Ostrovski I 2017

ARTICLE IN PRESS
Developments in Tetrazole
Chemistry (2009e16)
V.A. Ostrovskii*, 1, E.A. Popovax and R.E. Trifonov*, x
*Saint Petersburg State Institute of Technology (Technical University), Saint Petersburg, Russia
x
Saint Petersburg State University, Saint Petersburg, Russia
1
Corresponding author: E-mail: va_ostrovskii@mail.ru
Contents
1. Introduction 2
2. Fundamental Aspects and Theoretical Calculations 3
2.1 Electronic Structure and Geometry 3
2.2 Protolytic Equilibria 6
2.3 Thermochemical and Explosive Properties 8
2.4 Azido-Tetrazole Isomerism 9
2.5 Bioisosterism and Biological Modeling 10
3. Synthesis and Reactivity of Tetrazoles 11
3.1 1H-Unsubstituted Tetrazoles 11
3.2 1-Substituted- and 1,5-Disubstituted Tetrazoles 16
3.3 2-Substituted and 2,5-Disubstituted Tetrazoles 23
3.4 Tetrazoles with a Fused Ring 27
3.5 Functionalization of Tetrazoles 30
3.6 Metal Ion Complexes With a Tetrazole Moiety 33
4. Important Compounds and Applications 38
4.1 Biologically Active Derivatives 38
4.1.1 Antiviral Activity 38
4.1.2 Anticancer Agents 39
4.1.3 Antibacterials 40
4.1.4 Antifungal 41
4.1.5 Antioxidants 42
4.1.6 Receptor Antagonists of the Central Nervous System 42
4.1.7 Inhibitors of Metabolic Processes 43
4.2 Medicines With a Tetrazole Moiety 44
4.2.1 Hypotensive Action 44
4.2.2 Antihistamine Agents 45
4.2.3 Action on the Central Nervous System 46
4.2.4 Antimicrobial and Antiinflammatory Activity 46
4.3 Energetic Tetrazoles 47
4.4 Materials With Tetrazole as an Active Component 49
4.4.1 Polymer Membranes 49
Advances in Heterocyclic Chemistry, Volume 123

© 2017 Elsevier Inc.
j
ISSN 0065-2725
http://dx.doi.org/10.1016/bs.aihch.2016.12.003 All rights reserved. 1
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2 V.A. Ostrovskii et al.
4.4.2 Other Polymer Materials 50

4.4.3 Nanomaterials 51
4.4.4 Catalysts 52
4.4.5 Corrosion Inhibitors 52
5. Concluding Remarks 53
Acknowledgment 54
References 54
Abstract
This short review compiles the main results of the studies in tetrazole chemistry
published in the period 2009e2016. Attention is directed to the structure, reactivity,
synthetic problems, functionalization, and also to the application of derivatives of
this class of polynitrogen heterocyclic compounds. New conditions are revealed
of the tetrazole synthesis underpinned by the use of versatile catalytic systems,
ionic liquids, superacids, microwave activation, microreactor techniques, etc. Main
trends in the development of the tetrazole chemistry that are helping to focus the
efforts of researchers on novel, important, and promising directions of study are
considered.
Keywords: 1,2,3,4-Tetrazoles; Acid-base equilibrium; Applications; Aromaticity; Azido-

tetrazole isomerism; Bioisosterism; Catalysis; Complex formation; Electronic structure;
Fused ring; High nitrogen polymers; Reactivity; Ring formation; Ring fragmentation;
Synthesis; Tautomerism; Tetrazolides; Tetrazolium ions
1. INTRODUCTION
Nine years have elapsed since the publication of Comprehensive
Heterocyclic Chemistry, Edn III (CHEC-III) (08MI257). During this time
the scientific community has lost outstanding scientists who largely contrib-
uted to the development of tetrazole chemistry: Grigorii I. Koldobskii
(1933e2009), Pavel N. Gaponik (1941e2013), Alan R. Katritzky (1928e
2014), and Richard (Dick) N. Butler (1942e2016). The scientific base
created with the direct participation of these scientists turned out to be so
strong that tetrazole chemistry in the period 2009e16 continued its inten-
sive progress. The methods of tetrazole synthesis have been refined
(12ARK45; 12EJO6101; 15MD189), and more frequently the methods
of tetrazole preparation become ecofriendly (12T1769; 14TL6034).
Therefore, tetrazoles have become more available for scientific research
and industrial development. Researchers actively and bravely apply to
tetrazole synthesis new reagents (16MI31850), reaction media (12T1769),
catalysts (16MI31850), microwave activation (10AGE7101), microreactor
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Developments in Tetrazole Chemistry (2009e16) 3
technologies (11AGE3525), etc. The area of beneficial tetrazole application

is constantly broadening. Along with the traditional directions such as
medicinal chemistry (12RCB768; 15RCR891), the chemistry of energetic
compounds and materials (13JMC15383; 11MI16), and new application
fields have appeared. Tetrazoles become increasingly needed in the
designing of new types of electronic device (16L2277), in development of
nitrogen-rich polymer materials (12MI313), etc.
We have tried in this review to consider the main developments and
trends in the growth of tetrazole chemistry during 2009e16.
2. FUNDAMENTAL ASPECTS AND THEORETICAL

CALCULATIONS
To the end of the 20th and the beginning of the 21st centuries funda-
mental investigations were reported on the examination of the electronic
structure, geometry, and the other crucial properties of tetrazole and a large
number of its derivatives by applying experimental and theoretical methods.
The results of these studies have been fairly comprehensively compiled and
discussed in a series of original articles, reviews, and monographs
(1996MI621; 08MI257; 06RJO1585). Over the last 8e10 years the focus
of fundamental theoretic studies shifted to the field of forecasting specific
tetrazole characteristics, in particular, those related to energetic materials,
and to some aspects of their reactivity and biological activity. These issues
will be treated with particular attention.
2.1 Electronic Structure and Geometry

As previously mentioned, the tetrazole ring is a highly aromatic system
(08MI257). The aromaticity strongly depends on the prototropic form in
which tetrazoles are present and also on the nature and the position of the
substituents in the ring (compounds 1e6).
The greatest aromaticity is characteristic of the tetrazolate anions 3 and

2,5-disubstituted neutral tetrazoles 2. As noted by Ramsden, the highest
aromaticity of 2H-tetrazoles might be explained by high bond length equal-
ization as well as of uniformity of p-electron distribution for N2-substituted
derivatives and this trend is common to other azoles (10T2695). For
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instance, according to the calculations by the Pozharsky method, the

aromaticity of the tetrazole ring can vary in relative percentage (where ben-
zene is 100%, cyclopentadiene 0%) from 56% (for tetrazolium ions 4e6) to
96% (for tetrazolate anions 3) (04JST123). Evidently, the high aromaticity of
the tetrazole ring to a large extent governs the thermal and chemical stability
of some of its forms as compared to other azoles. For instance, in the case of
the tautomeric fused pyrrolotetrazoles (7e10), where in the neutral form
only one of the two rings may be aromatic, only the 5O-and 7O-forms 9
and 10 are the most preferable by energy (15CHE246). In tautomers 9
and 10 the tetrazole semicycle is more aromatic than the pyrrole semicycle.
The substituents on the carbon atoms may notably change the pattern.
Neutral NH-unsubstituted as well as 1,5- or 2,5-disubstituted 1H- and

2H-tetrazoles contain in the ring one pyrrole nitrogen atom and three
nitrogen atoms of the pyridine type. The latter, in keeping with
theoretical calculations of the electron density, the electrostatic potential
and NBO-analysis, are strong nucleophilic centers (08MI257; 04JST123;
15CHE246; 10EJM1868; 11T6316). The highest negative charge is located
on the pyridine-like nitrogen N4. Tetrazolate anions, e.g., 3, are highly
symmetric structures with respect to the delocalized negative charge. In the
case of positively charged tetrazolium ions the unprotonated nitrogen atoms
also retain the ability to react with electrophiles such as carbocations, metal
ions, etc. (15TL7020; 17S579; 14ICA124). A substituent on the ring
carbon affects the value of the charges of nitrogen atoms as well as the dipole
moments of tetrazoles (04JST123). In the case of unsubstituted tetrazole, as
well as tetrazoles containing an electron-donor or weak acceptor substituents
at position 5, the 1O-form is more polar compared with the 2O-form.
Whereas for 5-nitrotetrazole, for example, it is quite the opposite. Evidently,
these effects govern the fundamentally different reactivity and selectivity of
various 5-substituted tetrazoles, and this is discussed further.
The tetrazole ring is a strong electron-acceptor. The protonated tetrazole
ring demonstrates especially strong electron-acceptor properties. As was
recently determined from the analysis of equilibria in concentrated solutions
of sulfuric acid and oleum (see Scheme 1), the value of the Hammett’s
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Scheme 1
sigma-constant for the protonated tetrazole ring was determined to be

s 0.78 (16RJO1679). Oziminski and Krygowski have performed a compar-
ison of the substituent effects in tetrazole systems and benzene at the
B3LYP/6-31G(d,p) level, and it was shown that the individual occupancies
of 2pz orbitals at all atoms of the tetrazole and benzene derivatives correlate
with the sum of occupation overall 2pz orbitals (11T6316).
The spatial structure of tetrazoles, their salts, and coordination
compounds with metal ions continues to be the object of theoretical and
experimental studies. As we have comprehensively discussed previously
(08MI257), the tetrazole ring is planar in both the neutral and ionic forms.
The bond lengths in the cycle are in the range from 1.26 to 1.36 Å, and
usually the shortest is the N2eN3 bond. A number of structural studies
have concerned 2-(1H-tetrazol-1-yl)ethanol 14 and the coordination
compounds of this ligand with metal ions (Co, Cu) (09AX1397;
08AX1044; 07AX1573).
Quantum-chemical as well as X-ray investigations of geometry and rela-

tive stability of cis- and trans-isomers of N-substituted bis(tetrazol-5-yl)dia-
zenes show that in the case of 1-monosubstituted bis(tetrazol-5-yl)
diazenes 15 the s-trans-s-trans conformation is the most preferable, whereas
the conformations of the corresponding 2-isomers 16 depend on the nature
of substituents (10MI24).
Lately, important structural data on coordination polymers with tetrazole
ligands have been obtained with the use of X-ray powder diffraction methods
(09AX236; 11AX195; 10AX114; 10P2844; 12ZK702), as well as neutron and
synchrotron X-ray powder diffraction in the temperature range of 2e290K.
This has made it possible to determine a structural transformation of copper(II)
chloride complex with deuterated 1-ethyltetrazole at ca 180K (09ZK233).
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2.2 Protolytic Equilibria

Tetrazoles, due to the presence in their structure of four electronegative
nitrogen atoms, are involved in a large variety of prototropic processes.
These include: annular tautomerism characteristic both of neutral forms of
tetrazoles and tetrazolium ions; tautomerism involving functional substitu-
ents (amino-imine, ketoeenol, thione-thiol, etc.); acid dissociation (for
unsubstituted tetrazole: pKa 4.86); protonation (for unsubstituted tetrazole:
pKBH þ 2:68); the ability to play the role of proton donor and acceptor in
the formation of hydrogen bonds (08MI257). The numerous studies
concerning these topics, and some other related tetrazole properties, have
been comprehensively summerised previously (08MI257; 06RJO1585).
However, these key processes continue to be objects of studies.
The so-called incomplete protolytic equilibria connected with the
formation of hydrogen bonds are fundamentally important for biological
processes. With this taken into consideration, the hydrogen bonding acidity
and the hydrogen bonding basicity of tetrazoles have been the subject of
detailed studies. For instance, Fourier IR spectroscopy has been used (1)
for measuring the values of dissociation constants of complexes with
hydrogen bonds of 1- and 2-substituted tetrazoles 17 and 19 with para-
fluorophenol in tetrachloromethane and dichloromethane, and (2) for
evaluating the corresponding spectral shifts (Scheme 2). It was shown that
the position of the substituent strongly affects this value: for 1-methyl-5-
phenyltetrazole rLOC was 0.66, whereas for 2-methyl-5-phenyltetrazole
rLOC was 0.05 in dichloromethane (13RJO909) (Scheme 2).
Hydrogen bonds with the participation of the nitrogen atoms of
the tetrazole ring govern crystal packing and are responsible for the forma-
tion of a three-dimensional network (08MI257; 07AX1573; 13SAA229).
R2 R2
R1
R1 N
N
N + X-OH N H O X
N N N N
17 18
R2 R2
N N
N + X-OH N H O X
N N N N
R1 R1
19 20
R1=Me, Ph; R2=H, Alkyl, Ar

