Hz),
Amides 11a and 18b (general procedure).Acid chlo-
ride (30 mmol) was added to a cold (0°C) and vigorously
stirred mixture of 3.4 mL of 25% aqueous methylamine
and 25 mL of dioxane, and the resulting mixture was al-
lowed to stand at room temperature for 30 min and then
diluted with water, the precipitate that formed was filtered
off and recrystallized from ethanol.
6.69 d (1H, CH=, J 15.8 Hz), 7.32–7.50 m (4H, Harom
+
CH=), 7.56 d (2H, Ha2,r6om, J 6.9 Hz), 8.46 t (1H, NH,
J 5.8 Hz). Mass spectrum (CI), m/z: 234 [M + H]+.
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A CONVENIENT ONE-POT SYNTHESIS OF 1,5-DISUBSTITUTED TETRAZOLES
807
2-(1,3-Dioxoisoindolin-2-yl)-N-methylacetamide
(11a). Yield 5.6 g (85%), mp 250–252°C. 1H NMR spec-
trum (400 MHz, DMSO-d6), δ, ppm: 2.64 d (3H, CH3, J
4.5 Hz), 4.15 s (2H, CH2), 7.79–7.91 m (4Harom), 8.02 q
(1H, NH, J 4.5 Hz). Mass spectrum (CI), m/z: 219 [M +
H]+. Found, %: C 60.67; H 4.70; N 12.81. C11H10N2O3.
Calculated, %: C 60.55; H 4.62; N 12.84. The characteris-
tics of the product are consistent with published data [33].
1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm:
2,6
4.41 s (2H, CH2), 7.38 d (2H, H
, J 8.7 Hz), 7.53 d
arom
(2H, Ha3,r5om, J 8.7 Hz), 7.72–8.09 m (4Harom), 10.31 s
(1H, NH). Mass spectrum (CI), m/z: 359, 361 [M + H]+.
Found, %: C 53.66; H 3.02; N 7.88. C16H11BrN2O3. Cal-
culated, %: C 53.50; H 3.09; N 7.80. The characteristics
of the product are consistent with published data [36].
N-(3-Bromophenyl)-2-(1,3-dioxoisoindolin-2-yl)-
propanamide (11d). Yield 17.7 g (95%), mp 201–202°C.
1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm: 1.63 d
(3H, CH3, J 7.1 Hz), 4.89 q (1H, CH, J 6.8 Hz), 6.98–
7.38 m (2Harom), 7.54 d (1H, H4arom, J 7.4 Hz), 7.75–8.17
m (5Harom), 9.90 s (1H, NH). Mass spectrum (CI), m/z:
373, 375 [M + H]+. Found, %: C 54.60; H 3.46; N 7.43.
C17H13BrN2O3. Calculated, %: C 54.71; H 3.51; N 7.51.
N-Methyl-4-nitrobenzamide (18b). Yield 4.9 g
1
(90%), mp 214–215°C. H NMR spectrum (400 MHz,
DMSO-d6), δ, ppm: 2.87 d (3H, CH3, J 4.1 Hz), 8.10 d
3,5
(2H, Ha2,r6om, J 8.6 Hz), 8.30 d (2H, H
, J 8.6 Hz),
a rom
8.66 br.s (1H, NH). Mass spectrum (CI), m/z: 181 [M +
H]+. Found, %: C 53.37; H 4.59; N 15.39. C8H8N2O3. Cal-
culated, %: C 53.33; H 4.48; N 15.55. The characteristics
of the product are consistent with published data [34].
N-(4-Bromophenyl)-2-(1,3-dioxoisoindolin-2-yl)-
propanamide (11e). Yield 17.9 g (96%), mp 145–147°C.
1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm:
Amides 6, 11b–11d, 15, 19a, and 27 (general pro-
cedure). Acid chloride (50 mmol) was added to a cold
(0°C) and vigorously stirred solution of amine (50 mmol)
in 50 mL of dioxane and 9 mL of triethylamine (in the
synthesis of compounds 15 and 27, a double excess of
isopropylamine was used instead of triethylamine). The
mixture was allowed to stand for 1 h at room temperature
and then heated to boiling, cooled, and diluted with water.
The resulting amide was filtered off and washed with
saturated soda solution and ice water. When necessary,
recrystallization from ethanol was applied.
1.64 d (3H, CH3, J 7.1 Hz), 4.89 q (1H, CH, J 7.1 Hz),
3,5
7.37 d (2H, Ha2,r6om, J 8.6 Hz), 7.52 d (2H, H
, J
a rom
8.7 Hz), 7.72–8.02 m (4Harom), 9.89 s (1H, NH). Mass
spectrum (CI), m/z: 373, 375 [M + H]+. Found, %:
C 54.66; H 3.32; N 7.47. C17H13BrN2O3. Calculated, %:
C 54.71; H 3.51; N 7.51.
