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Recent Developments in the Synthesis of Tetrazoles and their Pharmacological

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DOI: 10.2174/1385272824999201210193344

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Current Organic Chemistry, 2021, 25, 1-16 1

REVIEW ARTICLE

Recent Developments in the Synthesis of Tetrazoles and their Pharmacological

Relevance

Socorro Leyva-Ramos1 and Jaime Cardoso-Ortiz2,*

1
Facultad de Ciencias Químicas, Universidad Autónoma de San Luis Potosí, San Luis Potosí, México; 2Unidad Académica de
Ciencias Químicas, Universidad Autónoma de Zacatecas, Zacatecas, México

ARTICLE HISTORY
Received: August 23, 2020
Revised: October 18, 2020
Accepted: November 16, 2020
DOI:
10.2174/1385272824999201210193344
Abstract: The heterocycle ring tetrazole is an important moiety relevant to medicinal chemis-
try since it is present in some drugs with clinical importance. Its primary biological activity is
a bioisosteric analogue of the carboxylic acid and cis-amide groups. Its metabolic stability and
other physicochemical properties make it an attractive structure for designing and synthesiz- Please provide
corresponding author(s)
ing new pharmaceuticals. The biological activity of tetrazoles is quite extensive and includes photograph
size should be 4" x 4" inches
antiviral, antibacterial, anticancer, antifungal, and antioxidant properties; all of them are dis-
cussed in this review. The most effective way to obtain tetrazoles is by azide derivatives, ei-
ther in the starting materials by the cycloaddition [3 + 2] of organic azides and nitriles or by
preparing a reactive imidoyl azide intermediate. The nucleophilic behavior of the azide group
is discussed when the raw materials include isocyanides. Some other methods include alterna-
tive synthetic routes like thermolysis. This review also highlights some of the developments regarding the use of dif-
ferent heterogeneous catalysts to synthesize different tetrazole derivatives.

Keywords: Tetrazole, isosteric substituent, biological activity, synthesis, structure-tautomerization.

1. INTRODUCTION
The tetrazole ring is an essential synthetic scaffold in medicinal
chemistry and drug design due to its broad interaction with biologi-
cal systems. This review discusses some of the main properties of
tetrazoles, methodologies to synthesize tetrazole derivatives and
their pharmaceutical applications. The first tetrazole to be synthe-
sized was 2-phenyl-5-cyanotetrazole by Bladin (1885) in Uppsala,
Sweden [1], then 5-azidotetrazole (1893) and azoditetrazole (1889)
were prepared.
Until the 1950s, the interest for this heterocycle grew consider-
ably, and the most important methodologies for its synthesis were
developed. From that moment onwards, it is no wonder that the
number of publications regarding its preparation has drastically
increased due to its broad biological activity, highlighting their role
as antiviral, anticancer, antibacterial, antifungal, and antimycobac-
terial agents, among others.
There are many examples of commercial drugs bearing the te-
trazole ring-like cilostazol, pentylenetetrazol, losartan, candesartan,
and valsartan, all of them clinically employed for the treatment of
different diseases (Fig. 1). The tetrazole ring is also used to design
new drugs because it is the bioisosteric analogue of the cis-amide
and carboxylic acid, and its high metabolic stability. Furthermore,
tetrazoles interact with both electon-donating and electon-
withdrawing group, and they also show π stacking interactions with
the receptor recognition sites found in target tissues.
*Address correspondance to this author at the Unidad Académica de
Ciencias Químicas, Universidad Autónoma de Zacatecas, 98160, Zacatecas,
Zac. Mexico; Tel: 52 492 925 6690, ext 4650;
E-mail: jaimecardoso@uaz.edu.mx
All of these properties are responsible for the extensive activity
of tetrazoles. Since the 1980s, several reviews of the chemical
properties, reactivity, and applications of tetrazoles have been pub-
lished, emphasizing their impact on medicinal chemistry and indus-
trial applications [2-8]. Some of the most important industrial ap-
plications of tetrazoles include stabilizers in photography, explo-
sives in rocket propellants, growth regulators in plants, herbicides,
fungicides, and lubricants [9-12].
1.1. Structure and Spectroscopic Properties
Tetrazoles can exist either alone or fused to another ring, such
as the 1H 1 or 2H 2-substituted 2 isomers (R2 ≠ H). They can also
exist as a tautomeric equilibrium involving these two forms 1H 1 y
2H 2, which have different chemical and physicochemical proper-
ties [13,14]. There are some tetrazole bicycles fused with pyridine,
diazine, or triazine. Some examples are: tetrazolo[1,5-a] pyridine 3,
tetrazolo[1,5-a] pyrimidine 4, y tetrazolo[1,5-b] [1,2,4] triazine 5
(Fig. 2).
One of the most efficient ways to elucidate tetrazole structures,
and identify regioisomers and tautomers is monodimensional (1H,
13
C, 1N, 15N) and bidimensional (COSY, HMBC, HSQC) Nuclear
Magnetic Resonance (NMR) [15]. For example, the heteronuclear
bidimensional study (HMBC) allows to identify interactions be-
tween nuclei separated from 2 or 3 bonds, or even directly connect-
ed (Fig. 3); therefore, the spectra corresponding to compounds 6
and 7 are fundamentally different [16]; 13C and 15N NMR are used
to differentiate between substituted tetrazoles [17].
Mass spectrometry of both positive and negative ions shows a
typical behavior in each case, losing HN3 and N2, respectively.
Therefore, different fragmentation patterns can be expected when
performing these types of analyses [18].

1385-2728/21 $65.00+.00 © 2021 Bentham Science Publishers

2 Current Organic Chemistry, 2021, Vol. 25, No. 00 Leyva-Ramos and Cardoso-Ortiz

7 8 3 5
2 2
6
OH 11 25 23
(Z) 24 O 8 10
(S) 2118 12 11 19
1 7 O (Z) 7
4 13 14 5 26
N N 1716 9 N 7 9
22(R) N N 4
18
10 N 304 29 N N
O
8
S
12 3 27 (Z) 28 34
19
13 10 N 179
N
1
10
15 16 9 6 16 3
N 6 20 14 15 5 (Z) 12
(Z) 2 8
11 NH 31 13
N 11
33
32 N 10 5
2 11 N (Z)
N 5 F
(Z)
N N
7
(Z) 6
10 14 15 Analgesic
Antiasthmatic 1 Antifungal

1
5 8 6 15
O 10
3 9 1 5 (Z)
NH2 14 N 14
7 20 4 N
4 4
10 15
N
6 N 2 O 19 13
12 74 4 (Z) N 3 2
3 10
12 (Z)
NH 11
S
6 (E)
18
11 12 (Z) 9
(Z)7 10 (E)
8 (Z)
N N 3
N 4 9 16
6
11
N N Cl 3 9 6 N
7 8 21 1 8
N NH 6 9 5 17 O
3 N N
(Z) N (Z) 13 7 8
3 4
5
5 12
5 5
Antibacterial Anticonvulsivant Anticancer

Fig. (1). Common drugs containing the tetrazole ring.