X= 4-FC6H4, Me
Scheme 2
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Allen and coworkers, using theoretical studies and crystallographic

data, thoroughly investigated the character of hydrogen bond formation
in neutral tetrazoles and tetrazolides with model functional groups
(12MI857).
The conformational and tautomeric composition of 2-(tetrazol-5-yl)
acetic acid in a matrix was comprehensively characterized by exper-
imental (vibrational spectroscopy) and theoretical calculations
(14JCP064306). It was shown that in crystals this compound exists exclu-
sively as the 1H-tautomer 21 whereas in cryogenic nitrogen matrices both
the 1H- and 2H-tautomers 21 and 22 are found in comparable amounts
(14JCP064306).
Also, intermolecular and intramolecular H-bonds affect the tautomerism

of N-(1,1-dioxo-1,2-benzisothiazol-3-yl)-amine-1H-tetrazole 23, as was
investigated using X-ray crystallography and infrared and Raman spectros-
copy in crystals and isolated in an argon matrix (11JMS103).
Adsorption of different 1H- and 2H-tautomeric forms of parent tetrazole
on surfaces of the anatase form of TiO2 have been simulated by density
functional theory (DFT) methods (14JMM2086).
Recently some additional data on the acidity and basicity of tetrazoles

have been published. Thus, a good agreement between experimen-
tally determined and DFT calculated gas-phase basicity and pKBHþ
values of 1H-tetrazoles is observed (15JCD18518). The gas-phase acidity
of 5-nitrotetrazole was calculated at the B3LYP/aug-cc-pVTZ level
(15JPC395). In highly acidic media the values of protonation constants
of 1-(4-carboxyphenyl)-5-methyltetrazole 11 for the first and the second
step were measured by spectrophotometry to obtain the following data:
1 þ 2 þ
pKBH 2:9 and pKBH 9:6 (16RJO1679). According to B3LYP
calculations, the CH acidity of 1-methyltetrazole is significantly lower
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than that for 2-methyltetrazole, both in the gas phase as well as in tetrahy-
drofuran (THF) and dimethyl sulfoxide (DMSO) solution, which is in
agreement with experimental observations (09JMT19).
2.3 Thermochemical and Explosive Properties

Tetrazoles are highly energetic systems. Some of these compounds are
powerful explosives and can be used practically as components of initiation
systems, special explosive compositions and rocket propellants (08MI257;
1999MI467; 11MI16). The results of experimental investigation of these
properties of tetrazoles are summarised in Section 4.5. Here we consider
separately some recent theoretical studies treating the thermodynamics,
thermal stability, and sensitivity as well as detonation or combustion properties
of tetrazoles.
Zhu and Xiao calculated thermodynamic properties of crystalline 1H-
tetrazole 24 and some of its derivatives using DFT methodology
(10MI847). A thorough investigation of the mechanism of thermal decompo-
sition of various prototropic forms of unsubstituted tetrazole associated with
the elimination of a nitrogen molecule was carried out by Kiselev et al.
(11JPC1743). In this study, at the W1 level procedure, not only the stable
1O- and 2O-tautomers 24 and 25 but also the labile 5O-form 26 and the
N-heterocyclic carbene 27 were considered as possible key intermediate in
such processes.
Using the PM3 method, a good linear relationship was established

between the experimental impact sensitivity of metal tetrazolate salts and
the reaction activation energy for formation of azide (1999CPH243).
Thermodynamic and detonation properties of positively charged
tetrazolium salts (protonated and methylated tetrazole cations) with
dinitroamide, azide, and perchlorate anions were also calculated using
DFT-B3LYP methodology and volume-based thermodynamics methods
(10JPC13142).
For the tetrazole derivatives 28, 29 and 30, theoretical calculations
of the heat of formation, thermal stability, impact sensitivity, and
density and velocity of detonation demonstrated that such compounds
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might be regarded as promising highly energetic substances (11MI775;

12JMM3467).
2.4 Azido-Tetrazole Isomerism

Azido-tetrazole isomerism is often observed in tetrazole chemistry. The
opening of the tetrazole ring with the formation of azidoimines is a common
pathway of the thermal and mass spectral decomposition of mononuclear
tetrazoles (08MI257). This process is especially characteristic of fused
tetrazoloazines or tetrazoloazoles. It is often impossible to predict whether
a certain compound exists in a cyclic or azide form. By an example of 2-
azidopyridine/tetrazolo[1,5-a]pyridine and the other heterocyclic systems,
this process was investigated in detail by Alkorta et al. at the B3LYP
and G3B3 level (10T2863). In simulation of these processes the possibility
of the E/Z-isomerism of the corresponding azide forms has to be taken
in consideration; however, the open-chain E-form 31, as a rule,
proves to be somewhat more stable than the Z-isomer 32 or the cyclic
form 33. The relative energies of the transition states are of several tens of
kJ/mol (Scheme 3).
In the case of diazines the process is complicated by the possibility of the
existence of two isomeric tetrazoloazines that can interconvert via the
corresponding azide intermediates, e.g., 35. For the tetrazoloquinazoline,
for example, the bent isomer 34 is considerably more stable than the linear
one 36 (Scheme 4) (10T2863).
Scheme 3
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Scheme 4
In the case of azido(tetrazolo)azoles the azide forms 37and 38 turned

out to be more thermodynamically preferable than the bicyclic form 39
(10T5071). The transition of the azide form into the tetrazole essentially
depends on the possible protolytic equilibria. For example, in the case of
deprotonated azido(tetrazolo)azoles (40 and 41) the bicyclic tetrazole form
42 appears to be preferable in most instances (Scheme 5) (10T5071).
Various factors may considerably affect the azido-tetrazole isomerism:
these include coordination to a metal (11T8724), the structure of the fused
ring (14JMS147), as well as the nature and the position of a substituent in
the ring (15CHE246; 14MI25302; 12SA316). It has been observed that sub-
stituents such as NO2 and CN shift this equilibrium to the side of the azide
form, whereas NH2 and OH groups favour the cyclic tetrazole form
(12SA316).
2.5 Bioisosterism and Biological Modeling

Simulation of biological interactions involving a tetrazole ring has been
the subject of versatile studies (08MI257; 15RCR891). Recently, the
understanding of this issue essentially widened. As is well known, the tetra-
zolyl fragment is a bioisosteric analog of carboxy and cis-amido groups, and
the tetrazolate anion simulates carboxylate groups (12RCB768; 14MI15;
14JCP064306). Basing on the calculated electrostatic potential and on the
electron density, a biological receptor to possess four positive regions with
Scheme 5
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a definite geometric position should be electrostatically complementary

simultaneously to both bioisosteres: carboxy and tetrazolate groups
(10EJM1868). A similar binding affinity of cis-amide fragments and 1,5-
disubstituted tetrazoles with the 5-HT6 receptor has also been shown
recently (16BML2333).
However, Allen and coworkers, based on crystallographic data and
theoretical calculations, have stated that a neutral tetrazolyl fragment and
tetrazolate anion form hydrogen bonds with functional fragments at a
distance exceeding 1.2 A, which is the distance that was observed for the
fragments COOH and COO (12MI857). Therefore, it is more correct
to regard tetrazoles as isosteres of the groups XCOOH and XCOO, where
X is some spacer, for instance, an atom or groups of atoms. The structural
analogues of 2H-tetrazoles with other pharmacophore fragments are not
so obvious (13CMC385; 15RCR891).
3. SYNTHESIS AND REACTIVITY OF TETRAZOLES

3.1 1H-Unsubstituted Tetrazoles
1H-Unsubstituted tetrazoles are valuable intermediates or target
products in the synthesis of practically useful compounds. The most
popular (08MI257) preparative methods for 1H-unsubstituted tetrazoles
are based on the reactions of nitriles with the salts and other derivatives
of hydrazoic acid. In general, the formation of 1H-unsubstituted tetrazoles
(43 or 44) can proceed along two alternative pathways: (1) [3 þ 2]-
cycloaddition of 1,3-dipole (XN3) to a dipolarophile (RCN) through an
intermediate A; or (2) a nucleophilic attack of the azide on the carbon
atom of the CN with the formation and subsequent unimolecular electro-
lytic cyclization to a tetrazole of an azidoazomethine B (Scheme 6)
(08MI257; 12JOC10882).
Scheme 6
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In this aspect, tetrazole chemistry has been very successful in the period
from 2009 to 2016. The previously unthinkable versatility of the reaction
conditions between the nitriles and azides is amazing. As seen from Table 1,
the synthesis of tetrazoles from nitriles is increasingly carried out
by applying new catalysts, solvents, etc. Presumably, this trend in the
chemistry of 1H-unsubstituted tetrazoles is indirectly connected to
the vigorous development of new catalytic methods occurring in this
time interval. It should be noted that in the papers cited below (Table 1)
the synthesis conditions are described for 1H-unsubstituted 5-alkyl, 5-
aryl, and 5-heteryl tetrazoles. In Table 1 data are cited for only one model
compound 5-phenyl-1H-tetrazole 45, whose synthesis was performed
under various conditions (Table 1, Entries i-xxx).
Unfortunately, in the majority of the cited articles (Table 1) the nature of

the catalytic effect and the influence of the catalysts and other reaction
conditions on the mechanism of reaction between nitriles and azides were
not considered. The question remains unsolved as to whether the process
is [3 þ 2]-cycloaddition of azides to the cyano group (Huisgen
reaction) (Scheme 6, intermediate A), as is stated in most cases, or under
these conditions alternative mechanisms are involved. It cannot be excluded
that under these conditions nucleophilic attack of the corresponding azide
onto the carbon atom of the cyano group occurs with the formation of
an intermediate azidoazomethine and subsequent cyclization to a tetrazole
(Scheme 6, intermediate B). The possible operation of this kind of mecha-
nism has been mentioned in the context of the effect of glycerol on nitrile
reactions with sodium azide (12MI161).
We believe that the traditional approaches to the synthesis of 1H-
unsubstituted tetrazoles from nitriles, with the use of ammonium azide
(Henry, Finnegan, Lofquist), alkylammonium azides (Ostrovskii, Koldob-
skii et al.), and also later protocols (Demko, Sharpless) have not lost their
importance (08MI257). These methods are successfully utilized in the lab-
oratory and industrial syntheses of 1H-unsubstituted tetrazoles from
nitriles.
It has been reported that these processes can be performed under the
conditions of flow microreactors (10AGE7101; 11AGE3525; 14MI241).
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Table 1 Examples of synthesis of 5-phenyl-1H-tetrazole 45

Entry Reagent/conditions/etc. Yield (%) References
i gFe2O3, nanoparticles, 0e0.2 g, 0e81 10MI1029

