A new method of synthesis of substituted 1-(1H-imidazole-4-yl)-1H-1,2,3-triazoles and their fungicidal activity

Article abstract of DOI:10.1016/j.tet.2017.12.043

Based on the deoxygenation reaction of 1-(1-tert-butyl-3-nitroazetidine-3-yl)-1H-1,2,3-triazoles a new method for the synthesis of substituted 1-(1H-imidazole-4-yl)-1H-1,2,3-triazoles has been developed. Fungicidal activity of these compounds has been investigated at a range of phytopathogenic fungi.

Full text of DOI:10.1016/j.tet.2017.12.043

Accepted Manuscript
A new method of synthesis of substituted 1-(1H-imidazole-4-yl)-1H-1,2,3-triazoles and
their fungicidal activity
Mikhail V. Dubovis, Gennady F. Rudakov, Alexander S. Kulagin, Kseniya V.
Tsarkova, Sergey V. Popkov, Alexander S. Goloveshkin, Georgiy V. Cherkaev
PII:
S0040-4020(17)31324-8
10.1016/j.tet.2017.12.043
TET 29199
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 16 August 2017
Revised Date: 16 December 2017
Accepted Date: 21 December 2017
Please cite this article as: Dubovis MV, Rudakov GF, Kulagin AS, Tsarkova KV, Popkov SV,
Goloveshkin AS, Cherkaev GV, A new method of synthesis of substituted 1-(1H-imidazole-4-
yl)-1H-1,2,3-triazoles and their fungicidal activity, Tetrahedron (2018), doi: 10.1016/j.tet.2017.12.043.
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A new method of Synthesis of Substituted 1-
(1H-imidazole-4-yl)-1H-1,2,3-triazoles and
their fungicidal activity
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Mikhail V. Dubovisa*, Gennady F. Rudakova, Alexander S. Kulagina, Kseniya V. Tsarkovaa, Sergey V. Popkova,
Alexander S. Goloveshkina, Georgiy V. Cherkaevb
D. Mendeleev University of Chemical Technology of Russia, Miusskaya sq. 9, 125047,Moscow, Russia
N
R
N
R
N
N
R
N
N
O2N
N
P(OEt)3
C6H6, t
DDQ
N
N
CH2Cl2
N
N
N
N
N

ACCEPTED MANUSCRIPT
Graphical Abstract
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A new method of synthesis of substituted 1-
(1H-imidazole-4-yl)-1H-1,2,3-triazoles and
their fungicidal activity
Leave this area blank for abstract info.
Mikhail V. Dubovisa*, Gennady F. Rudakova, Alexander S. Kulagina, Kseniya V. Tsarkovaa, Sergey V. Popkova,
Alexander S. Goloveshkina, Georgiy V. Cherkaevb
D. Mendeleev University of Chemical Technology of Russia, Miusskaya sq. 9, 125047,Moscow, Russia
N
R
N
R
N
N
R
N
N
O2N
N
P(OEt)3
C6H6, t
DDQ
N
N
CH2Cl2
N
N
N
N
N

1
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Tetrahedron
journal homepage: www.elsevier.com
A new method of synthesis of substituted 1-(1H-imidazole-4-yl)-1H-1,2,3-
triazoles and their fungicidal activity
Mikhail V. Dubovisa*, Gennady F. Rudakova, Alexander S. Kulagina, Kseniya V. Tsarkovaa, Sergey V.
Popkova, Alexander S. Goloveshkina, Georgiy V. Cherkaevb
a D. Mendeleev University of Chemical Technology of Russia, Miusskaya sq. 9, 125047,Moscow, Russia
b Enikolopov Institute of Synthetic Polymeric Materials, a foundation of the Russian Academy of Sciences, Profsoyuznaya st. 70117393 Moscow, Russia
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Based on the deoxygenation reaction of 1-(1-tert-butyl-3-nitroazetidine-3-yl)-1H-1,2,3-triazoles a
new method for the synthesis of substituted 1-(1H-imidazole-4-yl)-1H-1,2,3-triazoles has been
developed. Fungicidal activity of these compounds has been investigated at a range of
phytophatogenic fungi.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
Deoxygenation
2,5-Dihydro-1H-imidazol
1,2,3-Triazole
Nitro group
Triethylphosphite
Introduction
contain 1H-imidazole and monosubstituted or 1,4-disubstituted
1H-1,2,3-triazole rings. 1,2,3-Triazole moieties are interesting
molecules for this purpose. They are stable to metabolic
degradation and are capable of hydrogen bonding which can be
favorable in binding biomolecular targets and for solubility [6,7].
Imidazoles are an important class of heterocycles. Their
chemical and biological importance has been well investigated
[1]. Many bioactive heterocyclic compounds and natural products
containing this cycle show a wide spectrum of pharmacological
activities such as anticancer, antiviral, antibacterial,
antitubercular, anti-inflammatory and antidiabetic [2]. The
imidazole ring is a frequent structural unit found innumerous
natural products and biologically active compounds [3].
The 1,2,3-triazole moiety is not present in nature although
synthetic molecules containing 1,2,3-triazole unit show diverse
biological activities including antibacterial, herbicidal,
fungicidal, antiallergic and anti-HIV [4].
Antifungal agents including imidazole and triazole rings such
as bifonazole, clotrimazole, ketoconazole and fluconazole are
widely used in clinical practice for fungal infection treatment
(Figure 1) [5]. It is commonly considered that the imidazole ring
could efficiently coordinate with the iron(II) ion of heme to
restrain the biosynthesis of ergosterol thus inhibiting the growth
of fungi [6].
We studied the structures of different antifungal drugs both in
combinations with halogen-substituted aromatic residues and
with each other and found out that most of the combinations
contain 1H-imidazole as well as 1H-1,2,4-triazole. However
there is no information about the system that contains 1,2,3-
triazole in the fourth position of the imidazole ring. In this work
we focused our attention on the creation of new molecules which
R1
N
Cl
R
N
()
n N
N
O
N
N
N
O
R2
X
O
R
N
R2
R1
Cl
Cl
Cl
R1 = H, R2 = o-ClPh R1 = H, R2 = m-ClPh
R = H, X = CH
Aliconazole
R = Cl, X = NOCH2
n = 0, R = Cl
Climbazole
n = 1, R = H
Valconazole
Clotrimazole
R1 = F, R2 = o-FPh
Croconazole
R1 = SMe, R2 = n-Bu
Oxiconazole
Flutrimazole
R1 = Ph, R2 = H
Neticonazole
Bifonazole
Figure 1 Some imidazole-based antifungal compounds
The number of methods and reagents that allow the direct
introduction of 1H-1,2,3-triazole ring in the fourth position of the
1H-imidazole are limited by only 2- and 5- substituted
imidazoles [8]. The preparation method of these molecules
involves using n-buthyllithium or diazonium ion which is
impossible in our conditions.
In the current work we developed a new and original way to
synthesize
1-(1H-imidazole-4-yl)-1H-1,2,3-triazoles
(1a-k)
(Figure 2).

2
Tetrahedron
N
formation of trimethylsilyl-substituted triazole according to NMR
ACCEPTED MANUSCRIPT
R
N
spectroscopy and LC-MS. The 1,4-disubstituted triazoles 6c-k
N
were obtained by addition of 3-azido-3-nitro-azetidine 5 to
substitute acetylenes in the presence of ascorbic acid and
copper(II) sulphate. 1-(1-tert-Butyl-3-nitroazetidine-3-yl)-4-
trimethyl-silyl-1H-1,2,3-triazole 6b was synthesized from 3-
azido-3-nitro-azetidine 5 and TMS-acetylene without a catalyst
[15] (Table 1):
N
N
1
R = H (1a); SiMe3 (1b); cyclo-Pr (1c), C6H5 (1d), 2-FC6H4 (1e),
2-ClC6H4 (1f), 3-ClC6H4 (1g), 2,4-Cl2C6H3 (1h),
4-CF3C6H4 (1i), 3-CF3C6H4 (1j), 3-CH3OC6H4 (1k)
Table 1. Synthesis of substituted azetidines
Figure 2. Substituted1-(1H-imidazole-4-yl)-1H-1,2,3-triazoles.
NO2
N
NO2
N3
SiMe3
R
NO2
N
N
N
N
CuSO4, Ascirbic acid
CuSO4, K2CO3, Ascorbic acid
N
N
N
R
THF/H2O, 2-6h
N
MeOH/H2O, 24h
Results and Discussion
Several methods are currently known for deoxygenation of
6a
5
6c-k
Yield,
[%][a]
Entry
1
Acetylene
Time, [h]
Product
primary and secondary nitroalkanes with trivalent phosphorus
compounds, leading to the formation of nitriles [9], amines [10],
and derivatives of oximes [11]. Recently we have shown that
substituted 1-(5-nitro-1,3-dioxan-5-yl)-1H-1,2,3-triazoles easily
transform into a new 4,7-dihydro-1,3,5-dioxazepine heterocyclic
system by heating with triethyl phosphite [12]. The positive
results of this investigation did allow us to use 1-(1-tert-butyl-3-
nitroazetidine-3-yl)-1H-1,2,3-triazoles 6a-k as starting materials
for the 1-(1H-imidazole-4-yl)-1H-1,2,3-triazoles 1a-k synthesis.
3-Azido-3-nitro-azetidine 5 was used as a key intermediate for
the synthesis of 1-(1-tert-butyl-3-nitroazetidine-3-yl)-1H-1,2,3-
triazoles 6a-k. The heminal nitroazide 5 was obtained by a
previously developed scheme with nitromethane, formaldehyde
and tert-butyl amine [13]. The main method of the preparation of
α-nitroazides consists of oxidative coupling of the azide anion
with nitroalkane salts. The reaction is performed in an alkaline
medium in the excess of azide under the conditions of
electrochemical and chemical oxidation [14]. In the latter case,
ammonium persulfate or potassium ferricyanide are most widely
used as oxidants. In the current work the nitroazetidine salt was
obtained in situ using retro-Henry reaction from 4 (Sheme 1).
Potassium ferricyanide was used as an oxidant.
NO2
N
N
N
86[b]
78[c]
50[d]
74[d]
75[d]
77[d]
93[d]
Si
N
N
N
24
48
3
6a
NO2
N
N
N
Si
Si
2
6b
NO2
N
N
N
3
6c
NO2
N
N
N
N
N
4
2
N
N
N
6d
NO2
N
F
F
N
5
6
7
2
6e
NO2
N
Cl
Cl
N
4
6f
NO2
N
N
N
N
Cl
N
O2N
OH
Cl
4
N
N
N
NaOH
HCl
NH2
+
+
6g
CH3NO2
CH2O
H2O, 60oC, 6h
N
O
CH3OH, reflux, 8h
Cl
NO2
N
Cl
N
2, 94%
58[d]
Cl
8
9
3
4
6h
Cl
O2N
O2N
O2N
N3
NaN3, NaOH
K3[Fe(CN)6]
NO2
OH
N
H
DIAD, PPh3
N
OH
N
F
F
HCl
87[d]
THF, 50oC, 4h
N
N
H2O, 5h
F
HCl
HO
3, 95%
F
6i
F
F
4, 75%
5, 70%
NO2
N
N
N
F
F
N
F
N
N
Scheme 1. The synthesis of 3-Azido-1-tert-butyl-3-nitro-azetidine.
F
F
10
11
4
6
F
81[d]
6j
As it was shown in our previous work [15] heterocyclic α-
nitroazides are highly reactive in 1,3-dipolar cycloaddition to
terminal acetylenes under thermal cyclization conditions giving a
mixture of 1,4- and 1,5-triazoles regardless of the structure of the
aliphatic heterocycle. Performing the cyclization in the presence
of copper(I) salts resulted in a selective formation of 1,4-
disubstituted triazoles.
NO2
N
N
O
O
81[d]
6k
[a] Isolated yield. [b] Reaction conditions: K2CO3 (1.25 mmol), ascorbic acid (0.2
mmol), TMSA (1.2 mmol), CuSO4·5H2O (0.1 mmol), 3-azido-1-tert-butyl-3-nitro-
azetidine 5 (1 mmol), MeOH (10 ml), H2O (5 ml), 24h, rt. [c] Reaction conditions:
3-azido-1-tert-butyl-3-nitro-azetidine 5 (1 mmol), TMSA (10 mmol), CH2Cl2 (10
ml), reflux 48h. [d] Reaction conditions: Ascorbic acid (0.5 mmol), acetylene (1.05
In the current work we used both 1-substituted and 1,4-
disubstituted 1,2,3-triazoles. The monosubstituted triazole 6a was
synthesized from the 3-azido-3-nitro-azetidine
5
and
trimethylsilyl acetylene (TMS-acetylene). The reaction was
performed at room temperature in aqueous methanolic medium in
the presence of copper(II) sulfate, ascorbic acid, and potassium
carbonate [16]. The process was found to be selective without
mmol), CuSO4·5H2O (0.15 mmol), 3-azido-1-tert-butyl-3-nitro-azetidine
mmol), THF (10 ml), H2O (5 ml), 2-6h, rt.
5 (1