The main signals observed in infrared spectroscopy correspond 1.2. Tautomerism

to ring stretching of C=N, C-N, N=N, N-N, and they are located in
the range of 1640-1335 cm-1. Other vibrations correspond to ring Unsubstituted NH tetrazoles can exist in three different tauto-
deformations (CN4) located between 1200-900 cm-1. Most of these meric forms, 1H 8, 2H 9, and 5H 10 (Fig. 4). According to theoreti-
signals are weak [19]. cal calculations, isomer 10 has the highest energy (approximately
20 kcal·mol-1), making it unstable, and so far, it has not been de-
H H
tected experimentally [21, 22].
1 N2
H 5 N R R
N2 1N N3 R H
NH KT N N
N N N
4 3 5 4 N N N NH N N
H N N N
1 2
Solvent: acetone 85% 15% 1H 2H 5H
8 9 10
N N N N N Fig. (4). Tautomeric forms of tetrazole.
N N N
N N N When it comes to fused tetrazoles (pyrrolo-tetrazoles) 11-14,
N N N N
only one of the rings can be aromatic, with 5H and 7H isomers (13
3 4 5 and 14) being the most energetically favored (Fig. 5) [23].
Fig. (2). 1H / 2H tautomerism of tetrazoles and some examples of substitut- H
N N N N
ed tetrazoles 1-5. N N N N
N N N NH N N N N
N
N N N H2
N N C 1H 3H 5H 7H
N
N 11 12 13 14
H2C
Fig. (5). Pyrrolo-tetrazoles 11-14.
6
7
1.3. Acid-base Equilibrium
Fig. (3). NMR coupling interaction at two bonds. Compared to other azoles, tetrazoles are quite strong acids and
weak bases. An unsubstituted tetrazole behaves very much like
UV-Vis spectroscopy is of little use when it comes to unsubsti- organic acids with pKa values close to that of acetic acid. Mean-
tuted tetrazoles since they show maximum absorption in the region while, when they have some substitutions at position 5, pKa drops
of vacuum UV (π- π* < 200 nm). However, some substituents are to negative values of -0.8 up to about 6, depending on the substitu-
able to conjugate with the ring, causing a bathochromic effect, ent´s electronic nature [14]. When NH tetrazoles are deprotonated,
shifting the signals to a more useful UV region [20]. 1 and 2 substi- the resulting tetrazolate anion is characterized by high aromaticity
tuted tetrazoles can be differentiated from one another due to their and favors delocalization of π electrons. pKa values depend on the
normal absorption. For example, 1-phenyltetrazole and 2- substituent 5-R, for example: pKa = -0.83, 1.70, 2.07, 3.22, 4.70,
phenyltetrazole showed absorption bands at 236 and 250 nm, re- 5.63, 6.00; when the R = NO2, CF3, Cl, 2-NO2C6H4, H, CH3, NH2
spectively, while in unsubstituted NH tetrazoles, these bands are respectively. As mentioned before, the acidity of tetrazoles increas-
considerably affected by intermolecular interactions [20]. es when the 5-R substituents are more electron-withdrawing.
Recent Developments in the Synthesis of Tetrazoles Current Organic Chemistry, 2021, Vol. 25, No. 00 3

1.4. Azido-tetrazole Isomerism 3. SYNTHESIS OF TETRAZOLES

Ring-opening of tetrazole generates the formation of az-
idoimines, being a step commonly observed during thermal decom-
position and mass spectrometry analysis of this heterocycle. Theo-
retical simulations of this process suggest the formation of E/Z
isomerism of the corresponding azide, with the E isomer (15) even
more stable than the Z isomer (16) or the cyclic form (3) (Fig. 6)
[24].
N ical methods have been employed for this purpose, where azides
N react with hydrazones yielding tetrazoles [35]. The following sec-
N N
N N
N N
N N N
N activity.
E Z
15 16 3 3.1. From Imidoyl Azides
Fig. (6). Formation of tetrazolo[1,5-a] pyridine (3) from E/Z isomerism of
the 2-azidopyridine.
2. BIOISOSTERISM AND BIOLOGICAL MODELING
Several theoretical and experimental methodologies, such as
molecular dynamics, X-ray diffraction, and 1H NMR, have been
implemented to simulate the biological interactions of tetrazoles
[25-27]. The tetrazolyl fragment is a bioisosteric analogue of the
cis-amide and carboxyl groups, and the tetrazolate anion resembles
the carboxylate [28, 29]. Based on electrostatic potential, electronic
density, and crystallographic data, it has been established that car-
boxylate and tetrazolate anion form hydrogen bonds with other
functional groups at a distance greater than 1.2 Å [30]. So tetrazoles
can be referred to as isosteres of the XCOOH and XCOO- groups,
where X is any other atom or molecule [31].
All tetrazole isomers act as hydrogen bonding donors or accep-
tors, and their biological activity, reactivity and other properties are
mostly governed by their ability to form highly stable hydrogen
bonds. However, biological recognition can also occur between
tetrazole and the receptor site through π-π* stacking [32, 33].
Tetrazoles offer a broad spectrum of applications; they can be
used as catalysts, propellants, and even explosives. However, they
found a place in the medicinal chemistry area due to their particular
electronic characteristics and a wide range of biological activities.
There are many pathways to obtain tetrazoles, and most of them
include the use of azides either in the starting materials or as reac-
tion intermediates [34]. Different protocols are focused on develop-
ing new strategies to obtain this heterocycle, and even electrochem-
tions describe recent advances in the synthesis of tetrazole deriva-
tives; our primary goal is to report and discuss the methodologies
suitable for developing new compounds with potential biological
The presence of imidoyl azides is widespread when it comes to
synthesizing tetrazole derivatives. This reactive intermediate class
is prepared in situ using hydrazoic acid and the proper substrate
[34]. For example, the cyclization of imidoyl azide 17 to form 1,5-
disubstituted tetrazoles 18 (Fig. 7) [36] is a widely used procedure
both in the laboratory and at an industrial scale. Imidoyl azides are
generated in situ in a step-by-step process. These intermediates can
also be obtained by reacting an imidoyl chloride with HN3, NaN3 or
any other azide anion [6, 29, 37-39] to yield monocyclic 1,5-
disubstituted tetrazoles 1. The synthesis of bistetrazoles 19 and 20
is also achieved by a multicomponent reaction (MCR) in a pseudo
seven component double azido-Ugi reaction, where an imidoyl
azide is formed as an intermediate in order to get the desired prod-
uct [40].
This latter methodology can occur under phase-transfer condi-
tions (Fig. 8), so it avoids contact with HN3 solutions eliminating
the problem of low solubility of HN3 salts in organic solvents; the
reported yields vary in the range between 36-99% depending on the
substituents [41].
Some peptidomimetic structures bearing the 1-tetrazol-5-yl
moiety (Fig. 9) have been synthesized by these means [42, 43],

