Reaction of carbohydrazide with 1,2-dicarbonyl compounds

Article abstract of DOI:10.1007/s10593-012-1018-y

The reaction of carbohydrazide with 1,2-dicarbonyl compounds yields a series of ylidene derivatives, namely, mono- or bishydrazones, 5-hydroxy-, 5-alkoxy, or 5-methylene-4,5-dihydro-2H-[1,2,4]triazin-3-ones depending on the structure of the dicarbonyl compound and nature of the solvent.

Full text of DOI:10.1007/s10593-012-1018-y

Chemistry of Heterocyclic Compounds, Vol. 48, No. 3, June, 2012 (Russian Original Vol. 48, No. 3, March, 2012)
REACTION OF CARBOHYDRAZIDE WITH
1,2-DICARBONYL COMPOUNDS
V. V. Alekseyev1*, A. G. Saminskaya1, and S. I. Yakimovich2
The reaction of carbohydrazide with 1,2-dicarbonyl compounds yields a series of ylidene derivatives,
namely, mono- or bishydrazones, 5-hydroxy-, 5-alkoxy, or 5-methylene-4,5-dihydro-2H-[1,2,4]triazin-
3-ones depending on the structure of the dicarbonyl compound and nature of the solvent.
Keywords: carbohydrazones, 1,2-dicarbonyl compounds, 1,2,4-triazines.
1
In our previous work [1], H NMR, 13C NMR, and mass spectral data showed that the reaction of
1,2-dicarbonyl compounds with thiocarbohydrazide and its 1- and 1,4-substituted analogs may yield a series of
derivatives, whose structure depend both on the structure of the reactants and nature of the solvent used. Thus,
for example, compounds with monohydrazone structure and 5-methylene-4,5-dihydro-2H-[1,2,4]triazine-
3-thiones are formed using diacetyl. Reaction of phenylglyoxal and benzil with thiocarbohydrazide in alcohol
solutions results in the corresponding 5-alkoxy-4,5-dihydro-2H-[1,2,4]triazine-3-thiones. The derivatives
arising in the reaction of phenylglyoxal and benzil with 1,1-dimethylthiocarbohydrazide display an original
ring-chain tautomeric equilibrium involving thiocarbohydrazones and 5-hydroxy-4,5-dihydro-2H-[1,2,4]tria-
zine-3-thiones in solutions.
In a continuation of this work, we undertook a study of the reaction of 1,2-dicarbonyl compounds with
carbohydrazide, which is an oxygen analog of the previously used polynucleophile. We have chosen diacetyl
and benzil as starting objects of investigation. In early works [2], the products of condensation of these
1,2-diketones with carbohydrazide were considered as corresponding hydrazones.
R
N
R
N
N
R
H
H
N
N
R1OH
.
O
O
N N
H
N
H
R
1
_______
*To whom correspondence should be addressed, e-mail: alekseyevv.v@mail.ru.
1S. M. Kirov Military Medical Academy, 6 Akademika Lebedeva St., Saint Petersburg 194044, Russia.
2St. Petersburg State University, 2 Universitetskii Ave., Saint Petersburg 198504, Russia; e-mail:
viktoriapakalnis@mail.ru.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 506-511, March, 2012. Original
article submitted March 24, 2011.
476
0009-3122/12/4803-0476©2012 Springer Science+Business Media, Inc.