3-(1,3-Dioxoisoindolin-2-yl)-N-isopropylpropan-
1
amide (15). Yield 12.35 g (95%), mp 219–221°C. H
NMR spectrum (400 MHz, DMSO-d6), δ, ppm: 1.02 d
(6H, CH3, J 6.6 Hz), 2.36 t (2H, CH2, J 7.4 Hz), 3.73–
3.86 m (3H, CH2 + CH), 7.66 d (1H, H2arom, J 7.1 Hz),
7.77–7.87 m (3Harom). Mass spectrum (CI), m/z: 261
[M + H]+. Found, %: C 64.47; H 6.11; N 10.65.
C14H16N2O3. Calculated, %: C 64.60; H 6.20; N 10.76.
The characteristics of the product are consistent with
published data [37].
Ethyl 3-oxo-3-(phenethylamino)propanoate (6).
1
Yield 10.8 g (92%), mp 62–63°C. H NMR spectrum
(400 MHz, DMSO-d6), δ, ppm: 1.25 t (3H, CH3, J
7.1 Hz), 2.74 t (2H, CH2, J 7.3 Hz), 3.13 s (2H, CH2),
3.30 q (2H, CH2N, J 6.7 Hz), 4.10 q (2H, CH2O, J
7.1 Hz), 7.12–7.34 m (5Harom), 8.01 t (1H, NH, J 6.7 Hz).
Mass spectrum (CI), m/z: 236 [M + H]+. Found, %:
C 66.47; H 7.34; N 5.91. C13H17NO3. Calculated, %:
C 66.36; H 7.28; N 5.95. The characteristics of the product
are consistent with published data [35].
N-Isobutyl-3-nitrobenzamide (19a). Yield 10.3 g
1
(92%), mp 126–127°C. H NMR spectrum (400 MHz,
DMSO-d6), δ, ppm: 0.89 d (6H, CH3, J 6.5 Hz), 1.77–
1.97 m (1H, CH), 3.11 t (2H, CH2, J 6.2 Hz), 7.76 t (1H,
H5arom, J 7.9 Hz), 8.28 d (1H, H6arom, J 7.4 Hz), 8.37 d
(1H, H4arom, J 8.0 Hz), 8.67 s (1H, H2arom), 8.84 t (1H,
NH, J 5.2 Hz). Mass spectrum (CI), m/z: 223 [M + H]+.
Found, %: C 59.34; H 6.31; N 12.70. C11H14N2O3. Cal-
culated, %: C 59.45; H 6.35; N 12.61.
N-(3-Bromophenyl)-2-(1,3-dioxoisoindolin-2-yl)-
acetamide (11b). Yield 16.9 g (94%), mp 152–154°C.
1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm:
4.42 s (2H, CH2). 7.04–7.31 m (2Harom), 7.47 d (1Harom
,
J 7.7 Hz), 7.78–8.15 m (5Harom), 10.35 s (1H, NH).
Mass spectrum (CI), m/z: 359, 361 [M + H]+. Found, %:
C 53.54; H 3.14; N 7.87. C16H11BrN2O3. Calculated, %:
C 53.50; H 3.09; N 7.80.
3-Bromo-N-isopropylpropanamide (27). Yield
7.8 g (81%), viscous oil. 1H NMR spectrum (400 MHz,
DMSO-d6), δ, ppm: 1.08 d (6H, CH3, J 6.6 Hz), 2.61 t
(2H, CH2, J 6.7 Hz), 3.57 t (2H, CH2Br, J 6.7 Hz),
N-(4-Bromophenyl)-2-(1,3-dioxoisoindolin-2-yl)-
acetamide (11c). Yield 17.0 g (95%), mp 209–210°C.
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POKHODYLO et al.
3.78–3.96 m (1H, CHN), 7.68 d (1H, NH, J 5.8 Hz).
Mass spectrum (CI), m/z: 194, 196 [M + H]+. Found, %:
C 37.02; H 6.17; N 7.07. C6H12BrNO. Calculated, %:
C 37.13; H 6.23; N 7.22.
Found, %: C 48.52; H 4.28; N 18.81. C12H13ClN4O3.
Calculated, %: C 48.58; H 4.42; N 18.88.
Ethyl 2-{5-[(4-chlorophenoxy)methyl]-1H-tetrazol-
1
1-yl}acetate (3e). Yield 2.8 g (94%), mp 92–93°C. H
1,5-Disubstituted 1H-tetrazoles 3a–3e, 7, 12a–12e,
16, 20a, 20b, 23, 26a, 26b, and 28a–28c (general proce-
dure). Phosphorus oxychloride, 4.8 mL (7.7 g, 50 mmol)
and 1.3 g (20 mmol) of NaN3 were added to a vigorously
stirred solution of amide 2a–2e, 6, 11a–11e, 15, 19a, 19b,
22, 25a, 25b, or 27 (10 mmol) in 20 mL of acetonitrile.
The mixture was refluxed for 5–7 h, acetonitrile was
evaporated, the residue was dissolved in water with ice,
and the solution was neutralized with saturated soda solu-
tion. The precipitate that formed was filtered off. Liquid
tetrazoles were extracted with methylene chloride, and
the solvent was evaporated in a vacuum.