3
All compounds 6a-k are colorless, crystalline solids, with
their infrared spectra contained bands of asymmetric (1564-1589
cm-1) and symmetric (1333-1367 cm-1) vibrations of the nitro
group. All 1H-1,2,3-triazoles 6a-k gave clear mass spectral
signals of positively charged ions [M+H]+ (100%) under the
conditions of chemical ionization. Also every molecule showed
partial nitrogen extrusion and an intensive [M+H-N2]+ ion signal
conditions. In the LC-MS of the minor product 8d (rt 18.48
ACCEPTED MANUSCRIPT
min) was found stable ion which corresponds phenyl-1,2,3-
triazole (m/z (Irel, %) 269(8) [M]·+; 254 (21) [M-CH3]·+; 145 (71)
[M-123]·+).
The use of P(OPh)3 and PClPh2 in benzene gave no reaction.
We also found that the efficiency of triethylphosphite (P(OEt)3)
and triphenylphosphine (PPh3) in the boiling benzene is similar,
but the appropriate compound yield is lower with
triphenylphosphine. The LC-MS method showed that heating the
6d with triphenylphosphine leads to partial degradation of the
final compound with formation of monosubstituted 1H-1,2,3-
triazole. The best yield after a reasonable reaction time was
achieved using P(OEt)3 (8 mmol) in boiling benzene. We did not
find any molecular degradation and found that the reaction
selectivity was high and the second isomer was not obtained. We
also tried to use lower amounts of P(OEt)3, but when 2 mmol of
P(OEt)3 were used, the transformation proceeded much more
slowly and the starting material conversion was incomplete,
approximately 5 percent of azetidine did not react. Increasing the
amount of P(OEt)3 led us to a decrease of the reaction time from
48 to 10 hours.
1
(%), which characterizes for 1H-1,2,3-triazoles [17]. H NMR
spectra of these molecules are characterized by a large spin-spin
doublet type coupling constant of about 9.8 Hz and untypical
4.20 and 4.37 ppm values for CH2 protons. These are not regular
values for these molecules [18]. Apparently it can be explain to
the presence of an electron-withdrawing nitro group [15].
A key step of our investigation was deoxygenation of these
substituted azetidines 6a-k. In this work we studied the
possibility of the nitro group transformation by the action of
trivalent phosphorus compounds.
We began our research work by searching for an appropriate
phosphorus agent and a solvent for the deoxygenation reaction.
1-(1-tert-Butyl-3-nitro-azetidin-3-yl)-4-phenyl-1H-1,2,3-triazole
(6d) was chosen as a model compound. To find out the optimal
reaction conditions
a
range of phosphorus reagents
We also tested different solvents. In toluene and dioxane, the
reaction finished in 6 and 10 hours respectively, but there was
found the partial degradation product and the target compound
(i.e. 7d) could not be isolated in a good yield. In THF, starting
material conversion was incomplete and the yield did not exceed
58 percent. Although, using DCE led us to a good yield, but we
chose benzene that is the solvent the most frequently used in the
deoxygenation reaction.
Thus, the reaction of azetidine 6d with P(III) was found to
produce the maximal yield with 8 mmol of P(OEt)3 in boiling
benzene with the reaction time of 10 hours. Having identified
these optimal conditions for substance 6d we carried out
deoxygenation reactions of triethylphosphite with other
azetidines 6a-k. The reaction progress was monitored by LC-MS
and GC-MS analysis. The target products were isolated by
column chromatography after the removal of solvent (Table 3):
(triethylphosphite, triphenylphosphine, triphenylphosphite and
chlorodiphenylphosphine), solvents [toluene, benzene, dioxane,
1,2-dichloroethane (DCE) and tetrahydrofuran (THF)] and
amounts of the phosphorus reagents were tested (Table 2).
Table 2. Reaction of the nitro compound 6d with various phosphorus agents.
N
NO2
N
N
N
N
N
N
P (III)
t0
N
N
N
+
Ph
N
Ph
N
N
N
Ph
6d
8d
7d
Phosphorus
reagent
Amount of
P(III) [mmol]
Solvent
Reaction time
[h]
Yield of 7d
[%][a]
[P(III)]
P(OEt)3
P(OEt)3
P(OEt)3
P(OEt)3
P(OEt)3
P(OEt)3
P(OEt)3
P(OEt)3
P(OEt)3
PPh3
2
4
benzene
benzene
benzene
benzene
benzene
toluene
dioxane
DCE
48
30
14
10
10
6
72
83
Table 3. Synthesis of substituted 1-(1-tert-butyl-2,5-dihydro-1H-imidazole-4-yl)-1H-
1,2,3-triazoles 7a-k.
NO2
N
N
N
6
85
N
N
N
P(OEt)3
N
R
N
R
Benzene, reflux
10-16h
N
8
88
6a-k
7a-k
10
8
86
70
Starting
material
8
10
15
18
20
60
60
75
Entry
1
Time, [h]
14
Product
Yield, [%][a]
8
83
NO2
N
N
N
N
N
N
N
8
THF
58
71
N
N
N
7a
6a
NO2
2
benzene
benzene
benzene
60
N
N
N
N
N
N
N
P(OPh)3
PClPh2
2
trace
trace
Si
2
N
Si
13
87
2
7b
6b
NO2
N
N
N
N
N
N
N
N
[a] Isolated yield. Reaction conditions: 3 ml of solvent, reflux.
N
3
4
12
10
95
88
N
N
N
6c
The reaction progress was monitored by LC-MS and GC-MS
analysis. Besides triethylphosphite and triethylphosphate two
products were found in the reaction mixture by GC-MS method
with very close retention times (rt 18.35 and 18.48 min) and m/z
269. That corresponds to substituted 2,5-dihydro-1H-imidazoles
(7d and 8d). The major product 7d (rt 18.35 min) fragmented
with ejection of N2 (m/z (Irel, %) 269(5) [M]·+, 254 (40) [M-
CH3]·+, 226 (33) [M-CH3-N2]·+]) in the electron impact
7c
N
N
N
NO2
N
N
N
6d
7d

4
Tetrahedron
ACCEPTED MANUSCRIPT
F
NO2
N
N
Figure 3 Deoxygenation mechanism
N
N
N
F
N
N
N
The 2,5-dihydroimidazoles 7a-k are colorless, crystalline
solids. The infrared spectra of these compounds lacked
vibrational bands of nitro group while a strong band appeared in
the region of C=N bond vibration (1691-1700 cm-1). All
compounds gave clear mass spectral signals of positively charged
ions [M+H]+ (100%) under the conditions of chemical ionization.
Also every molecule showed partial nitrogen extrusion and an
5
6
10
10
62
N
N
N
6e
7e
Cl
NO2
N
N
N
N
Cl
N
N
N
68
N
N
6f
7f
N
N
N
Cl
NO2
N
intensive [M+H-N2]+ ion signal (%). The downfield region of 13
С
N
N
Cl
7
8
11
12
66
90
N
NMR spectrum contained resonance signals due to vicinal
triazole carbon atoms (average values are 120 and 140 ррm) and
another signal was found at 157 ppm. 2,5-Dihydroimidazole
proton spectra should be noted as methylene protons which are
characterized by a big spin-spin triplet type coupling constant of
7g
6g
Cl
N
N
N
NO2
N
N
N
N
Cl
N
N
Cl
N
N
4
7h
6h
about JH,H = 4.8-5.0 Hz. The obtained results indicated the
Cl
difference between hybridization of the carbon atoms adjacent to
methylеne groups (CH2N) and hybridization of the carbon atom
in the iminium fragment (С=N) in the structure. Finally the
structure of these new heterocyclic compounds was confirmed by
X-ray structural analysis using the example of 1-(1-tert-butyl-
2,5-dihydro-1H-imidazole-4-yl)-4-phenyl-1H-1,2,3-triazole 7d
(Figure 4).
NO2
N
N
N
N
N
N
F
N
9
10
72
F
F
6i
F
7i
F
F
F
NO2
N
N
N
N
N
F
N
N
F
N
N
F
N
F
N
N
10
10
11
75
61
F
6j
7j
N
NO2
N
O
N
N
N
O
N
11
6k
7k
[a] Yield isolated
Deoxygenation reactions in the studied series of compounds
were apparently stepwise and occurred analogously to
deoxygenation of geminal chloronitrocycloalkanes with
triphenylphosphine [19]. The performed study showed that the
reaction of 6a-k with triethylphosphite (P(OEt)3) occurred
without noticeable heat effect or changes of color of the solution
which was not specific to deoxygenation of nitroso compounds.
Any attempts to detect nitroso intermediate 1-(1-tert-butyl-3-
nitrozoazetidine-3-yl)-1Н-1,2,3-triazoles by chromatographic
methods also were not successful. With an insufficient amount
and gradual addition of triethylphosphite the target 2,5-
dihydroimidazoles 7a-k were detected immediately. Thus, the
most probable mechanism of azetidine ring expansion was
through the stage of ion pair; this can explain the second isomer 8
and partial degradation of some molecules (Figure 3):
Figure 4. X-ray crystallographic structure of 1-(1-tert-butyl-2,5-dihydro-1H-
imidazol-4-yl)-4-phenyl-1H-1,2,3-triazole 7d. Atoms are represented by spheres
indicating their isotropic thermal displacements (ρ = 50%). Key bond lengths (Å) and
angels [º] for 2,5-dihydro-1H-imidazol cycle: C12-N13 1.268(5), C12-C14 1.511(5),
N13-C15 1.456(5), C15-N16 1.457(5), C14-N16 1.467(5), N13-C12-C14 113.96, C12-
C14-N16 98.84, C14-N16-C15 108.00, N16-C15-N13 108.87, C15-N13-C12 106.14.
For details see CCDC 1554112.
The corresponding representation and important geometrical
parameters are shown in Figure 4. The torsion angle C(15)-
N(13)-C(12)-C(14) is (-16.86). It means, that the structure of 2,5-
dihydro-1H-imidazole cycle is not planar. There is no
conjugation between the C(12)=N(13) bond and the
phenyltriazole ring, because the C(12)–N(10) bond is single (its
length is 1.462(4) Å), while the C(12)=N(13) is a double bond
(its length is 1.268(5) Å), which is typical for 4-imidazoles and
N-imidoylbenzotriazole compounds [20, 21, 22]. A similar
picture was observed for the 4,7-dihydro-1,3,5-dioxazepine
heterocyclic system [12].
At the next step of our research we tried to transform 2,5-
dihydro-1H-imidazoles 7a-k into 1H-imidazoles 1a-k under the
influence of different oxidants. To screen the optimal reaction
conditions for this process 1-(1-tert-butyl-2,5-dihydro-1H-
imidazol-4-yl)-4-phenyl-1H-1,2,3-triazole 7d was chosen as the
model compound. Various oxidants (O2 (air), H2O2, MnO2,
DDQ,) and solvents (acetonitrile, THF, CH2Cl2) were tested to
find the optimal conditions (Table 4):
OEt
OEt
OEt
P
+
P
EtO
R
N
R
N
R
OEt
-
EtO
P(OEt)3
O -
+
O
O
+
O2N
N
N
N
N
N
N
N
O
N
N
N
N
N
-
P(OEt)3
PO(OEt)3
OEt
R
N
N
R
P
OEt
O
N
Table 4. Reaction of the 1-(1-tert-butyl-2,5-dihydro-1H-imidazol-4-yl)-4-phenyl-1H-
1,2,3-triazole 7d with various oxidant agents
OEt
:
N
N
N
N
N
+
-
N
PO(OEt)3
N
N
N
N
N
N
N
N
oxidant
solvent
N
Ph
Ph
N
N
R
7d
N
1d
N
N
N
N
N
N
+
R
N
N
N