In later studies, the compounds isolated upon carrying out the reaction in methanol in the presence of
hydrochloric acid were assigned macroheterocyclic structure 1 [3-8] derived from two molecules of the
substrate and two molecules of the polynucleophile.
Our investigation has shown that the final result of the reaction of diacetyl with carbohydrazide depends
significantly on the selected conditions. Thus, maintaining equivalent amounts of the reagents in water at room
temperature gave the biscarbohydrazone of diacetyl 3, which is formed upon the condensation of the two
carbohydrazide NH2 functions with two 1,2-diketone molecules. This conclusion follows, primarily, from the
1
elemental analysis (Table 1) and mass spectral data (m/z 226 [M]+). The H NMR spectrum of an isolated
product 3 solution in DMSO-d6 has signals at 1.94, 2.39, and 10.29 ppm with intensity ratio 3:3:1. These signals
may be assigned to the protons of the methyl groups at the C=N and C=O bonds and protons at the nitrogen
atoms. The most likely structure has symmetrical (Z,Z)-configuration relative to the C=N bonds, which permits
intramolecular chelation. The 13C NMR spectrum of biscarbohydrazone 3 is in accord with the proposed
1
13
structure (Table 2). We note that the shape of the H and C NMR spectra of biscarbohydrazone 3 does not
change over time, indicating the lack of transition to alternative geometrical isomers relative to the C=N bonds.
Biscarbohydrazone 3 is also formed when the reaction is carried out in methanol with ice cooling using a 1:2
ratio of carbohydrazide and diacetyl.
O
H2N
NH2
N
N
H
H
O
O
Me
N
N
R
N
N
NH
(R = Me)
– H2O
NH
H2N
N
+
HO
R
N
N
R
H
H
H2C
O
O
O
O
R
R
NH2
5
2a,b
NH2
4a,b
R
O
O
(R = Me)
R1OH
Me
Me
(R = Ph)
Ph
O
O
O
N
N
NH
O
N
N
N
1O
R
Me
N
H
Me
H
Ph
Me
Me
3
NH2
6a,b
2, 4 a R = Me, b R = Ph; 6 a R1 = Me, b R1 = Et
The reaction of equimolar amounts of diacetyl and carbohydrazide under milder conditions (ice cooling
in methanol or water) leads to a precipitate. The 1H and 13C NMR spectra (Table 2) suggest that the precipitate
is a mixture, consisting of the biscarbohydrazone of diacetyl 3, 5-hydroxy-4,5-dihydro-2H-[1,2,4]triazin-3-one
4a, and a compound with spectral data similar to macroheterocycle 1 studied in earlier work [3-5]. The ratio of
products 1, 3, and 4a in the isolated reaction mixture was approximately 2:2:1. The bishydrazone was identified
using the methyl group signals at 1.94 and 2.39 ppm in the 1H NMR spectrum of this mixture and the signals for
13
C=N and C=O carbon atoms at 147.7, 150.5, and 197.0 ppm in the C NMR spectrum, which is in complete
accord with previously examined spectra of bishydrazone 3 isolated as a pure compound after carrying out the
reaction in water.
The 5-hydroxytetrahydrotriazine component of the mixture 4a was reliably identified using the signal
for the hydroxyl proton at 7.80 ppm in the 1H NMR spectrum and characteristic resonance signal for quaternary
carbon C-5 at 86.7 ppm in the 13C NMR spectrum [7, 8].
477