NMR spectrum (400 MHz, DMSO-d6), δ, ppm: 1.22 t
(3H, CH3, J 7.1 Hz), 4.17 q (2H, CH2O, J 7.1 Hz), 5.48 s
2,6
(2H, CH2), 5.50 s (2H, OCH2), 7.01 d (2H, H
, J
a rom
8.9 Hz), 7.28 d (2H, Ha3,r5om, J 8.9 Hz). Mass spectrum (CI),
m/z: 297 [M + H]+. Found, %: C 48.64; H 4.45; N 19.03.
C12H13ClN4O3. Calculated, %: C 48.58; H 4.42; N 18.88.
Ethyl 2-[1-(2-phenylethyl)-1H-tetrazol-5-yl]acetate
1
(7). Yield 2.4 g (91%), viscous oil. H NMR spectrum
(400 MHz, DMSO-d6), δ, ppm: 1.26 t (3H, CH3, J
7.1 Hz), 3.19 t (2H, CH2Ph, J 7.5 Hz), 3.92 s (2H,
CH2), 4.16 q (2H, CH2O, J 7.1 Hz), 4.58 t (2H, CH2N,
J 7.5 Hz), 6.83–7.51 m (5Harom). Mass spectrum (CI),
m/z: 261 [M + H]+. Found, %: C 59.91; H 6.32; N 21.59.
C13H16N4O2. Calculated, %: C 59.99; H 6.20; N 21.52.
Ethyl 2-[5-(2-phenylethyl)-1H-tetrazol-1-yl]acetate
(3a). Yield 2.4 g (91%), viscous oil. 1H NMR spectrum
(400 MHz, DMSO-d6), δ, ppm: 1.28 t (3H, CH3, J
7.1 Hz), 3.03–3.18 m (4H, CH2), 4.21 q (2H, CH2O, J
7.0 Hz), 5.34 s (2H, CH2N), 7.12–7.40 m (5H, Ph). Mass
spectrum (CI), m/z: 261 [M + H]+. Found, %: C 59.91;
H 6.09; N 21.58. C13H16N4O2. Calculated, %: C 59.99;
H 6.20; N 21.52.
2-[(1-Methyl-1H-tetrazol-5-yl)methyl]isoindo-
line-1,3-dione (12a). Yield 2.2 g (89%), mp 270–
1
271°C. H NMR spectrum (400 MHz, DMSO-d6),
δ, ppm: 4.18 s (3H, CH3), 5.16 s (2H, CH2), 7.82–7.99 m
(4Harom). Mass spectrum (CI), m/z: 244 [M + H]+.
Found, %: C 54.28; H 3.53; N 28.65. C11H9N5O2. Calcu-
lated, %: C 54.32; H 3.73; N 28.79. The characteristics
of the product are consistent with published data [38].
(E)-Ethyl 2-(5-styryl-1H-tetrazol-1-yl)acetate (3b).
1
Yield 2.2 g (83%), mp 94–96°C. H NMR spectrum
(400 MHz, DMSO-d6), δ, ppm: 1.28 t (3H, CH3, J
7.1 Hz), 4.23 q (2H, CH2O, J 7.0 Hz), 5.58 s (2H, CH2N),
2-{[1-(3-Bromophenyl)-1H-tetrazol-5-yl]methyl}-
isoindoline-1,3-dione (12b). Yield 3.5 g (92%), mp
160–161°C. 1H NMR spectrum (400 MHz, DMSO-d6),
δ, ppm: 5.18 s (2H, CH2), 7.56 t (1H, H5arom, J 8.1 Hz),
7.75 d (2H, Ha4,r6om, J 7.9 Hz), 7.91–7.81 m (4Harom),
7.98 s (1H, H2arom). Mass spectrum (CI), m/z: 384,
386 [M + H]+. Found, %: C 50.12; H 2.67; N 18.11.
C16H10BrN5O2. Calculated, %: C 50.02; H 2.62; N 18.23.
3,4,5
2,6
7.32–7.47 m (4H, Harom + CH=), 7.73 d (2H, H
, J
arom
7.3 Hz), 7.80 d (1H, CH=, J 16.0 Hz). Mass spectrum (CI),
m/z: 259 [M + H]+. Found, %: C 60.29; H 5.34; N 21.74.
C13H14N4O2. Calculated, %: C 60.45; H 5.46; N 21.69.
Ethyl 2-[5-(phenoxymethyl)-1H-tetrazol-1-yl]-
1
acetate (3c). Yield 2.4 g (93%), viscous oil. H NMR
spectrum (400 MHz, DMSO-d6), δ, ppm: 1.21 t (3H,
CH3, J 7.0 Hz), 4.15 q (2H, CH2O, J 7.0 Hz), 5.48 s (2H,
2-{[1-(4-Bromophenyl)-1H-tetrazol-5-yl]methyl}-
isoindoline-1,3-dione (12c). Yield 3.6 g (95%), mp
OCH2), 5.50 s (2H, CH2N), 6.92–7.05 m (3H, Ha2ro,4m,6),
217–218°C. 1H NMR spectrum (400 MHz, DMSO-d6),
3,5
7.30 t (2H, H
, J 7.4 Hz). Mass spectrum (CI), m/z:
arom
2,6
263 [M + H]+. Found, %: C 55.09; H 5.33; N 21.23.