H
N O N Cl N N3 N N
Bn PCl5 NaN3 Bn
Bn
N N
R1 R1 H2O R1 Bn
17 R1
R1 = -CH 2Cl
18 54%

N
Bn N
N
N
2BnNC MeOH
NH2 + 2TMSN3 Bn
R2 Et3 N
2HCHO N N R2
N
N N
O 19 81%
R2 =

20 78%

Fig. (7). Cyclization of imidoyl azide to form 1,5-disubstituted tetrazoles and a pseudo seven component version of the azido-Ugi reaction.
4 Current Organic Chemistry, 2021, Vol. 25, No. 00 Leyva-Ramos and Cardoso-Ortiz

R1 R1 = C6H5
R2 N R2 = Me, 87%
R2 CH2Cl2/H2O/NaN3 /
P-T cat N Et, 90%
N
20 °C, 1h N Ph 92%
Cl R1 N
1 4-MeC6H4, 93%
4-ClC6H4, 90%
P-T cat= phase transfer catalyst:
5-butyl-2,3-diphenyl-5-butyltetrazolium bromide or tetrabutylammonium bromide
Fig. (8). Preparation of 1,5-disubstituted tetrazoles under phase-transfer conditions.

showing activity similar to 21 as inhibitors of the HIV-protease
with an inhibitory concentration IC50 of 94 µM. Even when these
structures are promising for the treatment of HIV infections, the
synthesis becomes a problem since only a discrete 17% yield is
obtained due to the complex structure and chiral centers [44].
Tetrazoles 23 a-d can also be prepared with high yields (77-
90%) when substituting chlorine by a N3 group employing sodium
azide. This reaction is exemplified with the 2-chloro(1H)-
pyrazinone that forms the imidoyl azide 22 a-d, followed by a cy-
clization step (Fig. 10) [45]. This particular synthetic route shows
the equilibrium between the azide group and the tetrazole ring,
depending on physical properties like temperature and the solvent
used.
Elmorsy and co-workers [46] have successfully obtained im-
idoyl azides 24 from primary or secondary carboxamides and a
mixture of SiCl4-NaN3 using acetonitrile as a solvent, resulting in
the corresponding 1H-unsubstituted tetrazole derivative 8 (Fig. 11).
Experimental results indicate that SiCl4 or SiCl3N3 is of great im-
portance for imidoyl azide´s chemical transformation, which makes
it a clean reaction with almost complete transformations yielding up
to 92%.

O PCl5, HN3 N N
N
O
HN N quinoline HN N
H O
O
O O O O
O

O N N
H N
N
N N N
H H
O OH N
CONH2
21 17%
O
Fig. (9). Synthesis of some inhibitors of the HIV-protease tetrazole-based peptidomimetics.
R1 R1 R1

R2 N O R2 N O R2 N O
NaN3, CH3CN
reflux, 6h
Cl N Cl Cl N N3 Cl N N
N N
22 a-d 23 a-d
a) R1 = 4MeOC6H4, R2= H; b) R1 =C6H5, R2 = H
c) R1 = C6H5, R2= 4MeOC6H4; d) R1 =C6H5, R2 =4MeO2CC6H4

Fig. (10). Synthesis of tetrazoles 23 a-d from imidoyl azides.

R R R SiX 3 R SiX 3
NH2 3 eq NaN3 NH 3 eq NaN3 HN3,
N N
O SiCl 4 SiCl 4 -X3SiOH
X3SiO X3SiO N3
24

R SiX 3 R SiX 3 R H
N N H2O N R= 4-chloropnehyl
SiX 3= SiCl n(N3)3-n
N N N N N N
N (n = 0, 1, 2 ó 3)
N N
8 94%

Fig. (11). 1H-tetrazoles obtained from carboxamides and a mixture of SiCl4-NaN3.

Recent Developments in the Synthesis of Tetrazoles Current Organic Chemistry, 2021, Vol. 25, No. 00 5

The SiCl3-NaN3 system has also been employed in the synthesis methods can only be applied to the preparation of 1,5-substituted
of 1,5-disubstituted tetrazoles 1 [47, 48] and bis or tris-tetrazoles tetrazoles (Fig. 14) [54].
25, 26 (Fig. 12) bearing the respective amides [49-51].
3.2. From Azides and Nitriles
N
N One of the most efficient and direct ways to obtain tetrazoles is
N
N using [3+2] cyclization of organic azides and different dipolar rea-
N gents such as nitriles. For this reaction to happen, the nitrile must be
N
N somehow activated by electron-withdrawing groups, contrary to
N NH
N azide salts, where only high temperature is needed [55]. Nowadays,
HN N N
N N the reaction between nitriles and azides is efficiently catalyzed by
N
N N N N N different metals and polymers.
H
25 68% 26 84%
A typical way to synthesize 5-substituted tetrazoles 8 is by re-
acting organic nitriles and NaN3 or (CH3)3SiN3. The nitrile sub-
Fig. (12). Bis and tris-tetrazoles obtained under the SiCl3-NaN3 system. strate is activated by a Brönsted-Lowry or Lewis acid giving rise to
The synthesis of 1,5-disubstituted tetrazoles 1 from secondary an open-chain intermediate followed by a final cyclization step
amides and NaN3 using POCl3 as the solvent, has been described in (Fig. 15a) [56, 57].
some reports. Heating or microwave irradiation was employed as an The use of silicon, tin and organoaluminium azides has also
alternative source of energy. Some advantages of this methodology been employed to synthesize tetrazoles (Fig. 15b) [58,59].
are the immediate availability of precursors, complete conversion
Nowadays, catalysts have become more relevant than ever to
into products in one step, good yields, low-cost chemicals, and
improve the synthesis of organic compounds, especially the ones
short reaction times (Fig. 13) [52].
containing nitrogen heterocycles [60, 61]. The desired features for a
When the synthetic goal is to obtain sterically hindered 1,5- catalyst are: being environmentally friendly, non-toxic, cheap, and
disubstituted tetrazoles 27, some researchers found that the reaction recyclable; so, in this scenario, heterogeneous catalysts play an
between N-benzoilamides and SiCl4 with NaN3 worked efficiently important role because they cover most of these features. To obtain
[53]. On the other hand, Duncia and co-workers prepared a sterical- efficient heterogeneous catalysts, some bio-materials have been
ly hindered ortho-tetrazole by three different routes; however, these