NaN3, dimethylformamide (DMF),
36 h; 120 C
ii Fe3O4@SiO2/SalenCu(II), NaN3, DMF, 90 13JOM87
7 h, 120 C
iii Fe3O4@chitin, [bmim]N3a, 110 C, 20 min 95 16MI31850
iv NaN3, [emim][HSO4]b, 100 C, 10 h 85 11MC334
v FeCl3-SiO2, NaN3, DMF, 12 h, 120 C 79 09TL4435
vi Fe(OAc)2 (10 mol%), TMS-N3, DMF/H2O 56 09CEJ4543
(9/1), 24 h, 80 C
vi Ln(OTf )3-SiO2), NaN3, DMF/MeOH (4:1), 88 14TL3557
7.5 h, 100 C
vii Yb(OTf )3 x H2O, NaN3, DMF, 16 h, 100 C 87 14TL2718
viii ZrOCl2 x 8H2O, NaN3, DMF, 6 h, 100 C 95 11MI75
ix CAN/HY-Zeolitec (30 mol%), NaN3, DMF, 93 14TL5683
4 h, 110 C
x Zeolite, sulfated Zirconia, NaN3, 98d 11POL2606
DMF/MeOH(9/1), 24 h, 80 C
xi Mesoporous cuttlebonee, 0.05 g, NaN3, 98 15MI49849
DMSO, 20 min, 140 C
xii Cu(II)immobilized on aminated 95 15MI12372
epichlorohydrine activated silica (CAES)
(1 mol%), NaN3, DMSO, 1 h, 130 C
xiii CuFe2O4 magnetically recoverable and 82 11TL3565
reusable nanoparticles, NaN3, DMF,
12 h, 120 C
xiv Su-MCM-41f nanoparticles, NaN3, DMF, 92 16JCS93
120 min, 120 C
xv 5 mg Mont-K10-Cug, NaN3, DMF, 85 11HAC168
2 h, reflux
xvi MoO3 e SiO2, NaN3, DMF, 14 h, 120 C 86 12MI12
xvii BaWO4, NaN3, DMF, 24 h, 120 C 75 09JMO135
xvii SiO2 e H2SO4, NaN3, DMF, 5 h, reflux 88 12JMS4696
xix ArNPsh, NaN3, DMF, 8 h, 120 C 92 14JMO150
xx (NH4)2Ce(NO3)6, NaN3, DMF, 6 h, 110 C 97 14TL6034
xxi Amberlyst-15 (solid acidic resin), NaN3, 91 13TL106
DMSO, 12 h, 85 C
xxii Cu-Zn alloy nanopowder, NaN3, DMF, 95 11EJO6343
10 h, 120 C
xxiii ZnCl2, NaN3, solvent-free, 8 h, 100 C 84 09MI1311
xxiv ZnS (MZNSS)i, NaN3, DMF, 36 h, 120 C 96 10CC448
(Continued)
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Table 1 Examples of synthesis of 5-phenyl-1H-tetrazole 45dcont'd

Entry Reagent/conditions/etc. Yield (%) References
xxv ZnO/Co3O4 nano (size, 40e50 nm), NaN3, 90 12MI1324
DMF, 12 h, 120 C
xxvi Glycerole (catalyst free conditions), NaN3, 94 12MI161
2 h, 110 C
xxvii MW or flow reactor, NaN3, AcOH, NMPj, 84e95 10AGE7101
H2O, 5e10 min, 220 C,
xxviii AlPO-5k, NaN3, DMF, 24 h, 120 C 87 14NJC3078
xxix B(C6F5), NaN3, DMF, 8 h, 120 C 94 14TL3507
xxx NH4OAc, LiB(N3)4, DMF/MeOH(9/1), 86 13TL6729
8 h, 100 C
a
1-butyl-3-methylimidazolium azide.
b
1-ethyl-3-methylimidazolium hydrogen sulfate.
c
Ceric ammonium nitrate supported HY-zeolite.
d
Conversion followed by HPLC.
e
The flattened internal skeleton of the cuttlefish.
f
Mobil Composition of Matter N41.
g
Montmorillonite K-10 including Cu2þ.
h
Silver nanoparticles.
i
Mesoporous ZnS nanospheres, treated with 0.1 M HNO3.
j
N-methylpyrrolidone.
k
Aluminaphosphate molecular sieves with AFI topology.
It has been demonstrated for the reaction of benzonitrile with dimethylam-

monium azide in DMF that under the conditions of both a batch reactor and
a flow microreactor the formation of 1H-unsubstituted tetrazoles proceeds
in keeping with a [3 þ 2] cycloaddition mechanism (14MI241). It has
been shown (15BJO2326) that in the synthesis of 1-amino-4-bromo-2-
tetrazolylanthraquinone 47 from the corresponding nitrile 46 the most
efficient conditions were those described in Entry xxv (Table 1)
(10AGE7101), whereas the modified version of the synthesis described by
Demko and Sharpless in the presence of ZnBr2 did not provide the expected
result (Scheme 7).
N
O NH2 O NH2 N
i N
CN N
ii H
O Br O Br
46 47
i, NaN3 , NMP, AcOH, H2O, MW, 220oC, 20 min, yield, 92%;

ii, NaN3 , ZnBr2, MW, 80-100oC, 10-120 min.
Scheme 7
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Scheme 8
Although the reaction of nitriles with derivatives of hydrazoic acid is

most often used with various modifications (Table 1) in the synthesis of
1H-unsubstituted tetrazoles, new alternative approaches are often consid-
ered by their authors as being fairly competitive. It was reported
(12TL3706) that 1H-unsubstituted 5-aryltetrazoles 48 are obtained in
good yields from the corresponding oximes and sodium azide using copper
acetate as a catalyst (Scheme 8).
It should be stressed that all the above cited methods and synthesis con-
ditions provide the possibility of obtaining good yields, as a rule, only for
1H-unsubstituted 5-phenyl, 5-aryl-, and 5-hetaryltetrazoles. The yields of
5-alkyltetrazoles prepared under the conditions reported in Table 1, or
similar, usually do not exceed 30e40%. However, some exceptions do exist.
For instance, the calixarene 49 was converted in the ditetrazole 50 in 87%
yield (Scheme 9) (09EJO4770).
A study of the preparation of 5-alkylaminotetrazoles 51 from secondary
amines and cyanogen azide, obtained in situ from cyanogen bromide and
NaN3, is worthy of mention (Scheme 10) (09EJO3573). This method
makes it possible to prepare a diverse range of compounds with general
structure 51, among them the energetic derivatives of 5,50 -ditetrazole (see
Section 4.2).
Scheme 9
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Scheme 10
An efficient method for the preparation of arylaminotetrazoles deriva-

tives using aluminum chloride as an effective Lewis acid has been reported
(11SC2135). Generally, 5-arylamino-1H-tetrazoles are obtained from
arylcyanamides carrying electron-withdrawing substituents on the aryl
ring. As the electropositivity of the substituent is increased, however,
the reaction pathway is shifted toward the formation of 1-aryl-5-amino-
1H-tetrazole isomers (11SC2135).
Efficient methods for the synthesis of 5-substituted 1H-tetrazoles via multi-
component reactions of a-dicarbonyl compounds, 2,3-diaminomalononitrile
and sodium azide without any catalyst have been reported (12T3351). These
general protocols provide a wide variety of (1H-tetrazole-5-yl)pyrazines, e.g.,
52, and di(1H-tetrazole-5-yl) pyrazines, in good yields (Scheme 11).
A green and convenient method for the preparation of the 1H-
unsubstituted tetrazoles 53 has been developed using a multicomponent
domino Knoevenagel condensation and 1,3-dipolar cycloaddition
(Scheme 12) (12T1769; 14MI1217).
Tisseh et al. (12T1769) and Mahkam et al. (14MI1217) believe that these
results once again demonstrate the possibility of tetrazoles synthesis under
ecofriendly conditions.
3.2 1-Substituted- and 1,5-Disubstituted Tetrazoles

The search for optimization of regioselective synthetic methods for
N1-substituted tetrazoles has remained urgent in the years since publication
Scheme 11
ARTICLE IN PRESS
Scheme 12
of CHEC-III (08MI257). In this regard, a three-component domino-

reaction involving appropriate amines, sodium azide, and ethyl orthofor-
mate is noteworthy, since it has become increasingly popular. Traditionally
glacial acetic acid is the preferred reaction medium (08MI257). Sardarian
and coworkers synthesized 1-phenyltetrazole from aniline, sodium azide,
and ethyl orthoformate using a nanocatalyst based on (Fe3O4@SiO2)
in THF or DMF solution and also under solvent free condition
(13JOM87). The yield of 1-phenyltetrazole under these conditions may
reach 92%. Similar results have been obtained by Sharghi and coworkers
who prepared 1-aryltetrazoles in 80e95% yields from respective anilines,
sodium azide, and ethyl orthoformate using a recyclable heteroge-
neous catalyst prepared by immobilization of the copper(II) complex of
40-phenyl-2,20:60,200-terpyridine on activated multiwalled carbon
nanotubes (13JOM41).
1-Substituted 1H-tetrazoles 54 have been efficiently synthesized in a
reaction of primary amines, triethyl orthoformate, and sodium azide in
the presence of a catalytic amount of P2O5eSiO2 under conventional heat-
ing and ultrasound irradiation in solvent-free conditions (Scheme 13)
(13M725).
A synthesis of 1-substituted 1H-tetrazoles using a similar procedure from
primary amines, ethyl orthoformate, and sodium azide has been described.
The only difference is that the process is carried out in Brønsted acidic ionic
Scheme 13
ARTICLE IN PRESS
Scheme 14
liquids [(EtNH3)NO3 or (pmim(SO3H))OTf] (11EJO2827). Using this

method the yields of 1-substituted 1H-tetrazoles were sufficiently high
(64e96%).
4-(Tetrazol-1-yl)-3-phenylbutanoic acid 56 was obtained from 4-
amino-3-phenylbutanoic acid hydrogen chloride 55 in good yield under
conventional conditions in glacial acetic acid without exotic nanocatalysts
(Scheme 14) (09ARK64).
Similarly tetrazolyl analogs of L-ornithine 59a and L-lysine 59b have
been successfully synthesized (15RJO1671). The syntheses of these amino
acid analogues were performed in two stages. First, the natural amino
acid, 57a or 57b, with Fmoc-protection of the a-amino group was brought
into the reaction with sodium azide and triethyl orthoformate in glacial
acetic acid. Further treatment with morpholine of the obtained tetrazol-
1-yl derivatives made it possible to remove the protecting group and
to obtain (S)-2-amino-5-(1O-tetrazol-1-yl)pentanoic (59a) and (S)-2-
amino-5-(1O-tetrazol-1-yl)hexanoic (59b) acids (Scheme 15).
Ostrovskii and coworkers have described another example of the successful
application of traditional conditions for performing a three-component “dom-
ino” reaction (16CHE849). 1-(6,7,9,10,17,18,20,21-Octahydrodibenzo[b,k]
Scheme 15
ARTICLE IN PRESS
Scheme 16
[1,4,7,10,13,16]hexaoxacyclo-octadecen-2-yl)-1H-tetrazole 61 was obtained

from the amino derivative 60, triethyl orthoformate, and sodium azide in
glacial acetic acid (Scheme 16).
The synthesis of 1,5-disubstituted tetrazoles from amides via interme-
diate chloroazomethines and azidoazomethines was originally developed
by Herbst et al. (1952JOC1597). Recently, following this classic proced-
ure, 1-benzyl-5-(chloromethyl)-1H-tetrazole 63 was prepared by treating
N-benzyl-2-chloroacetamide 62 with PCl5, subsequent work up of the
intermediate chloroazomethine with sodium azide, and cyclization of the
corresponding imidoyl azide (Scheme 17) (15MOL22351).
In contrast, the reagent system NaN3eSiCl4 was suggested relatively
recently (02RJO1370), but has already gained a stable position in the range
of modern methods of converting secondary amides into 1,5-disubstituted
tetrazoles. 5-Methyl-1-(6,7,9,10,17,18,20,21-octahydro-dibenzo[b,k]
[1,4,7,10,13,16]hexaoxacyclooctadecen-2-yl)-1H-tetrazole 65 has been
prepared by treatment of the acetamide 64 with the NaN3eSiCl4 system
(Scheme 18) (16CHE849).
Scheme 17
Scheme 18
ARTICLE IN PRESS
Scheme 19
The application of the reagent system NaN3eSiCl4 resulted in convert-

ing the corresponding secondary amide into the 5-methyltetrazole-1-yl
analog of compound 56 (Scheme 14) (16CHE849).
Various methods for desulfurization and electrocyclization of thiopepti-
des, e.g., 66, to corresponding 1,5-disubstituted tetrazole peptidomimetics,
e.g., 67, under the action of desulfurizing reagent, azide transfer reagent and
base have been investigated (16MI127). One example of this process is
shown in Scheme 19.
Aube and coworkers (16JOC1593) have investigated the Schmidt
rearrangement as a method of converting ketones into 1,5-disubstituted tetra-
zoles. The classic procedure for this reaction often results in the formation of
the corresponding amides along with tetrazoles (08MI257). It was shown that
when trimethylsilyl azide (TMSN3) reacts with ketones in the presence of
triflic acid as promoter and using hexafluoroisopropanol (HFIP) as solvent,
1,5-disubstituted tetrazoles are obtained as major products (16JOC1593). A
complete profile of the arising products was described for the Schmidt reaction
of 4-phenylcyclohexanone 68 (Scheme 20). Intrigued by the formation of
bicyclic product 71, together with compounds 69 and 70, Aube et al. have
advanced an ingenious reaction mechanism involving double ring expansion
to explain this phenomenon (Scheme 20) (16JOC1593).
Scheme 20
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Scheme 21
Thirty new N1-[(1-alkyl-1H-tetrazol-5-yl)(aryl)methyl]-4-methyl-N3-