δ, ppm: 5.16 s (2H, CH2), 7.71 d (2H, H
, J 8.5 Hz),
arom
7.77 d (2H, Ha3,r5om, J 8.5 Hz), 7.82–7.96 m (4Harom). Mass
spectrum (CI): m/z 384, 386 [M + H]+. Found, %: C 50.11;
H 2.49; N 18.19. C16H10BrN5O2. Calculated, %: C 50.02;
H 2.62; N 18.23.
C12H14N4O3. Calculated, %: C 54.96; H 5.38; N 21.36.
Ethyl 2-{5-[(2-chlorophenoxy)methyl]-1H-tetrazol-
1
1-yl}acetate (3d). Yield 2.63 g (89%), viscous oil. H
NMR spectrum (400 MHz, DMSO-d6), δ, ppm: 1.20 t
(3H, CH3, J 7.1 Hz), 4.15 q (2H, CH2O, J 7.1 Hz), 5.56 s
2-{1-[1-(3-Bromophenyl)-1H-tetrazol-5-yl]ethyl}-
isoindoline-1,3-dione (12d). Yield 3.6 g (91%), mp
215–216°C. 1H NMR spectrum (400 MHz, DMSO-d6),
δ, ppm: 1.86 d (3H, CH3, J 6.6 Hz), 5.92 q (1H, CH, J
(2H, OCH2), 5.59 s (2H, CH2N), 7.00 t (1H, H5arom, J
4,6
7.1 Hz), 7.33–7.21 m (2H, H
), 7.37 d (1H, H3arom
,
arom
J 7.7 Hz). Mass spectrum (CI), m/z: 297 [M + H]+.
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A CONVENIENT ONE-POT SYNTHESIS OF 1,5-DISUBSTITUTED TETRAZOLES
809
4,6
6.5 Hz), 7.35 t (1H, H5arom, J 8.1 Hz), 7.74 d (2H, H
,
5-Chloromethyl-1-methyl-1H-tetrazole (26a) [24].
Yield 0.7 g (51%), mp 61–62°C. H NMR spectrum
(400 MHz, DMSO-d6), δ, ppm: 4.13 s (3H, CH3), 5.09 s
(2H, CH2). Mass spectrum (CI), m/z: 133 [M + H]+.
Found, %: C 27.09; H 3.76; N 42.36. C3H5ClN4. Calcu-
lated, %: C 27.18; H 3.80; N 42.27.
arom
1
J 7.9 Hz), 7.76–7.98 m (5Harom). Mass spectrum (CI),
m/z: 398, 400 [M + H]+. Found, %: C 51.21; H 3.13;
N 17.50. C17H12BrN5O2. Calculated, %: C 51.27; H 3.04;
N 17.59.
2-{1-[1-(4-Bromophenyl)-1H-tetrazol-5-yl]ethyl}-
isoindoline-1,3-dione (12e). Yield 3.7 g (93%), mp
155–156°C. 1H NMR spectrum (400 MHz, DMSO-d6),
δ, ppm: 1.88 d (3H, CH3, J 6.9 Hz), 5.92 q (1H, CH, J
5-Chloromethyl-1-phenyl-1H-tetrazole (26b) [39].
Yield 1.2 g (62%), mp 72–73°C. Mass spectrum (CI),
m/z: 195 [M + H]+. Found, %: C 49.31; H 3.58; N 28.86.
C8H7ClN4. Calculated, %: C 49.37; H 3.63; N 28.79.
2,6
3,5
6.9 Hz), 7.34 d (2H, H
, J 8.7 Hz), 7.40 d (2H, H
,
arom
arom
J 8.7 Hz), 7.60–7.69 m (2Harom), 7.74–7.90 m (2Harom).
Mass spectrum (CI), m/z: 398, 400 [M + H]+. Found, %:
C 51.44; H 3.11; N 17.71. C17H12BrN5O2. Calculated, %:
C 51.27; H 3.04; N 17.59.
5-(2-Bromoethyl)-1-isopropyl-1H-tetrazole (28a).
Yield 0.76 g (35%), viscous oil. H NMR spectrum
1
(400 MHz, DMSO-d6), δ, ppm: 1.53 d (6H, CH3, J 6.6 Hz),
3.42 t (2H, CH2, J 6.6 Hz), 3.99 t (2H, CH2Br, J 6.6 Hz),
4.85 septet (1H, CH, J 6.6 Hz). Mass spectrum (CI), m/z:
219, 221 [M + H]+. Found, %: C 32.98; H 5.00; N 25.49.
C6H11BrN4. Calculated, %: C 32.89; H 5.06; N 25.57.
