Highly efficient azido-Ugi multicomponent reactions for the synthesis of bioactive tetrazoles bearing sulfonamide scaffolds

Article abstract of DOI:10.1016/j.tet.2021.132243

Recent studies revealed that the contribution of the different bioactive scaffolds in one structure creates modern drugs/compounds with unique synergistic biological properties. In this regard, thanks to the interesting biological and medicinal properties

Full text of DOI:10.1016/j.tet.2021.132243

Tetrahedron 91 (2021) 132243
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Highly efficient azido-Ugi multicomponent reactions for the synthesis
of bioactive tetrazoles bearing sulfonamide scaffolds
a
a
a
a
Mohammad Taghi Nazeri , Ali Beygzade Nowee , Siamak Javanbakht , Hassan Farhid ,
Ahmad Shaabani
a
a,
b,
*
a
, Behrouz Notash
Faculty of Chemistry, Shahid Beheshti University, G.C., P.O. Box 19396-4716, Tehran, Iran
b
Рeoples’ Friendship University of Russia (RUDN University), 6, Miklukho-Maklaya Street, Moscow, 117198, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 February 2021
Received in revised form
Recent studies revealed that the contribution of the different bioactive scaffolds in one structure creates
modern drugs/compounds with unique synergistic biological properties. In this regard, thanks to the
interesting biological and medicinal properties of sulfonamide and tetrazole skeletons, this study de-
scribes the engagement of sulfonamides in the Ugi tetrazole reaction to access a library of tetrazole
4
May 2021
Accepted 13 May 2021
Available online 31 May 2021
bearing sulfonamide. This four-component reaction was performed in a one-pot among available starting
ꢀ
material, i.e., an isocyanide, a sulfonamide, an aldehyde and sodium azide in MeOH at 45 C using ZnCl
2
as a catalyst, for the synthesis of very versatile products with high atom economy and yields. The key
point in this strategy is the formation of an intermediate Schiff base and its activation in the azido-Ugi
reaction by a Lewis acid catalyst. Importantly, all products are purified through the group-assisted pu-
rification (GAP) chemistry, which can avoid traditional purification such as recrystallization and chro-
matography methods. Also, the docking study between the synthesized compounds and human serum
albumin (HSA) was stimulated to theoretically rationalize their biological activity and potential binding
interactions.
Keywords:
Tetrazole
Isocyanide
Sulfonamide
Multicomponent reactions
Azido-ugi
©
2021 Elsevier Ltd. All rights reserved.
1
. Introduction
drug, anticonvulsant, receptor tyrosine kinase inhibitors, and
antitumor [15e17]. During recent years studies discovered that the
contribution of the different bioactive scaffolds in one structure
creates modern drugs/compounds with unique synergistic biolog-
ical properties. In this regard, due to the interesting biological and
medicinal properties of sulfonamide and tetrazole skeletons, they
have created modern drugs and bioactive compounds with unique
synergistic biological properties when these structures are
assembled in one molecule [18]. Recently, these compounds have
potentially been employed as diuretic agents azosemide (a drugs
loop diuretic used to treat hypertension, edema, and ascites) [19],
experimental drugs on 1,3-dehydroquinate dehydratase [1], pro-
piedades antimicrobial [20], PTP1B inhibitors [21] and inhibitor of
death-associated protein kinase 3 (DAPK3) (Fig. 1) [22]. The syn-
thesis of these types of tetrazole bearing sulfonamide structures is
rarely reported in the literature; thus, this is a pristine and very
attractive field for synthesizing and studying innovative biological
properties of this class of structures.
Tetrazoles have been known as an important class of unsatu-
rated five-membered aromatic heterocycles with four nitrogen
atoms in the ring [1]. They are significant synthetic scaffolds
founding broad applications in numerous fields such as medicinal
chemistry, biochemistry, pharmacology [2], organometallic [3],
coordination chemistry [4], organocatalysis [5,6], and materials
chemistry (photography, and imaging chemicals) [7e9]. Also, tet-
razoles are investigated as rocket propellant components and
environmentally friendly fuel in a gas generator [10e12]. However,
the most important and useful application of tetrazoles with many
future outlooks is their utility in medicinal chemistry [13,14].
Moreover, sulfonamide-based scaffolds are another core part of
many clinical drugs, which have a wide range of applications in
medicine, pharmacology, and pharmaceutics such as antiviral, anti-
inflammatory, antibacterial, antifungal, anti-cancer, anti-epileptic
According to the applications of tetrazole and sulfonamide, the
synthesis of conjugated structure has concerned a significant in-
terest. In this regard, the application of multicomponent reaction
*
Corresponding author. Faculty of Chemistry, Shahid Beheshti University, G.C.,
P.O. Box 19396-4716, Tehran, Iran.
E-mail address: a-shaabani@sbu.ac.ir (A. Shaabani).
https://doi.org/10.1016/j.tet.2021.132243
0
040-4020/© 2021 Elsevier Ltd. All rights reserved.

M.T. Nazeri, A.B. Nowee, S. Javanbakht et al.
Tetrahedron 91 (2021) 132243
Fig. 1. Representative natural products and bioactive compounds.
(
MCRs) is known and they are a very efficient approach for the
methods [50,51].