R2
R1 R2 10 eq POCl3, 4 eq NaN3 N
NH R1 a) R1 = C6H5 R2 = C6H5 90%
N
O 80 ˚C, 8-12h/ b) R1 = 2-thiophene R2 = C6H5 88%
N N
MW 120 W, 80 ˚C, 5-9 min
1
Fig. (13). Synthesis of 1,5-disubstituted tetrazoles from secondary amides.
O N
N N
R HN 42 - 54 h R=
CH3CN N a) CF3 86%
+ NaN3 + SnCl 4
reflux b) F 83%
R c) Cl 88%

27

Fig. (14). Sterically hindered 1,5-disubstituted tetrazoles obtained from N-benzoilamides with SiCl4 and NaN3.

catalyst
a)
catalyst N Bu3SnOR 3
N
R1 -CN + Me3SiN 3 (10 mol %) R1 ó
Bu2O N SnR 22OR3
N
140 ˚C H P
8 R2 = Me, Bu
R1 - C6H5 99%; C 4H9 55% R3 = Me, Et
toluene R = methyl, ethyl, isobutyl
b) R2AlCl + NaN3 R2AlN3 + NaCl
0 ˚C to T amb
4-6h

N O
N H
R2AlN3 R' =
´R
R´-CN toluene N
-40 to 120 ˚C N
H
99% 97% 97%
8

Fig. (15). a) Synthesis of 5-substituted tetrazole by reacting nitriles and azides. b) Synthesis of 5-substituted tetrazole by reacting nitriles and organoalumini-
um azide.
6 Current Organic Chemistry, 2021, Vol. 25, No. 00 Leyva-Ramos and Cardoso-Ortiz

Expan
ded p
( erlite
Solve 0.05 g)
nt-fre
e, 110
84-96 ˚C
%
N
HN N N cuttlebone
R
N (0.05 g) R-CN + NaN
N3 N 3
DMSO
H 110 ˚C
+ R-CN @C hitin 8 85-98%
Fe 3O 4 0 ˚C
11 R = C6H5
8%
70-9 4-CNC6H4
4-pyridine
4-NO2C6H5

Fig. (16). Synthesis of 5-substituted tetrazole by reacting nitriles, azide and environmentally friendly catalyst.

proposed for this task, showing somewhat variable results; among
these materials cuttlefish bone, perlite, and magnetite-chitin are best
for the synthesis of tetrazoles (Fig. 16) [62-64].
Some heterogeneous catalysts can be employed in the synthesis
of 5-substituted 1H-tetrazoles having bioactive N-heterocyclic
cores 28. These recyclable catalysts proved to be effective in sever-
al consecutive runs without significant loss of activity (Fig. 17).
The main advantages of this methodology are its simplicity of the
reaction procedure, mild reaction conditions, and good yields. The-
se derivatives were evaluated as antifungal agents showing activity
against some microorganisms like Candida albicans, Candida gla-
brata, and Aspergillus fumigatus [65-68].
Metallic catalysts [69], ionic liquids [70], or both [71] are other
alternatives used to prepare tetrazoles 29, 30 and 31 with high
yields (Fig. 18).
The multicomponent Knoevenagel condensation reaction and
1,3 dipolar cycloaddition have been developed to obtain a mixture
of two isomers 1,5 and 2,5-disubstituted tetrazoles 32a and 32b
(Fig. 19) [72, 73]. Initially, NiO nanoparticles act as a Lewis acid
interacting with the carbonyl group, and at the same time, as a Lew-
is base interacting with one of the acid hydrogens in the malono-
nitrile in order to promote the Knoevenagel reaction. Later in the
reaction pathway, NiO also interacts with one of the nitriles, facili-
tating the addition of the azide group to the tetrazole ring. Some of
the different synthesized compounds obtained through this method-
ology showed medium to high activity as bacterial growth inhibi-
tors, especially against gram-positive bacteria such as Staphylococ-
cus epidermidis [72].
Some other reports describe the synthesis of tetrazoles 33 using
aromatic aldehydes with electron-withdrawing groups such as bro-
mine, chlorine, iodine, fluoro, and cyanide in the para position with
excellent yields, contrasting the case of electron-donating groups
like ethyl, isopropyl, methoxy, and tertbutyl in the same position
where only a discreet yield was obtained. These reactions were
triggered by a bifunctional catalyst prepared by immobilizing a
complex of Cu(II) and secondary amine chains on the silica-coated
surface with Fe3O4 nanoparticles [74].
Other examples of catalyzed tetrazole synthesis include the re-
action among amines, sodium azide, and triethyl orthoformate using
a heterogeneous catalyst as a suitable pathway to prepare 1-
substituted tetrazoles 34 (Fig. 20). Borosilicate glass is also an ex-
cellent support for metallic nanoparticles due to its high surface
area, chemical stability, highly porous, and ordered surface [75].
Other catalysts that proved to be efficient for this matter include
ZnS or Yb(OTf)3 [76, 77].
Tetrazoles are also obtained by the Ugi-Azide reaction employ-
ing four components simultaneously: an aldehyde or a ketone,
amine, trimethylsilyl azide, and an isocyanide to form 1,5-
disubstituted tetrazoles (Fig. 21) [40, 78-80]. This general, concise,
and novel strategy can use aldo/keto-acids/esters in the Ugi-Azide
reaction to acquire a large number of new heterocycle scaffolds,
such as lactam-tetrazoles 35 [81].
Kiseloyv [82] proposed a variant to the Ugi multicomponent re-
action, where it generates an N-fluoropyridinium fluoride 36 in situ
followed by a reaction with isonitriles and MeSiN3 to form an
iminocarbonium intermediate. This latter compound was attacked

catalyst
Copper bis diacethyl curcumin-1,2-diamino benzene
Cu-BDACDABSBC
N N
CN SiO 2 - Cu-BDACDABSBC N
N O O
NaN3, H2O, i-PrOH,reflux N
n
n N AcO OAc
H
n=1,2 28
NH2 O 75-94%
N N N
N N
NH : HN Cu
, , N N
N N N
H O N H
H