2-[2-(1-Isopropyl-1H-tetrazol-5-yl)ethyl]isoin-
doline-1,3-dione (16). Yield 2.2 g (90%), mp 118–119°C.
1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm:
1.57 d (6H, CH3, J 6.8 Hz), 3.29 t (2H, CH2, J 6.9 Hz),
3.99 t (2H, CH2, J 6.9 Hz), 4.83 septet (1H, CH, J 7.1 Hz),
7.78–7.93 m (4Harom). Mass spectrum (CI), m/z: 286
[M + H]+. Found, %: C 58.82; H 5.37; N 24.65.
C14H15N5O2. Calculated, %: C 58.94; H 5.30; N 24.55.
5-(2-Chloroethyl)-1-isopropyl-1H-tetrazole (28b).
1
Yield 0.46 g (26.5%), viscous oil. H NMR spectrum
(400 MHz, DMSO-d6), δ, ppm: 1.53 d (6H, CH3, J
6.6 Hz), 3.53 t (2H, CH2, J 6.7 Hz), 3.83 t (2H, CH2Cl,
J 6.7 Hz), 4.85 septet (1H, CH, J 6.4 Hz). Mass spec-
trum (CI), m/z (Irel, %): 175 (100), 177 (30) [M + H]+.
Found, %: C 41.21; H 6.47; N 32.01. C6H11ClN4. Calcu-
lated, %: C 41.27; H 6.35; N 32.08.
1-Isobutyl-5-(3-nitrophenyl)-1H-tetrazole (20a).
1
Yield 2.2 g (90%), mp 82–83°C. H NMR spectrum
(400 MHz, DMSO-d6), δ, ppm: 0.79 d (6H, CH3, J 6.6 Hz),
1.98–2.22 m (1H, CH), 4.36 d (2H, CH2, J 7.2 Hz),
7.92 t (1H, H5arom, J 8.0 Hz), 8.23 d (1H, H6arom, J 7.7 Hz),
8.48 d (1H, H4arom, J 8.3 Hz), 8.60 s (1H, H2arom). Mass
spectrum (CI), m/z: 248 [M + H]+. Found, %: C 53.39;
H 5.38; N 28.45. C11H13N5O2. Calculated, %: C 53.43;
H 5.30; N 28.32.
1-Isopropyl-5-vinyl-1H-tetrazole (28c). Yield 0.15 g
1
(10.6%), viscous oil. H NMR spectrum (400 MHz,
DMSO-d6), δ, ppm: 1.53 d (6H, CH3, J 6.6 Hz),
4.96 septet (1H, CH, J 6.6 Hz), 5.85 d.d (1H, =CH2, J
11.2, 1.1 Hz), 6.40 d.d (1H, =CH2, J 17.2, 1.1 Hz),
6.93 d.d (1H, CH=, J 17.2, 11.2 Hz). Mass spectrum (CI),
m/z: 139 [M + H]+. Found, %: C 52.22; H 7.35; N 40.52.
C6H10N4. Calculated, %: C 52.16; H 7.30; N 40.55.
1-Methyl-5-(4-nitrophenyl)-1H-tetrazole (20b).
1
Yield 1.8 g (88%), mp 112–113°C. H NMR spectrum
(400 MHz, DMSO-d6), δ, ppm: 4.23 s (3H, CH3), 8.17 d
Tetrazolylacetic acids 4a–4e, 8, and 24 (general
procedure). A solution of 1 g (25 mmol) of NaOH in
10 mL of water was added to a solution of the cor-
responding ester (10 mmol) in 50 mL of ethanol. The
reaction mixture was heated for 3 h at 50°C, ethanol was
evaporated, the residue was dissolved in water, and the
aqueous solution was treated with methylene chloride.
The aqueous layer was made acidic with conc. HCl, and
the white precipitate that formed was filtered off and
dried in a vacuum.
2,6
3,5
(2H, H
, J 8.7 Hz), 8.42 d (2H, H
, J 8.7 Hz). Mass
arom
arom
spectrum (CI), m/z: 206 [M + H]+. Found, %: C 46.91;
H 3.52; N 34.06. C8H7N5O2. Calculated, %: C 46.83;
H 3.44; N 34.13.
Ethyl 4-(5-methyl-1H-tetrazol-1-yl)benzoate (23).
1
Yield 2.0 g (86%), mp 72–73°C. H NMR spectrum
(400 MHz, DMSO-d6), δ, ppm: 1.40 t (3H, CH3, J 7.2 Hz),
2.50 s (3H, CH3), 4.38 q (2H, CH2O, J 7.2 Hz), 7.81 d
3,5
2,6
(2H, H
, J 7.2 Hz), 8.20 d (2H, H
, J 7.2 Hz). Mass
arom
arom
spectrum (CI), m/z: 232 [M + H]+. Found, %: C 57.00;
H 5.06; N 24.05. C11H12N4O2. Calculated, %: C 56.89;
H 5.21; N 24.12.