[4-(pyridine-3-yl)pyrimidin-2-yl]-benzene-1,3-diamines have been synthe-
sized in moderate to good yields (50e85%) via a microwave-assisted Ugi
azide reaction (16M1277). Reaction conditions were optimized for the
preparation of derivative 72 (Scheme 21).
Wang et al. have developed an original metal-free tandem oxidative
coupling process for the synthesis of 1,5-disubstituted tetrazoles
(16JOC3380). This version of 5-aryltetrazoles alkylation using primary
aliphatic alcohols is performed in the presence of tert-butyl hydroperoxide
(TBHP). The key stage of the process is assumed to be a nucleophilic
attack of the azole on an oxonium ion intermediate. Electron-withdrawing
substituents on the phenyl ring are known to favor increasing yields of the
N2-isomers in the alkylation products (08MI257). However, under the con-
ditions of the synthesis described by Wang and coworkers (16JOC3380) this
rule is invalid. Actually, the alkylation of 5-(4-nitrophenyl)tetrazole afforded
exclusively the 1,5-disubstituted tetrazoles 73 (Scheme 22).
Recently the synthesis of 1,5-disubstituted tetrazoles utilizing various
versions of the Ugi reaction have become popular. The three-component
reaction of isocyanides, carbodiimides, and trimethylsilyl azide occurs
at room temperature, and the resulting 1,5-disubstituted 1H-tetrazole
Scheme 22
ARTICLE IN PRESS
Scheme 23
derivatives are formed in 81e98% yield (12HCA594). The reaction proceeds

smoothly and cleanly under mild conditions, and no side reactions are
observed. 1-Ethoxycarbonyl-1-(2-oxoethyl)cycloalkanes in the azido-Ugi
reaction with primary amines, isocyanides, and TMSN3 afford 3-(tetrazol-
5-yl)-2-azaspiro[4.n]alkan-1-ones (13MS108). Domling et al. have
described the synthesis of 5-(hydrazinomethyl)-1-methyl-1H-tetrazoles
78 via a two-step procedure (16S1122). This Ugi tetrazole reaction,
using tert-butyl carbazate (Boc-hydrazine 74), aldehydes or ketones 75,
isocyanides 76, together with TMSN3, and subsequent deprotection of
the N-Boc-protected intermediates 77 gives the hydrazines 78 (Scheme 23).
Roh, Hrabalek et al. have reported on the synthesis of 1-alkyl/aryl-5-
alkylselanyl-1H-tetrazoles from relatively easily available alkyl/aryl isosele-
nocyanates (13T8798). As seen in the example shown in Scheme 24,
one-pot reactions of aryl isoselenocyanates with sodium azide and an
alkylating agent lead to the target 5-alkylselanyl-1-aryl-1H-tetrazoles, e.g.,
79, but also to other products, namely, N-alkyl-N-arylcyanamides, e.g.,
80 and (Z)-Se-alkyl-N-cyano-N,N0 -diaryl-isoselenoureas, e.g., 81.
Occasionally reports appear on the synthesis of 1,5-disubstituted
tetrazoles through 1,3-dipolar cycloaddition of organic azides to nitriles.
Scheme 25 shows an example of the utilization of this approach for the
synthesis of 1-benzyl- and 1-(4-nitrobenzyl)-5-acyltetrazoles 82 (11T8902).
An unusual transformation of (E)-1,3-diphenylprop-1-ene into (E)-
1-phenyl-5-styryl-1H-tetrazole 83 by treatment with TMSN3, CuI,
Scheme 24
ARTICLE IN PRESS
Scheme 25
2,3-dichloro-5,6-dicyano-1,4-benzoquinolone (DDQ), and molecular

sieves has been reported by Jiao et al. (Scheme 26) (11AC11487).
Related conversions were also described by these author, e.g., the
transformations of 1,3-diarylprop-1-enes and diarylmethanes into the corre-
sponding 1,5-disubstituted tetrazoles (11AC11487).
3.3 2-Substituted and 2,5-Disubstituted Tetrazoles

The set of procedures for regioselective preparation of N2-substituted
tetrazoles has been limited from the very beginning. It is necessary to
mention the pioneering works of Lippmann and K€ onnecke (1975M437)
who prepared 2-aryltetrazoles from 2-(2-arylhydrazono)acetic acids and 1-
azido-2,4,6-tribromobenzene and also the study of Ito and coworkers
using condensation of arylsulfonylhydrazones and arene diazonium salts
(1976BCJ1920).
Similar strategies for 2-substituted tetrazole preparation have been
successfully developed in the course of the period from 2009 to 2016.
Patouret and Kamenecka (16TL1597) have summarized the results of
previous regioselective syntheses of 2-aryltetrazoles that employ the cyclo-
addition of compounds having in their structure aza or diaza functions.
Ramanathan et al. reported recently on the synthesis of 2-aryltetrazoles by
a reaction between an aryldiazonium salt and formamidine in the presence
of iodide (15OL5886). As it was shown by Chen et al. a synthesis of 2-
aryl-5-trifluoromethyltetrazoles may be proceeded by means of silver-
catalyzed regioselective [3 þ 2] cycloaddition reaction of arenediazonium
salts with 2,2,2-trifluorodiazoethane (15CC16545). As a result of an analysis
of the previously cited studies, Patouret and Kamenecka have reported a
Scheme 26
ARTICLE IN PRESS
Scheme 27
regioselective procedure for the preparation of 2-aryltetrazoles 84 based on

the reaction of arenediazonium salts with trimethylsilyldiazomethane
(Scheme 27) (16TL1597).
The alkylation of NH-unsubstituted tetrazoles is still among the most
utilized methods for the synthesis of 2-substituted tetrazoles. As a rule, this
method provides a mixture of 1-alkyl- and 2-alkyl-substituted tetrazoles.
Only a few exceptions to this general rule were known until recently.
We mention two typical examples here (08MI257): (1) the alkylation
of 5-nitrotetrazole salts leads to the formation predominantly of 2-alkyl-
5-nitrptetrazoles; (2) the reaction of 5-substituted tetrazoles with secondary
and tertiary alcohols that are capable of carbocation formation in solutions
with concentrated sulfuric acid.
The use of primary alcohols in the latter reaction leads to the formation
of both regioisomers. The reaction of 5-aryltetrazoles with salicylic alcohol
affords a mixture of regioisomeric 1,5- and 2,5-disubstituted tetrazoles
(15CHE984). Osyanin et al. assumed the formation from 2-hydroxybenzyl
alcohol of an ortho-quinone methide (an intermediate possessing high elec-
trophilicity) followed by the addition of 5-aryltetrazole under the conditions
of an aza-Michael reaction. The ratio of 2-[(5-aryl-1H-tetrazol-1-yl)
methyl]- 85 and 2-[(5-aryl-2H-tetrazol-2-yl)methyl]phenols 86 is governed
by electronic characteristics of the substituents in the phenyl ring. In all cases
2-substituted 5-aryltetrazole prevails (Scheme 28) (15CHE984).
Scheme 28
ARTICLE IN PRESS
Scheme 29
In this context the material of a recent publication describing the

alkylation of 5-substituted tetrazoles with primary alcohols in a superacid
environment is of particular interest (15TL7020). In particular, both the
structure of the tetrazole and the nature of alcohol were found to dramati-
cally influence the selectivity of the reaction and the yields of products.
Tetrazoles-bearing phenyl, electron-donating aryl, or benzyl groups in the
5-position have been alkylated using various alcohols (including MeOH
and EtOH) in CF3SO3H to afford 2-alkyl-2H-tetrazoles 88 (Scheme 29).
A regioselective version of an aza-Michael reaction involving 5-
aryltetrazoles and alkyl acrylate has been described (16MI441). The
alkylation of NH-unsubstituted tetrazoles with activated alkenes has
been investigated under diverse conditions varying substrate nature,
solvents, reaction time, and the molar ratio of reagents. Catalysts used
were Et3N or APMCM-41 (aminopropyl mobile crystalline material 41)
(Scheme 30) (16MI441).
The use of triethylamine as a basic catalyst provided the possibility of
obtaining regioselectively the isomers 90 as the major product, but only
in the case of Ar ¼ NO2C6H4. In other cases the selectivity for 2-alkyl
derivative formation did not exceed 70%. In contrast, the use of APMCM
made it possible to increase the selectivity of formation of regioisomers 90
by up to 99% and also to reduce considerably the reaction time (16MI441).
Scheme 30
ARTICLE IN PRESS
Scheme 31
The alkylation of 5-substituted tetrazoles with dibromoethane in

the presence of triethylamine with subsequent dehydrobromination
affords mixtures of regioisomeric N-vinyltetrazoles (91e96, Scheme 31)
(11RJO1882).
Han et al. have reported an efficient method of N2-arylation of
NH-unsubstituted 5-aryltetrazoles through a CuO-catalyzed aerobic
oxidative direct cross-coupling with boronic acid (12SS2719; 14CEJ2373).
Formation of the diaryl derivatives 97 from 5-phenyltetrazole 45 using this
arylation procedure is illustrated in Scheme 32 (12SS2719).
Practically simultaneously, Han et al. (14CEJ2373) and Onaka et al.
(14JOC6703) published the results of a comprehensive investigation of
related arylation reactions of NH-unsubstituted 5R-tetrazoles with boronic
acids. Improved conditions have been reported. For example, Cu2O can be
replaced by the more sophisticated catalyst [Cu(OH)(TMEDA)]2Cl2
(TMEDA is N,N,N0 ,N0 -tetramethyl-ethylenediamine) and a lower temper-
ature (14JOC6703). These new conditions make it possible to effectively
Scheme 32
ARTICLE IN PRESS
perform regioselective arylations with arylboronic acids on a wide range of

NH-unsubstituted 5R-tetrazoles (R ¼ alkyl, thioalkyl, halogen, carbonyl,
aryl) (14JOC6703).
Yamamoto and coworkers have reported the palladium-catalyzed three-
component coupling reaction of cyano-compounds, allyl methyl carbonate,
and trimethylsilyl azide in the presence of a catalytic amount of Pd2(dba)3
CHCl3 (2.5 mol%) and tri(2-furyl)phosphine (10 mol%). This procedure
can give a variety of 2-allyltetrazoles 98 in good yields (Scheme 33)
(02JOC7413).
3.4 Tetrazoles with a Fused Ring