5
N
N
N
N
N
ACCEPTED MANUSCRIPT
N
N
N
Amount of oxidant,
mmol
Reaction
time, h
Yield,
[%][a]
F
N
F
Oxidant
O2 (air)
Solvent
CH3CN
9
1
1
1
60
74
78
N
F
F
F
7i
F
F
F
1i
-
10
24
48
1
53
F
H2O2
MnO2
DDQ
10
20
2
CH3CN
THF
27
50
95
N
N
N
N N
F
N
N
F
F
N
N
N
10
N
CH2Cl2
7j
1j
N
N
O
[a] Yield isolated
N
N
N
N
O
N
N
11
N
7k
1k
We found that the 2,5-dihydro-1H-imidazoles 7a-k are not
stable in air and eventually these compounds transform into 1H-
imidazoles. Thus, we decided to bubble air into the reaction
mixture of 7d in acetonitrile but this process gave no good
results. We also used hydrogen peroxide and MnO2 in
acetonitrile and THF respectively but the final compound (i.e.,
1d) was not isolated in a good yield. The best result after 1 hour
was achieved using DDQ (2 mmol) in CH2Cl2. Having identified
these optimal conditions for substance 7d, we obtained new
series of 1-(1-tert-butyl-1H-imidazole-4-yl)-1H-1,2,3-triazoles
1a-k (Table 5):
[a] Isolated yield.
The 1H-imidazoles 1a-k are colorless, crystalline solids. All
compounds gave clear mass spectral signals of positively charged
ions [M+H]+ (100%) under the conditions of chemical ionization.
The downfield region of 13С NMR spectrum contained resonance
signals due to vicinal triazole carbon atoms and carbon signals
typical for 1H-imidazole. In the proton spectrum we registered
imidazole proton signals with a typically low spin-spin coupling
constant of 1.6 Hz [23]. The structure of these new heterocyclic
compounds was finally confirmed by X-ray structural analysis
using the example of 1-(1-tert-butyl-1H-imidazole-4-yl)-4-
phenyl-1H-1,2,3-triazole 1d (Figure 5).
Table 5. Synthesis of substituted 1-(1-tert-butyl-1H-imidazole-4-yl)-1H-1,2,3-triazoles
1a-k.
N
N
N
N
N
N
N
N
DDQ
R
R
N
N
CH2Cl2
7a-k
1a-k
Time,
[h]
Figure 5. X-ray crystallographic structure of 1-(1-tert-butyl-1H-imidazol-4-yl)-4-
phenyl-1H-1,2,3-triazole 1d. Atoms are represented by thermal displacement ellipsoids
(ρ = 50%). Key bond lengths (Å) and angels [º] for 2,5-dihydro-1H-imidazol cycle: C12-
N13 1.357(2), C12-C14 1.356(2), N13-C15 1.316(2), C15-N16 1.344(2), C14-N16
1.380(2), N13-C12-C14 111.82, C12-C14-N16 104.73, C14-N16-C15 106.43, N16-C15-
N13 112.92, C15-N13-C12 104.10. For details see CCDC 1554111.
Entry
Starting material
Product
Yield, [%][a]
N
N
N N
N
N
N
N
N
1
1
1
1
99
99
N
N
N
7a
1a
N
N
N
N
N
N
N
N
Si
Si
2
N
Corresponding representation and important geometrical
parameters are shown in Figure 5. The structure is absolutely
planar. The torsion angle C(15)-N(13)-C(12)-C(14) is (-0.1).
Thus, the bond lengths and angles of the imidazole ring are the
same for dimensions of imidazole [24].
1b
7b
N
N
N
N
N
N
N
N
N
N
N
3
92
95
N
7c
1c
N
N
N
N
The conformation of the reaction mechanism was obtained by
deoxygenation of 6a with 2 moles of P(OEt)3 in boiling benzene
(Scheme 2):
N
N
4
5
1
1
N
7d
1d
F
N
N
N
NO2
F
N
N
N
N
N
N
N
N
N
N
N
N
P(OEt)3
N
N
N
N
+
N
N
N
N
85
92
Benzene, reflux
36h
N
7e
7a
8a
1e
6a
Cl
DDQ
CH2Cl2
N
N
Cl
N
N
N
N
N
N
N
6
1
N
N
N
N
N
N
7f
1f
N
N
N
+
N
N
N
N
N
N N
Cl
Cl
N
N
N
1a
9a
N
N
7
8
1
1
93
95
N
N
N
Scheme 2. Deoxygenation of 6a with 2 moles of P(OEt)3.
7g
1g
Cl
Cl
N
N
N
N
N
It was found by GC-MS method that besides the starting material
6a there were only triethylphosphate, diethylphosphonate and
two products with similar m/z 193, which corresponds to 7a and
N
N
Cl
Cl
7h
1h

6
Tetrahedron
ACCEPTED MANUSCRIPT
8a. It should be noted that nitroazetidine 6a or others azetidine
majority of fungi at concentration 30 ꢀg mL-1. The modification
cycle transformation products were not found in the reaction
mixture. When the reaction was completed benzene and
triethylphosphate were evaporated under reduced pressure. The
crude product was dissolved in CH2Cl2 and DDQ was added.
After the reaction was completed (TLC control) the mixture of 1a
and 9a was separated by RP-HPLC to afford 1a (31%) as a white
solid and 9a (23 %) as a white solid.
of the triazole ring showed that the fungicidal activity increased
in this row. The compound 1d showed much more activity than
its non-substituted or alkyl-substituted analogs. Its impact on the
agricultural plant scab R. solani was higher than triadimefon and
equivalent in activity to triadimefon towards plant pathogenic
fungus S. sclerotiorum and B. sorokiniana. Further modification
of the triazole ring of the halogen-substituted aromatic residues
showed an increase of fungicidal activity of the final compounds.
So 1e, 1f, 1i and 1j had equal activity against Rhizoctonia solani,
Venturia inaequalis and Bipolaris sorokiniana fungus like
triadimefon. However the 1g and 1h compounds showed much
more activity than the triadimefon against agricultural plant scab
R. solani and the same activity as the triadimefon against the
other fungi. And finally the introduction of metoxy group in
phenyl ring decreased the fungicidal activity of compound 1k.
Fungicidal activity
The 1-(1H-imidazole-4-yl)-1H-1,2,3-triazoles 1a-k were
tested in vitro for the fungicidal activity according to a very
common
conventional
procedure
[25]
with
seven
phytopathogenic fungi from different taxonomic classes: R.s. –
Rhizoctonia solani, F.o. – Fusarium oxysporum, F.m. – Fusarium
moniliforme, F.g. – Fusarium graminearum, S.s. — Sclerotinia/
sclerotiorum, V.i. – Venturia inaequalis, B.s. – Bipolaris
sorokiniana (Table 6). The effect of the tested compounds on the
mycelium radial growth in the potato-saccharose agar with
widely used fungicide triadimefon as a reference compound was
measured in a 30 ꢀg mL-1 concentration.
Conclusions
The current work first showed the possibility of
deoxygenation of the nitrogroup by the action of trivalent
phosphorus compounds in the 1-(1-tert-butyl-3-nitroazetidine-3-
yl)-1Н-1,2,3-triazole row. We found that the 1-(1-tert-butyl-2,5-
dihydro-1H-imidazole-4-yl)-1H-1,2,3-triazoles represent useful
intermediates for the synthesis of 1-(1-tert-butyl-1H-imidazole-4-
yl)-1H-1,2,3-triazoles. A series of compounds showed that some
of those imidazoles demonstrated a satisfactory fungicidal
activity and could be the prototypes for the synthesis of new
bioactive compounds.
Table 6. Fungicidal activity of the synthesized copmpounds 1a-k
№
Mycelium growth inhibition, % (C = 30 ꢀg mL-1)
R.s.
23
F.o.
13
F.m.
F.g.
20
S.s.
V.i.
1
B.s.
Experimental Section
1a
1b
1c
1d
1e
1f
3
3
1
General Remarks: IR spectra were recorded on a Thermo
Nicolet 360 FTIR instrument in KBr pellets. Н and 13С NMR
1
53
35
55
49
45
78
88
46
46
41
43
14
12
17
28
29
47
60
22
11
19
60
11
20
48
53
29
36
65
33
17
33
79
20
14
44
53
57
68
66
26
14
51
78
10
15
66
29
16
16
27
10
5
3
2
spectra were obtained with Varian Mercury Plus instrument (400
and 100 MHz, respectively) in DMSO-d6 and CDCl3. The LC-
MS analysis was performed on Thermo Finnigan Surveyor MSQ
with gradient elution and chemical ionization at atmospheric
pressure with simultaneous recording of positive and negative
ions. The GS-МS was performed on Trace 1310/ISQ-LT
(Thermo Scientific) using a capillary column TG-SQC (15 m,
0.25 mm, 0.25 ꢀm). High-resolution ESI mass spectra (HRMS)
were recorded on a Bruker micrOTOF II instrument. Elemental
analysis was performed on a Perkin Elmer 2400 Series II CHN-
analyzer. Melting points were determined on a Boetius hot stage.
Durasil H silica gel (40-63 ꢀm) was used for purification of the
obtained compounds by column chromatography. Compounds
1a, 9a and 9d also were purified by preparative RP-HPLC on
Gilson Combinatorial Chromatography System using 100×30 00
mm 10 micron Phenomenex Gemini column and flow rate of 30
mL/minute. Separations were accomplished with a gradient of 5-
40% acetonitrile in water containing ammonium acetate and
ammonium water (pH=9) over 15 minutes. TLC was carried out
on precoated silica plates (Sorbfil UV-254), which were
visualized with UV light and/or staining with ninhydrin solution.
All solvents and reagents for the reactions were used without
20
15
45
36
53
68
70
38
35
65
44
30
42
45
62
49
56
25
33
41
1g
1h
1i
1j
1k
11
47
Triadi
mefon
further
purification
or
drying.
Phenylacetylenes,
trimethylsilylacetylene and triethylphosphite used in this work
were purchased from Sigma-Aldrich. Compounds 2, 3, 4, 5 [13]
and 6b [15] were synthesized according to published procedures.
3-Azido-1-tert-butyl-3-nitro-azetidine (5): (1-tert-butyl-3-
nitro-azetidin-3-yl)-methanol 4 (1.9 g 10 mmol) was added to a
solution of NaOH (2.0 g, 50 mmol) in water (10 mL). The
mixture was stirred at room temperature for 30 min; then treated
with a solution of NaN3 (3.25 g, 50 mmol) in water (10 mL) and
poured into a vigorously stirred solution of K3Fe(CN)6 (16.46 g,
50 mmol) in water (70 mL). The reaction mixture was stirred for
5 h at room temperature and extracted with EtOAc (3×20 mL).
[a] R.s. – Rhizoctonia solani, F.o. – Fusarium oxysporum, F.m. – Fusarium moniliforme,
F.g. – Fusarium graminearum, S.s. — Sclerotinia/ sclerotiorum, V.i. – Venturia inaequalis,
B.s. – Bipolaris sorokiniana
The first three members (1a, 1b and 1c) in the sequence of the
1-(1H-imidazole-4-yl)-1H-1,2,3-triazoles 1a-k demonstrated low
fungicidal activity. Their potency is much lower than the
commercial fungicide (triadimefon) with respect to all
phytopatogens – they do not inhibit the mycelium growth in the