TABLE 1. Physicochemical Characteristics of Compounds 3, 4b, 6a,b
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Mp, °C
Yield, %
С
Н
N
C9H14N4O3
C15H14N4O2
C16H16N4O2
C17H18N4O2
47.65
47.78
63.68
63.82
64.98
64.85
65.88
65.79
6.34
6.24
5.16
5.00
5.56
5.44
5.76
5.85
24.85
24.76
19.69
19.85
18.79
18.91
18.19
18.05
195-196
233-235
180-182
218-220
78
68
76
49
3
4b
6a
6b
TABLE 2. 1H and 13C NMR Spectra of Compounds 1, 3-6
Chemical shifts (DMSO-d6), , ppm (J, Hz)
Com-
pound
1Н NMR spectrum
R, СН2
13С NMR spectrum
NH, OH (s)
С=О
С-5, С=N
R
2.15 (12Н, s, 4СН3)
9.98 (4NH)
159.6
137.9
147.7
10.8
1
3
1.94 (6Н, s, 2СН3);
10.29 (2Н, 2NH) 150.5;
9.3; 24.4
2.39 (6Н, s, 2СОСН3)
197.0
1.90 (3Н, s, СН3);
2.04 (3Н, s, СН3)
4.15 (2Н, NH2);
7.80 (1H, ОН);
9.61 (1H, NH)
151.3
86.7; 141.9 10.8; 18.8
81.8; 141.7 126.5-141.9
4a
4b
5
7.10-7.60 (10H, m, H Ph)
4.05 (2Н, NH2);
7.90 (1Н, ОН);
10.68 (1Н, NH)
150.2
2.03 (3Н, s, СН3);
4.95 (2Н, NH2);
4.25 (1Н, d, Jgem = 0.9) and
4.63 (1Н, d, Jgem = 0.9, =CH2)
10.70 (1H, NH)
6a*
7.10-7.60 (10H, m, H Ph)
4.14 (2Н, NH2);
11.03 (1Н, NH)
150.9
150.8
91.4; 140.2 126.6-140.8
90.7; 141.2 126.6-141.2
6b*2
7.10-7.60 (10H, m, H Ph)
4.08 (2Н, NH2);
11.07 (1Н, NH)
_______
*Methoxy group signal: 3.24 ppm (protons), 50.1 ppm (carbon).
*2Ethoxy group signals: protons – 1.27 (3H, t, J = 6.9, CH3); 3.30 (1H, dq, J =
8.9, J = 6.9); 3.51 ppm (1H, dq, J = 8.9, J = 6.9, CH2); carbon atoms – 14.7 and
58.2 ppm.
In contrast to the pure biscarbohydrazone 3, the shape of the 1H NMR spectrum of the discussed product
mixture of the diacetyl reaction with carbohydrazide changes over time. Upon maintenance of the solution in
DMSO-d6, two doublets arise at 4.25 and 4.63 ppm with coupling constant 0.9 Hz, indicating formation of a
new species, 5-methylene-4,5-dihydro-2H-[1,2,4]triazin-3-one (5) comprising about 10% of the mixture (Table
2) due to compound 4a dehydration. The above-mentioned doublets may be reliably assigned to the geminal
protons at the C=C(5) bond. Support for this hypothesis is found in a comparison with the spectral data of 5-
methylene-4,5-dihydro-2H-[1,2,4]triazine-3-thione obtained and isolated as a pure compound in the reaction of
diacetyl with thiocarbohydrazide [1].
Unfortunately, we were unable to separate the components of the mixture formed in the reaction of
diacetyl with carbohydrazide either by recrystallization or chromatography.
The synthesis of compounds 1, 3, and 4a surely proceeds through the initial formation of
monohydrazone 2a. Thus, macrocyclic structure 1 may be formed due to the conversion of monohydrazone 2a
into bishydrazone 3 upon reaction with an additional diacetyl molecule, subsequent condensation with second
478

equivalent of carbohydrazide at one of the carbonyl groups, and further intramolecular cyclization, leading to
macrocycle 1. Triazinone 4a is a cyclic tautomer of monohydrazone 2a and is formed by cyclization upon attack
of the amide NH group at the carbonyl function.
Carrying out the synthesis in ethanol at reflux leads to the formation of a precipitate, which, as shown
by Guha [2], is virtually insoluble in ordinary solvents. Guha et. al. [2] described this product as the diacetyl
monocarbohydrazone. However, the poor solubility and high melting point (285-288°C) are more
likely evidence for oligomeric structure, which was previously noted for its sulfur analogs, namely, derivatives
of thiocarbohydrazide with glyoxal [3, 4]. We observed similar behavior in attempt to obtain macrocycle 1 by
the reaction of the diacetyl biscarbohydrazone 3 with carbohydrazide in methanol.
The reaction in methanol in the presence of about 5 vol% hydrochloric acid, by analogy with previous
works [3-5], leads to a complex mixture of products, which could not be separated or even identified.
The reaction of benzil with carbohydrazide in various solvents proceeds extremely slowly even at
elevated temperature. The reaction in benzene at reflux in the presence of catalytic amounts of trifluoroacetic
acid gives 5-hydroxy-4,5-dihydro-2H-[1,2,4]triazin-3-one 4b as the product. The cyclic triazine structure is
1
indicated by the broad signal at 7.90 ppm in the H NMR spectrum, which can be assigned to the OH group
proton. The 13C NMR spectrum shows a resonance signal at 81.8 ppm, unequivocally indicating cyclic structure
of the reaction product (quaternary ring carbon atom C-5) [1, 5, 9]. The signals for the carbon atoms of the C=N
and C=O groups are found at 141.7 and 150.2 ppm, respectively.
Carrying out the reaction in methanol or ethanol permits us to obtain 5-alkoxy derivatives 6a,b (Tables
1 and 2) (m/z 296 [M]+ and 310 [M]+, respectively). The 5-alkoxy-4,5-dihydro-2H-[1,2,4]triazin-3-one structure
of these compounds follows from the NMR spectral data. In particular, the 1H NMR spectra show signals for the
amino group protons at 4.08-4.14 ppm and for the amide proton at 11.0 ppm. The 13C NMR spectra have a
signal for C-5 at 90-91 ppm. These results are quite similar to the data for the analogous cyclic 5-alkoxy
derivatives formed in the reaction of 1,2-dicarbonyl compounds with semicarbazide, thiosemicarbazide [7-9],
and thiocarbohydrazide [1].
The formation of triazin-3-ones 6a,b evidently proceeds due to nucleophilic replacement of the hydroxy
group by an alkoxy group in intermediate 5-hydroxy-4,5-dihydro-2H-[1,2,4]triazin-3-one 4b. Additional
evidence for this hypothesis was found in the virtually quantitative formation of triazin-3-one 6a upon heating
triazin-3-one 4b in methanol at reflux for 5 h in the presence of catalytic amounts of trifluoroacetic acid.
Even partial formation of the benzil and carbohydrazide reaction product in 2:1 ratio was not observed
upon the reaction of these reagents, which is characteristic for the reaction of diacetyl with this polynucleophile.
This failure possibly reflects the complete inability of cyclic form 4b to undergo even partial transition to an
open monohydrazone structure, in which the NH2 group is more sterically accessible for condensation with a
second 1,2-diketone molecule.
These studies have shown that the reaction of 1,2-dicarbonyl compounds with carbohydrazide upon the
proper selection of reaction conditions may be used for the synthesis of triazine heterocycles.
EXPERIMENTAL
1
13
The H and C NMR spectra were recorded on a Bruker WM-400 spectrometer at 400 and 100 MHz,
respectively, in DMSO-d6 with HMDS as internal standard ( 0.05 ppm). The electron impact mass spectra were
recorded on a Finnigan MAT 95 mass spectrometer. The ionizing electron energy was 70 eV. The elemental
analysis of the products was carried out on a Carlo Erba Strumentazione Model 1105 analyzer. The course of
the reactions and purity of the products were monitored by thin-layer chromatography on Silufol UV-254 plates
with development by iodine vapor.
The characteristics of products 3, 4b, and 6a,b are given in Table 1.
479