The synthesis, study of properties and reactivity of tetrazoles with a fused
ring frequently is complicated by their involvement in an azido-tetrazole
equilibrium. Theoretical studies of this problem using quantum chemical
methods have been described (10T2863; 10T5071; 12SAA316;
15CHE246) and are discussed in Sections 2.1 and 2.4. An experimental
method has been suggested for monitoring the azido-tetrazole equilibrium
based on the analysis of spinespin coupling constants of azido-1,2,4-triazine
and azidopyrimidine enriched with 15N isotope (13JOC6975).
This section deals with the problems of the synthesis of tetrazoles with a
fused ring. A notable current trend for performing the synthesis of tetrazoles
with a fused ring employs a multicomponent one-pot process. Examples of
such reactions are given as follows.
A stereocontrolled synthesis of substituted isonitriles from the Baylise
Hillman adducts of acrylates has been developed (10TL510). Ugi reaction
of these isonitriles with TMSN3, aliphatic amines, and aldehydes or ketones
affords 1-substituted tetrazoles 99 that have been demonstrated to be suitable
Scheme 33
ARTICLE IN PRESS
Scheme 34
substrates for producing tetrazolo-fused diazepinones 101 via the carboxylic

acids 100 (Scheme 34).
A similar method of synthesis of tetrazoles with fused tetrazoleebenzo-
diazepine rings has been described (10OL3894). This process, named as a
“Ugi five-center four-component reaction (U-5C-4CR),” yields
substituted tetrazolo[1,5-a][1,4]benzodiazepines.
1-Thioxycarbonyl-1-(2-oxoethyl)cycloalkanes in a similar azido-Ugi
reaction with primary amines, isocyanides, and TMSN3 afford 3-(tetrazol-
5-yl)-2-azaspiro[4.n]alkan-1-ones (13MC108).
A three-component reaction of methyl 2-furanoylpyruvate with
an aromatic aldehyde and 5-aminotetrazole monohydrate affords methyl
6-aryl(hetaryl)-5-(2-furanoyl)-3,6-dihydrotetrazolo[1,5-a]pyrimidine-4-
carboxylates 102 (Scheme 35) (16RJO286).
Some new tetrazoles fused to pyrido[2,3-c]coumarine derivatives have
been synthesized (yields 72e86%) by a one-pot three-component reaction
of 4-chloro-3-formylcoumarins, sodium azide, and alkyl/aryl/indolylaceto-
nitriles (12TL5034). Examples of this approach to the derivatives 103 are
shown in Scheme 36.
Scheme 35
ARTICLE IN PRESS
Scheme 36
Synthesis of a new heterocyclic fused system, namely pyrazolo[4,3-e]

tetrazolo[4,5-b][1,2,4]triazines (104 and 105), has been reported
(14JMS147). The tetrazole ring is formed by cyclization of an intermediate
azidoazomethine; the predominant direction of the equilibrium 104/105
depends on the nature of the substituent in the pyrazole ring (Scheme 37).
Based on the retrosynthetic analysis shown in Scheme 38 (106e108), a
strategy has been developed for the preparation of tetrazole-fused glycosides
Scheme 37
Scheme 38
ARTICLE IN PRESS
by a tandem fragmentationecyclization reaction (12OL3386). Structures

109e112 (Scheme 38) are examples of tetrazolo-sugars obtained using
this strategy.
To conclude this section we highlight the useful possibility of using the
azido-tetrazole equilibrium of tetrazoles with a fused ring for the synthesis
of other heterocyclic systems. For example, it has been shown that various
pyrido-, quinolino-, pyrazino-, and quinoxalinotetrazoles can efficiently
be used as an azide source in Cu-catalyzed click reactions with alkynes
(10OL2166). This method allows for the efficient synthesis of a wide
variety of N-heterocyclic derivatives of 1,2,3-triazoles, e.g., 114 from
113 (Scheme 39).
3.5 Functionalization of Tetrazoles

The functionalization of tetrazoles has been considered in a short review by
Hrabalek et al. (12EJO6101). It is appropriate to supplement this with an
indication of some new ingenious approaches and methods extending
the opportunities for functionalization. For instance, noteworthy are
methods that significantly increase the availability of 5-vinyltetrazole and
its N-alkyl derivatives. In this respect two articles that describe an original
synthetic procedure for 5-(b-dimethylaminoethyl)tetrazole 115 have key
importance (09RCB2147; 10RJO1678). By alkylation of this key
product with dimethyl sulfate in aqueous solution both NH-unsubstituted
5-vinyltetrazole 116 (10RJO1678) and N-alkyl derivatives have been pre-
pared, e.g., 1-methyl-5-vinyltetrazole 117 and 2-methyl-5-vinyltetrazole
118 (Scheme 40) (09RCB2147).
Due to the developments described previously, vinyltetrazoles have
become attractive and relatively available intermediates for the preparation
of tetrazole-containing substrates. For example, new functionalization
procedures have been developed for C- and N-vinyltetrazoles based
on the Heck reaction (12RJO1464). Applying this methodology, diverse
Scheme 39
ARTICLE IN PRESS
Scheme 40
(E)-styryl- 119 and (E)-distyryltetrazoles have been obtained for the first
time in 76e85% yields (Scheme 41).
Rh(III)-catalyzed direct olefination of aromatic CeH bonds has
been described using tetrazole as the directing group (14OBC7923). This
reaction provides a straightforward synthesis of the aryl tetrazole 121
(Scheme 42).
C-Vinyltetrazoles are more reactive in Heck cross-coupling than N-
vinyltetrazoles. Interesting results were obtained by Heck arylation of
1(2)-vinyltetrazoles (12RJO1464). The arylation of 1-vinyltetrazole
by Heck reaction with PhI proceeds with CeH activation and leads to
the formation of 5-phenyl-1-[2-(E)-phenylethenyl]tetrazole 122. In
Scheme 41
Scheme 42
ARTICLE IN PRESS
Scheme 43
contrast, arylation of 2-vinyltetrazole occurs exclusively at the double bond

with the formation of 2-(E)-styryltetrazole 123 (Scheme 43).
Microwave irradiation has been shown to considerably promote the
arylation of vinyltetrazoles by Heck cross-coupling (14RJO888).
SuzukieMiyaura coupling reactions of 5-chloro-1-phenyl-tetrazole
with various functionalized arylboronic acids have been investigated
(10TL3473). In the presence of catalytic amounts of SPhos/Pd(OAc)2
(SPhos ¼ 2-dicyclohexylphosphino-20 ,60 -dimethoxybiphenyl) or similar
systems, the reaction proceeds smoothly to afford 1,5-diaryltetrazoles, e.g.,
124, in good yields (Scheme 44).
(E)-2-Methyl-5-(2-phenylethenyl)-2H-tetrazole 125 effectively reacts
with various arenes containing electron-donating substituents in the pres-
ence of Brønsted or Lewis superacids to give 5-(2-aryl-2-phenylethanyl)-
2-methyl-2H-tetrazoles 126 (Scheme 45) (15RJO1356).
Scheme 44
Scheme 45
ARTICLE IN PRESS
Scheme 46
5-Bromoacetyl-1H-tetrazoles 128, prepared from the acetyl derivatives

127, react with hydroxylamine hydrochloride in CH2Cl2eMeOH
furnishing the corresponding bromo oximes 129 (10TL6756; 11T8902).
Nitrosoalkenes 130, generated in situ from the corresponding bromo
oximes 129 by treatment with sodium carbonate, react with some cyclic
dienes to form DielseAlder cycloadducts. For instance, reaction with
cyclopentadiene afforded the corresponding: 3-(1-substituted-1H-tetrazol-
5-yl)-4,4a,5,7a-tetrahydrocyclopenta[e][1,2]oxazine cycloadducts 131
(Scheme 46) (11T8902).
The kinetics and mechanism of the electrophilic nitration of 1-phenyl-5-
methyltetrazole 132 in the system HNO3eH2SO4 have been studied
(16RJO1679). These conditions lead to the formation of isomeric
nitro products (133e135) with the prevalence of para- and meta-derivatives.
1-Phenyl-5-methyltetrazole 132 reacts in the form protonated on the N4
atom (Scheme 47).
3.6 Metal Ion Complexes With a Tetrazole Moiety

The neutral forms of NH-unsubstituted tetrazoles (44), and monosubsti-
tuted and disubstituted tetrazole species (1 and 2) contain in their structures
Scheme 47
ARTICLE IN PRESS
three endocyclic pyridine-type nitrogen atoms and one pyrrole-type

nitrogen atom. The former N atoms can bind to various metal centers giving
stable complexes. The ability of the tetrazole ring to form coordination
bonds has been known for a long time and is widely applied (08MI257).
Interest in the coordination chemistry of polynitrogen azoles is connected
with attempts at their implementation in metal-based drug design. Among
the metal-tetrazole complexes, compounds exhibiting high and versatile
biological action are present. For example, numerous tetrazole-containing
coordination compounds of various metal ions (especially platinum group
metals) are known to form a special group of promising substances exhibit-
ing antitumor activity (06RCR507; 12ARK45). In addition, tetrazole-
containing complexes can be considered as promising contrast agents for
magnetic resonance imaging techniques, effective lead-free safe primary
explosives and gas generators (08MI257). In several reviews the available
data on the synthesis, structural features, as well as physical, chemical, and
biological properties of tetrazole complexes have been summarized
(06RCR507; 08CSR84; 08MI257; 11CCR485; 12ARK45).
Currently metal complexes containing both the negatively charged
tetrazolate anions and neutral 1H- and 2H-tetrazoles as ligands are known.
Tetrazole-containing complexes can be prepared by several ways. One
process is based on a reaction of tetrazoles with metal bases, salts, or
complexes. Using NH-unsubstituted tetrazoles as substrates, they are depro-
tonated and complexes are obtained as polymeric structures. The coordina-
tion polymers are hybrid inorganic/organic structures formed by metal
cation centers that are linked by organic ligands, in the form of one-,
two-, or three-dimensional architectures (11CCR485).
Using 1H- and 2H-substituted tetrazoles allows, in some cases, the
formation of molecular complexes. Depending on the ratio of the reagents
in the reaction, the complexes obtained may have different compositions
and structural types. Also, the acidity of the reaction solution can cause
drastic changes in the structure of the products (08MI257). For example,
a recent study varying reaction conditions (temperature, pH, solvent)
yielded the water-soluble cis and trans-platinum(II) complexes 137e139
featuring 2-alkyl-2H-tetrazol-5-ylacetic acids (Scheme 48) (16EJI4659). In
these molecular complexes the N(4) atoms of the tetrazolyl moieties are
exclusively involved in coordination to the platinum(II) centers.
It should be noted that, in recent years, there have been a significant
number of studies concerned with different metal complexes bearing tetra-
zolecarboxylic and tetrazolylacetic acids (10ICC254; 12ZAAC826;
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Scheme 48
13CGD510; 14ICC9; 14ICC207; 14JMS14; 14NJC269; 15MI186;