. Results and discussion
Initially, we evaluated the four-component reaction of cyclo-
hexyl isocyanide 1a, benzenesulfonamide 2a, benzaldehyde 3a and
sodium azide 4a. The reaction mixture containing a 1:1:1:1 mixture
of 1a, 2a, 3a and 4a was investigated in various conditions and
obtained results are summarized in Table 1. The optimization pro-
cess indicated that the reaction did not occur in MeOH under
catalyst-free conditions even by raising temperature (Table 1, En-
tries 1 and 2). Also, the reaction did not proceed in the presence of
synthesis of numerous kinds of complex molecules [23e25]. It is
well established that MCRs chemistry has several advantages over
sequential step-by-step chemistry. They show a high grade of va-
riety due to the nature of the starting materials as well as they are
one-pot, mild, high atom economy and avoid purification of all
intermediate products [26e28]. The Ugi four-component reactions
2
(
U-4CR) is a well-known MCR since it has a very powerful tool and
efficient for making peptides and peptide mimics [29e31]. In the
classical Ugi reaction, the replacement of carboxylic acids with
other compounds such as azide, carbonic acid, and phenol opens up
a new avenue for the synthesis of diverse U-4CR products (tetra-
zole, pseudo-peptide, etc.). Furthermore, in classical U-4CR, a wide
diversity of primary amines can be successfully employed [32,33].
acid catalysts (PTSA.H
Entries 3 and 4). In continuation, a 5 mol% of various Lewis acid
catalysts such as FeCl , InCl , SnCl and ZnCl were examined that
only the reaction was occurred in the presence of ZnCl and the
product 5a was obtained in an acceptable yield (Table 1, Entry 9).
2
O and HCl) in MeOH after 24 h (Table 1,
3
However, NH already gives poor to no yield or hydroxylamine, N-
3
3
2
2
acylated hydrazine, N-sulfonated hydrazine gives mixed or poor
yields [34e38]. Usually, these types of processes require an acti-
vating agent to successfully advance the reaction. Various synthetic
approaches have been developed for this transformation. Most of
them are performed through activation of the amine by different
Lewis acids. Recently, D o€ mling reported an efficient method for the
2
The reaction was investigated in various solvents such as CH
EtOH, toluene, water and under the neat conditions at 60
3
CN,
C
ꢀ
(Table 1, Entries 10e14). Among all the solvents, methanol was
found to be an optimum medium in terms of yield and reaction
synthesis of tetrazoles using catalytic amounts of ZnCl
2
in methanol
efficiency. We proceeded further to optimize the increasing tem-
[
39]. These features make U-4CR as a potent tool to be utilized in
ꢀ
perature. Subsequently, by increasing temperature from 25 C to
designing and constructing tetrazole bearing sulfonamides through
selecting appropriate starting compounds like azide and sulfon-
amide. In our continuing interest in sulfonamide chemistry and
designing new MCRs for the synthesis of heterocycles [40e48], we
have previously reported a two-step protocol for the synthesis of
ꢀ
45
C the yield of product 5a was improved over 72% after 6 h,
(Table 1, Entry 16). On the other hand, the reaction under reflux
conditions was tested and no significant change was observed in
the reaction yield (Table 1, Entry 17). For the effectiveness of the Zn
catalyst, a variety of Zn salts including Zn(OAc) , Zn(OTf) , and
2 2
1
,5-disubstituted tetrazoles containing b-sulfonamide via an
Zn(NO
obtained in the presence of Zn(NO
Entry 18e20). However, since ZnCl
than Zn(NO
3
)
2
were also investigated. A comparatively high yield was
isocyanide-based multicomponent reaction (I-MCRs) [49]. But we
report here our findings of the first successful use of sulfonamide in
the azido-Ugi reaction (AU-4CR) to yield a tetrazole bearing sul-
fonamide in a one-pot protocol, performing among an isocyanide
ꢀ
3
)
2
at 45 C in methanol (Table 1,
2
is safer and more economical
3
)
2
, it was considered as a suitable catalyst for the
synthesis of tetrazoles. It is worth mentioning that product 5a was
isolated via GAP chemistry, which can avoid traditional purification
such as recrystallization and chromatography methods [50,52,53].
Upon optimization of the reaction conditions, we investigated
the scope and limitations of the four-component reaction synthesis
of tetrazole bearing sulfonamide 5. These reactions were extended
to various isocyanides 1, sulfonamides 2, and aldehydes 3 (Scheme
1
a, a sulfonamide 2a, an aldehyde 3a, and sodium azide 4a in MeOH
ꢀ
using ZnCl
2
as a catalyst at 45 C (Scheme 1). In this method, sul-
fonamide (as an inactive amine) was purposefully used instead of
ordinary amine. It is noteworthy that this synthesis procedure was
also designed to follow the GAP chemistry, which can avoid tradi-
tional purification such as recrystallization and chromatography
2

M.T. Nazeri, A.B. Nowee, S. Javanbakht et al.
Tetrahedron 91 (2021) 132243
Scheme 1. The model reaction for the synthesis of tetrazole bearing sulfonamide.
þ
Table 1
mass spectra of 5g displayed the molecular ion peak at 412 for M
consistent with the molecular structure. The IR spectrum of 5g
displayed characteristic absorption bands at 3332, 1598, 1327, and
a
Optimization of the second step reaction conditions
.
ꢁ1
1
158 cm
respectively. The H NMR spectrum of 5g consisted of signals for
the cyclohexyl ring (
¼ 1.13e1.88 ppm, 10H) and signals with
multiple splitting for NHeCH (
¼ 4.90e4.61 ppm, 1H); the two
singlet peaks ( ¼ 6.16 ppm) for the eCH and CHBn
¼ 2.29, and
groups, respectively; the peaks for aromatic protons (
¼ 7.17e7.53,
9H) and a signal for the NH group (
¼ 9.19 ppm, bs, 1H). The
NMR spectrum of 5g revealed characteristic signals at 57.2 and
1.2 ppm due to the presence of C-Ncyclohexyl and CBn, respectively.
2
due to NH, N]N and SO stretching vibrations,
1
d
d
d
d
3
d
13
ꢀ
Yieldb (%)
d
C
Entry
Catalyst (mol%)
Solvent
T ( C)
Time (h)
1
2
3
4
5
6
7
8
9
e
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
25
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
6
0
0
0
0
5
e
reflux
25
HCl (5)
Finally, the structure of 5g was unambiguously verified by
single-crystal X-ray analysis, displaying in Fig. 2 (Detailed infor-
mation can be seen in the Supporting Information).
