Formation of 1,2,4-triazole derivatives by oxidation of 4-phenyl-1-pivaloylsemicarbazide

Article abstract of DOI:10.1007/s10593-020-02768-4

[Figure not available: see fulltext.] Oxidation of 4-phenyl-1-pivaloylsemicarbazide leads to the formation of two structural isomers: 5-tert-butyl-5-hydroxy-4-phenyl-4,5-dihydro-3H-1,2,4-triazol-3-one and 1-tert-butyl-4-phenyl-1,2,4-triazolidine-3,5-dione

Full text of DOI:10.1007/s10593-020-02768-4

DOI 10.1007/s10593-020-02768-4
Chemistry of Heterocyclic Compounds 2020, 56(8), 1015–1020
Formation of 1,2,4-triazole derivatives by oxidation
of 4-phenyl-1-pivaloylsemicarbazide
1
1
Boris А. Gostevskii , Aleksander I. Albanov ,
1
1
Aleksander V. Vashchenko , Nataliya F. Lazareva *
1
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences,
1
Favorsky St., Irkutsk 664033, Russia;
е-mail: nataly_lazareva@irioch.irk.ru
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
Submitted November 19, 2019
Accepted after revision February 10, 2020
2
020, 56(8), 1015–1020
Oxidation of 4-phenyl-1-pivaloylsemicarbazide leads to the formation of two structural isomers: 5-tert-butyl-5-hydroxy-4-phenyl-
4
,5-dihydro-3H-1,2,4-triazol-3-one and 1-tert-butyl-4-phenyl-1,2,4-triazolidine-3,5-dione. Isomerization of 5-tert-butyl-5-hydroxy-
-phenyl-4,5-dihydro-3H-1,2,4-triazol-3-one to 1-tert-butyl-4-phenyl-1,2,4-triazolidine-3,5-dione proceeds upon heating and is
4
accompanied by the migration of the tert-butyl group from the carbon atom to the nitrogen atom.
Keywords: 4-phenyl-1-pivaloylsemicarbazide, 1,2,4-triazol-3-one, 1,2,4-triazolidine-3,5-dione, C,N-migration of tert-butyl group,
cyclization, oxidation, structural isomers.
The development of chemistry of nitrogen-containing
compounds is one of the priority directions in organic
chemistry, because the molecules of a significant part of drugs
contain nitrogen atoms and the reactions of formation of
rization. The results of studies of the light-driven dynamic
behavior of molecular systems based on azodicarboxamide
by time-resolved IR spectroscopy and quantum chemistry
methods show that conformational changes in such
1
11
the C–N bond play an important role in their synthesis. In
molecules occur by a pedal-type mechanism.
recent years, there has been a steady interest in studying
Azocarboxamides are universal azo ligands: the
presence of several functional groups in the molecule
ensures their ability to coordinate interactions of various
types.12 These compounds are convenient building blocks
in synthetic chemistry, provide a simple and selective
1
2
1
,4-disubstituted semicarbazides R NHC(O)NHNHR as
pharmacophores responsible for the anti-inflammatory,
antiviral, antibacterial, and antitumor activity of target
2
compounds. 1,4-Disubstituted semicarbazides are widely
used as building blocks in synthetic organic and medicinal
introduction of nitrogen-containing functional groups into
chemistry.3
organic compounds,
12e,13
and are successfully used in the
During the oxidation of substituted semicarbazides by
Mitsunobu reaction.14
4
typical oxidizing systems (Fe(NO
NaHSO
NaHSO
)
3 3
·9H
O, MnO –H
, NBS–Py ), azocarboxamides (diazene-
2
O, Fe(NO
3
)
3
·9H
2
O–
2
Azocarboxamides exhibit biological activity and are of
13f,15
5
6
7
4
·H
·H
2
O, FeCl
3
·6H
2
2
2
SO
4
–SiO
2
, NaNO
–
significant interest for medicinal chemistry.
In
8
9
4
2
O–SiO
2
addition, azocarboxamides containing substituents labeled
1
2
3
1
2
18
carboxamides) R R NC(O)N=NR (R , R = H, Alk, Ar;
with the isotope F are potentially useful as radioactive
3
1
2
16
R = Ar, R R NC(O)) are easily formed. Azocarboxamide
molecules contain two structural fragments that determine
the properties of this class of compounds – the azo group,
N=N–, which can induce structural changes in azo-
carboxamides upon irradiation with light, and the
carboxamide group, capable of forming intra- and
tracers for positron emission tomography. Some azo-
carboxamides have been isolated from natural products.17
Thus, lyophyllin was isolated from the fungus Lyophyllum
17
18
shimeji and showed antibiotic and teratogenic activity.
2-(4-Hydroxyphenyl)- and 2-(4-methoxyphenyl)diazene-
carboxamides, which have nematicidal activity against the
parasitic nematode Meloidogyne incognita, were isolated
1
0
intermolecular hydrogen bonds. Unlike azobenzene,
azocarboxamides are not capable of cis-trans photoisome-
17
from the fungus Lycoperdon pyriforme.
0
009-3122/20/56(8)-1015©2020 Springer Science+Business Media, LLC
1015