7
The combined extract was washed with water and dried over
Na2SO4. The solvent was removed at reduced pressure, the
residue was purified by flash chromatography (EtOAc/n-hexane,
1:1). To afford the pure 5 (1.55 g, 78%), as a light yellow oil,
and the residue was purified by flash chromatography
ACCEPTED MANUSCRIPT
(EtOAc/n-hexane, 2:3) to give the desired products 6c-k as
colorless solids.
1-(1-tert-Butyl-3-nitro-azetidin-3-yl)-4-cyclopropyl-1H-
º
1
m.p. 3-5 C; H NMR (400 MHz, DMSO-d6, 50ºC): δ= 0.96 (s,
1,2,3-triazole (6c): White solid (50%), m.p. 62-64ºC. H NMR
(400 MHz, DMSO-d6, 50ºC): δ= 0.83-0.77 (m, 2H, cyclopropyl),
0.98 (s, 9H, CH3), 1.00-0.94 (m, 2H, CH2, cyclopropyl), 2.08-
1.98 (m, 1H, CH, cyclopropyl), 4.08 (d, JH,H=10.2 Hz, CH2-N),
1
2
9H, CH3), 3.50 (dd, JH,H=8.3 Hz, 4JH,H=1.7 Hz, 2H, CH2), 3.89
2
(dd, JH,H=8.3 Hz, 4JH,H=1.7 Hz, 2H, CH2). 13C NMR (100 MHz,
DMSO-d6, 50ºC): δ= 23.5 (CH3), 51.7 (C-CH3), 55.3 (CH2), 92.5
(C-NO2). IR (KBr): ν= 1353, 1558 (NO2), 2128 (N3), 2968 (C-H)
cm-1. MS (APCI, 30 EV), m/z (Irel,%): 200 (100) [М+Н]+.
C7H13N5O2: C 42.20, H 6.58, N 35.16; found C 42.11, H 6.50, N
35.06.
2
2
4.29 (d, JH,H=10.2 Hz, 2H, CH2-N), 8.36 (s, 1H, H-5 triazole)
ppm. 13C NMR (100 MHz, DMSO-d6, 50ºC): δ= 6.4 (CH-
cyclopropyl), 7.8 (CH2-cyclopropyl), 23.6 (CH3), 52.1 (C-CH3),
55.6 (CH2-N), 89.6 (C-NO2), 121.9 (C-5 triazole), 149.9 (C-4
triazole) ppm. IR (KBr): ν= 1365, 1565 (NO2), 2963 (C-H
aliphatic), 3096 (C-H Ar) cm-1. MS (APCI, 30 EV), m/z (Irel,%):
265 (100) [М+Н]+. C12H19N5O2: C 54.32, H 7.22, N 26.40; found
C 54.30, H 7.20, N 26.35
1-(1-tert-Butyl-3-nitro-azetidin-3-yl)-1H-1,2,3-triazole (6a):
A solution of K2CO3 (862 mg, 6.25 mmol) and ascorbic acid (176
mg, 1 mmol) in water (10 mL) was stirred at room temperature
and treated by adding a solution of trimethylsilylacetylene (588
mg, 6 mmol) in MeOH (20 mL), followed by solution of
CuSO4·5H2O (125 mg, 0.5 mmol) in water (10 mL) and then
solution of 3-azido-1-tert-butyl-3-nitro-azetidine 5 (995 mg, 5
mmol) in MeOH (20 mL). The reaction mixture was stirred for
24 h at room temperature and extracted with CH2Cl2 (3×10 mL).
The combined extract was washed with water (20 mL) and dried
over Na2SO4. The solvent was removed at reduced pressure, and
the residue was purified by flash chromatography (EtOAc/n-
hexane, 1:1) to afford the pure 6a (967 mg, 86%) as a white
1-(1-tert-Butyl-3-nitro-azetidin-3-yl)-4-phenyl-1H-1,2,3-
triazole (6d): White solid (74%), m.p. 120-121ºC. 1H NMR (400
MHz, DMSO-d6, 50ºC): δ= 1.01 (s, 9H, CH3), 4.19 (d, 2JH,H=10.2
Hz, 2H, CH2), 4.38 (d, 2JH,H=10.2 Hz, 2H, CH2), 7.40 (t, 3JH,H=7.4
Hz, 1H, Ar), 7.51 (t, 3JH,H=7.6 Hz, 2H, Ar), 7.92 (d, 3JH,H=7.2 Hz,
2H, Ar), 9.12 (s, 1H, H-5 triazole) ppm. 13C NMR (100 MHz,
DMSO-d6, 50ºC): δ= 23.5 (CH3), 51.9 (C-CH3), 55.5 (CH2), 89.8
(C-NO2), 122.3 (C-5 triazole), 125.3 (Ar), 128.3 (Ar), 128.8 (Ar),
129.5 (Ar), 147.0 (C-4 triazole) ppm. IR (KBr): ν= 1365, 1567
(NO2), 2970 (C-H aliphatic), 3128 (C-H Ar) cm-1. MS (APCI, 30
EV), m/z (Irel,%): 302 (100) [М+Н]+. HRMS (ESI): calcd. for
C15H19N5O2 [M+H]+ 302.1612; found 302.1621.
1
solid; m.p. 86-88ºC; H NMR (400 MHz, DMSO-d6, 50ºC): δ=
2
0.99 (s, 9H, CH3), 4.13 (d, JH,H=10.2 Hz, 2H, CH2), 4.35 (d,
2JH,H=10.2 Hz, 2H, CH2), 7.96 (d, 3JH,H=1.3 Hz, 1H, H-4 triazole),
3
8.68 (d, JH,H=1.3 Hz, 1H, H-5 triazole) ppm. 13C NMR (100
MHz, DMSO-d6, 50ºC): δ= 23.5 (CH3), 51.9 (C-CH3), 55.6
(CH2), 89.6 (C-NO2), 126.1 (C-5 triazole), 134.0 (C-4 triazole)
ppm. IR (KBr): ν= 1365, 1567 (NO2), 2975 (C-H aliphatic), 3129
(C-H Ar) cm-1. MS (APCI, 30 EV), m/z (Irel,%): 226 (100)
[М+Н]+. HRMS (ESI): calcd. for C9H15N5O2 [M+H]+ 226.1299;
found 226.1305.
1-(1-tert-Butyl-3-nitro-azetidin-3-yl)-4-(2-fluoro-phenyl)-
1H-1,2,3-triazole (6e): Light yellow solid (75%), m.p. 149-
1
151ºC. H NMR (400 MHz, DMSO-d6, 50ºC): δ= 1.00 (s, 9H,
2
2
CH3), 4.22 (d, JH,H= 9.2 Hz, 2H, CH2), 4.38 (d, JH,H= 9.2 Hz,
2H, CH2), 7.37 (t, 3JH,H= 8.5 Hz, 2H, Ar), 7.45-7.50 (m, 1H, Ar),
8.19 (t, JH,H= 7.6 Hz, 1H, Ar), 8.99 (s, 1H, H-5 triazole) ppm.
3
13C NMR (100 MHz, DMSO-d6, 50ºC): δ= 23.5 (CH3), 51.9 (C-
CH3), 55.7 (CH2), 90.0 (C-NO2), 115.9 (d, J= 21.2 Hz, C-F),
117.3 (d, J= 13.1 Hz, Ar), 124.5 (C-5 triazole), 124.9 (Ar),127.6
(Ar), 130.2 (d, J= 8.4 Hz, Ar), 140.6 (C-4 triazole), 157.2 (Ar),
159.7 (Ar) ppm. IR (KBr): ν= 1366, 1564 (NO2), 2972 (C-H
aliphatic), 3168 (C-H Ar) cm-1. MS (APCI, 30 EV), m/z (Irel,%):
292 [М-N2]+ (17), 320 [M+H]+ (100), 361 [M+H+CH3CN]+ (20).
HRMS (ESI): calcd. for C15H18FN5O2 [M+H]+ 320.1517; found
320.1518.
1-(1-tert-Butyl-3-nitro-azetidin-3-yl)-4-(trimethylsilyl)-1H-
1,2,3-triazole (6b): A mixture of a 3-azido-1-tert-butyl-3-nitro-
azetidine 5 (995 mg, 5 mmol) and trimethylsilylacetylene (4900
mg, 50 mmol) was kept in anhydrous CH2Cl2 at 55ºC for 48 h.
The reaction mixture was cooled to room temperature and
concentrated in vacuo. The residue was purified by flash
chromatography (EtOAc/n-hexane, 1:1) to afford the pure 6b
1
(1158 mg, 78%) as a white solid; m.p. 76-78ºC. H NMR (400
MHz, DMSO-d6, 50ºC): δ= 0.32 (s, 9H, Si-CH3), 0.99 (s, 9H,
2
2
CH3), 4.13 (d, JH,H=10.2 Hz, 2H, CH2), 4.34 (d, JH,H=10.2 Hz,
2H, CH2), 8.69 (s, 1H, CH) ppm. 13C NMR (100 MHz, DMSO-
d6, 50ºC): δ= 1.4 (C-Si), 23.5 (CH3), 51.8 (C-CH3), 55.6 (CH2),
89.4 (C-NO2) 131.4 (C-5 triazole), 145.9 (C-4 triazole) ppm. IR
(KBr): ν= 1367, 1569 (NO2), 2974 (C-H aliphatic), 3129 (C-H
Ar) cm-1. MS (APCI, 30 EV), m/z (Irel,%): 298 (100) [М+Н]+.
HRMS (ESI): calcd. for C12H23N5O2Si [M+H]+ 298.1694; found
298.1700.
1-(1-tert-Butyl-3-nitro-azetidin-3-yl)-4-(2-chlorophenyl)-
1
1H-1,2,3-triazole (6f): White solid (77%), m.p. 109-111ºC. H
NMR (400 MHz, DMSO-d6, 50ºC): δ= 1.01 (s, 9H, CH3), 4.22
2
2
(d, JH,H= 10.0 Hz, 2H, CH2), 4.39 (d, JH,H= 10.0 Hz, 2H, CH2),
7.42-7.54 (m, 2H, Ar), 7.61 (d, 3JH,H= 7.8 Hz, 1H, Ar), 8.07-8.13
(m, 1H, Ar), 9.17 (s, 1H, H-5 triazole) ppm. 13C NMR (100 MHz,
DMSO-d6, 50ºC): δ= 23.5 (CH3), 51.9 (C-CH3), 55.7 (CH2), 90.0
(C-NO2), 125.2 (C-5 triazole), 127.4 (Ar), 128.1 (Ar), 129.7 (Ar),
129.9 (Ar), 130.1 (Ar), 130.6 (Ar), 143.5 (C-4 triazole) ppm. IR
(KBr): ν= 1367, 1568 (NO2), 2962 (C-H aliphatic), 3099 (C-H
Ar) cm-1. MS (APCI, 30 EV), m/z (Irel,%): 308 [М-N2]+ (40), 336
[М]+ (100), 338 [M+2] (40), 377 [М+Н+CН3CN]+ (25). HRMS
(ESI): calcd. for C15H18ClN5O2 [M+H]+ 336.1222; found
336.1216.
General Procedure for the Synthesis of Substituted 1H-
1,2,3-triazoles (6c-k): A solution of 3-azido-1-tert-butyl-3-nitro-
azetidine 5 (995 mg, 5 mmol) and substituted acetylene (c-k)
(5.25 mmol.) in THF (40 mL) was treated at room temperature
by adding a solution of ascorbic acid (440 mg, 2.5 mmol) in
water (20 mL), followed by a solution of CuSO4·5H2O (188 mg,
0.75 mmol) in water (10 mL). The reaction mixture was stirred
for 2-6 h at room temperature. After the reaction was complete
according to TLC, the mixture was diluted with water (20 mL)
and extracted with CH2Cl2 (4×20 mL). The organic layer was
dried over Na2SO4, the solvent was removed at reduced pressure,
1-(1-tert-Butyl-3-nitro-azetidin-3-yl)-4-(3-chlorophenyl)-
1
1H-1,2,3-triazole (6g): White solid (93%), m.p. 124-126ºC. H
NMR (400 MHz, DMSO-d6, 50ºC): δ= 1.00 (s, 9H, CH3), 4.18
2
2
(d, JH,H= 9.8 Hz, 2H, CH2), 4.38 (d, JH,H= 9.8 Hz, 2H, CH2),
3
3
7.46 (d, JH,H= 7.7 Hz, 1H, Ar), 7.54 (t, JH,H= 7.8 Hz, 1H, Ar),
7.89 (d, 3JH,H= 7.8 Hz, 1H, Ar), 7.96 (s, 1H, Ar), 9.23 (s, 1H, H-5