The proposed mechanism for the formation of 5 is shown in
Scheme 4 [55]. The first reaction is the condensation of sulfonamide
2 with aldehyde 3 in the presence of ZnCl for the formation of a
2
Schiff base 7 that is a key intermediate in all Ugi-type multicom-
ponent reactions. Upon Schiff base 7 activation by Lewis acid
PTSA.H
FeCl
AlCl
InCl
SnCl
2
O (5)
25
25
25
25
25
25
25
25
25
25
60
45
3
(5)
(5)
(5)
(5)
(5)
(5)
(5)
(5)
(5)
(5)
(5)
(5)
(5)
Trace
Trace
23
17
40
25
15
10
e
3
3
2
ZnCl
ZnCl
ZnCl
ZnCl
ZnCl
ZnCl
ZnCl
ZnCl
ZnCl
2
2
2
2
2
2
2
2
2
10
11
12
13
14
15
16
17
18
19
20
MeCN
Toluene
(
2
ZnCl ), the isocyanide attacks the activated Schiff base 8 (imine) to
2
H O
e
25
73
72
70
25
65
71
form the intermediate nitrilium ion 9, the process is then followed
in the presence of azide ion [39]. Finally, the Ugi tetrazole product 5
is prepared by an irreversible sigmatropic rearrangement.
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
45
reflux
45
6
6
6
6
Zn(OAc)
Zn(OTf)
Zn(NO
2
(5)
(5)
(5)
2
45
45
3. Molecular docking
3
)
2
a
Conditions: The one-pot four-component domino reaction: 1a (0.25 mmol), 2a
Molecular docking is a technique that calculates the binding of a
(
0.25 mmol), 3a (0.25 mmol), 4a (0.25 mmol), 2 mL solvent. bIsolated yields.
molecule with a specific direction to another (macro)molecule,
arranging a stable complex [56]. This simulation is essentially used
to estimate either interaction or binding between a ligand and
targeted protein [57,58]. In human plasma, HSA is the most sig-
nificant carrier of endogenous and exogenous molecules. Therefore,
molecular docking was performed on the synthesized compounds
2
), the results are summarized in Scheme 3. The aromatic alde-
hydes with substituent electron-withdrawing groups and halogens
NO , F, Cl and Br) and electron-donating groups (Me, OMe) were
(
2
investigated for preparing the desired product (Scheme 3). In this
strategy, increasing the electron-withdrawing effect of substituents
on the benzaldehyde leads to an increase in the yield of the final
products. But, the electron-donating effect of substituents on the
benzaldehyde leads to a drastic reduction in the yield of the final
products. To further explore the versatility of this protocol, the
feasibility of variation of aldehyde to aliphatic aldehydes was
investigated (Scheme 2), which they well tolerated under the re-
action conditions and afforded the desired products in satisfactory
yields (Scheme 3). Interestingly, placing the substituent electron
donor groups in the sulfonamide 2 increases afforded the desired
yields for products [54]. A different trend was observed for the
isocyanides, whereas the yields obtained of products for the
cyclohexyl isocyanide 1a were excellent, but relatively lower yields
were obtained using tert-butyl isocyanide 1b.
(
5a-p) with HSA to theoretically rationalize their biological activity
and potential binding interactions. Docking results in binding with
HAS protein were summarized in Table S1. The synthesized com-
pounds 5a-p have a MolDock Score from ꢁ86.63 to 108.52. Among
the tested compounds, compound 5l that binds with Lys 439 amino
acid residue showed a higher MolDock Score (108.52) and
hydrogen bonding (ꢁ8.96), Fig. 3. Results revealed that the tetra-
zole, sulfonamide and also polar groups like nitroxide effectively
enhanced the binding ability of ligand with protein. The findings of
the docking study may develop the theoretical understanding of
the pharmacokinetic properties of tetrazole bearing sulfonamide
scaffolds and also their possible clinical application as an effective
therapeutic agent.
For example, the structure of compound 5g confirming by their
analytical and spectral data was considered in this section. The
4. Conclusions
In summary, an efficient synthesis of tetrazole bearing
3

M.T. Nazeri, A.B. Nowee, S. Javanbakht et al.
Tetrahedron 91 (2021) 132243
Scheme 2. The variety of reactants.
sulfonamide via a AU-4CR has been developed in this work. The AU-
code: 1AO6) has been downloaded from Protein Data Bank (PDB)
online. Afterward, structures of synthesized compounds 5a-p were
drawn in ChemBioDraw Ultra 14.0, copied to ChemBio3D Ultra 14.0,
and minimized their energy then saved as Mol2 format. The
possible binding sites of HSA were determined based on the
established grid-based cavity prediction algorithm. According to
the searching algorithm of MolDock Optimizer and energetic
evaluation of the complex with MolDock, the finest binding pose of
the formed complex between HAS and compounds was achieved.
4
CR carried out among the isocyanide, sulfonamide, aldehyde, and
ꢀ
sodium azide in MeOH using ZnCl
2
as a catalyst at 45 C, for pro-
ducing high diversity of tetrazoles. In this protocol, the bottleneck is
Schiff base (as a key intermediate) formation, which is formed by
the catalytic participation of Lewis acid (ZnCl ) and subsequently
2
activates it to continue the reaction. This reaction is done in a one-
pot with high atom economy and available starting material for the
synthesis of products with very versatile and high yielding prod-
ucts. All products are purified through GAP chemistry. Besides, the
docking investigation revealed the binding ability of the synthe-
sized compounds with HAS protein.
5.3. Representative synthesis of (E)-2-phenylethene-1-sulfonamide
(2d)
The (E)-2-phenylethene-1-sulfonyl chloride 12 was synthesized
according to the reported methods [59]. Then, to of this synthesized
5
. Experimental section
compound 12 (1 mmol 202.6 mg), 1.2 mmol (20.0 mg) of ammonia
was added. Afterward, the mixture was stirred for 4 h at 40 C.