AcO OAc
O O

Fig. (17). Synthesis of tetrazoles attached to other nitrogen heterocycles, by a heterogeneous catalyst.
Recent Developments in the Synthesis of Tetrazoles Current Organic Chemistry, 2021, Vol. 25, No. 00 7

N
GWE N
Cu2(OTf) 2
EWG-CN + PG-N3 CH2Cl2 N N
20 ˚C
GP
4-48 h
29 81-97%
EWG - electron withdrawing group (EtOCO-, MeCO-, C6H5CO-)
PG - protecting group (4-CH3OCH2C6H5-, C6H5-)

1) NaN3
2) HCl
R
N N
N
X
HN
NC MW 200 W N 30
60 min N
80%

N N
N N
CN NH O O HN HN N
BF4 BF4 R = H- 95%
Cu
4-Br- 96%
O O
3-Cl- 96%
+ NaN3 DMF, 130 ˚C, MW, 20-25 min 4-Cl- 95%

R 31
R

Fig. (18). Alternative catalysts in tetrazole synthesis.

H
N N
Br
N R
Na+ N CN
N N 32a
N
NC N N
N H
N
nano NiO
N
H
R CN

32b R

R=
nano NiO
32a) y 32b) 3-OH 86%
DMF
32a) y 32b) 4-OH 85%

CN
+ NaN3 N
CN H HN
O N
+
NH-Cu(II)@MNP N
H R=
R EtOH, 80˚C CN a) 4-CN 95%
33 b) 4-CH3 87%
OAc
AcO
Cu
O
Fe3O4 Si N
SiO 2 O H
OEt
NH-Cu(II)@MNP

Fig. (19). The multicomponent Knoevenagel condensation reaction.

AgNO3 Aleurites moluccana AgNPs

leaf extract

N N sodium borosiclicate
N
34 N NH2
88% Ag/sodium borosiclicate
NaN3, CH(OEt)3
solvent free, 120 ˚C

Fig. (20). Synthesis of 1-substituted tetrazole with a heterogeneous catalyst.

8 Current Organic Chemistry, 2021, Vol. 25, No. 00 Leyva-Ramos and Cardoso-Ortiz

O R1 R2

NH2 NC O
X
R1 R2 TMSN3 N R1
Y 66%
O O
1-3 steps R
N O
R X Y OR R2 N
N O
N 78%

X-Y = linker (CH 2-CH 2, C6H4) 35

R = H o CH3

Fig. (21). The Ugi-Azide reaction.

by the nucleophile azide giving rise to the imidoyl azide, which 3.3. From Geminal Diazides
after cyclization, formed the tetrazol-5-yl pyridine derivatives 37 The thermolysis of geminal diazides was reported by
with high yields in the range of 75-84% (Fig. 22). Even when many Holzschneider and co-workers [83] as a new approach for the syn-
different substituents were employed, there was no clear tendency thesis of tetrazoles. Under simple conditions, they managed to ob-
favoring a specific type of product regardless of their electronic tain five different groups of tetrazole derivatives without the need
properties (electron-withdrawing or electron-donating) or size. to isolate hazardous organic azide intermediates. Their experi-
R1
mental work included the first step of oxidative diazidation of sim-
R1 R1
ple substrates followed by thermolysis giving rise to five com-
F2, CHCl3 R2
R2-NC, Me3SiN 3 pounds: tetrazoloquinoxalinone 38, benzoylaryltetrazole 39, te-
N
N
-60°C
N F -60°C to RT N
N
trazoloazepinone 40, and tetrazolotriazinone 41 (Fig. 23). These
F 37 N N
reactions showed good yields ranging from 77% to 92%. This rela-
36
tively simple methodology offers a suitable option for developing a
a) R1 = H; R2= p-NO 2-C6H4 83%
b) R1 = 4-Cl; R2= p-CF3-C6H4 84% broad scope of new tetrazole derivatives with potential biological
activity due to the similarities with existing compounds such as
Fig. (22). Synthesis of tetrazol-5-yl pyridine derivatives.
azepines.

N3 N3
O O
N3 O
N3 N3

N3 N Br
O N3 N3
N N
H

o-xylene, mw o-xylene, mw
o-xylene, mw o-xylene, mw
140 ˚C, 3h 140 ˚C, 3h
140 ˚C, 2h 140 ˚C, 2h

N N
N N
N O N O
N O N
N N
N N N N Br
N
N O N
H N N

38 77% 39 92% 40 91% 41 71%

Fig. (23). Some tetrazoles synthetized by thermolysis of germinal diazides.

R1 R2 R2 R2
SiCl 4, NaN3 R1 R1
SiCl 4, NaN3
SiX 3
O MeCN O -X3SiOSiX 3
N3 N3 N3

42

R1 R2 R2 R1 R2
-N 2 R1 a) R1 = CH3; R2= C6H5 87%
N
N3 N b) R1 = C6H5; R2= C6H5 97%
N N N
N3 c) R1 = CH3; R2= CH3 98%
N
1
SiX 3 = SiCl n(N3)3-n
(n = 0, 1, 2 ó 3)

Fig. (24). Preparation of 1,5-disubstituted tetrazoles using ketones and SiCl4-NaN3.