8
Tetrahedron
CCEPTED MANUSCRIPT
triazole) ppm. 13C NMR (100 MHz, DMSO-d6, 50ºC): δ= 23.5
General Procedure for the Synthesis of Substituted 1-(1-
A
(CH3), 51.9 (C-CH3), 55.4 (CH2), 89.8 (C-NO2), 123.8 (C-5
triazole), 125.0 (Ar), 128.1 (Ar), 130.8 (Ar), 131.6 (Ar), 133.7
(Ar), 145.6 (C-4 triazole) ppm. IR (KBr): ν= 1367, 1568 (NO2),
2962 (C-H aliphatic), 3099 (C-H Ar) cm-1. MS (APCI, 30 EV),
m/z (Irel,%): 308 [М-N2]+ (20), 336 [М]+ (100), 338 [M+2] (40),
377 [М+Н+CН3CN]+ (20). HRMS (ESI): calcd. for
C15H18ClN5O2 [M+H]+ 336.1222; found 336.1216.
tert-butyl-2,5-dihydro-1H-imidazol-4-yl)-1H-1,2,3-triazoles
(7a-k): The mixture of 1-(1-tert-butyl-3-nitro-azetidin-3-yl)-1H-
1,2,3-triazole 6a-k (1 mmol) and triethyl phosphite (1328 mg, 8
mmol) in benzene (3 mL) was stirred at reflux for 10-14h. After
the completion of reaction (TLC control), the solvent was
removed under reduced pressure. The residue was purified by
flash chromatography (EtOAc/n-hexane, 50:50) to give the
desired products 7a-k as colorless solids.
1-(1-tert-Butyl-3-nitro-azetidin-3-yl)-4-(2,4-
dichlorophenyl)-1H-1,2,3-triazole (6h): White solid (58%),
1-(1-tert-Butyl-2,5-dihydro-1H-imidazol-4-yl)-1H-1,2,3-
1
1
m.p. 137-139ºC. H NMR (400 MHz, DMSO-d6, 50ºC): δ= 1.01
triazole (7a): Light yellow solid (88%), m.p. 65-71ºC. H NMR
2
4
(s, 9H, CH3), 4.22 (d, JH,H= 10.0 Hz, 2H, CH2), 4.38 (d,
(400 MHz, CDCl3, 50ºC): δ= 1.15 (s, 9H, CH3), 4.34 (t, JH,H
=
3
4
2JH,H=10.2 Hz, 2H, CH2), 7.59 (dd, JH,H= 8.5, 3JH,H=2.1 Hz, 1H,
4.8 Hz, 2H, CH2-C), 4.86 (t, JH,H = 4.8 Hz, 2H, CH2-N=), 7.75
(s, 1H, H-4 triazole) 8.32 (s, 1H, H-5 triazole) ppm. 13C NMR
(100 MHz, CDCl3, 50ºC): δ= 26.1 (CH3), 51.3 (CH2-C), 52.5 (C-
CH3), 74.9 (CH2-N=), 121.3 (C-5 triazole), 134.2 (C-4 triazole),
158.3 (-C=N) ppm. IR (KBr): ν= 1682 (C=N) cm-1. MS (APCI,
30 EV), m/z (Irel,%): 194 (100) [М+Н]+. MS (EI, 70 EV), m/z
(Irel,%): 193 (5), 178 (50), 136 (10), 82 (50), 70 (40). C9H15N5: C
55.94, H 7.82, N 36.24; found C 55.92, H 7.79, N 36.29.
3
3
Ar), 7.76 (d, JH,H= 2.0 Hz, 1H), 8.15 (d, JH,H= 8.5 Hz, 1H, Ar),
9.20 (s, 1H, H-5 triazole) ppm. 13C NMR (100 MHz, DMSO-d6,
50ºC): δ= 23.5 (CH3), 51.9 (C-CH3), 55.7 (CH2), 90.0 (C-NO2),
125.3 (C-5 triazole), 127.2 (Ar), 127.7 (Ar), 129.6 (Ar), 130.8
(Ar), 131.4 (Ar), 133.6 (Ar), 142.5 (C-4 triazole) ppm. IR (KBr):
ν= 1367, 1565 (NO2), 2965 (C-H aliphatic), 3128 (C-H Ar) cm-1.
MS (APCI, 30 EV), m/z (Irel,%): 370 [М]+ (60), 372 [M+2] (100),
374 [M+4] (10), 411 [М+Н+CН3CN]+ (60). HRMS (ESI): calcd.
for C15H17Cl2N5O2 [M+H]+ 370.0832; found 370.0822.
1-(1-tert-Butyl-2,5-dihydro-1H-imidazol-4-yl)-4-
trimethylsilanyl-1H-1,2,3-triazole (7b): White solid (87%),
1
1-(1-tert-Butyl-3-nitro-azetidin-3-yl)-4-[4-
m.p. 80-86ºC. H NMR (400 MHz, DMSO-d6, 50ºC): δ= 0.31 (s,
4
(trifluoromethyl)phenyl)-1H-1,2,3-triazole (6i): Light yellow
9H, Si-CH3), 1.10 (s, 9H, C-CH3), 4.24 (t, JH,H = 4.8 Hz, 2H,
1
4
solid (87%), m.p. 149-150ºC. H NMR (400 MHz, DMSO-d6,
CH2-C), 4.79 (t, JH,H = 4.8 Hz, 2H, CH2-N=), 8.68 (s, 1H, H-5
2
50ºC):: δ= 1.01 (s, 9H, CH3), 4.20 (d, JH,H= 9.8 Hz, 2H, CH2),
triazole) ppm. 13C NMR (100 MHz, DMSO-d6, 50ºC): δ= -1.52
(Si-CH3), 25.6 (CH3-C), 50.9 (CH2-C), 51.8 (C-CH3), 74.2 (CH2-
N=), 127.7 (C-5 triazole), 146.2 (C-4 triazole), 157.3 (-C=N)
ppm. IR (KBr): ν= 1683 (C=N) cm-1. MS (APCI, 30 EV), m/z
(Irel,%): 238 [M-N2]+ (40), 266 [M+H]+ (100). C12H23N5Si: C
54.30, H 8.73, N 26.38 found C 54.33, H 8.74, N 26.39.
4.39 (d, 2JH,H= 9.8 Hz, 2H, CH2), 7.87 (d, 3JH,H= 8.2 Hz, 2H, Ar),
3
8.14 (d, JH,H= 8.2 Hz, 2H, Ar), 9.30 (s, 1H, H-5 triazole) ppm.
13C NMR (100 MHz, DMSO-d6, 50ºC): δ= 23.5 (CH3), 51.9 (C-
CH3), 55.5 (CH2), 89.9 (C-NO2), 123.8 (C-5 triazole), 125.9 (Ar),
128.0 (Ar), 128.4 (Ar), 128.7 (Ar), 133.5 (Ar), 145.5 (C-4
triazole) ppm. IR (KBr): ν= 1333, 1589 (NO2), 2975 (C-H
aliphatic), 3111 (C-H Ar) cm-1. MS (APCI, 30 EV), m/z (Irel,%):
370 (100) [М+Н]+, 411 [М+Н+CН3CN]+ (20). HRMS (ESI):
calcd. for C16H18F3N5O2 [M+H]+ 370.1485; found 370.1485.
1-(1-tert-Butyl-2,5-dihydro-1H-imidazol-4-yl)-4-
cyclopropyl-1H-1,2,3-triazole (7c): White solid (95%), m.p. 50-
1
53ºC. H NMR (400 MHz, DMSO-d6, 50ºC): δ= 0.77-0.84 (m,
2H, cyclopropyl), 0.93-1.00 (m, 2H, cyclopropyl), 1.09 (s, 9H,
1-(1-tert-Butyl-3-nitro-azetidin-3-yl)-4-(3-trifluoromethyl-
phenyl)-1H-1,2,3-triazole (6j): Light yellow solid (81%), m.p.
CH3), 1.99-2.03 (m, 1H, cyclopropyl), 4.20 (t, 4JH,H = 4.8 Hz, 2H,
4
CH2-C), 4.77 (t, JH,H = 4.8 Hz, 2H, CH2-N=), 8.39 (s, 1H, H-5
1
94-95ºC. H NMR (400 MHz, DMSO-d6, 50ºC): δ= 1.01 (s, 9H,
triazole) ppm. 13C NMR (100 MHz, DMSO-d6): δ= 6.1 (CH-
cyclopropyl), 7.6 (CH2-cyclopropyl), 25.7 (CH3), 50.5 (CH2-C),
51.8 (C-CH3), 74.1 (CH2-N=), 117.7 (C-5 triazole), 150.2 (C-4
triazole), 157.4 (-C=N) ppm. IR (KBr): ν= 1672 (C=N) cm-1. MS
(APCI, 30 EV), m/z (Irel,%): 206 [M-N2]+ (70), 234 [M+H]+
(100). HRMS (ESI): calcd. for C12H19N5 [M+H]+ 234.1718;
found 234.1715.
2
CH3), 4.19 (d, JH,H= 10.1 Hz, 2H, CH2), 4.39 (d, J = 10.1 Hz,
3
2H, CH2), 7.71-7.80 (m, 2H, Ar), 8.24 (t, JH,H= 3.6 Hz, 2H, Ar)
9.33 (s, 1H, H-5 triazole) ppm. 13C NMR (100 MHz, DMSO-d6,
50ºC): δ= 23.5 (CH3), 51.9 (C-CH3), 55.4 (CH2), 89.8 (C-NO2),
2
121.7 (q, JC,F= 3.9 Hz, C-CF3) 122.5 (Ar), 123.5 (C-5 triazole),
1
124.8 (q, JC,F= 3.8 Hz, CF3), 125.2 (Ar), 129.0 (Ar), 130.1 (Ar),
130.6 (Ar), 145.5 (C-4 triazole) ppm. IR (KBr): ν= 1328, 1596
(NO2), 2978 (C-H aliphatic), 3144 (C-H Ar) cm-1. MS (APCI, 30
EV), m/z (Irel,%): 370 (100) [М+Н]+, 411 [М+Н+CН3CN]+ (20).
HRMS (ESI): calcd. for C16H18F3N5O2 [M+H]+ 370.1485; found
370.1485.
1-(1-tert-Butyl-2,5-dihydro-1H-imidazol-4-yl)-4-phenyl-
1
1H-1,2,3-triazole (7d): White solid (88%), m.p. 83-86ºC. H
NMR (400 MHz, CDCl3, 50ºC): δ= 1.18 (s, 9H, CH3), 4.38 (t,
4JH,H = 4.8 Hz, 2H, CH2-C), 4.90 (t, 4JH,H = 4.8 Hz, 2H, CH2-N=),
3
3
7.38 (t, JH,H = 7.4 Hz, 1H, Ar), 7.45 (t, JH,H = 7.4 Hz, 2H, Ar),
7.86-7.93 (m, 2H, Ar), 8.52 (s, 1H, H-5 triazole) ppm. 13C NMR
(100 MHz, DMSO-d6, 50ºC): δ= 25.7 (CH3), 50.7 (CH2-C), 51.8
(C-CH3), 74.2 (CH2-N=), 118.3 (Ar), 125.6 (C-5 triazole), 128.4
(Ar), 128.7 (Ar), 129.3 (Ar), 147.0 (C-4 triazole), 157.5 (-C=N)
ppm. IR (KBr): ν= 1683 (C=N) cm-1. MS (APCI, 30 EV), m/z
(Irel,%): 270 [M+H]+ (100). HRMS (ESI): calcd. for C15H19N5
[M+H]+ 270.1718; found 270.1725.
1-(1-tert-Butyl-3-nitro-azetidin-3-yl)-4-(3-methoxyphenyl)-
1
1H-1,2,3-triazole (6k): White solid (61%), m.p. 114-116ºC. H
NMR (400 MHz, DMSO-d6, 50ºC): δ= 1.01 (s, 9H, C-CH3), 3.84
(s, 3H, O-CH3), 4.19 (d, 2JH,H= 10.1 Hz, 2H, CH2), 4.38 (d, 2JH,H
=
10.1 Hz, 2H, CH2), 6.98 (dd, 3JH,H= 8.1, 3JH,H = 2.1 Hz, Ar), 7.41
(t, 3JH,H= 7.9 Hz, 1H, Ar), 7.46-7.54 (m, 2H, Ar), 9.18 (s, 1H, H-5
triazole) ppm. 13C NMR (100 MHz, DMSO-d6, 50ºC): δ= 23.7
(C-CH3), 52.1 (C-CH3), 55.2 (O-CH3), 55.7 (CH2), 89.9 (C-NO2),
110.6 (Ar), 114.4 (Ar), 117.7 (Ar), 122.9 (C-5 triazole), 130.3
(Ar), 130.9 (Ar), 146.9 (C-4 triazole), 159.7 (Ar) ppm. IR (KBr):
ν= 1370, 1596 (NO2), 2962 (CH aliphatic), 3115 (C-H Ar) cm-1.
MS (APCI, 30 EV), m/z (Irel,%): 332 (100) [М+Н]+. C16H21N5O3:
C 57.99, H 6.39, N 21.13; found C 57.96, H 6.40, N 21.10
1-(1-tert-Butyl-2,5-dihydro-1H-imidazol-4-yl)-4-(2-
fluorophenyl)-1H-1,2,3-triazole (7e): White solid (62%), m.p.
1
91-95ºC. H NMR (400 MHz, DMSO-d6, 50ºC):: δ= 1.12 (s, 9H,
CH3), 4.30 (t, 4JH,H = 4.9 Hz, 2H, CH2-C), 4.84 (t, 4JH,H = 4.9 Hz,
2H, CH2-N=), 7.33-7.42 (m, 2H, Ar), 7.45-7.54 (m, 1H, Ar), 8.16
5
(m, 1H, Ar), 8.78 (d, JH,F= 3.2 Hz, 1H, H-5 triazole) ppm. 13C
NMR (100 MHz, DMSO-d6, 50ºC): δ= 25.7 (CH3), 50.7 (CH2-C),