5.1. Materials and methods
ꢀ
Upon the completion of the reaction (monitored by TLC), the solid
precipitate was filtered and washed with water (2 mL ꢂ 2) and
dried to yield the pure product 2d 179.3 mg, yield 98% [60].
All commercially available chemicals and reagents were pur-
chased from Merck Co. and used without further purification.
Melting points were measured with an Electrothermal 9200
apparatus. Fourier-transform infrared (FT-IR) spectra were recor-
ꢁ
1 1
ded on a THERMO NICOLET spectrophotometer in cm . H NMR
spectra were recorded on a Bruker DRX-500 and BRUKER DRX-300
5.4. Representative synthesis of N-((1-cyclohexyl-1H-tetrazol-5
yl)(phenyl)methyl)benzenesulfonamide (5a)
13
AVANCE spectrometer at 500 and 300.13 MHz C NMR spectra
were recorded on Bruker DRX-500 and DRX-300 Avance spec-
trometers at 125 and 75.47 MHz. NMR spectra were obtained in
A mixture of cyclohexyl isocyanide 1a (0.25 mmol, 27.2 mg),
benzenesulfonamide 2a (0.25 mmol, 39.2 mg), benzaldehyde 3a
3 6
CDCl and DMSO‑d . Mass spectra of the products were obtained
(
(
0.25 mmol, 26.5 mg), NaN
0.005 mmol, 1.6 mg) in MeOH (2 mL) was stirred for 6 h at 45 C.
3
4 (0.25 mmol, 16.2 mg) and ZnCl
2
with an HP (Agilent technologies) 5937 Mass Selective Detector.
Elemental analyses were performed on an elementaranalyse sys-
tem GmbH VarioEL CHN mode.
ꢀ
Upon the completion of the reaction (monitored by TLC), the solid
precipitate was filtered and washed with methanol (2 mL ꢂ 2) and
dried to yield the pure product 5a 71.4 mg, yield 72%.
5.2. Molecular docking
5
.4.1. N-((1-Cyclohexyl-1H-tetrazol-5-yl)(phenyl)methyl)
benzenesulfonamide (5a)
White powder (71 mg, 72%); mp 297e299 C.
300 MHz): 1.23e1.72 (m, 10H, Hcyclohexyl), 4.69 (bs, 1H, NHCH), 6.03
The docking study between the synthesized compounds and
HSA were stimulated using the Molegro Virtual Docker version
013. The three-dimensional (3D) crystal structure of HSA (PDB ID
ꢀ
H
d (DMSO,
2
4

M.T. Nazeri, A.B. Nowee, S. Javanbakht et al.
Tetrahedron 91 (2021) 132243
Scheme 3. Substrate Scope a
.
5

M.T. Nazeri, A.B. Nowee, S. Javanbakht et al.
Tetrahedron 91 (2021) 132243
(
(
s, 1H, CHBn), 7.13e7.29 (m, 7H, HAr), 7.57 (d, 2H, J¼9 Hz, HAr), 7.84
13
bs, 1H, NH). C NMR
d (75 MHz, DMSO) 156.31, 142.79, 137.95,
134.66, 132.42, 128.62, 127.93, 126.65, 124.36, 57.24 (NCH), 54.93
(
CHBn), 33.72, 25.05, 24.92, 21.96. max (ATR), 3468 (NH), 2933 (CH),
n
ꢁ1
1
558 (N]N), 1279, 1148 (SO
7.60. C20 S requires C, 60.43; H, 5.83; N, 17.62%. m/z (EI,
0 eV) 397 (M , 4.19), 313 (20.51), 246 (14.50), 236 (62.11), 112
17.95), 84 (89.85), 57 (100).
2
) cm . Found: C, 60.40; H, 5.80; N,
1
7
(
23 5 2
H N O
þ
5
.4.2. N-((4-Bromophenyl)(1-cyclohexyl-1H-tetrazol-5-yl)methyl)
benzenesulfonamide (5b)
White powder (111 mg, 85%); mp 151-150 C.
00 MHz): 1.20e1.45 (m, 3H, Hcyclohexyl), 1.65e1.86 (m, 6H, Hcyclo-
ꢀ
H
d (DMSO,
3
hexyl), 1.94e1.98 (m, 1H, Hcyclohexyl), 4.62 (m, 1H, NHCH), 6.23 (s, 1H,
CHBn), 7.25 (d, 2H, J¼6 Hz, HAr), 7.37e7.41 (m, 4H, HAr), 7.48e7.53
1
3
(
d
m, 1H, HAr), 7.62 (d, 2H, J¼6 Hz, HAr), 9.30 (bs, 1H, NH). C NMR
(75 MHz, DMSO) 153.87, 141.15, 136.10, 132.78, 131.48, 130.39,
29.32, 126.77, 121.83, 57.30 (NCH), 50.62 (CHBn), 32.94, 32.63,
1
2
5.12, 24.92. nmax (ATR), 3248 (NH), 2952 (CH), 1590 (N]N), 1156,
ꢁ1
1335 (SO
2
) cm . Found: C, 50.39; H, 4.63; N, 14.67. C20H22BrN O S
5
2
þ
79
requires C, 50.42; H, 4.65; N, 14.70%. m/z (EI, 70 eV) 477 (M
[
Br],
Br], 2.04), 411 (12.67), 330 (9.81), 228 (28.89), 199
100), 141 (26.47), 77 (67.01).
þ
81
2
(
.71), 475 (M [
5
.4.3. N-((1-Cyclohexyl-1H-tetrazol-5-yl)(p-tolyl)methyl)
benzenesulfonamide (5c)
White powder (80 mg, 69%); mp 269e270 C.
00 MHz): 1.24e1.73 (m, 10H, Hcyclohexyl), 2.23 (s, 3H, CH
H, NHCH), 5.98 (s, 1H, CHBn), 7.04e7.34 (m, 6H, HAr), 7.59e7.87 (m,
ꢀ
d
H
(DMSO,
), 4.73 (bs,
3
1
3
3
Fig. 2. X-ray crystal structure of compound 5g (CCDC code. 2053125).