Chemistry of Heterocyclic Compounds 2020, 56(8), 1015–1020
The goal of this work was to develop a method for the
heterocyclic system A remains poorly studied, in contrast
to its regioisomer B (Fig. 1).
synthesis of 4-phenyl-1-pivaloylsemicarbazide (1) and to
study its reactivity. 4-Phenyl-1-pivaloylsemicarbazide (1)
was synthesized in 94% yield by acylation of 4-phenyl-
semicarbazide (2) with pivalic acid chloride in the presence
of Et N (Scheme 1).
3
Scheme 1
Figure 1. Derivatives of 4,5-dihydro-3H-1,2,4-triazol-3-one A
and 2,4-dihydro-3H-1,2,4-triazol-3-one B.
To date, only a few type A heterocycles (Fig. 1)
containing alkyl groups at position
5 have been
investigated.19 However, we have not found compounds
containing any heteroatoms at position 5. Compound 5 was
first synthesized in the reaction of 4-phenylurazole with
isobutylene (61% yield).20 1,2,4-Triazole derivatives 4 and
5 are stable at room temperature for several months,
although, as noted above, compound 4 quantitatively
transforms upon heating into its regioisomer 5.
We expected that the oxidation of compound 1 would
lead to the formation of N-phenyl-2-pivaloyldiazene-
carboxamide (3). For the oxidation of compound 1, the
NBS–Py system was chosen, since diazenecarboxamides
ArNHC(O)N=NC(O)OAlk were obtained in 90–97%
yields by the oxidation of 1,4-disubstituted semicarbazides
The mechanism for the formation of heterocycles 4 and
5 requires further study. At present, based on the analysis
of the literature data and the obtained results, one can
suggest a possible route for their formation. N-Phenyl-
2-pivaloyldiazenecarboxamide (3) and heterocycles 4, 5 are
structural isomers, and the prototropic tautomerism of
N-phenyl-2-pivaloyldiazenenecarboxamide (3) can lead to
the formation of compounds 4 and 5. Diazenecarboxamide
3 is probably formed during the oxidation of semicarbazide
1; however, under the reaction conditions, it easily cyclizes
with the formation of a mixture of compounds 4 and 5. The
9
с
according to this method. The reaction of semicarbazide 1
with NBS in the presence of pyridine takes place at room
temperature (Scheme 2). As a result of the reaction, a
1
yellow crystalline substance was isolated. Its H NMR
spectrum exhibits two peaks at 0.90 ppm and 1.43 ppm
with a 1.75:1.00 intensity ratio corresponding to two tert-
butyl groups, which indicates the possible formation of two
products. By recrystallization from CH
-hydroxy-4-phenyl-4,5-dihydro-3H-1,2,4-triazol-3-one (4)
was isolated from the resulting mixture in 38% yield
Scheme 2) in the form of yellow crystals. Heating
compound 4 forms its regioisomer 1-tert-butyl-4-phenyl-
,2,4-triazolidine-3,5-dione (5) in quantitative yield. This
2
2
Cl , 5-tert-butyl-
5
Scheme 3
(
1
1
NBS, Py
O
property was used in the isolation of compound 5 from the
reaction mixture. After removing the crystals of
heterocycle 4, the mother liquor containing a mixture of
residual 5-tert-butyl-5-hydroxy-4-phenyl-4,5-dihydro-
Ph
N
t-Bu
~
H
N
H
N
3
~ H
O
3
H-1,2,4-triazol-3-one (4) and its isomer 5 was evaporated
OH
N N
to dryness. The solid residue was heated at 130°С for
N
C
t-Bu
Ph
N
t-Bu
N
N
3
1
0 min. Subsequent recrystallization from Et
2
O afforded
Ph
O
O
H
O
-tert-butyl-4-phenyl-1,2,4-triazolidine-3,5-dione (5) as
O
colorless crystals in 41% yield.
Ph
N
t-Bu
~
H
N
N
C
Scheme 2
OH
C
Path II Path I
Ph
N
O
OH
t-Bu
Ph
N
CMe3
O
N
N
C
O
N N
H
4
Py
Ph
N
130°C, 30 min
Ph
N
O
O
O
O
Analysis of the literature data indicates that compound 4
is the first example of 4,5-dihydro-3H-1,2,4-triazol-3-one
A derivatives containing an OH group at position 5. The
N N
HN N
PyH
t-Bu
t-Bu
5
1
016