Recent Developments in the Synthesis of Tetrazoles Current Organic Chemistry, 2021, Vol. 25, No. 00 9

In a different methodology, Elmorsy and co-workers [84] pre- Zarubaev and co-workers [91] reported a potential inhibition of
pared a series of 1,5-disubstituted tetrazoles using ketones and the influenza virus by adamantyltetrazoles and other similar deriva-
SiCl4-NaN3 (Fig. 24). The geminal azide 42 lost molecular N2, tives with the tetrazole ring. A plausible mechanism consists of the
forming a nitrene, rearranging to the corresponding imidoyl azide, inhibition of the RNA polymerase.
which subsequently underwent cyclization resulting in the 1,5-
disubstituted tetrazole 1. 4.2. Anticancer
A series of tetrazole chlorine complexes containing Pt(II) and
4. BIOLOGICAL APPLICATIONS Pd(II) have been synthesized, properly characterized, and tested for
Tetrazoles and derivatives are appealing synthetic scaffolds due antineoplastic activity. The most promising complexes being: cis-
to their diverse biological activity as they are already present in [Pt(5-amino-1-phenyltetrazole)2Cl2]·H2O 46a and cis-[Pt(5-amino-
clinically used drugs. They are also accessible starting materials for 1-ter-butyltetrazole)2Cl2]·H2O 46b (Fig. 27). They were effective
the development of new pharmaceuticals [85-88]. against the human cell line HeLa, a model for cervix carcinoma
[92].
4.1. Antivirals 23 19
10
The replacement of a carboxylic acid by a tetrazole ring al- 14
15 Cl
9
14 Cl
N 13
lowed to obtain compound 43; this modification turned out to be of N (E) 24 N (E) 20
H Cl N H Cl
(Z) N Pt (Z) N Pt
great interest for researchers since it was proved that 43 could in- N 11 22
6
N 10 18
13 N 12 3 5 12 N 11 6
21
hibit the HIV-1 integrase [8]. In this scenario, 14 analogues of HIV- 16 17
NH 7 15 NH
(E) 24 25 2 3 7 22
1 integrase inhibitors were prepared by replacing two carboxylic 21
16 (E)
1 N 1
N 4 8 N N
groups with tetrazoles in the L-chicoric acid (L-CA) to form com- 18
9
17
23 8
N N N
pound 44 (Fig. 25). The resulting product was up to 30 times more 20
19
2 (Z) 26
N
(Z) 4
5
potent than L-CA with respect to inhibition of the enzyme. Experi- 46a 46b
mental results indicate that these compounds are suitable for devel- Fig. (27). Tetrazole chlorine complexes containing Pt(II) and Pd(II).
oping new HIV-1 integrase inhibitors [89].
Tetrazole derivatives like 47 showed a high inhibitory effect
Cl
against breast cancer cell lines (MCF-7). Furthermore, steroidal
O O tetrazoles like 48 exhibited a strong selectivity activity against
H
N MCF-7 cells, without having toxicity against normal MRC-5 cells
N (Fig. 28) [93-95].
HN N N 20
4
43 N N (Z)
14 7 (Z)
N N OH 5 N 21 7 13
O 7 12
N (E) 8
HN N OH 17
8 3 H
7 2 N 11
O N
O 16 1 NO2
18 6 19
HO O 7 15
9
O OH O 10
47 14
13
O 12
HO N NH 44 27 11
10 9
OH N N 28 N (Z)
26 (R)
(S) N
19 N 9
Fig. (25). Analogues of HIV-1 integrase inhibitors. 18 2423 25
20 N
8
(Z)
The reverse transcriptase can also be the target of new drugs 4 5
15 7 6
since non-nucleoside derivatives containing the tetrazole function- 8
O 17
22
3
ality (45a and 45b) (Fig. 26) can inhibit this enzyme [90]. 14 16 21
3 2 48
4
8 1
N 9
(Z) N
(E) 4
H (E) 8 7 12 Fig. (28). Tetrazole derivatives with high inhibitory effect against breast
9 N 6 6
N OH cancer cell lines (MCF-7).
N 8 S N 7
10
1 5 1314 4 Shaikhand co-workers [96] prepared a series of tetrazolylme-
5 O 3 5 thyl quinolines and evaluated their cytotoxic activity with molecu-
5 11
2
8 lar docking and in vitro tests against the human tumoral cell line
6 NCI-60. Experiments were carried out in a single dose of 10-5 M. It
7 4
11 45a was demonstrated that compounds 49a and 49b were effective
7
3 against melanoma (SK-LEL-5) and breast cancer (T-47D) (Fig. 29).
N 8
(Z) N 6
9 15
(E) 3
H (E) 11 18 17 7 20
4 N 10 12 R 13
19
C6H5
N 8 N (E)
N 3 S N 10 14 N X
1 16 12 11 4
5 6 98 3 7 9 N N
4 O 13 N Cl 5
8 (Z) 2
4 2 OH 3 1
10
6
3 49a) R = H, X = CH2
5
49b) R = OCH3, X = CH2
3 7 45b
6
Fig. (29). Tetrazolylmethyl quinolines against melanoma (SK-LEL-5) and
Fig. (26). Reverse transcriptase inhibitors. breast cancer (T-47D).
10 Current Organic Chemistry, 2021, Vol. 25, No. 00 Leyva-Ramos and Cardoso-Ortiz

Dileep and co-workers [97] synthesized and characterized a se- 4.3. Antibacterial
ries of quinolone hybrids that contain the 1H-tetrazole-5-thiol moie- The veterinary antibiotic, Kefzol (Cefazolin) 52a and its de-
ty in the C-7 of the piperazine. Preliminary results indicated that methylated analogue, Ceftezole 52b belong to the first generation
compounds 50a-b and 51a-b had anti-proliferative activity in some of cephalosporins with a wide range of activity against aerobic
human cell lines such as cervical carcinoma (SiHA), breast adeno- Gram-positive bacteria (Staphylococcus aureus, Streptococcus
carcinoma (MDA-MB-235), and pancreas carcinoma (PANC-1) pyogenes, Streptococcus pneumoniae sensitive to penicillin) and
(Fig. 30). some Gram-negative (Escherichia Coli, Proteus mirabilis, Hae-
40 mophilus influenzae y Klebsiella spp) [98, 99]. Cefamandole 53 and
R
13 16
Latamoxef 54 belong to the second and third generation of cephalo-
35 34 sporins, respectively (Fig. 31) [99].
36 O O
41 7
33 F 6 10 4.4. Antifungal
37 27 1
11 14 OH
32 29
28
18
17 2 8 (E) 15 Compounds 55-57 contained not only the 1H-tetrazole moiety
N S 26 19
30 N 5 N
9 but also a triazole ring (Fig. 32). This combination of heterocycles
N (E) 3
(Z) N 23 N
20
12 allowed them to have a pronounced activity towards Candida spp,
N 25 22
4
31 Cryptococcus neoformans, and Aspergillus spp [99].
21 38 39
O Kaplancikli and co-workers [100] reported the synthesis of te-
24 50a) R = CH2CH3 trazole derivatives 58a-c and their antifungal activity was tested
50b) R = Br
24 against Candida albicans and Candida glabrata (Fig. 33). One of
R the main advantages of these compounds was low cytotoxicity.
14 17
8 7
9 O O 4.5. Antioxidants
22
6 1 21 12 Figueiredo and co-workers [101] reported that compounds 59a-
36 N 13 11 OH
10
5 19 27
2612 23 (E) 16 c and 60 (Fig. 34) had an antioxidant activity similar to gallic acid
18 S
N 35 28
N N 20 N
11 and without cytotoxic effects towards human lymphocytes.
2 N (E) 29 13
(Z)
N N 34
32 N 31 15 4.6. Action on the Central Nervous System
4
3 25
30 Compound 61 is known under the generic name of alfentanil,
O
33
and it is used for general anesthesia. Cilostazol 62 is a pharmaceuti-
51a) R = CH2CH3
51b) R = Br
cal employed to treat intermittent claudication to reduce pain in
lower extremities, approved by FDA in 1999. Compound 63 is a
Fig. (30). Quinolone hybrids containing the 1H-tetrazole-5-thiol moiety peptidomimetic inhibitor of the β-secretase (BACE1) that is used to
with anti-proliferative activity. treat Alzheimer´s disease (Fig. 35) [2].