13
H, HAr), 9.24 (bs, 1H, NH). C NMR
45.03, 136.98, 132.14, 129.41, 128.99, 128.56, 127.52, 126.47, 126.04,
6.88 (NCH), 52.38 (CHBn), 33.04, 32.28, 25.10, 21.07. max (ATR),
d (75 MHz, DMSO) 155.96,
1
5
n
Scheme 4. The plausible mechanism of compound 5.
6

M.T. Nazeri, A.B. Nowee, S. Javanbakht et al.
Tetrahedron 91 (2021) 132243
Fig. 3. Binding modes for compounds 5l in different views. Hydrogen bonds are displayed by yellow dashes.
3
6
310 (NH), 2922 (CH), 1560 (N]N),1147, 1335 (SO
2
) cmꢁ1. Found: C,
S requires C, 61.29; H, 6.12; N,
500 MHz): 1. 43 (s, 9H, Htert-Bu), 3. 66 (s, 3H, eOCH
CHBn), 6.69e6.85 (m, 1H, HAr), 7.06e7.17 (m, 2H, HAr), 7.37e7.45 (m,
3
), 5.94 (s, 1H,
1.25; H, 6.09; N, 17.98. C21
H
25
N
5
O
2
þ
13
17.02%. m/z (EI, 70 eV) 411 (M , 0.99), 347 (15.53), 266 (12.64), 213
6H, HAr), 7.83 (bs, 1H, NH). C NMR
144.26, 139.34, 135.76, 132.81, 129.16, 128.01, 125.33, 63.44 (Ctetr-Bu),
7.19 (-OCH ), 50.30 (CHBn), 29.87 (CH ). max (ATR), 3330 (NH),
3057 (CH), 1591 (N]N), 1143, 1270 (SO ) cm . Found: C, 56.80; H,
5.75; N,17.40. C19 S requires C, 56.84; H, 5.77; N,17.44%. m/z
d (126 MHz, DMSO) 150.86,
(
100), 155 (13.03), 106 (25.55), 91 (33.14), 77 (16.01), 55 (19.03).
5
3
3
n
ꢁ
1
5
.4.4. N-((1-Cyclohexyl-1H-tetrazol-5-yl)(4-nitrophenyl)methyl)
benzenesulfonamide (5d)
White powder (99 mg, 90%); mp 247e248 C.
00 MHz): 1.20e1.45 (m, 3H, Hcyclohexyl), 1.54e1.86 (m, 7H, Hcyclo-
2
23 5 3
H N O
ꢀ
þ
d
H
(DMSO,
(EI, 70 eV) 401 (M 0.98), 368 (3.79), 285 (68.37), 236 (11.26), 131
(100), 104 (13.99), 77 (22.50), 57 (15.59).
3
hexyl), 4.72e4.78 (bs, 1H, NHCH), 6.23 (s, 1H, CHBn), 7.02 (d, J ¼ 9 Hz,
2
1
H, HAr), 7.31e7.41 (m, 4H, HAr), 9.97 (d, J ¼ 9 Hz, 2H, HAr), 9.30 (bs,
5.4.7. N-((1-Cyclohexyl-1H-tetrazol-5-yl)(phenyl)methyl)-4-
1
3
H, NH). C NMR
33.16, 132.15, 131.02, 129.30, 127.33, 57.36 (NCH), 50.49 (CHBn),
0.45, 24.91, 21.97, 20.99. max (ATR), 3279 (NH), 3062 (CH), 1554
d
(75 MHz, DMSO) 151.31, 141.83, 139.33, 137.39,
methylbenzenesulfonamide (5g)
ꢀ
1
3
(
White powder (81 mg, 79%); mp 171-170 C; N,16.98.
d
H
(DMSO,
n
300 MHz): 1.13e1.39 (m, 3H, Hcyclohexyl), 1.52e1.88 (m, 7H, Hcyclo-
hexyl), 2.29 (s, 3H, CH ), 4.90e4.61 (m, 1H, NHCH), 6.16 (s, 1H, CHBn),
7.17e7.31 (m, 7H, HAr), 7.53 (d, 2H, J¼9 Hz, HAr), 9.19 (bs, 1H, NH).
ꢁ
1
N
2
), 1268, 1148 (SO
S requires C, 54.29; H, 5.01; N, 18.99%. m/z (EI, 70 eV)
42 (M , 6.87), 368 (85.08), 313 (68.25), 236 (100), 109 (44.07), 83
2
) cm . Found: C, 54.25; H, 5.00; N, 18.96.
3
C
4
20 22 6 4
H N O
þ
13
C NMR
128.72, 128.50, 128.05, 126.85, 57.21 (NCH), 51.28 (CHBn), 32.79,
2.69, 25.04, 24.91, 21.35. max (ATR), 3332 (NH), 2937 (CH), 1598
(N]N), 1327, 1158 (SO ) cm . Found: C, 61.26; H, 6.09; N, 16.98.
S requires C, 61.29; H, 6.12; N,17.02%. m/z (EI, 70 eV) 412
d (75 MHz, DMSO) 154.26, 143.06, 138.38, 136.77, 129.67,
(
74.36), 57 (96.17).
3
n
ꢁ
1
5
.4.5. N-((1-(Tert-butyl)-1H-tetrazol-5-yl)(4-chlorophenyl)methyl)
benzenesulfonamide (5e)
White powder (78 mg, 77%); mp 249e250 C.
00 MHz): 1.64 (s, 9H, Htert-Bu), 6.15 (s, 1H, CHBn), 7.25 (bs, 4H, HAr),
.37 (t, 2H, J ¼ 6 Hz, HAr), 7.50 (t, 1H, J ¼ 6 Hz, HAr), 7.57 (d, 1H,
2
21 25 5 2
C H N O
ꢀ
þ
d
H
(DMSO,
(M , 0.99), 347 (15.53), 266 (12.64), 213 (100), 155 (13.03), 106
(25.55), 91 (33.14),77 (16.01), 55 (19.03).