9
4
51.9 (C-CH3), 74.2 (CH2-N=), 115.8 (Ar), 116.0 (Ar), 124.8 (C-5
triazole), 127.8 (Ar), 130.3 (Ar), 130.4 (Ar), 140.7 (C-4 triazole),
157.4 (-C=N) ppm. IR (KBr): ν= 1683 (C=N) cm-1. MS (APCI,
30 EV), m/z (Irel,%): 260 [М-N2]+ (100), 288 [M+H]+ (92), 329
[M+H+CH3CN]+ (10). C15H18FN5: C 62.70, H 6.31, N 24.34;
found C 62.79, H 6.34, N 24.28.
50ºC): δ= 1.12 (s, 9H, CH3), 4.29 (t, JH,H = 4.6 Hz, 2H, CH2-
ACCEPTED MANUSCRIPT
C), 4.85 (t, 4JH,H = 4.6 Hz, CH2-N=), 7.65-7.83 (m, 2H, Ar), 8.27-
8.41 (m, 2H, Ar), 9.41 (s, 1H, H-5 triazole) ppm. 13C NMR (100
MHz, DMSO-d6, 50ºC): δ= 25.7 (CH3), 50.7 (CH2-C), 51.9 (C-
CH3), 74.2 (CH2-N=), 119.6 (C-5 triazole), 122.0 (q, JC,F = 3.8
Hz, CH-CF3), 122.5 (CF3), 124.9 (q, JC,F = 3.8 Hz, CH-CF3),
3
3
125.2 (CF3), 129.4 (Ar), 129.6 (Ar), 129.9 (Ar), 130.5 (Ar), 145.6
(C-4 triazole), 157.5 (-C=N) ppm. IR (KBr): ν= 1677 (C=N) cm-
1. MS (APCI, 30 EV), m/z (Irel,%): 310 [М-N2]+ (20), 338 [M+H]+
(100), 345 [М+Н+CН3CN]+ (15). HRMS (ESI): calcd. for
C16H18F3N5 [M+H]+ 338.1592; found 338.1596.
1-(1-tert-Butyl-2,5-dihydro-1H-imidazol-4-yl)-4-(2-
chlorophenyl)-1H-1,2,3-triazole (7f): White solid (68%), m.p.
1
101-105ºC. H NMR (400 MHz, DMSO-d6, 50ºC):: δ= 1.11 (s,
9H, CH3), 4.31 (t, 4JH,H = 4.8 Hz, 2H, CH2-C), 4.84 (t, 4JH,H = 4.8
Hz, 2H, CH2-N=), 7.42-7.55 (m, 2H, Ar), 7.58-7.66 (m, 1H, Ar),
3
3
8.07 (dd, JH,H = 7.4, JH,H = 1.8 Hz, 1H, Ar), 8.99 (s, 1H, H-5
triazole) ppm. 13C NMR (100 MHz, DMSO-d6): δ= 25.7 (CH3),
50.7 (CH2-C), 51.9 (C-CH3), 74.2 (CH2-N=), 120.6 (Ar), 120.8
(Ar), 127.4 (Ar), 127.8 (C-5 triazole), 130.0 (Ar), 130.1 (Ar),
130.9 (Ar), 143.5 (C-4 triazole), 157.5 (-C=N) ppm. IR (KBr): ν=
1682 (C=N) cm-1. MS (APCI, 30 EV), m/z (Irel,%): 276 [М-N2]+
(100), 304 [M+H]+ (90), 306 [M+2] (30), 345 [М+Н+CН3CN]+
(20). C15H18ClN5: C 59.30, H 5.97, N 23.05; found C 59.35, H
6.04, N 23.02.
1-(1-tert-Butyl-2,5-dihydro-1H-imidazol-4-yl)-4-(3-
methoxy-phenyl)-1H-1,2,3-triazole (7k): White solid (61%),
1
m.p. 108-111ºC. H NMR (400 MHz, DMSO-d6, 50ºC): δ= 1.12
4
(s, 9H, C-CH3), 3.83 (s, 3H, O-CH3), 4.28 (t, JH,H = 4.8 Hz, 2H,
4
3
CH2-C), 4.84 (t, JH,H = 4.8 Hz, 2H, CH2-N=), 6.96 (dd, JH,H
=
8.2, 3JH,H = 2.4 Hz, 1H, Ar), 7.39 (t, 3JH,H = 7.9 Hz, 1H, Ar), 7.52-
7.59 (m, 2H, Ar), 9.22 (s, 1H, H-5 triazole) ppm. 13C NMR (100
MHz, DMSO-d6, 50ºC): δ= 25.7 (CH3), 50.7 (CH2-C), 51.9 (C-
CH3), 55.1 (O-CH3), 74.2 (CH2-N=), 110.9 (Ar), 114.4 (Ar),
117.9 (Ar), 118.6 (C-5 triazole), 129.9 (Ar), 130.6 (Ar), 146.9
(C-4 triazole), 157.5 (-C=N), 159.6 (Ar) ppm. IR (KBr): ν= 1671
(C=N) cm-1. MS (APCI, 30 EV), m/z (Irel,%): 272 [М-N2]+ (100),
300 [M+H]+ (92). HRMS (ESI): calcd. for C16H21N5O [M+H]+
300.1824; found 300.1824.
1-(1-tert-Butyl-2,5-dihydro-1H-imidazol-4-yl)-4-(3-
chlorophenyl)-1H-1,2,3-triazole (7g): White solid (66%), m.p.
1
147-150ºC. H NMR (400 MHz, DMSO-d6, 50ºC): δ= 1.11 (s,
9H, CH3), 4.28 (t, 4JH,H = 4.7 Hz, 2H, CH2-C), 4.84 (t, 4JH,H = 4.7
Hz, 2H, CH2-N=), 7.45 (d, 3JH,H = 8.0 Hz, 1H, Ar), 7.52 (t, 3JH,H
=
3
7.8 Hz, 1H, Ar), 7.97 (d, JH,H = 7.7 Hz, 1H, Ar), 8.06 (s, 1H,
Ar), 9.30 (s, 1H, H-5 triazole) ppm. 13C NMR (100 MHz,
DMSO-d6, 50ºC): δ= 25.7 (CH3), 50.7 (CH2-C), 51.9 (C-CH3),
74.3 (CH2-N=), 124.1 (Ar), 125.3 (C-5 triazole), 128.2 (Ar),
130.7 (Ar), 131.4 (Ar), 133.6 (Ar), 145.7 (C-4 triazole), 157.5 (-
C=N) ppm. IR (KBr): ν= 1682 (C=N) cm-1. MS (APCI, 30 EV),
m/z (Irel,%): 276 [М-N2]+ (85), 304 [М+Н]+ (100), 306 [M+2]
(30), 345 [М+Н+CН3CN]+ (15). C15H18ClN5: C 59.30, H 5.97, N
23.05; found C 59.35, H 6.04, N 23.02.
General Procedure for the Synthesis of Substituted 1-(1-
tert-butyl-1H-imidazol-4-yl)-1H-1,2,3-triazoles (1a-k):
4,5-dichloro-3,6-dioxo-cyclohexa-1,4-diene-1,2-dicarbonitrile
(DDQ) (147 mg, 0.65 mmol) was added portionwise to the
solution of 1-(1-tert-butyl-2,5-dihydro-1H-imidazol-4-yl)-1H-
1,2,3-triazoles 7 a-k (0.5 mmol) in anhydrous dichloromethane.
The reaction mixture was stirred for 1h at room temperature.
After the reaction was complete according to TLC the solvent
was removed at reduced pressure and the residue was purified by
flash chromatography (EtOAc/n-hexane, 30:70) to give the
desired products 1a-k as colorless solids.
1-(1-tert-Butyl-2,5-dihydro-1H-imidazol-4-yl)-4-(2,4-
dichloro-phenyl)-1H-1,2,3-triazole (7h): White solid (90%),
1
m.p. 142-147ºC, H NMR (400 MHz, CDCl3, 50ºC): δ= 1.18 (s,
1-(1-tert-Butyl-1H-imidazol-4-yl)-1H-1,2,3-triazole
(1a):
9H, CH3), 4.39 (t, 4JH,H = 4.8 Hz, 2H, CH2-C), 4.91 (t, 4JH,H = 4.8
1
White solid (91%), m.p. 80-81ºC. H NMR (400 MHz, DMSO-
3
3
Hz, 2H, CH2-N=), 7.39 (dd, JH,H = 8.5, JH,H = 1.9 Hz, 1H, Ar),
7.51 (d, 3JH,H = 1.9 Hz, 1H, Ar), 8.24 (d, 3JH,H = 8.5 Hz, 1H, Ar),
8.91 (s, 1H, H-5 triazole) ppm. IR (KBr): ν= 1682 (C=N) cm-1.
MS (APCI, 30 EV), m/z (Irel,%): 312 [М-N2]+ (10), 338 [M]+
(70), 340 [M+2] (100), 342 [M+4] (10), 345 [М+Н+CН3CN]+
(15). C15H17Cl2N5: C 53.26, H 5.07, N 20.71; found C 53.35, H
5.11, N 20.69.
d6, 50ºC): δ= 1.55 (s, 9H, CH3), 7.79 (d, 4JH,H = 1.5 Hz, 1H, CH-
4
N), 7.82 (d, 3JH,H = 1.0 Hz, 1H, H-4 triazole), 7.84 (d, JH,H = 1.5
3
Hz, 1H, CH-C), 8.39 (d, JH,H = 1.0 Hz, 1H, H-5 triazole) ppm.
13C NMR (100 MHz, DMSO-d6): δ= 29.6 (CH3), 55.7 (C-CH3),
107.5 (C-5-imidazole), 122.5 (C-5 triazole), 133.0 (C-2-
imidazole) 133.1 (C-4 triazole) 136.5 (C-4-imidazole) ppm. IR
(KBr): ν= 3133 (C-H Ar), 1592 (C=N) cm-1. MS (APCI, 30 EV),
m/z (Irel,%): 192 [M+H]+ (100). C9H13N5: C 56.53, H 6.85, N
36.62; found C 56.60, H 6.88, N 36.52.
1-(1-tert-Butyl-2,5-dihydro-1H-imidazol-4-yl)-4-(4-
trifluoromethyl-phenyl)-1H-1,2,3-triazole (7i): Light yellow
1
solid (72%); m.p. 127-130ºC. H NMR (400 MHz, DMSO-d6,
1-(1-tert-Butyl-1H-imidazol-4-yl)-1H-1,2,3-triazole
(1a)
50ºC): δ= 1.12 (s, 9H, CH3), 4.29 (t, 4JH,H = 4.8 Hz, 2H, CH2-C),
4.85 (t, 4JH,H = 4.8 Hz, 2H, CH2-N=), 7.84 (d, 3JH,H = 8.2 Hz, 2H,
and 2-(1-tert-Butyl-1H-imidazol-4-yl)-2H-1,2,3-triazole (9a):
The mixture of 1-(1-tert-butyl-3-nitro-azetidin-3-yl)-1H-1,2,3-
triazole 6a (225 mg, 1 mmol) and triethyl phosphite (332 mg, 2
mmol) in benzene (3 mL) was stirred at reflux for 60h. After the
completion of reaction (GC-MS control), the solvent was
removed under reduced pressure. The residue was dissolved in
3
Ar), 8.22 (d, JH,H = 8.2 Hz, 2H, Ar), 9.37 (s, 1H, H-5 triazole)
ppm. 13C NMR (100 MHz, DMSO-d6, 50ºC): δ= 25.7 (CH3), 50.7
(CH2-C), 51.9 (C-CH3), 74.3 (CH2-N=), 119.8 (C-5 triazole),
122.6 (CF3), 125.3 (Ar), 125.7 (q, 3JC,F = 3.5 Hz, CH-CF3), 126.2
(Ar), 128.6 (sept, 2JC,F = 31.9 Hz, C-CF3), 133.3 (Ar), 145.6 (C-4
triazole), 157.5 (-C=N) ppm. IR (KBr): ν= 1682 (C=N) cm-1. MS
(APCI, 30 EV), m/z (Irel,%): 310 [М-N2]+ (20), 338 [M+H]+
(100), 345 [М+Н+CН3CN]+ (15). HRMS (ESI): calcd. for
C16H18F3N5 [M+H]+ 338.1592; found 338.1597.
anhydrous
dichloromethane
and
4,5-dichloro-3,6-dioxo-
cyclohexa-1,4-diene-1,2-dicarbonitrile (DDQ) (454 mg, 2 mmol)
was added portionwise to this solution. The reaction mixture was
stirred for 1h at room temperature. After the reaction was
complete according to TLC the solvent was removed at reduced
pressure The residue was purified by preparative RP-HPLC to
afford the pure 1a (60 mg 31%) as a white solid and 9a (44 mg,
1-(1-tert-Butyl-2,5-dihydro-1H-imidazol-4-yl)-4-(3-
1
23 %) as a white solid, m.p. 127-130ºC. H NMR (400 MHz,
trifluoromethyl-phenyl)-1H-1,2,3-triazole (7j): Light yellow
4
DMSO-d6, 50ºC): δ=1.57 (s, 9H, C-CH3), 7.68 (d, JH,H = 1.67
1
solid (75%), m.p. 114-117ºC. H NMR (400 MHz, DMSO-d6,