Chemistry of Heterocyclic Compounds 2020, 56(8), 1015–1020
key intermediate of this reaction is tautomer C, and its
cyclization can occur via two different routes. The first of
them (path I) is a kinetically controlled one-step process of
intramolecular cyclization with the formation of compound
4
. Path II is accompanied by an extraordinary process of
migration of the tert-butyl group from the carbon atom to
the nitrogen atom and ends with the formation of a
thermodynamically more stable product 5. This rearrange-
ment is most likely catalyzed by pyridine and proceeds
concertedly (Scheme 3).
The structures of compounds 1, 4, and 5 were proved by
NMR spectroscopy and X-ray structural analysis, as well as
by elemental analysis. The unit cell contains four
independent molecules of 4-phenyl-1-pivaloylsemicarb-
azide (1). Figure 2 shows only one of four crystallo-
graphically independent molecules. The molecules of
compound 1 form a chain with an alternating "head to
head" and "head to tail" arrangement of molecules, bonded
by two types of intermolecular hydrogen bonds.
Intermolecular three-center hydrogen bonds are formed
between the carbonyl group of the PhNHC=O fragment
and two NH groups of the urea fragment PhHNC(O)NH of
the neighboring molecule. In addition, an intermolecular
hydrogen bond exists between the t-BuC=O group and the
t-BuC(O)NH fragment of the neighboring molecule
Figure 2. Molecular structure of compound 1 with atoms
represented as thermal vibration ellipsoids of 50% probability.
The molecular structure of compound 4 is shown in
Figure 4a, the geometric parameters of this heterocycle are
close to those of 1,2,4-triazol-3-one derivatives.1 In the solid
state, compound 4 has an intermolecular bifurcation hydrogen
bond as a result of the interaction of the C=O group with
the OH groups of two neighboring molecules. A short
OH···O=C bond (l 2.034 Å) leads to the formation of di-
9a,b
Table 1. Lengths of hydrogen bonds (Å) between the molecules
of compound 1
The arrangement of molecules in the
solid state
(
Fig. 3a). These hydrogen bonds lead to the formation of
Hydrogen bond
"
head to head"
"head to tail"
an infinite helical structure (Fig. 3b). It should be noted that
the lengths of these bonds are somewhat different for
molecules with the "head to head" and "head to tail"
arrangement (Table 1).
PhNHC=O···HN(Ph)C(O)NH
PhNHC=O···HNC(O)NHPh
t-BuC=O···HNC(O)t-Bu
1.985
1.999
2.430
2.421
2.034
2.018
Figure 3. Hydrogen bonds in the solid state of compound 1: a) intermolecular bonds between three semicarbazide molecules 1,
b) an infinitive helical structure composed of hydrogen-bonded molecules of semicarbazide 1 (l, Å).
1
017

Chemistry of Heterocyclic Compounds 2020, 56(8), 1015–1020
mers, which are linked into a continuous polymeric chain as a
result of a longer OH···O=C bonding (l 2.541 Å) (Fig. 4b).
The molecular structure of compound 5 is shown in
Figure 5a. The existence of an intermolecular hydrogen
bond NH···O=C (l 1.898 Å) leads to the formation of
dimers (Fig. 5b). Similar structural assemblies are
described for 4-phenylurazole derivatives containing an
2
1
unsubstituted NH group.
Figure 5. a) Molecular structure of compound 5 with atoms
represented as thermal vibration ellipsoids of 50% probability
and b) hydrogen bonds in the solid state of compound 5 (l, Å).
Butyl-5-hydroxy-4-phenyl-4,5-dihydro-3H-1,2,4-triazol-3-one
is the first example of 1,2,4-triazol-3-ones containing the
OH group in position 5. Its rearrangement into the
thermodynamically more stable 1-tert-butyl-4-phenyl-1,2,4-
triazolidine-3,5-dione is accompanied by an extraordinary
migration of the tert-butyl group from the carbon atom to
the nitrogen atom.
Experimental
IR spectra were registered on a Varian 3100 spectro-
1
13
meter in petroleum jelly. Н and С NMR spectra were
acquired on Bruker DPX-400 and Bruker AV-400
Figure 4. a) Molecular structure of compound 4 with atoms
represented as thermal vibration ellipsoids of 50% probability
and b) hydrogen bonds in the solid state of compound 4 (l, Å).
spectrometers (400 and 100 MHz, respectively) in DMSO-d
6
(compound 1) and CD CN (compounds 4 and 5), with
3
TMS as internal standard. Elemental analysis was
performed on a Thermo Scientific Flash 2000 CHNS-
analyzer. Melting points were determined on a Boetius
heating bench.
To conclude,
a
previously unknown 4-phenyl-
1
-pivaloylsemicarbazide was synthesized. Its oxidation by
the NBS–pyridine system led to the formation of two
heterocycles, 5-tert-butyl-5-hydroxy-4-phenyl-4,5-dihydro-
Before use, solvents and reagents were prepared
3
H-1,2,4-triazol-3-one and 1-tert-butyl-4-phenyl-1,2,4-
according to standard procedures.22
triazolidine-3,5-dione in a 1.75:1.00 ratio according to
N-Phenyl-2-pivaloylhydrazine-1-carboxamide (1). A
solution of pivaloyl chloride (5.58 g, 46.3 mmol) in
anhydrous MeCN (10 ml) was added dropwise over 3 h to
a solution of 4-phenylsemicarbazide (2) (7.00 g, 46.3 mmol)
1
H NMR spectroscopy. The structure of the compounds has
been proven by NMR spectroscopy and X-ray structural
analysis. Each of these heterocycles is of interest for
synthetic organic chemistry and medicinal chemistry. 5-tert-
and Et N (9.37 g, 92.6 mmol) in MeCN (40 ml). The
3
1
018