3
7
13
J ¼ 6 Hz, HAr), 9.34 (bs, 1H, NH). C NMR
41.46, 133.39, 132.77, 130.49, 129.18, 128.73, 126.79, 62.48 (Ctetr-Bu),
2.44 (CHBn), 29.74 (CH ). max (ATR), 3290 (NH), 2998 (CH), 1593
N]N), 1270, 1143 (SO ) cm . Found: C, 53.22; H, 4.94; N, 17.22.
S requires C, 53.26; H, 4.97; N, 17.25%. m/z (EI, 70 eV)
d
(75 MHz, DMSO) 153.72,
5.4.8. N-((4-Bromophenyl)(1-(tert-butyl)-1H-tetrazol-5-yl)
1
5
(
C
4
methyl)-4-methylbenzenesulfonamide (5h)
ꢀ
3
n
White powder (170 mg, 93%); mp 245e246 C.
d
H
(DMSO,
ꢁ
1
2
300 MHz): 1.16 (s, 9H, Htert-Bu), 2.32 (s, 3H, CH
3
), 6.09 (s, 1H, CHBn),
18
H
08 (M
20ClN
5
O
2
7.16 (d, 4H, J ¼ 9 Hz, HAr), 7.37e7.45 (m, 4H, HAr), 9.21 (bs, 1H, NH).
þ
37
þ
35
13
[
Cl], 0.29), 406 (M
[
Cl], 0.55), 341 (20.05), 280 (100),
C NMR
130.79, 129.53, 126.85, 121.90, 62.50 (Ctetr-Bu), 52.38 (CHBn), 29.74
CH ), 21.40 (CH ). max (ATR), 3335 (NH), 2926 (CH), 1597 (N]N),
1146, 1278 (SO ) cm . Found: C, 49.11; H, 4.75; N, 15.06.
S requires C, 49.14; H, 4.78; N, 15.08%. m/z (EI, 70 eV)
d (75 MHz, DMSO) 153.72, 142.79, 139.21, 135.99, 131.57,
180 (50.97), 141 (66.85), 77 (68.06), 41 (47.09).
(
3
3
n
ꢁ
1
5
.4.6. N-((1-(Tert-butyl)-1H-tetrazol-5-yl)(4-methoxyphenyl)
methyl)benzenesulfonamide (5f)
White powder (74 mg, 74%); mp 255e256 C.
2
C
19
H
22BrN
5
O
2
ꢀ
þ
79
þ 81
d
H
(DMSO,
465 (M
[
Br], 0.04), 463 (M [ Br], 0.03), 401 (7.86), 343 (21.79),
7

M.T. Nazeri, A.B. Nowee, S. Javanbakht et al.
Tetrahedron 91 (2021) 132243
2
24 (13.99), 184 (32.31), 155 (57.43), 91 (100), 57 (49.38).
145.58, 138.98, 133.44, 128.52, 62.73 (NCH), 57.53 (CHBn), 42.08
(
SO
(CH), 1598 (N]N), 1276, 1143 (SO
N, 18.90. C15 20ClN S requires C, 48.71; H, 5.45; N, 18.94%. m/z
(EI, 70 eV) 371 (M
2
CH
3
) 34.50, 32.18, 27.62, 24.32.
nmax (ATR), 3331 (NH), 2939
ꢁ1
5.4.9. N-((1-(Tert-butyl)-1H-tetrazol-5-yl)(4-fluorophenyl)
2
) cm . Found: C, 48.68; H, 5.43;
methyl)-4 methylbenzenesulfonamide (5i)
White powder (95 mg, 94%); mp 208e209 C.
00 MHz): 1.59 (s, 9H, Htert-Bu), 2.27 (s, 3H, CH ), 6.07 (s, 1H, CHBn),
.98e7.01 (m, 2H, HAr), 7.10 (d, 2H, J ¼ 5 Hz, HAr), 7.27 (bs, 2H, HAr),
H
5 2
O
ꢀ
þ
37
þ 35
d
H
(DMSO,
[ Cl], 0.02), 369 (M [ Cl], 0.05), 260 (100),
5
6
7
3
232 (24.33), 204 (21.03), 124 (53.68), 109 (30.97), 91 (25.06), 65
(4.59).
13
.42 (d, 2H, J ¼ 5 Hz, HAr), 9.18 (bs, 1H, NH). C NMR
DMSO) 163.51, 160.28 (CeF, J
¼ 242.3 Hz), 155.66, 141.59, 135.34
Ar), 130.43, 130.33 (CeCeCeF, J
¼ 7.5 Hz), 129.17, 128.85, 126.72,
26.16, 126.11 (CeCeCeCeF, J
¼ 3.8 Hz), 115.40, 115.13 (CeCeF,
¼ 20.2 Hz), 62.22 (Ctetr-Bu), 53.24 (CHBn), 29.80 (CH ), 21.28 (CH ).
max (ATR), 3477 (NH), 2909 (CH), 1525 (N]N), 1278, 1122 (C]C)
d (75 MHz,
1
5
.4.14. N-((4-Bromophenyl)(1-(tert-butyl)-1H-tetrazol-5-yl)
methyl)methanesulfonamide (5n)
Yellow powder (100 mg, 94%); mp 222e223 C.
00 MHz): 1.66 (s, 9H, Htert-Bu), 2.76 (s, 3H, CH ), 6.22 (s, 1H, CHBn),
7.44 (d, 2H, J ¼ 3 Hz, HAr), 7.62 (d, 2H, J ¼ 3 Hz, HAr), 8.67 (bs, 1H,
(
C
3
1
4
ꢀ
d
H
(DMSO,
J
4
3
3
5
3
n
ꢁ1
cm . Found: C, 56.53; H, 5.47; N, 17.32. C19
H
22FN
5
O
2
S requires C,
13
þ
NH). C NMR
22.02, 62.01 (Ctetr-Bu), 51.91 (CHBn), 41.69 (SO
max (ATR), 3307 (NH), 2985 (CH), 1597 (N]N), 1158, 1327 (SO
d
(125 MHz, DMSO) 154.35, 136.37, 131.83, 130.67,
5
6.56; H, 5.50; N, 17.36%. m/z (EI, 70 eV) 403 (M , 2.01), 339 (6.05),
1
n
2
CH ), 29.23 (CH ).