10
Tetrahedron
4
5
Hz, 1H, CH-N), 7.84 (d, JH,H = 1.5 Hz, 1H, CH-C), 7.94 (s,
Hz, 1H, Ar), 8.61 (d, JH,F = 3.5 Hz, 1H, H-5 triazole) ppm. 13C
ACCEPTED MANUSCRIPT
2H, CH-triazole) ppm. 13C NMR (100 MHz, DMSO-d6, 50ºC):
δ= 29.6 (CH3-C), 55.6 (C-CH3), 107.9 (C-5-imidazole), 132.7 (C-
2-imidazole), 134.9 (C-4,5 triazole) , 139.6 (C-4-imidazole) ppm.
IR (KBr): ν= 3109 (C-H Ar), 2977 (C-H aliphatic), 1587 (C=N)
cm-1. MS (APCI, 30 EV), m/z (Irel,%): 192 [M+H]+ (100).
C9H13N5: C 56.53, H 6.85, N 36.62; found C 56.60, H 6.88, N
36.52.
NMR (100 MHz, DMSO-d6, 50ºC): δ= 29.6 (CH3), 55.9 (C-CH3),
4
107.8 (C-5-imidazole), 115.7 (d, JC,F = 21.3 Hz, C-5 triazole),
117.9 (Ar), 120.8 (d, JC,F = 10.55 Hz, C-F), 124.7 (Ar), 127.5
2
(Ar), 129.7 (Ar), 133.3 (C-2-imidazole), 136.1 (C-4-imidazole),
139.7 (C-4 triazole), 159.7 (Ar) ppm. IR (KBr): ν= 3116 (C-H
Ar), 1602 (C=N) cm-1. MS (APCI, 30 EV), m/z (Irel,%): 258 [М-
N2]+ (10), 286 [M+H]+ (100). C15H16FN5: C 63.14, H 5.65, N
24.55; found C 63.17, H 5.60, N 24.56.
1-(1-tert-Butyl-1H-imidazol-4-yl)-4-(trimethylsilyl)-1H-
1,2,3-triazole (1b): White solid (76%), m.p. 132-133ºC. 1H NMR
(400 MHz, DMSO-d6, 50ºC): δ= 0.31 (s, 9H, Si-CH3), 1.58 (s,
1-(1-tert-Butyl-1H-imidazol-4-yl)-4-(2-chlorophenyl)-1H-
1,2,3-triazole (1f): White solid (92%), m.p. 146-148ºC. 1H NMR
(400 MHz, DMSO-d6, 50ºC): δ= 1.60 (s, 9H, CH3), 7.38-7.53 (m,
4
4
9H, C-CH3), 7.79 (d, JH,H = 1.6 Hz, 1H, CH-N), 7.85 (d, JH,H
=
1.6 Hz, 1H, CH-C), 8.40 (s, 1H, H-5 triazole) ppm. 13C NMR
(100 MHz, DMSO-d6, 50ºC): δ= -1.3 (CH3-Si), 29.6 (CH3-C),
55.7 (C-CH3), 107.6 (C-5-imidazole), 128.1 (C-5 triazole), 133.1
(C-2-imidazole), 136.3 (C-4-imidazole), 144.7 (C-4 triazole)
ppm. IR (KBr): ν= 3101 (C-H Ar), 1583 (C=N) cm-1. MS (APCI,
30 EV), m/z (Irel,%): 236 (10) [М-N2]+, 264(100) [М+Н]+.
C12H21N5Si: C 54.72, H 8.04, N 26.59; found C 54.80, H 8.08, N
26.52.
2H, Ar), 7.59 (d, 3JH,H = 7.9 Hz, 1H, Ar), 7.92 (d, JH,H = 1.6 Hz,
4
1H, CH-N), 7.93 (d, 4JH,H = 1.6 Hz, 1H, CH-C), 8.10 (dd, JH,H
=
3
3
7.7, JH,H = 1.5 Hz, 1H, Ar), 8.80 (s, 1H, H-5 triazole) ppm. 13C
NMR (100 MHz, DMSO-d6, 50ºC): δ= 29.6 (CH3), 55.9 (C-CH3),
107.9 (C-5-imidazole), 121.4 (C-5 triazole), 127.3 (Ar), 128.7
(Ar), 129.5 (Ar), 129.6 (Ar), 130.0 (Ar), 130.5 (Ar), 133.3 (C-2-
imidazole), 136.1 (C-4-imidazole), 142.6 (C-4 triazole) ppm. IR
(KBr): ν= 3126 (C-H Ar), 1596 (C=N) cm-1. MS (APCI, 30 EV),
m/z (Irel,%): 274 [М-N2]+ (10), 302 [М+Н]+ (100), 304 [M+2]
(30). C15H16ClN5: C 59.70, H 5.34, N 23.21; found C 59.73, H
5.40, N 23.25.
1-(1-tert-Butyl-1H-imidazol-4-yl)-4-cyclopropyl-1H-1,2,3-
triazole (1c): White solid (92%), m.p. 93-95ºC. H NMR (400
1
MHz, DMSO-d6, 50ºC): δ= 0.74-0.82 (m, 2H, CH2), 0.88-0.97
(m, 2H, CH2), 1.55 (s, 9H, CH3), 1.93-2.10 (m, 1H, CH), 7.81 (d,
1-(1-tert-Butyl-1H-imidazol-4-yl)-4-(3-chlorophenyl)-1H-
1,2,3-triazole (1g): White solid (93%), m.p. 163-165ºC. 1H NMR
(400 MHz, DMSO-d6, 50ºC): δ= 1.60 (s, 9H, CH3), 7.40 (dd,
4
4JH,H = 1.6 Hz, 1H, CH-N), 7.86 (d, JH,H = 1.6 Hz, 1H, CH-C),
8.16 (s, 1H, H-5 triazole) ppm. 13C NMR (100 MHz, DMSO-d6,
50ºC): δ= 6.5 (CH2), 7.8 (CH-CH2), 29.8 (CH3), 55.9 (C-CH3),
107.5 (C-5-imidazole), 118.6 (C-5 triazole), 133.2 (C-2-
imidazole), 136.7 (C-4-imidazole), 149.2 (C-4 triazole) ppm. IR
(KBr): ν= 3134 (C-H Ar), 1599 (C=N) cm-1. MS (APCI, 30 EV),
m/z (Irel,%): 204 (50) [М-N2]+, 232 (100) [М+Н]+. HRMS (ESI):
calcd. for C12H17N5 232.1562; found 232.1560.
3
3
3JH,H = 7.1, JH,H = 1.9 Hz, 1H, Ar), 7.49 (t, JH,H = 7.9 Hz, 1H,
4
4
Ar), 7.88 (d, JH,H = 1.7 Hz, 1H, CH-N), 7.91 (d, JH,H = 1.7 Hz,
3
3
1H, CH-C), 7.94 (d, JH,H = 7.8 Hz, 1H, Ar), 8.02 (t, JH,H = 1.8
Hz, 1H), 9.02 (s, 1H, H-5 triazole) ppm. 13C NMR (100 MHz,
DMSO-d6, 50ºC): δ= 29.6 (CH3), 55.9 (C-CH3), 107.7 (C-5-
imidazole), 119.7 (C-5 triazole), 123.7 (Ar), 124.8 (Ar), 127.6
(Ar), 130.6 (Ar), 132.3 (Ar), 133.3 (C-2-imidazole), 133.5 (Ar),
136.2 (C-4-imidazole), 144.8 (C-4 triazole) ppm. IR (KBr): ν=
3122 (C-H Ar), 1604 (C=N) cm-1. MS (APCI, 30 EV), m/z
(Irel,%): 274 [М-N2]+ (10), 302 [М+Н]+ (100), 304 [M+2] (30).
C15H16ClN5: C 59.70, H 5.34, N 23.21; found C 59.73, H 5.40, N
23.25.
1-(1-tert-Butyl-1H-imidazol-4-yl)-4-phenyl-1H-1,2,3-
1
triazole (1d): White solid (95%), m.p. 99-101ºC. H NMR (400
3
MHz, DMSO-d6, 50ºC): δ= 1.60 (s, 9H, CH3), 7.34-7.38 (t, JH,H
3
= 7.38 Hz, 1H, Ar), 7.45-7.49 (t, JH,H = 7.64 Hz, 2H, Ar), 7.88
4
(d, JH,H = 1.6 Hz, 1H, CH-N), 7.93-8.00 (m, 2H, Ar), 7.91 (d,
4JH,H = 1.6 Hz, 1H, CH-C), 8.90 (s, 1H, H-5 triazole) ppm. 13C
NMR (100 MHz, DMSO-d6, 50ºC): δ= 29.6 (CH3), 55.8 (C-CH3),
107.6 (C-5-imidazole), 118.9 (C-5 triazole), 125.2 (Ar), 127.8
(Ar), 128.6 (Ar), 130.2 (Ar), 133.2 (C-2-imidazole), 136.3 (C-4-
imidazole), 146.1 (C-4 triazole) ppm. IR (KBr): ν= 3118 (C-H
Ar), 1598 (C=N) cm-1. MS (APCI, 30 EV), m/z (Irel,%): 268
[M+H]+ (100). C15H17N5: C 67.39, H 6.41, N 26.20; found C
67.45, H 6.48, N 26.07.
1-(1-tert-Butyl-1H-imidazol-4-yl)-4-(2,4-dichlorophenyl)-
1
1H-1,2,3-triazole (1h): White solid (95%), m.p. 153-154ºC. H
NMR (400 MHz, DMSO-d6, 50ºC):: δ= 1.60 (s, 9H, CH3), 7.56
3
3
3
(dd, JH,H = 8.5, JH,H = 2.2 Hz, 1H, Ar), 7.75 (d, JH,H = 2.1 Hz,
4
4
1H, Ar), 7.92 (d, JH,H = 1.7 Hz, 1H, CH-N), 7.94 (d, JH,H = 1.7
Hz, 1H, CH-C), 8.12 (d, 3JH,H = 8.5 Hz, 1H, Ar), 8.84 (s, 1H, H-5
triazole) ppm. 13C NMR (100 MHz, DMSO-d6, 50ºC): δ= 29.6
(CH3), 55.9 (C-CH3), 108.0 (C-5-imidazole), 121.5 (C-5 triazole),
127.6 (Ar), 127.7 (Ar), 129.5 (Ar), 130.7 (Ar), 131.3 (Ar), 133.2
(C-2-imidazole), 133.4 (Ar), 136.0 (C-4-imidazole) 141.7 (C-4
triazole) ppm. IR (KBr): ν= 3116 (C-H Ar), 1602 (C=N) cm-1.
MS (APCI, 30 EV), m/z (Irel,%): 307 [М-N2]+ (36), 336 [M]+
(100), 338 [M+2] (71), 340 [M+4] (31). C15H15Cl2N5: C 53.58, H
4.50, N 20.83; found C 53.55, H 4.40, N 20.80.
2-(1-tert-Butyl-1H-imidazol-4-yl)-4-phenyl-2H-1,2,3-
triazole (9d): product was obtained similarly 9a. White solid
º
1
(42%), m.p. 208-210 C. H NMR (400 MHz, DMSO-d6, 50ºC):
δ= 1.59 (s, 9H, CH3), 7.41 (m, 1H, Ar), 7.50 (m, 2H, Ar), 7.76 (d,
4
4J = 1.7 Hz, 1H, CH-C), 7.83 (d, J = 1.7 Hz, 1H, CH-N), 7.93
(m, 2H, Ar), 8.42 (s, 1H, H-5 triazole) ppm. 13C NMR (100 MHz,
DMSO-d6, 50ºC): δ= 29.62 (CH3), 55.63 (C-CH3) , 107.97 (C-5-
imidazole), 125.58 (Ar), 128.41 (Ar), 128.74 (Ar), 129.55 (Ar),
132.12 (C-5 triazole), 132.79 (C-2-imidazole), 139.55 (C-4
triazole), 147.31(C-4-imidazole) ppm. IR (KBr): ν= 3081 (C-H
Ar), 1571 (C=N) cm-1. MS (APCI, 30 EV), m/z (Irel,%): 268
[M+H]+ (100). C15H17N5: C 67.39, H 6.41, N 26.20; found C
67.45, H 6.48, N 26.07.
1-(1-tert-Butyl-1H-imidazol-4-yl)-4-[4-
(trifluoromethyl)phenyl)-1H-1,2,3-triazole (1i): White solid
1
(60%), m.p. 134-136ºC. H NMR (400 MHz, DMSO-d6, 50ºC)::
3
δ= 1.60 (s, 9H, CH3), 7.82 (d, JH,H = 8.2 Hz, 2H, Ar), 7.91 (d,
4
4JH,H = 1.7 Hz, 1H, CH-N), 7.93 (d, JH,H = 1.7 Hz, 1H, CH-C),
3
8.20 (d, JH,H = 8.2 Hz, 2H, Ar), 9.10 (s, 1H, H-5 triazole) ppm.
13C NMR (100 MHz, DMSO-d6, 50ºC): δ= 29.6 (CH3), 55.9 (C-
CH3), 107.8 (C-5-imidazole), 120.2 (C-5 triazole), 125.6 (CF3),
125.8 (Ar), 128.2 (Ar), 133.3 (C-2-imidazole), 134.2 (Ar), 136.1
(C-4-imidazole), 144.8 (C-4 triazole) ppm. IR (KBr): ν= 3196
(C-H Ar), 1634 (C=N) cm-1. MS (APCI, 30 EV), m/z (Irel,%): 308
1-(1-tert-Butyl-1H-imidazol-4-yl)-4-(2-fluorophenyl)-1H-
1,2,3-triazole (1e): White solid (85%), m.p. 138-140ºC. 1H NMR
(400 MHz, DMSO-d6, 50ºC):: δ= 1.60 (s, 9H, CH3), 7.32-7.40
4
(m, 2H, Ar), 7.41-7.49 (m, 1H, Ar), 7.91 (d, JH,H = 1.6 Hz, 1H,
4
3
CH-N), 7.93 (d, JH,H = 1.6 Hz, 1H, CH-C), 8.17 (t, JH,H = 7.5