7
6 6
1 N N
(Z) N N
(Z)
7 (Z)
7 (Z)
N
N N 9
N 9 8
8
12 2
7 20 O
O 3 2
19 15
11 HN 9 6 S
18 HN 16 10 S 5
14 2 3
2 19 (E) 5
(E) 13 N S 5
N S 3 S
S 18 10
17 O 2 4 (Z) 8
O 11 12
4 (Z)
20
8 4
(Z)
8 (Z) COO- Na+ N N
COO- Na+ N N 6
5 1 7
9 17 52b
52a
6 13 14 4
12 O OH 5
5 N N (Z)
5 4 5 (E)
13 O 10
16 15 (E) N 4

3 4 4 N S 17 N 3
14
9 MeO 11 18
HO 8 16 13
16 O 9 (R) 3 O 8
7 16 HN
HO 12
HN 3 6 8
6 4 1 S 15 O 7
10 15
(E) 15
O
(E) 7 16 1
N S N
5 6
O 2 3 11 N 14
10 9 12
COO- Na+ N N (Z) 2
5
53 11 13 4
14
OH 54
15

Fig. (31). Antibacterial compounds containing tetrazoles.

Recent Developments in the Synthesis of Tetrazoles Current Organic Chemistry, 2021, Vol. 25, No. 00 11

15 13 17
10
6 O 7 (Z) 9
1 14HO 8
12 (E) 16 11 6 9 N N
O 1014
11
6
N N (R) N N
12 N N
11
O 2 N8 8
8 9 5 7 (Z)
12 13 3 (Z) 4 7 F5 13 12
9
6 11
10 55
13 N 6
(Z) F
(Z) 5 9 7
5 11 N (Z)
9 12
N (Z) 2 8 6
14 N 5HO 11 7 (Z) 16
5
N
N N 10 4
N N
11 4 N 1HO12 5 11 (Z) 7
8
6 98 N 5
12
8 N 10 N N
6 10 14 10
7 (Z) 13
F 8 11 11 15
7
N N 3 5
10 9 9 (Z)
N F 6 7
5
2
10 5
7 1 5 5
N 9 4 6 7
F
8
12 56 12 F
6 57
6 10

3
5

Fig. (32). Antifungal compounds containing the 1H-tetrazole moiety and a triazole ring.
2 4
7
N 6 3
(Z) N 2 58a) 2-Cl
10
3 N (E)
5
58b) 2,4 -diCl
N 9 S 11
12 58c) 2,5 -diCl
1 8
R
4 1
O
13
2

Fig. (33). Antifungal tetrazole derivatives.

9
6 3 3 (Z) 1 4 (Z)
(Z)
N N N N
(Z) N 7 5 N
5 N N 5 N N 8
4 NH 6
2
HN N 4 3 N 7
(Z)
OCH4 C H 62
HN 3 10 2 6 5
5 (R)
HN OH5
7(Z) 8 (Z)
5
O (Z)
5
4 O
(R)
2 5 7 (R)
4
O 1 5 2
O 4 (R) (R)O 3 1 6
8
(R) (R) (R) 7 8
O 9 8 10 (R)
(S) 2 O 16 4 O 12
7
O O
O (S) 5 O (R)
7 O C6H5H2CO O 6
6 6 9 7
7 8 3
8 13 6
5 11 3
59a 59b 59c 60
2

Fig. (34). Antioxidant compounds.

11
21
20 22 O
26
17
N 25 19
18 27
4 N N 12
16
23
N 18 11
10 3 N
(Z) 9
19 13 10 16 13 H 14
2 24 28 17 8
15 9 5 N O
11 (Z) N N
N 5 O 15
13 9 4
1 6 14 18 N 5 5
8 3
O
10 N (Z) O 7
7 6 15 1 6 2
62 10
61 15
12

14 16 9 13 26
15 NH212 12 2 12
24 O O 14 OH
24
(Z) 1819 H (R)
16 1 H (R)
7
11
H 19
12
N N N N COOH
25 10 N (R) 3 4 N (R) 23(S) 23
N 12 H H
(Z)
N NH 11 O 5 O18 22O 20 22
10 6 17
6 17 7 8 16 17 21

19 21 COOH
63 20
20

Fig. (35). Tetrazoles with activity on the central nervous system.

12 Current Organic Chemistry, 2021, Vol. 25, No. 00 Leyva-Ramos and Cardoso-Ortiz

8 8

NH3 Cl 1 O
6
6 3
HO 6 1
5 OH
2 7 9
O N
5 7
7 N N
(Z) (E)
N
7 4
R
64 a-e 10
2 4
6 5 6 5 5 3
(Z) (Z) (Z)
5 1 6 3
1 1 3
R= a) 4b) 4 c) 2d) e)
S (Z) HN (Z)
O (Z) 6 8 2
2 2 4 7 2
3 3 1 5
1
3
4

Fig. (36). Inhibitors of the N-methyl-D-aspartate (NMDA) receptors.