3
3
313 (5.95), 278 (28.13), 155 (59.57), 121 (69.76), 91 (100), 57 (61.50).
2
)
ꢁ
1
cm . Found: C, 40.17; H, 4.64 N, 18.01. C13
4
(M [ Br], 1.38), 334 (11.23), 308 (28.50), 252 (53.75), 226 (76.21),
H
18BrN
5
O
2
S requires C,
Br], 1.97), 388
5
.4.10. N-((1-(Tert-butyl)-1H-tetrazol-5-yl)(p-tolyl)methyl)-4-
methylbenzenesulfonamide (5j)
White powder (78 mg, 76%); mp 239e240 C.
), 3.31 (s, 3H, CH
þ
79
0.21; H, 4.67; N, 18.04%. m/z (EI, 70 eV) 390 (M
[
þ
81
ꢀ
d
H
(DMSO,
),
184 (100), 117 (17.15), 57 (47.10).
5
5
H
00 MHz): 2.31 (s, 9H, Htert-Bu), 2.50 (s, 3H, CH
3
3
.90 (s, 1H, CHBn), 7.07 (d, 4H, J ¼ 5 Hz, HAr), 7.60 (d, 4H, J ¼ 10 Hz,
13
Ar), 9.44 (bs, 1H, NH). C NMR d (125 MHz, DMSO) 159.71, 145.95,
5
.4.15. N-(1-(1-Cyclohexyl-1H-tetrazol-5-yl)butyl)
benzenesulfonamide (5o)
White powder (67 mg, 74%); mp 203e205 C.
NH), 2982 (CH), 1584 (N]N), 1155, 1330 (SO
1
5
(
42.65, 138.72, 135.07, 130.15, 128.36, 125.64, 123.27 63.44 (Ctetr-Bu),
6.56 (CHBn), 26.65 (CH ), 21.03 (CH ). max (ATR), 3416 (NH), 2924
CH), 1521 (N]N), 1270, 1116 (SO ) cm . Found: C, 60.10; H, 6.28;
S requires C, 60.13; H, 6.31; N, 17.53%. m/z (EI,
n
ꢁ
ꢀ
3
3
n
max (ATR), 3338
1
ꢁ1
2
(
3
) cm
.
d
H
(DMSO,
),
2
N, 17.50. C20
7
H
25
N
5
O
2
00 MHz): 0.80 (t, 3H, J ¼ 6 Hz, CH
3
), 1.06e1.13 (m, 2H, CH
cyclohexyl), 1.38e1.41 (m, 1H,
cyclohexyl), 1.99e2.02 (m, 1H,
2
þ
0 eV) 399 (M , 1.81), 361 (1.56), 327 (3.63), 383 (13.63), 171
1.21e1.26 (m, 1H,
H
H
H
cyclohexyl),
cyclohexyl),
(
15.45), 91 (75.45), 57 (56.36), 48 (100).
1.65e1.84 (m, 7H,
H
2
.27e2.30 (m, 2H, CH
2
), 4.57e4.67 (m, 1H, NHCH), 5.15 (t, 1H,
5
.4.11. N-((1-(Tert-butyl)-1H-tetrazol-5-yl)(4-chlorophenyl)
methyl)-4-methylbenzenesulfonamide (5k)
Yellow powder (102 mg, 97%); mp 251e252 C.
00 MHz): 1.64 (s, 9H, Htert-Bu), 2.30 (s, 3H, CH ), 6.10 (s, 1H, CHBn),
.15 (d, 2H, J ¼ 10 Hz, HAr), 7.19e7.27 (m, 4H, HAr), 7.43 (d, 2H,
J ¼ 6 Hz, CHNSO
2
), 7.49e7.57 (m, 3H, HAr), 7e89 (d, 2H, J¼3 Hz, HAr),
13
8.45 (bs, 1H, NH). C NMR
d
(75 MHz, DMSO) 158.28, 149.16, 129.87,
), 37.25, 33.32, 26.87,
ꢀ
d
H
(DMSO,
128.41, 125.98, 57.85 (NCH), 50.42 (CHNSO
2
5
7
3
25.61, 14.61, 10.76. Found: C, 56.14; H, 6.90, N, 19.23. C17
H
25
N
5
O
2
S
þ
requires C, 56.18; H, 6.93; N, 19.27%. m/z (EI, 70 eV) 363 (M , 1.78),
2
13
J ¼ 10 Hz, HAr), 9.18 (bs, 1H, NH). C NMR
61.38, 153.80, 147.55, 142.99, 133.09, 130.02, 129.07, 128.20, 126.47,
2.02 (Ctetr-Bu), 52.26 (CHBn), 29.35 (CH ), 20.66 (CH ). max (ATR),
421 (NH), 2931 (CH), 1591 (N]N), 1275, 1105 (C]C) cm . Found:
22ClN S requires C, 54.34; H, 5.28;
d (125 MHz, DMSO)
31 (18.75), 171 (20.33), 155 (35.45), 91 (100), 65 (36.36).