2-[5-(2-Phenylethyl)-1H-tetrazol-1-yl]acetic acid
1
(4a). Yield 2.2 g (94%), mp 108–109°C. H NMR
spectrum (400 MHz, DMSO-d6), δ, ppm: 3.03–3.18 m
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POKHODYLO et al.
(4H, CH2), 5.18 s (2H, CH2N), 7.15–7.21 m (1Harom),
7.22–7.36 m (4Harom). Mass spectrum (CI), m/z: 233
[M – H]+. Found, %: C 56.71; H 5.25; N 24.19.
C11H12N4O2. Calculated, %: C 56.89; H 5.21; N 24.12.
H 3.90; N 27.26. C9H8N4O2. Calculated, %: C 52.94;
H 3.95; N 27.44.
Amines 13a–13e and 17 (general procedure). Hydra-
zine hydrate, 2.5 mL, was added to a solution of 10 mmol
of phthalimide derivative in 100 mL of ethanol, and the
reaction mixture was heated under reflux for 1 h. After
cooling to –10°C, and phthalazine dione was filtered off.
Ethanol was evaporated, and the residue was dissolved
in methylene chloride. A little of phthalazine dione was
filtered off, and the solvent was evaporated to obtain a
pure amine.
(E)-2-(5-Styryl-1H-tetrazol-1-yl)acetic acid (4b).
1
Yield 2.2 g (95%), mp 128–129°C. H NMR spectrum
(400 MHz, DMSO-d6), δ, ppm: 5.45 s (2H, CH2N),
3,4,5
2,6
7.31–7.50 m (4H, Harom + CH=), 7.75 d (2H, H
,
arom
J 6.9 Hz), 7.80 d (1H, CH=, J 16.1 Hz). Mass spectrum
(CI), m/z: 231 [M + H]+. Found, %: C 57.33; H 4.43;
N 24.21. C11H10N4O2. Calculated, %: C 57.39; H 4.38;
N 24.34.
(1-Methyl-1H-tetrazol-5-yl)methanamine (13a).
1
2-[5-(Phenoxymethyl)-1H-tetrazol-1-yl]acetic acid
(4c). Yield 2.3 g (97%), mp 112–113°C. 1H NMR spec-
trum (400 MHz, DMSO-d6), δ, ppm: 5.37 s (2H, OCH2),
5.46 s (2H, CH2N), 6.95–7.04 m (3Harom), 7.29 t (2H,
Ha3,r5om, J 7.7 Hz). Mass spectrum (CI), m/z: 235 [M +
H]+. Found, %: C 51.18; H 4.35; N 23.97. C10H10N4O3.
Calculated, %: C 51.28; H 4.30; N 23.92.
Yield 1.0 g (91%), viscous oil. H NMR spectrum
(400 MHz, CDCl3), δ, ppm: 1.52 br.s (2H, NH2), 4.09 s
(3H, CH3), 4.11 s (2H, CH2). Mass spectrum (CI), m/z:
114 [M + H]+. Found, %: C 31.78; H 6.19; N 62.02.
C3H7N5. Calculated, %: C 31.85; H 6.24; N 61.91. The
characteristics of the product are consistent with pub-
lished data [37].
2-{5-[(2-Chlorophenoxy)methyl]-1H-tetrazol-1-
yl}acetic acid (4d). Yield 2.6 g (96%), mp 127–128°C.
1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm:
[1-(3-Bromophenyl)-1H-tetrazol-5-yl]methana-
mine (13b). Yield 2.3 g (92%), mp 73–74°C. 1H NMR
spectrum (400 MHz, DMSO-d6), δ, ppm: 2.35 br.s (2H,
NH2), 4.06 s (2H, CH2), 7.58 t (1H, H5arom, J 8.0 Hz),
7.67–7.84 m (2H, Ha4,r6om), 7.99 s (1H, H2arom). Mass spec-
trum (CI), m/z: 254, 256 [M + H]+. Found, %: C 37.97;
H 3.21; N 27.51. C8H8BrN5. Calculated, %: C 37.82;
H 3.17; N 27.56.
5.45 s (2H, CH2N), 5.58 s (2H, OCH2), 6.99 t (1H,
4,6
H5arom, J 7.2 Hz), 7.35–7.23 m (2H, H
), 7.38 d (1H,
arom
H3arom, J 7.8 Hz). Mass spectrum (CI), m/z: 269 [M + H]+.
Found, %: C 44.77; H 3.44; N 20.71. C10H9ClN4O3.
Calculated, %: C 44.71; H 3.38; N 20.85.
2-{5-[(4-Chlorophenoxy)methyl]-1H-tetrazol-1-
yl}acetic acid (4e). Yield 2.6 g (97%), mp 142–143°C.
[1-(4-Bromophenyl)-1H-tetrazol-5-yl]methana-
mine (13c). Yield 2.4 g (94%), mp 77–78°C. H NMR
spectrum (400 MHz, DMSO-d6), δ, ppm: 2.60 br.s (2H,
1
1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm: 5.29 s
2,6
2,6
(2H, OCH2), 5.45 s (2H, CH2N), 7.03 d (2H, H
, J
NH2), 4.04 s (2H, CH2), 7.72 d (2H, H
, J 8.6 Hz),
arom
arom
8.8 Hz), 7.27 d (2H, Ha3,r5om, J 8.8 Hz). Mass spectrum (CI),
m/z: 269 [M + H]+. Found, %: C 44.59; H 3.40; N 20.75.