16TMC125). The tetrazolecarboxylic and tetrazolylacetic acids contain
several potential coordination sites such as the endocyclic N-atoms of the
tetrazolyl moiety and the O-atoms of the carboxyl group, e.g., 140e142.
In this regard, these acids are potentially multifunctional ligands and,

depending on the reaction conditions, can form a variety of coordination
patterns (15RCR891). For example, the Co(II) complex with tetrazolate-
5-carboxylate 143 has been described (10ICA3750).
By substitution of other ligands by tetrazoles in coordination

compounds, tetrazolato-complexes can be obtained. For example, the 5-
substituted tetrazolato-bridged binuclear complexes 144 with N2,N3
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Scheme 49
coordination of the Pt atoms have been synthesized via the reaction of the
corresponding 5-substituted-tetrazoles with ½cis PtðNH3 Þ2 ðm OHÞ2þ 2
(Scheme 49). These complexes exhibit high cytotoxicity toward some
cancer cell lines (11CMC987; 13JIB169; 13MI461; 12MI686).
Another approach to the preparation of tetrazolate-containing
complexes was developed in 2001 by the Sharpless team (01JOC7945).
This reaction involves inorganic azides and organic nitriles in the presence
of Zn(II) salts under hydrothermal conditions. Later publications
have appeared describing the synthesis of coordinated 5-substituted tetrazo-
lates by azidation of nitriles in the presence of inorganic salts containing
ions of Cd(II), Cu(II), Hg(II), Ag(I), etc. (12ARK45). For example,
Nasani at al. have synthesized either the organometallic compound
{[Cu3(m3-4-ptz)4(m2-N3)2(DMF)2](DMF)2}n 145 or compound {[Cu(4-
ptz)2(H2O)2]}n 146 {4-ptz ¼ 5-(4-pyridyl)tetrazolate},with 3D and 2D
coordination networks, by varying the reaction conditions of the1,3-dipolar
cycloaddition between 4-cyanopyridine and azide in the presence
of copper(II) chloride (Scheme 50) (14JCD9944). Interestingly, both
Scheme 50
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Scheme 51
compounds show high activity as catalyst precursors toward the microwave-

assisted homogeneous oxidation of secondary alcohols leading to ketone
yields up to 99% under solvent-free conditions.
Alternatively, tetrazolato-complexes can be generated via addition of
coordinated azides to organic nitriles or by azidation of metal-bound nitriles
(12ARK45). For example, [2 þ 3] cycloaddition of the diazidonickel(II)
complex cis-[Ni(N3)2(phen)2] with organonitriles (RNC) under microwave
irradiation yields the corresponding tetrazolato-complexes 147 (Scheme 51)
(13P24).
It has been shown that the coordination of RCN to metals
increases the nitrile reactivity in reactions with azides. For example, the
azidation of the nitriles coordinated to Pt(II) trans-[PtCl2(RCN)2] and
Pt(IV) trans-[PtCl4(RCN)2] (R ¼ Et, Ph) make it possible to synthesize
the corresponding tetrazolate-complexes trans-[PtCl2(RCN4)2]2 148
and trans-[PtCl4(RCN4)2]2 149 with counterions Ph3PCH2Phþ and
(CH3)2NHþ 2 at room temperature (Scheme 52) (11ICA242). In these com-
pounds the coordination occurs at the nitrogen N1 atom.
Scheme 52
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4. IMPORTANT COMPOUNDS AND APPLICATIONS

4.1 Biologically Active Derivatives
Since the publication of CHEC-III (08MI257), the number of
publications and patents concerning biological activity of tetrazoles has
continued to grow intensively. In the period 2009e16 reviews were
published containing analysis and summaries of this rich and versatile field.
Mohite and Bhaskar gave a forecast of the development of the medicinal
chemistry of tetrazoles in the new millennium (11MI1557). Hrabalek
et al. (12EJO6101) and also Gong et al. (15MOL5528) considered the
general procedures for tetrazole synthesis and reported the formulas
of some pharmaceutical substances and biologically active compounds
containing a tetrazole fragment. Ostrovskii et al., in a review dedicated
to the medicinal chemistry of tetrazoles, considered the spectrum of the
biological activity of tetrazoles derivatives with respect to definite
infectious agents. In this review, a complete list was given of the
corresponding active pharmaceutical ingredients (12RCB768) and also
potential candidates for drugs. The chemical and biological activities of
metabolically stable tetrazole bioisosteric analogs of carboxylic acids have
been treated in surveys by Malik et al. (14MI15) and by Fausto et al.
(14JCP064306). A minireview by Bag et al. contains information about
abnormal nucleosides with a tetrazole moiety (16BML2044). Finally,
the structure and biological activity of abnormal amino acids and peptides
containing a tetrazole fragment constitute the content of a recent review by
Popova and Trifonov (15RCR891). In this section we refer to some recent
studies that reflect the main trends in the study of the biological activity of
tetrazole derivatives.
4.1.1 Antiviral Activity

As shown by the early example of 5-CITEP (150), the replacement of a
carboxylic acid by tetrazole was successful in research on HIV-1 integrase
inhibitors (12RCB768). Fourteen analogues of the anti-HIV-1 integrase
inhibitor L-chicoric acid (L-CA) were prepared. The trihydroxyphenyl
analogue 151 is 30-fold more potent than L-CA at relatively nontoxic
concentrations. These data indicate that L-CA analogues are attractive
candidates for development into clinically relevant inhibitors of HIV-1 inte-
grase (10JME8161).
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A series of new N0 -arylidene-2-[1-(naphthalen-1-yl)-1H-tetrazol-5-

ylthio]acetohydrazides has been synthesized and evaluated as nonnucleoside
reverse transcriptase inhibitors (10MCR652).
As described by Zarubaev and coworkers (10BMC839), the influenza
virus can be inhibited by adamantyltetrazoles and similar derivatives of
tetrazole, therefore, have the potential for development as antiviral agents
with an alternative mechanism of action.
4.1.2 Anticancer Agents

Two series of tetrazole-containing platinum(II) and palladium(II) chloro
complexes (trans-[ML2Cl2] (M ¼ Pt, Pd) and cis-[PtL2Cl2]$nH2O
(n ¼ 0, 1), where L is 1- or 2-substituted 5-aminotetrazole) have been
synthesized and fully characterized. The most promising complexes
are cis-[Pt(1-apt)2Cl2]$H2O and cis-[Pt(2-abt)2Cl2]$H2O, where 1-apt is
5-amino-1-phenyltetrazole and 2-abt is 5-amino-2-tert-butyltetrazole.
As compared with cisplatin, they show similar cytotoxic potency against
cisplatin-sensitive human cancer cell lines, with cis-[Pt(2-abt)2Cl2]$H2O
exhibiting substantially higher activity against cisplatin-resistant cell lines
(13JIB44).
A series of new 1,2-substituted tetrazole derivatives have been
synthesized and evaluated on MCF-7 (ER positive), MDA-MB-231, and
ZR-75 (ER negative) breast cancer cell lines (14EJM229). Gold (I)
complexes with phosphane and thiotetrazolate ligands have been prepared
and investigated as a new type of bioactive gold metallodrugs. These
complexes triggered very efficient inhibition of the enzyme thioredoxin
reductase (TrxR), which is an important molecular target for gold species.
Strong cytotoxic effects were observed in MDA-MB-231 breast adenocar-
cinoma and HT-29 colon carcinoma cells, and the complexes also caused
strong effects in vincristine resistant Nalm-6 leukemia cells (15JCD1161).
Tetrazole derivative 152 showed higher inhibitory effects on MCF-7 cells.
It has been shown that the D-homo fused steroidal tetrazoles 153 display
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strong yet selective antiproliferative activity against MCF-7 ER þ breast

cancer cells [IC50 12.63 mM (R ¼ H) and 4.58 mM (R ¼ Me)], being
nontoxic to normal MRC-5 cells (13MI317).
4.1.3 Antibacterials
A reliable method has been described for growing and quantifying
methicillin-resistant Staphylococcus aureus (MRSA) biofilms (11MI3691).
Also in this article the use of this procedure for evaluating the new antibac-
terial compound SEQ-914 (154), [(Z)-5-(pentadec-8-enyl)-1H-tetrazole],
and comparing it to clinically used MRSA antibiotics is described. A series
of pyrazoline derivatives of tetrazole has been synthesized and screened
in vitro to investigate the effect on the growth of the HM1: IMSS strain
of Entamoeba histolytica. 1-(4,5-Dihydro-3,5-di-p-tolylpyrazol-1-yl)-2-(5-
(4-methoxyphenyl)-1H-tetrazol-1-yl)ethanone 155 showed the most
promising results with IC50 0.86 mM, which is half that of the metronida-
zole, the standard drug used for protozoal infection. Cell viability tests in
human hepatocellular carcinoma cell line (HepG2) revealed the nontoxic
nature of these compounds. Safety index calculations marked compound
155 as highly antiamoebic and the least cytotoxic (SI 116.28; almost twice
that of metronidazole) (12EJM845).
The synthesis and in vitro antitubercular activity of a new series of thia-

zolone piperazine tetrazole derivatives has been described (14BML4166).
Among all the synthesized derivatives, four compounds (156aed) exhibited
more potent activity (MIC 3.08, 3.01, 2.62, and 2.51 mM) than ethambutol
(MIC ¼ 9.78 mM) and pyrazinamide (MIC 101.53 mM) against Mycobacte-
rium tuberculosis. Furthermore, they displayed no toxicity against Vero cells
(C1008) and mouse bone marrow derived macrophages (MBMDMf).
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Microcin C and albomycin analogues with aryl-tetrazole substituents as

nucleobase isosters have been shown to be selective inhibitors of bacterial
aminoacyl tRNA synthetases (12CBC1959). In the same year, Harusava
et al. (12TL5891). reported a method of synthesis and the properties of
the abnormal nucleosides 157 and 158.
4.1.4 Antifungal
The most complete description of fungicidal pharmaceuticals containing
tetrazole rings is given in two surveys (12RCB768; 15MOL5528). In
most cases these compounds possess general structural characteristics of the
known fungicidal drug fluconazole. The main transformations in structure
concern the azole fragment and consist of the replacement of the 1,2,4-
triazole ring for a tetrazole analog; the presence of a 2,4-difluorophenyl
group is often retained. A combination of the 1,2,4-triazole and tetrazole
rings is present in the promising antifungal agent TAK-456 (159). It is inter-
esting that molecule 159 does not contain the 2,4-difluorophenyl moiety
characteristic of many antifungal agents.
A new series of phenyl(2H-tetrazol-5-yl)methanamine derivatives has
been synthesized by reaction of a-amino nitriles with sodium azide and
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ZnCl2 in the presence of isopropyl alcohol. They were evaluated for anti-
fungal activity against Candida albicans and Aspergillus niger and subjected to
docking study against 1EA1. As seen from structure 160, the most active
compound of this series also does not contain the 2,4-difluorophenyl moiety
(14MI29). Malik et al. (12IMS10880). reported on the synthesis of a new
series of potential antifungal agents 161, whose structures are similar to
that of compound 152. The authors stated that the biological activity
strongly depended on the nature of substituent R in the phenyl ring.
4.1.5 Antioxidants
Sompounds 162e165 show antioxidant activity in the b-carotene/linoleic
acid assay, some of them exhibiting IC50 values of the same order of magni-
tude as those of gallic acid. The bioactive compounds did not show
cytotoxic effects to human lymphocytes, using the MTT method adapted
for nonadherent cells, nor genotoxicity determined by the short-term in
vitro chromosomal aberration (12CR47).
4.1.6 Receptor Antagonists of the Central Nervous System

The tetrazole-substituted 2-amino-adipic acids 166 are an interesting series
of new N-methyl-D-aspartate (NMDA) receptor antagonists (11MI913).
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This approach, according to Lenda and coworkers (11MI913), may be

regarded as a new strategy to develop ligands specifically targeted to synaptic
or extra-synaptic NMDA receptors. Tricyclic pyrazole-tetrazoles that
are potent partial agonists of the high affinity niacin receptor GPR109a
have been discovered and optimized (10BML20). One of these com-
pounds (þ)167 has proven to be effective at reducing free fatty acids in vitro
and in vivo.
4.1.7 Inhibitors of Metabolic Processes

As shown by recent studies, tetrazole derivatives are increasingly regarded
as efficient and selective inhibitors of enzymes governing the metabolic
processes in the human body, such as aldose reductase, 5a-reductase,
dicyclooxygenase-2 (COX-2), matrix metalloproteinase-13 (MMP-13), etc.
The in vitro aldose reductase inhibitory activity of the pyrrolyl-tetrazole
isomers 168 and 169 have been estimated (10BMC2107). In general, the
data indicate that the present chemotypes are promising lead compounds
for the development of selective aldose reductase inhibitors, aimed at
prevention of the long-term complications of diabetes mellitus.
A series of steroidal tetrazole derivatives of androstane and pregnane in

which the tetrazole moiety is appended at the C-3 and 17a-aza locations
has been prepared. Some of the synthesized compounds were evaluated
for their in vitro 5a-reductase (5AR) inhibitory activity by measuring the
conversion of [3H] androstenedione in human embryonic kidney (HEK)
cells. In vivo 5AR inhibitory activity also showed a significant reduction
(P < .05) in rat prostate weight. The most potent compound 170 showed
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5AR-2 inhibition with an IC50 of 15.6 nM as compared to the clinically

used drug finasteride (40 nM). There was also a significant inhibition of
5AR-1 with IC50 547 nM compared to finasteride with IC50 453 nM
(16BMC779).
A series of new 5-substituted 1H-tetrazoles were prepared as potential
cyclooxygenase-2 (COX-2) inhibitors via treatment of various diaryl amides
with tetrachlorosilane/sodium azide. All compounds were tested in
cyclooxygenase assays in vitro to determine COX-2 inhibitory potency
and selectivity. The most potent compounds (for example, compound
171) showed IC50 values of 7 mM for COX-2 (12BML2235).
Potent, highly selective, and orally bioavailable MMP-13 inhibitors have
been identified based on a (pyridin-4-yl)-2H-tetrazole scaffold. Cocrystal
structure analysis revealed that the inhibitors bind at the S01 active site pocket
and are not ligands for the catalytic zinc atom. Compound 172 demonstrated
reduction of cartilage degradation biomarker (TIINE) levels associated with
cartilage protection in a preclinical rat osteoarthritis model (10BML576).
4.2 Medicines With a Tetrazole Moiety