1
6
3
3
3
n
ꢁ
1
5.4.16. N-(1-(1-Cyclohexyl-1H-tetrazol-5-yl)-3-phenylpropyl)-4-
methylbenzenesulfonamide (5p)
C, 54.30; H, 5.25; N, 16.63. C19
N, 16.68%. m/z (EI, 70 eV) 421 (M
13 (6.27), 265 (3.99), 239 (8.16), 123 (8.29), 97 (23.84), 69 (48.13),
H
5 2
O
þ
37
þ
35
White powder (87 mg, 79%); mp 226e228
NH), 2994 (CH), 1590 (N]N), 1150, 1327 (SO
ꢀ
C.
n
max
(ATR), 3345
[
Cl], 0.92), 419 (M
[
Cl], 2.72),
ꢁ
1
(
2
) cm
00 MHz): 1.17e1.39 (m, 3H, Hcyclohexyl), 1.56e1.67 (m, 4H, Hcyclo-
), 2.29 (s,
), 4.50e4.59 (m, 1H, NHCH), 4.83
), 7.17e7.31 (m, 5H, HAr), 7.54 (d, 2H, J¼9 Hz,
H
. d (DMSO,
3
3
57 (83.00), 43 (100).
hexyl), 1.74e1.88 (m, 3H, Hcyclohexyl), 2.07e2.13 (m, 2H, CH
H, CH
), 2.63 (t, 2H, J ¼ 6 Hz, CH
t, 1H, J ¼ 6 Hz, CHNSO
), 7.73 (d, 2H, J¼9 Hz, HAr), 8.82 (bs, 1H, NH). C NMR
2
3
(
3
2
5.4.12. (E)-N-((4-chlorophenyl)(1-cyclohexyl-1H-tetrazol-5-yl)
methyl)-2-phenylethene-1-sulfonamide (5l)
Yellow powder (95 mg, 83%); mp 295e296 C.
00 MHz): 1.13e1.39 (m, 3H, Hcyclohexyl), 1.52e1.88 (m, 7H, Hcyclo-
hexyl), 2.29 (s, 3H, CH ), 4.90e4.61 (m, 1H, NHCH), 6.16 (s, 1H, CHBn),
.17e7.31 (m, 7H, HAr), 7.53 (d, 2H, J¼9 Hz, HAr), 9.19 (bs, 1H, NH).
2
13
ꢀ
H
Ar
d
(75 MHz,
DMSO) 156.66, 146.01, 142.79, 139.56, 128.88, 127.15, 125.88, 123.10,
1.42 (NCH), 50.42 (CHNSO -), 34.93, 31.43, 29.82, 25.89, 24.00,
1.32. Found: C, 62.80; H, 6.61, N, 15.90. C23 S requires C,
62.85; H, 6.65; N, 15.93%. m/z (EI, 70 eV) 439 (M , 1.73), 309 (1.30),
71 (35.65), 155 (33.04), 109 (25.86), 91 (100), 65 (37.39).
d
H
(DMSO,
3
6
2
2
3
29 5 2
H N O
7
þ
1
3
C NMR
30.37, 129.25, 128.78, 126.59, 120.50, 57.43 (NCH), 50.84 (CHBn),
2.93, 32.68, 25.04, 24.88. max (ATR), 3330 (NH), 2937 (CH), 1597
N]N), 1276, 1143 (SO ) cm . Found: C, 57.66; H, 5.25; N, 15.26.
S requires C, 57.70; H, 5.28; N, 15.29%. m/z (EI, 70 eV)
d (75 MHz, DMSO) 155.12, 144.23, 139.60, 133.29, 130.49,
1
1
3
(
C
4
n
ꢁ1
2
Declaration of competing interest
22
H
59 (M
24ClN
5
O
2
þ
37
þ
35
[
Cl], 1.48), 457 (M
[
Cl], 3.01), 340 (1.99), 235 (16.00),
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
188 (18.46), 149 (28.11), 105 (100), 77 (23.42), 57 (9.25).
5
.4.13. N-((4-Chlorophenyl)(1-cyclohexyl-1H-tetrazol-5-yl)methyl)
methanesulfonamide (5m)
White powder (95 mg, 96%); mp 205e206 C.
00 MHz): 1.21e1.41 (m, 3H, Hcyclohexyl), 1.65e1.84 (m, 6H, Hcyclo-
hexyl), 2.02 (s, 1H, Hcyclohexyl), 2.79 (s, 3H, -SO CH ), 4.59e4.61 (m,
H, NHCH), 6.28 (s, 1H, CHBn), 7.50 (d, 2H, J¼3 Hz, HAr), 7.57 (d, 2H,
ꢀ
d
H
(DMSO,
Acknowledgments
5
2
3
This paper has been supported by the Research Council of
Shahid Beheshti University and the RUDN University Strategic Ac-
ademic Leadership Program (A. Shaabani).
1
13
J¼3 Hz, HAr), 8.73 (bs, 1H, NH). C NMR
d (125 MHz, DMSO) 153.80,
8

M.T. Nazeri, A.B. Nowee, S. Javanbakht et al.
Tetrahedron 91 (2021) 132243
Appendix A. Supplementary data
[30] A. Shaabani, R. Mohammadian, R. Afshari, S.E. Hooshmand, M.T. Nazeri,
S. Javanbakht, Mol. Divers. (2020) 1e66.
[
[
31] Z.-Y. Gu, J.-H. Li, S.-Y. Wang, S.-J. Ji, Chem. Commun. 53 (2017) 11173e11176.
32] U. Kazmaier, C. Hebach, Synlett 2003 (2003) 1591e1594.
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2021.132243.
[33] D.S. Ryabukhin, A.D. Lisakova, A.S. Zalivatskaya, I.A. Boyarskaya, G.L. Starova,
R.E. Trifonov, V.A. Ostrovskii, A.V. Vasilyev, Tetrahedron 74 (2018)
1
838e1849.
34] S. Ramezanpour, S. Balalaie, F. Rominger, H.R. Bijanzadeh, Tetrahedron 69
2013) 3480e3485.
[35] S.J. Welsch, C. Kalinski, M. Umkehrer, G. Ross, J. Kolb, C. Burdack,
L.A. Wessjohann, Tetrahedron Lett. 53 (2012) 2298e2301.
[36] O. García Manche n~ o, C. Bolm, Org. Lett. 9 (2007) 2951e2954.
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