Chemistry of Heterocyclic Compounds 2020, 56(8), 1015–1020
reaction mixture was heated under reflux for 1 h. Volatile
organic compounds were removed under reduced pressure,
and the white solid was stirred with H O (50 ml). The
O (3×20 ml),
software package.23 The positions of non-hydrogen atoms
were refined in the anisotropic approximation using the
SHELX program.23 The full set of X-ray structural data for
compounds 1, 4, and 5 was deposited at the Cambridge
Crystallographic Data Center (deposits CCDC 1922936,
CCDC 1922937, and CCDC 1922938, respectively).
2
precipitate was filtered off, washed with H
dried under reduced pressure, and recrystallized from
2
i-PrOH. Yield 10.20 g (94%), white powder, mp 217–218°С.
–1
IR spectrum, ν, cm : 3325 (NH), 3215, 3148, 3108, 1693
1
Supplementary information file containing Н and 13С
NMR spectra, as well as X-ray structural analysis data for
compounds 1, 4, and 5, can be accessed at the journal
website at http://link.springer.com/journal/10593.
1
(
C=O), 1643. H NMR spectrum, δ, ppm: 1.16 (9Н, s,
C(CH ) ); 6.94–7.00 (1Н, m, H-4); 7.24–7.30 (2Н,
3
3
m, H-3,5); 7.42–7.44 (2Н, m, H-2,6); 7.81 (1Н, br. s,
PhNHC(O)NH); 8.71 (1H, s, PhNH); 9.34 (1Н, br. s,
13
t-BuC(O)NH). C NMR spectrum, δ, ppm: 27.2 (C(CH
3 3
) );
3
1
%
7.5 (CMe
39.6 (С-1); 155.7 (PhNHC=O); 178.0 (t-BuC=O). Found,
: С 61.30; H 7.32; N 17.80. C12 . Calculated, %:
3
); 118.3 (C-2,6); 122.1 (С-4); 128.8 (C-3,5);
This work was financially supported by the Russian
Foundation for Basic Research (grant 19-03-00143) using
analytical equipment of the Baikal Center for Collective Use
of the Siberian Branch of the Russian Academy of Sciences.
H
17
N
3
O
2
С 61.26; H 7.28; N 17.86.
Oxidation of compound 1. NBS (3.72 g, 21.0 mmol)
was gradually with vigorous stirring added over 1 h to a
mixture of compound 1 (4.72 g, 20.0 mmol), pyridine (3.16 g,
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0.0 mmol), and CH
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·6H
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.
5
-tert-Butyl-5-hydroxy-4-phenyl-4,5-dihydro-3H-1,2,4-
2
007, Vol. 42, p. 229.
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2
–1
1
28°С. IR spectrum, ν, cm : 3351 (OH), 1756 (C=O).
1
H NMR spectrum, δ, ppm: 0.90 (9H, s, C(CH
3
)
3
); 5.91
1H, s, OH); 7.38–7.49 (5H, m, H Ph). C NMR spectrum,
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C-2',6'); 129.1 (C-4'); 130.3 (С-3',5'); 136.4 (С-1'); 158.5
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1
3
(
5
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3
)
3
3
4
301.
(
(
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H
15
N
3 2
O .
Calculated, %: С 61.79; Н 6.48; N 18.01.
1-tert-Butyl-4-phenyl-1,2,4-triazolidine-3,5-dione (5).
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20
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–
1
IR spectrum, ν, cm : 3166 (NH), 3060, 1761 (C=O), 1697.
2
002, 49, 397.
1
H NMR spectrum, δ, ppm: 1.43 (9Н, s, C(CH ) ); 7.37–
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13
7
.50 (5Н, m, H Ph); 8.20 (1Н, br. s, NH). C NMR
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3
)
3
3
(
1
was performed on a Bruker D8 Venture diffractometer,
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1
2
(
1
019

Chemistry of Heterocyclic Compounds 2020, 56(8), 1015–1020
1
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