C10H9ClN4O3. Calculated, %: C 44.71; H 3.38; N 20.85.
7.78 d (2H, Ha3,r5om, J 8.6 Hz). Mass spectrum (CI), m/z:
254, 256 [M + H]+. Found, %: C 37.88; H 3.09; N 27.68.
C8H8BrN5. Calculated, %: C 37.82; H 3.17; N 27.56.
2-[1-(2-Phenylethyl)-1H-tetrazol-5-yl]acetic acid
(8). Yield 2.2 g (95%), mp 98–99°C. 1H NMR spectrum
(400 MHz, DMSO-d6), δ, ppm: 3.18 t (2H, CH2Ph, J
7.4 Hz), 3.82 s (2H, CH2), 4.56 t (2H, CH2N, J 7.4 Hz),
7.07–7.39 m (5Harom). Mass spectrum (CI), m/z: 233
[M + H]+. Found, %: C 56.93; H 5.28; N 24.19.
C11H12N4O2. Calculated, %: C 56.89; H 5.21; N 24.12.
1-[1-(3-Bromophenyl)-1H-tetrazol-5-yl]ethana-
mine (13d). Yield 2.4 g (90%), viscous oil. H NMR
spectrum (400 MHz, DMSO-d6), δ, ppm: 1.46 d (3H,
CH3, J 6.6 Hz), 2.21 br.s (2H, NH2), 4.21 q (1H, CH, J
1
4,6
6.4 Hz), 7.57 t (1H, H5arom, J 8.0 Hz), 7.75 t (2H, H
,
arom
J 7.8 Hz), 7.98 s (1H, H2arom). Mass spectrum (CI), m/z:
268, 270 [M + H]+. Found, %: C 40.42; H 3.71; N 26.03.
C9H10BrN5. Calculated, %: C 40.32; H 3.76; N 26.12.
4-(5-Methyl-1H-tetrazol-1-yl)benzoic acid (24).
1
Yield 2.0 g (97%), mp 262–263°C. H NMR spectrum
1-[1-(4-Bromophenyl)-1H-tetrazol-5-yl]ethana-
1
(400 MHz, DMSO-d6), δ, ppm: 2.50 s (3H, CH3), 7.81 d
mine (13e). Yield 2.5 g (95%), viscous oil. H NMR
2,6
(2H, Ha3,r5om, J 7.2 Hz), 8.20 d (2H, H
, J 7.2 Hz). Mass
spectrum (400 MHz, DMSO-d6), δ, ppm: 1.46 d (3H, CH3,
J 6.7 Hz), 2.17 br.s (2H, NH2), 4.21 q (1H, CH, J 6.6 Hz),
arom
spectrum (CI), m/z: 205 [M – H]+. Found, %: C 52.83;
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A CONVENIENT ONE-POT SYNTHESIS OF 1,5-DISUBSTITUTED TETRAZOLES
811
2,6
3,5
2. Sabbah, M., Fontaine, F., Grand, L., Boukraa, M.,
Efrit, M.L., Doutheau, A., Soulère, L., and Queneau, Y.,
Bioorg. Med. Chem., 2012, vol. 20, p. 4727.
7.70 d (2H, H
, J 8.7 Hz), 7.78 d (2H, H
, J 8.7 Hz).
arom
arom
Mass spectrum (CI), m/z: 268, 270 [M + H]+. Found, %:
C 40.45; H 3.72; N 26.23. C9H10BrN5. Calculated, %:
C 40.32; H 3.76; N 26.12.
https://doi.org/10.1016/j.bmc.2012.06.007
3. Kang, S.K., Lee, S-K., Seo, H.J., Jung, M.E., Ahn, K.,
Kim, J., and Lee, J., Bioorg. Med. Chem. Lett., 2008,
vol. 18, p. 2385.
2-(1-Isopropyl-1H-tetrazol-5-yl)ethanamine (17).
Yield 1.4 g (92%), viscous oil. H NMR spectrum
1
(400 MHz, CDCl3), δ, ppm: 1.56 br.s (2H, NH2), 1.59 d
(6H, CH3, J 6.7 Hz), 2.92 t (2H, CH2, J 6.3 Hz), 3.17 t
(2H, CH2, J 6.2 Hz), 4.68 septet (1H, CH, J 6.4 Hz).