This section contains only concise information on tetrazole derivatives that
are actual and constant participants in the contemporary pharmaceutical
market together with some promising drug candidates. We previously
comprehensively considered this topic in a review (12RCB768).
4.2.1 Hypotensive Action

The rennin-angiotensin system (RAS) plays a key role in the regulation of
blood pressure and homeostasis. Angiotensin II (AII) is an octapeptide,
which is formed from angiotensin I within the RAS in a reaction catalyzed
by angiotensin-converting enzyme, and it is a powerful vasoconstrictor. The
most promising approach to the control of RAS is based on the inhibition of
the activity of AII by blocking its active sites. Losartan 173 (Dup-753,
Cozaar) was the first representative of nonpeptide AII antagonists. All
representatives of this group of AII receptor antagonists (losartan 173,
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valsartan 174, irbesartan 175, and candesartan 176) contain (1H-tetrazol-5-

yl)biphenyl as a common structural fragment. Focusing attention on the
position of the tetrazole ring in the biphenyl moiety, molecular docking is
most efficient for molecules 173e176. Compounds 173e176, as well as
some modified structures such as the corresponding benzofuran derivative
177, have been a focus of attention for pharmaceutical manufacturers for
almost 20 years and have held a strong position in the pharmaceutical
market. Methods for the synthesis of active substances of this type of
hypotensive agent are continuously improved; therefore, these agents
have become more available in the world pharmaceutical market. The
tetrazole-containing diuretic agent azosemude (178) is widely used in the
complex therapy of the patients with hypertonic disease.
4.2.2 Antihistamine Agents

Tazanoplast 179 has been used effectively for the treatment of acute revers-
ible airway obstruction since the 1980s. The drugs pemiroplast 180
and pranlukast 181 containing the NH-unsubstituted tetrazole ring belong
to a new generation antihistamine drugs, which effectively act on both H1-
and H2-receptors of mast cells (12RCB768).
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4.2.3 Action on the Central Nervous System

N-{4-(Methoxymethyl)-1-[2-(4-ethyl-5-oxo-4,5-dihydro-1H-tetrazol-1-
yl)ethyl]piperidin-4-yl}-N-phenyl-propanamide 182, known under
the generic name alfentanil, is an effective and fast-acting medication
used for general anesthesia. In 1999 the FDA (Food and Drug Administra-
tion, USA) approved 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-
dihydro-2(1H)quinolinone 183 (generic name cilostazol) for use in clinical
practice. Cilostazol relieves the symptoms of intermittent claudication by
reducing the lower-extremity pain induced by walking.
The molecule 184 (KMI-429) is an inhibitor of b-secretase (BACE1)
relevant to the treatment of Alzheimer’s disease. This compound is
a peptidomimetic containing a terminal NH-unsubstituted tetrazole
ring, which is believed to serve as a bioisostere of a carboxy group
(12RCB768).
4.2.4 Antimicrobial and Antiinflammatory Activity

Cefazolin 185 and its demethylated analog ceftezole 186 belong
to the first-generation cephalosporin antibiotics exhibiting a wide spec-
trum of activities. Both drugs, although no longer having a leading
position in the pharmaceutical market, are actively used in veteri-
nary medicine. Cefamandole 187, containing the 1-methyltetrazol-5-yl
moiety, belongs to the second-generation cephalosporin antibiotics,
and latamoxef 188 is a third-generation cephalosporin antibiotic. As
can be seen by a comparison of structures 187 and 188, latamoxef 188
contains an oxygen atom instead of sulfur in the six-membered ring of
the bicyclic core.
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Among promising antiinflammatory and antimicrobial agents, an analog

of the macrolide antibiotic rapamycin, namely 40-epi-tetrazole-1-rapamycin
(ABT-578) 189, and an analog of nocathiacin I, namely compound 190, are
worthy of note (12RCB768).
4.3 Energetic Tetrazoles

Tetrazoles are thermodynamically stable in the condensed phase. They are
relatively weakly sensitive to impact and friction, and not very toxic, in
contrast to HN3, which is notorious for its high sensitivity to impact,
friction, and thermal and electric impulses, and also its toxicity
(1999MI467; 08MI257; 11MI16). Current attention is focused on
compounds 191e205 which combine a tetrazole ring, possessing a high
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enthalpy, and explosophoric groups such as N3 (191, 200, and 203)

(11AGE4227; 14MI793), NHNH2 (192, 199, and 202) (10EJO1169),
NO2 (194, 195, and 197) (12JCD9451; 12MOL5040; 13AGE4875;
15RJC2878), NHNO2 (196) (10AGE7320; 14AGE8172), N]N
(195) (13AGE4875), C(NO2)3 (13IC5551), and NHC6H2(NO2)3
(14JMC4127). In keeping with predictions given in earlier reviews
(1999MI467; 08MI257), growing attention has been directed to nitrogen-
rich binuclear tetrazoles. These include 5-(tetrazol-5-yl)tetrazole
201 (12JCD9451; 13POL201; 13AGE4875; 14MI550; 14AGE8172), 5-
(1,2,4-triazol-5-yl)tetrazole 200 (14ZFA2759; 14MI793), as well as bicyclic
analogs where both rings are linked by spacers (10CEJ3753; 13JMC15383).
Coordination compounds, e.g., 197, containing nitrogen-rich tetrazole
ligands have been examined (15MI623; 15RJA226). In designing multi-
component energetic systems and materials, polymers containing the
tetrazole ring in the monomer unit are of particular importance, e.g., macro-
molecule 202e205 (10EJO1169; 12MI313).
CAUTION: In conclusion of this section it is necessary to warn readers
about the need for extreme caution in handling samples of this group
energetic compounds. The authors of this chapter have themselves experi-
enced the high sensitivity to mechanical impact and the low thermal stability
of some of these compounds (191e205).
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4.4 Materials With Tetrazole as an Active Component

4.4.1 Polymer Membranes
Increasing numbers of publications are appearing on the manufacturing of
polymer membrane materials containing tetrazole derivatives as compo-
nents. In the following discussion, works are cited where the methods of
synthesis and properties of such materials are described.
A fuel cell is an electrochemical device that can directly convert the
chemical energy of fuel into electricity. Among all types of fuel cells demon-
strated so far, proton exchange membrane (PEM) fuel cells are considered
the best candidate for the next generation of electrical vehicles.
5-(Methacrylamido)tetrazole monomer prepared by the reaction of
methacryloyl chloride with 5-aminotetrazole is polymerized, via a conven-
tional free radical mechanism, to afford poly(5-(methacrylamido)tetrazole)
homopolymer. New composite membranes (SPSU-PMTetX) have been
successfully produced by incorporating sulfonated polysulfone (SPSU) into
poly(5-(methacrylamido)tetrazole) (PMTet). The sulfonation of polysulfone
was performed with trimethylsilyl chlorosulfonate and a high degree of
sulfonation was obtained. The maximum proton conductivity of anhydrous
SPSU-PMTet0.5 at 150 C was determined as 2.2 106 S/cm while in
humidified conditions at 20 C a value of 6 103 S/cm was found for
SPSU-PMTet2 (13MI242; 14MI269; 14MI526).
5-Vinyltetrazole (VT)-based polymer is mainly produced by “click
chemistry” from polyacrylonitrile due to the unavailability of VT mono-
mer, which usually produces copolymers of VT and acrylonitrile rather
than pure poly(5-vinyltetrazole) (PVT). The proton conductivity of
PVT decreases at least two orders of magnitude after methylation of
tetrazole. PVT and PVT/H3PO4 composite membranes are thermally
stable up to 200 C. The glass transition temperature (Tg) of PVT/
xH3PO4 composite membranes is shifted from 90 C for x ¼ 0.5 to
55 C for x ¼ 1. The temperature dependence of DC conductivity for
pure PVT exhibits a simple Arrhenius behavior in the temperature range
90e160 C, while PVT/xH3PO4 composite membranes with higher
H3PO4 concentration can be fitted by the Vogel-Tamman-Fulcher
(VTF) equation. PVT/1.0H3PO4 exhibits an anhydrous proton conduc-
tivity of 3.05 103 at 110 C. The transmission of the PVT/xH3PO4
composite membrane is above 85% in the wavelength of visible light
and changes little with acid content. Thus, PVT/xH3PO4 composite
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membranes have potential applications not only in intermediate tempera-

ture fuel cells but also in solid electrochromic devices (08MI392).
Poly(5-vinyltetrazole) (PVT) with 85% molar content of tetrazole can be
prepared by [3 þ 2] cycloaddition of polyacrylonitrile (PAN) with sodium
azide (14MI128). Membranes of PVT (SPS)x have been prepared by
blending different ratios of PVT to sulfonated polystyrene (SPS) (SD
72%). The onset of degradation temperature of the PVT(SPS)x is above
180 C. The degradation behaviors related to the acidebase interaction
were analyzed. The membranes were confirmed to retain 0e5% water
vapor at 80e140 C in air due to the hydrophilicity of highly sulfonated
polystyrene. The membrane PVT(SPS)2 shows proton conductivity of
102 S/cm at 100 C and even around 4.102 S/cm at 120 C without ex-
tra humidity supply and is very promising for high temperature fuel cells
with low humidity. The high proton conductivity is ascribed to the unique
composition in which the heterocyclic polymer provides the proton motion
by construction diffusion and the highly sulfonated polymer retains water
vapor to lower the activation energy for proton conduction.
Liu and coworkers have studied 5-(4-hydroxyphenyl)-1H-tetrazole as
a model compound and synthesized inorganic-organic hybrid polymer
membranes using an in situ polymerization (solegel) process in the
presence of H3PO4 as catalyst and dopant, and porous expanded-
polytetrafluoroethylene (e-PTFE) film as reinforcement to provide
mechanical strength (14MI1277). This paper also refers to earlier published
articles on polymers containing a tetrazole fragment, which have
previously been tested as PEM for fuel cell applications. Results of a
study of the gas transport properties of polymeric membranes based on
poly(2-methyl-5-vinyltetrazole) for helium, oxygen, nitrogen, and
methane have been reported (14MI539). It has been found that these
properties depend on the membrane thickness. The permeability and
diffusion coefficients increase with the decreasing kinetic diameter of
penetrant molecules or the increasing temperature.
4.4.2 Other Polymer Materials

Nitrogen-rich polymers as candidates for energetic applications have been
considered in the review by Pasquinet (12MI313) (see also Section 4.3).
Cellulose-tetrazoles with two degrees of substitution (0.14 and 0.23)
were synthesized in a solution-based transesterification procedure in an ionic
liquid. Two bismaleimides with either a trioxatridecane or a dithiodipro-
pionyl backbone were used as cross-linkers to form fluorescent, covalently
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cross-linked cellulose networks, and films, which were characterized by