Lenda and co-workers [102] reported the synthesis of 5 deriva- turned out to be compound 68, containing the tetrazole and sulfon-
tives of 2-aminoadipic acid with a tetrazole moiety 64a-e. These amide as pharmacophores (Fig. 39).
compounds proved to be selective antagonists of the N-methyl-D- 10

aspartate (NMDA) receptors with no evident neurotoxicity (Fig. 11

N (Z)
1
36). N N
(Z) 9
7 N 17
Boatman and co-workers [103] reported that pyrazole-tetrazole 8
12
6
tricycle 65 was a potent agonist of the niacin GPR109a receptor; it 2 16
5 13
was able to lower the levels of free fatty acids both in vitro and in 19
15
22
O
vivo (Fig. 37). 23
N
3 4 14
S
10 O 18 NH2
68 21
(Z) 24 20
N 2
11 N
N Fig. (39). A COX-2 inhibitor.
1 (Z) NH 2
7 15 16 3 5
4 11 10 17 18
(E) 4 5 9 7 8
13 (Z) 2 21
H N 9
5
12
22 19
10
9 8
7 13 16 6 68 O
N 2
12 5 6 N 3 (Z) 9 15 2014 (Z) 7 8 5
H H N
(E) 9
N 3
1
6 (Z) 5
N
7
6 COOH
4
11 6 115
14 65 8 10
OH N N 4
HN N
3 10
(S)
6 1
Cl 8 (Z) N N N
Fig. (37). Pyrazole-tetrazole tricycle agonist of the niacin GPR109a recep- 6
69
5 K 1 7 (Z) 4 70 7 8

tor. 21 22

4.7. Inhibitors of Metabolic Processes 20 18

23
17 19
Recent studies indicate that tetrazole derivatives are efficient N O
28

(Z) 11 12 1 2
and selective inhibitors of some enzymes involved in the human 24 16
N 15
10 7 6
metabolism, such as the aldose reductase, 5α-reductase, cyclooxy- 14
3
25
genase-2 (COX-2), matrix metalloproteinase-13 (MMP-13), among 26 9 32 8 13 5 4
HN (Z)
others. Pyrrolyl-tetrazole compounds 66 and 67 are selective inhibi- 71
N N 29
27 31
tors of the aldose reductase, they can be used to prevent long term (Z) N
30
complications of diabetes mellitus (Fig. 38) [104]. 5
10
12
8
12 N (E)
6 5 9
12 14
24 O
(Z) 25 5
13 15 11 N 6 18
13 O 26
11 2
7 4 11 10
2 16 21 23 11
(Z) 6
9 3 14 6 5 12
O 3
2 (Z) O 19 O O
14 10 1 N 17
10 3 9
15 8 7 5 18 20 22 7 12
12 (Z) N (Z)
10 11
4 14
(Z)
N 4 N
(Z) N (E)
N
72 7 13
16
O 3 N O N
N 11
(Z) 13 8 10
NH
1 N 4 6 7 18 (Z) N 8

HN N H
18 66 9
67 10
Cl 17 9
17 7 19 11 O
9 12
6 S HN S NH2
Fig. (38). Pyrrolyl-tetrazole inhibitors of the aldose reductase. 22
14
15
(Z)
321 (Z) 8 13
O
5 (Z) 20
N 16
Al-Hourani and co-workers [105] synthesized a series of 1H 5- 4
NH
N 7
substituted tetrazoles and tested them as potential COX-2 inhibitors. 2
(Z) N 73
Some experiments were conducted in order to determine selectivity 1

towards COX-1 and COX-2. The most effective COX-2 inhibitor Fig. (40). Tetrazole derivatives used as antihypertensives.
Recent Developments in the Synthesis of Tetrazoles Current Organic Chemistry, 2021, Vol. 25, No. 00 13

5 O
3 (Z) 3 6
3 7
O 7 7
4 6 5 8
3 (Z) 7 5 10 5 4
2 1 7 (Z) (Z)
5 3 O (Z)
4 4 5 O
HN 1 N N 52 N
6 4 8
8 O 4
9 7
5 3 6 3 4 8 N
3 4 O 2 5
6 NH
1
HN (Z)
7 O 3 6 N
3 5 (Z) 4 8 4
4
3
3 H (Z) 5 4 8 4
5 N 6 5 O 76
(Z) N 3 N NH
3 7
N N (Z) 74 N N
3 4 (Z) 5
75
6

Fig. (41). Antihistaminic agents containing the tetrazole ring.

4.7.1. Antihypertensives open a new field of opportunity in the synthesis of this and other
The renin-angiotensin system (RAS) plays a fundamental role related heterocycles.
in the regulation of blood pressure and homeostasis. Angiotensin II The field of heterogeneous catalysis also plays a vital role in the
(AII) is an octapeptide and a potent vasoconstrictor. In the RAS, the development of new compounds by diminishing reaction times and
reaction that converts angiotensin I into angiotensin II is catalyzed preparing a broader range of derivatives with potential biological
by the angiotensin-converting enzyme (ACE), so the most promis- activity. Several synthetic routes mentioned in this review have
ing strategy for the design of antihypertensives is focused on the proved to be efficient and cost-effective; however, it is still neces-
inhibition of AII. sary to improve these routes to obtain a more diverse set of final
Losartan 69 is the archetypical non-peptide compound of the products.
AII inhibitors family. Valsartan 70, irbesartan 71, and candesartan
CONSENT FOR PUBLICATION
72 also belong to this family. They all have the (1H-tetrazole-5-il)-
biphenyl moiety in their structure. Azosemide 73 is a diuretic agent Not applicable.
with the tetrazole ring; it is also widely used for treating hyperten- FUNDING
sion (Fig. 40) [2].
Consejo Nacional de Ciencia y Tecnología (CONACYT) grant
4.8. Antihistaminic Agents SEP-82585.
Compound 74, known as Tazanoplast, has been used to treat CONFLICT OF INTEREST
acute airway obstruction since the 1980s. The pharmaceuticals,
known as pemiroplast 75 and pranlukast 76, belong to a new gener- The authors declare no conflict of interest, financial or other-
ation of antihistaminic agents containing the tetrazole ring in their wise.
structure; they efficiently block the H1 and H2 receptors on masto- ACKNOWLEDGEMENTS
cytes (Fig. 41) [2].
Declared none.
CONCLUSION
REFERENCES
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efficient approach of many investigations is to prepare the azide free, aqueous and highly diastereoselective synthesis of new 5-substituted 1H-
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