Mass spectrum (CI), m/z: 156 [M + H]+. Found, %:
C46.49;H8.41;N45.07. C6H13N5. Calculated, %:C46.43;
H 8.44; N 45.12.
https://doi.org/10.1016/j.bmcl.2008.02.061
4. Al-Hourani, B.J., Sharma, S.K., Mane, J.Y., Tuszyn-
ski, J., Baracos, V., Kniess, T., Suresh, M., Pietzsch, J.,
and Wuest, F., Bioorg. Med. Chem. Lett., 2011, vol. 21,
p. 1823.
https://doi.org/10.1016/j.bmcl.2011.01.057
3-(1-Isobutyl-1H-tetrazol-5-yl)aniline (21a). Pal-
ladium on carbon (0.22 g) was added to a solution of
2.2 g (10 mmol) of nitro compound 20a in 50 mL of
methanol. The reaction mixture was stirred in an argon
atmosphere for 12 h, filtered through a thin bed of silica
gel, and methanol was evaporated to leave a pure amine.
5. Romagnoli, R., Baraldi, P.G., Salvador, M.K., Pre-
ti, D., Tabrizi, M.A., Brancale, A., Fu, X.-H., Li, J.,
Zhang, S.-Z., Hamel, E., Bortolozzi, R., Basso, G., and
Viola, G., J. Med. Chem., 2012, vol. 55, p. 475.
https://doi.org/10.1021/jm2013979
6. Jedhe, G.S., Paul, D., Gonnade, R.G., Santra, M.K.,
Hamel, E., Nguyen, T.L., and Sanjayan, G.J., Bioorg.
Med. Chem. Lett., 2013, vol. 23, p. 4680.
1
Yield 2.1 g (98%), mp 85–86°C. H NMR spectrum
(500 MHz, DMSO-d6), δ, ppm: 0.78 d (6H, CH3, J
6.7 Hz), 2.03–2.16 m (1H, CH), 4.29 d (2H, CH2, J
7.3 Hz), 5.48 s (2H, NH2), 6.78 d (1Harom, J 8.0 Hz),
6.82 d (1Harom, J 7.4 Hz), 6.89 s (1H, H2arom), 7.23 t (1H
H5arom, J 7.8 Hz). Mass spectrum (CI), m/z: 218 [M +
H]+. Found, %: C 60.91; H 6.83; N 32.38. C11H15N5.
Calculated, %: C 60.81; H 6.96; N 32.23.
https://doi.org/10.1016/j.bmcl.2013.06.004
7. Arshad, M., Bhat, A.R., Pokharel, S., Kim, J-E., Lee, E.J.,
Athar, F., and Choi, I., Eur. J. Med. Chem., 2014, vol. 71,
p. 229.
https://doi.org/10.1016/j.ejmech.2013.11.008
8. Surmiak, E., Neochoritis, C.G., Musielak, B., Twarda-
Clapa, A., Kurpiewska, K., Dubin, G., Camacho, C.,
Holak, T.A., and Dömling, A., Eur. J. Med. Chem.,
2017, vol. 126, p. 384.
4-(1-Methyl-1H-tetrazol-5-yl)aniline (21b). Nitro
compound 20b (6 g, 0.03 mol) was added at 50°C to a
solution of 21 g of SnCl2·2H2O in 70 mL of HCl, and
the mixture was heated at 70°C for 3 h. After cooling,
HCl was evaporated, and the amine hydrochloride was
stirred with 20% aqueous NaOH until a strongly alkaline
reaction. The precipitate that formed was filtered off and
recrystallized from dilute ethanol. Yield 4.3 g (82%), mp
163–164°C. 1H NMR spectrum (400 MHz, DMSO-d6),
δ, ppm: 4.13 s (3H, CH3) 5.59 s (2H, NH2), 6.71 d (2H,
https://doi.org/10.1016/j.ejmech.2016.11.029
9. Chauhan, K., Singh, P., Kumar, V., Shukla, P.K., Sid-
diqi, M.I., and Chauhan, P.M.S., Eur. J. Med. Chem.,
2014, vol. 78, p. 442.
https://doi.org/10.1016/j.ejmech.2014.03.069
10. Tukulula, M., Sharma, R-K., Meurillon, M., Mahajan, A.,
Naran, K., Warner, D., Huang, J., Mekonnen, B., and
Chibale, K., ACS Med. Chem. Lett., 2013, vol. 4,
p. 128.
2,6
3,5
H
, J 8.2 Hz), 7.49 d (2H, H
, J 8.1 Hz). Mass
arom
arom
spectrum (CI), m/z: 176 [M + H]+. Found, %: C 54.91;
H 5.09; N 39.91. C8H9N5. Calculated, %: C 54.85;
H 5.18; N 39.98.
https://doi.org/10.1021/ml300362a
11. Pandey, S., Agarwal, P., Srivastava, K., Rajakumar, S.,
Puri, S.K., Verma, P., Saxena, J.K., Sharma, A., Lal, J., and
Chauhan, P.M., Eur. J. Med. Chem., 2013, vol. 66, p. 69.
https://doi.org/10.1016/j.ejmech.2013.05.023
12. Cano, P.A., Islas-Jácome, A., González-Marrero, J.,
Yépez-Mulia, L., Calzada, F., and Gámez-Montaño, R.,
Bioorg. Med. Chem., 2014, vol. 22, p. 1370.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
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