UV/Vis spectroscopy, fluorescence spectroscopy, DSC, and TGA. The
films showed a broad emission band from 500 to 700 nm and were thermally
stable up to 200 C (16MI139).
The new functionality of aromatic tetrazole derivatives with high
nitrogen content has generated a great interest in tetrazole-containing
polymers. Poly(5-vinyltetrazole) is one of the most attractive polymers
containing tetrazoles. 4-Chloromethyl styrene (CMS) was copolymerized
with acrylonitrile (in various mole ratios) by free radical polymerization
methods at 70 C using a,a-azobis(isobutyronitrile) as an initiator. In copol-
ymers, simultaneously with replacement of all chlorine atoms in CMS units,
conversion of the nitrile groups entirely to tetrazole occurs in dimethylfor-
mamide at elevated temperatures. The polymers, obtained in quantitative
yields, were characterized by FT-IR and 1H NMR spectroscopy, differential
scanning calorimetry, and gel permeation chromatography. Thermal prop-
erties of nitrogen-rich polymers show that explosive thermal degradation
takes place at around 260 C (14MI453).
A new stationary phase for weak cation exchange and hydrophilic interac-
tion chromatography was prepared with surface-initiated atom transfer radical
polymerization. Vinyltetrazole was grafted onto the surface of the beads in
water medium with the polyglycidylmethacrylate beads (PGMA/EDMA)
previously modified with 2-bromoisobutryl bromide as the macromolecule
initiators and CuCl as catalyst. The poly(vinyltetrazole)-grafted beads obtained
with different atom transfer radical polymerization formulations were tried as
chromatographic packings in ion-exchange chromatography. The results
showed that the prepared columns could separate the tested proteins with
high efficiency and high capacity, and the retention time of protein had a
positive relationship with increasing chain lengths of the grafted PVT. The
prepared column was also found to be able to separate nucleosides by hydro-
philic interaction chromatographic mode (11MI482).
4.4.3 Nanomaterials
Tetrazoles are increasingly subject to investigation as components of
nanomaterials for various goals. This relatively new area for the tetrazole
chemistry is treated in a recent review (15MI5728), where work published
up to 2014 is summarized and analyzed. A later publication describes a
simple method to pattern self-assembled monolayers of tetrazole triethoxyl-
silane with a variety of different molecules by photochemical microcontact
printing (16L2277). Under irradiation, tetrazoles form highly reactive nitrile
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imines, which react with alkenes, alkynes, and thiols. The covalent linkage
to the surface can be unambiguously demonstrated by fluorescence micro-
scopy because the reaction product is fluorescent in contrast to tetrazole.
The modified surfaces were further analyzed by X-ray photoelectron
spectroscopy, time-of-flight secondary ion mass spectrometry , atomic force
microscopy, and contact angle goniometry. Protein-repellent micropatterns,
a biotinstreptavidin array, and structured polymer brushes can be fabri-
cated using this straightforward method for surface functionalization.
4.4.4 Catalysts
The oxidation of organosulfides catalyzed by hydrogen bonding donors
derived from aminotetrazole has been studied. The oxidation reaction was
performed in CH2Cl2 solution using tert-butyl hydroperoxide (TBHP)
(1.1 equiv.) as a versatile and chemoselective new catalyst for sulfoxides.
Catalyst loading of 5 mol% afforded organosulfoxides with complete
conversion and yields around 90e95%. Tetrazole amide derivatives can
be easily recovered by simple filtration and reused several times (14MI1407).
A highly enantioselective method (up to 98% ee) for the preparation of
b-amino alcohols has been achieved by using readily available proline-
tetrazole as the catalyst for the N-nitroso aldol reaction of aldehydes with
in situ generated nitrosocarbonyl compounds. The key to the success of
this reaction is the use of MnO2 as oxidant and catechol as a Br€ onsted
acid additive (14AGE8714).
4.4.5 Corrosion Inhibitors

In Section 3.6 attention is drawn to the high complexing activity of NH-
unsubstituted tetrazoles toward metal ions. This property underlies the
application of NH-unsubstituted tetrazoles to corrosion inhibition
(08RCR219). It has been shown by Avdeev and coworkers (11MI28)
that 5-(b-dimethylaminoethyl)tetrazole essentially decreases the dissolution
rate of low-carbon steel in mineral acids in the temperature range 25e95 S.
The effect of 5-(3-aminophenyl)tetrazole (APT) as a corrosion inhibitor
for Mg-Mn alloy after its immersion in naturally aerated stagnant Arabian
Gulf water (AGW) for 1 h and 150 h have been reported by Sherif
(11MI5372). The study was carried out using a combination of electro-
chemical and gravimetric measurements along with scanning electron
microscope (SEM) and X-ray energy dispersive (EDX) investigations.
Electrochemical measurements showed that the corrosion of Mg-Mn alloy
in AGW decreases with increasing exposure time as well as in the presence of
ARTICLE IN PRESS
APT and the increase in its concentration. Weight-loss tests after varied
exposure intervals proved that the corrosion rate of the alloy decreases
with increasing time and 5-(3-aminophenyl)tetrazole content. The SEM
and EDX investigations revealed that 5-(3-aminophenyl)-tetrazole
molecules inhibit the corrosion of Mg through repairing the weak areas
on its surface, which leads to increasing the corrosion resistance for the alloy
against the corrosive attack of AGW. A later study by the same author
(14MI5372) demonstrated that 5-(3-aminophenyl)tetrazole is an efficient
corrosion inhibitor for steel in 2.0 M H2SO4 solutions. The reduced
corrosion of the maraging steel in this solution is achieved via the adsorption
of 5-(3-aminophenyl)tetrazole molecules onto the steel and protecting its
surface from easy dissolution.
An electrochemical and DFT-investigation of the corrosion of stainless
steel inhibited by 1-(4-nitrophenyl)-5-amino-1H-tetrazole in an acid envi-
ronment has been reported (14MI20031). The results of the investigation
show that this newly synthesized compound provides excellent inhibition
against the corrosion of stainless steel in acidic solution.
However, not only NH-unsubstituted tetrazoles but also tetrazolium
salts show pronounced protective properties for metallic surfaces in acid
solutions. The inhibition effect of triazolyl blue tetrazolium bromide
(TBTB) on the corrosion of cold rolled steel (CRS) in 1.0 M HCl and
0.5 M H2SO4 solution was investigated for the first time by weight loss,
potentiodynamic polarization curves, and electrochemical impedance
spectroscopy methods. The results show that TBTB is a very good
inhibitor and is more efficient in 1.0 M HCl than in 0.5 M H2SO4. The
adsorption of TBTB on CRS surface obeys Langmuir adsorption isotherm.
Polarization curves reveal that TBTB acts as a mixed-type inhibitor in both
acids (11MI302).
5. CONCLUDING REMARKS
Tetrazole chemistry continued to develop intensively in the period
2008e16 in all directions that were described in CHEC-III (08MI257).
Obvious advances were attained in the creation of highly efficient, selective,
environmentally friendly methods for the generation and functionalization
of the tetrazole ring. These goals have been reached by applying new
catalysts, complex catalytic systems, diverse versions of cross-coupling,
superelectrophilic activation, multicomponent domino reactions, micro-
wave activation, microreactor techniques, and the other advances of modern
ARTICLE IN PRESS
organic chemistry. Tetrazoles are used more and more often and are
successful as components of energetic systems, nanomaterials, polymers,
membranes, substances for medical applications, corrosion inhibitors, and
other modern technique. Drugs containing active pharmaceutical ingredi-
ents with a tetrazole fragment keep a firm position in the global pharmaceu-
tical market. The medicinal chemistry of tetrazoles progresses, as shown by
the appearance of new compounds with a wide range of biological activity
and promising medicinal candidates. All the above properties and applica-
tions show the evident progress of tetrazole chemistry nowadays. We
hope that this chapter will contribute to the successful development of
the tetrazole chemistry in the near future.
ACKNOWLEDGMENT
The authors gratefully acknowledge financial support from the Russian Foundation for
Basic Research (grants nos. 16-53-00047 Bel_a and 15-03-02936-a) and St. Petersburg State
University (grant. no. 12.38.428.2015).
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ARTICLE IN PRESS

Advances in Heterocyclic Chemistry, Volume 123

4.4.2 Other Polymer Materials 50

Keywords: 1,2,3,4-Tetrazoles; Acid-base equilibrium; Applications; Aromaticity; Azido-

technologies (11AGE3525), etc. The area of beneﬁcial tetrazole application

2. FUNDAMENTAL ASPECTS AND THEORETICAL

2.1 Electronic Structure and Geometry

The greatest aromaticity is characteristic of the tetrazolate anions 3 and

instance, according to the calculations by the Pozharsky method, the

Neutral NH-unsubstituted as well as 1,5- or 2,5-disubstituted 1H- and

sigma-constant for the protonated tetrazole ring was determined to be

Quantum-chemical as well as X-ray investigations of geometry and rela-

2.2 Protolytic Equilibria

R1=Me, Ph; R2=H, Alkyl, Ar

Allen and coworkers, using theoretical studies and crystallographic

Also, intermolecular and intramolecular H-bonds affect the tautomerism

Recently some additional data on the acidity and basicity of tetrazoles

2.3 Thermochemical and Explosive Properties

Using the PM3 method, a good linear relationship was established

might be regarded as promising highly energetic substances (11MI775;

2.4 Azido-Tetrazole Isomerism

In the case of azido(tetrazolo)azoles the azide forms 37and 38 turned

2.5 Bioisosterism and Biological Modeling

a deﬁnite geometric position should be electrostatically complementary

3. SYNTHESIS AND REACTIVITY OF TETRAZOLES

Unfortunately, in the majority of the cited articles (Table 1) the nature of

Table 1 Examples of synthesis of 5-phenyl-1H-tetrazole 45

i gFe2O3, nanoparticles, 0e0.2 g, 0e81 10MI1029

Table 1 Examples of synthesis of 5-phenyl-1H-tetrazole 45dcont'd

It has been demonstrated for the reaction of benzonitrile with dimethylam-

i, NaN3 , NMP, AcOH, H2O, MW, 220oC, 20 min, yield, 92%;

Although the reaction of nitriles with derivatives of hydrazoic acid is

An efﬁcient method for the preparation of arylaminotetrazoles deriva-

3.2 1-Substituted- and 1,5-Disubstituted Tetrazoles

of CHEC-III (08MI257). In this regard, a three-component domino-

liquids [(EtNH3)NO3 or (pmim(SO3H))OTf] (11EJO2827). Using this

[1,4,7,10,13,16]hexaoxacyclo-octadecen-2-yl)-1H-tetrazole 61 was obtained

The application of the reagent system NaN3eSiCl4 resulted in convert-

Thirty new N1-[(1-alkyl-1H-tetrazol-5-yl)(aryl)methyl]-4-methyl-N3-

derivatives are formed in 81e98% yield (12HCA594). The reaction proceeds

2,3-dichloro-5,6-dicyano-1,4-benzoquinolone (DDQ), and molecular

3.3 2-Substituted and 2,5-Disubstituted Tetrazoles

regioselective procedure for the preparation of 2-aryltetrazoles 84 based on

In this context the material of a recent publication describing the

The alkylation of 5-substituted tetrazoles with dibromoethane in

perform regioselective arylations with arylboronic acids on a wide range of

3.4 Tetrazoles with a Fused Ring

substrates for producing tetrazolo-fused diazepinones 101 via the carboxylic

Synthesis of a new heterocyclic fused system, namely pyrazolo[4,3-e]

by a tandem fragmentationecyclization reaction (12OL3386). Structures

3.5 Functionalization of Tetrazoles

contrast, arylation of 2-vinyltetrazole occurs exclusively at the double bond

5-Bromoacetyl-1H-tetrazoles 128, prepared from the acetyl derivatives

3.6 Metal Ion Complexes With a Tetrazole Moiety

three endocyclic pyridine-type nitrogen atoms and one pyrrole-type

13CGD510; 14ICC9; 14ICC207; 14JMS14; 14NJC269; 15MI186;

In this regard, these acids are potentially multifunctional ligands and,

By substitution of other ligands by tetrazoles in coordination

compounds show high activity as catalyst precursors toward the microwave-

4. IMPORTANT COMPOUNDS AND APPLICATIONS

4.1.1 Antiviral Activity

A series of new N0 -arylidene-2-[1-(naphthalen-1-yl)-1H-tetrazol-5-

4.1.2 Anticancer Agents