11
[М-N2]+ (14), 336 [M+H]+ (100). HRMS (ESI): calcd. for
Reischer; C.W. Ford, G.E. Zurenko; J.C. Hamel; R.D.
ACCEPTED MANUSCRIPT
C16H16F3N5 [M+H]+ 336.1435; found 336.1432.
Schaadt; D. Stapert; B.H. Yagi, J. Med. Chem., 2000, 43,
953; b) H. Wamhoff, In Comprehensive Heterocyclic
Chemistry; A.R. Katritzky, C.W. Rees, Eds.; Pergamon:
Oxford, 1984; pp 669–732; c) D.R. Buckle; C.J.M. Rockell;
H. Smith; B.A. Spicer, J. Med. Chem., 1986, 29, 2262; d)
R. Alvarez; S. Velazquez, A. San-Felix; S. Aquaro; E. De
Clercq; C.F. Perno; A. Karlsson; J. Balzarini; M.J.
Camarasa, J. Med.Chem., 1994, 37, 4185.
1-(1-tert-Butyl-1H-imidazol-4-yl)-4-[3-
(trifluoromethyl)phenyl)-1H-1,2,3-triazole (1j): White solid
1
(74%), m.p. 152-154ºC. H NMR (400 MHz, DMSO-d6, 50ºC)::
4
δ= 1.60 (s, 6H, CH3), 7.69-7.75 (m, 2H, Ar), 7.90 (d, JH,H = 1.7
4
Hz, 1H, CH-N), 7.93 (d, JH,H = 1.7 Hz, 1H, CH-C), 8.23-8.34
(m, 2H, Ar), 9.15 (s, 1H, H-5 triazole) ppm. 13C NMR (100 MHz,
DMSO-d6, 50ºC): δ= 29.6 (CH3), 55.9 (C-CH3), 107.7 (C-5-
imidazole), 119.9 (C-5 triazole), 121.5 (CF3), 122.6 (Ar), 124.2
(Ar), 125.3 (CF3), 129.0 (Ar), 129.5 (Ar), 129.8 (Ar), 131.3 (Ar),
133.3 (C-2-imidazole), 136.2 (C-4-imidazole), 144.7 (C-4
triazole) ppm. IR (KBr): ν= 3144 (C-H Ar), 1596 (C=N) cm-1.
MS (APCI, 30 EV), m/z (Irel,%): 308 [М-N2]+ (20), 336 [M+H]+
(100). HRMS (ESI): calcd. for C16H16F3N5 [M+H]+ 336.1435;
found 336.1431.
5. a) M. Artico, R. Di Santo, R. Costi, S. Massa, A. Retico, M.
Artico, G. Apuzzo, G. Simonetti and V. Strippoli, J. Med.
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Theophanides, M. Botta, F. Corelli, S. Massa, M. Artico, R.
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K. Asai, N. Tsuchimori, K. Okonogi, J.R. Perfect, O.
Ogotoh and Y. Yoshida, Antimicrob. Agents Chemother.,
1999, 43, 1163.
1-(1-tert-Butyl-1H-imidazol-4-yl)-4-(3-methoxyphenyl)-1H-
1,2,3-triazole (1k): White solid (78%), m.p. 115-117ºC. 1H NMR
(400 MHz, DMSO-d6, 50ºC): δ= 1.60 (s, 9H, C-CH3), 3.84 (s,
3H, O-CH3), 6.93 (dd, 3JH,H = 8.2, 3JH,H = 1.8 Hz, 1H, Ar), 7.37 (t,
7. a) D.K. Dalvie, A.S. Kalgutkar, S.C. Khojasteh-Bakht, R.S.
Obach, J.P. O’Donnell, Chem. Res. Toxicol., 2002, 15, 269;
b) W.S. Horne, M.K. Yadav, C.D. Stout, M.R. Ghadiri, J.
Am. Chem. Soc., 2004, 126, 15366.
3
3JH,H = 7.9 Hz, 1H, Ar), 7.54 (t, JH,H = 5.7 Hz, 2H, Ar), 7.87 (d,
4
4JH,H = 1.6 Hz, 1H, CH-N), 7.91 (d, JH,H = 1.6 Hz, 1H, CH-C),
8.94 (s, 1H, H-5 triazole) ppm. 13C NMR (100 MHz, DMSO-d6,
50ºC): δ= 29.6 (CH3), 55.0 (CH3-O), 55.8 (C-CH3), 107.6 (C-5-
imidazole), 110.5 (Ar), 113.8 (Ar), 117.5 (Ar), 119.2 (C-5
triazole), 129.7 (Ar), 131.5 (Ar), 133.2 (C-2-imidazole), 136.3
(C-4-imidazole), 146.0 (C-4 triazole), 159.6 (Ar) ppm. IR (KBr):
ν= 3115 (C-H Ar), 1596 (C=N) cm-1. MS (APCI, 30 EV), m/z
(Irel,%): 270 [М-N2]+ (30), 298 [M+H]+ (100). HRMS (ESI):
calcd. for C16H19N5O [M+H]+ 298.1667; found 298.1669.
8. a) P. Zanirato and S. Cerini, Org. Biomol. Chem., 2005, 3,
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12. G. F. Rudakov, M. V. Dubovis Chemistry of Heterocyclic
Compounds, 2015, Vol 50, No11, 1634-1646.
13. D. V. Katorov, G. F. Rudakov, and V. F. Zhilin Russian
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12
Tetrahedron
21. K. Niedermann, N. Früh, E. Vinogradova, M. S. Wiehn,
ACCEPTED MANUSCRIPT
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