Reaction of Carbohydrazide with Diacetyl. A suspension of carbohydrazide (0.180 g, 2 mmol) in
methanol (10 ml) was mixed upon ice cooling with solution of diacetyl (0.172 g, 0.18 ml, 2 mmol) in methanol
(10 ml). The mixture was left for 24 h at 0°C. The precipitate was filtered off and washed with methanol and
1
ether to give 0.270 g of an approximately 2:2:1 mixture of compounds 1, 3, and 4a as indicated by H NMR
spectroscopy.
Diacetyl Biscarbohydrazone (3). A suspension of carbohydrazide (0.180 g, 2 mmol) in water (10 ml)
was mixed at room temperature with solution of diacetyl (0.344 g, 0.35 ml, 4 mmol) in water (5 ml). The
mixture was maintained for 24 h at this temperature. The precipitate was filtered off and washed with ether to give
0.350 g (78%) of biscarbohydrazone 3.
4-Amino-5-hydroxy-5,6-diphenyl-4,5-dihydro-2H-[1,2,4]triazin-3-one (4b). A mixture of carbo-
hydrazide (0.18 g, 2 mmol) with a solution of benzil (0.42 g, 2 mmol) in benzene (20 ml) was heated at reflux
for 15 h with a catalytic amount of trifluoroacetic acid. The precipitate was filtered off, washed with benzene,
and dried in vacuum to give 0.38 g (68%) of triazinone 4b.
4-Amino-5-methoxy-5,6-diphenyl-4,5-dihydro-2H-[1,2,4]triazin-3-one (6a). A. A solution of
carbohydrazide (0.18 g, 2 mmol) and benzil (0.42 g, 2 mmol) in methanol (20 ml) was heated at reflux for 15 h
with a catalytic amount of trifluoroacetic acid. The solvent was removed from the mother liquor in vacuum. The
residue was recrystallized from 1:4 benzene–hexane mixture and dried in vacuum to give 0.45 g (76%) of
triazinone 6a (Rf 0.55, 1:1 benzene–acetone as eluent).
B. A suspension of triazinone 4b (0.282 g, 1 mmol) in methanol (20 ml) with a catalytic amount of
trifluoroacetic acid was heated at reflux for 30 min, after which the solution became transparent. Heating at
reflux was continued for an additional 4.5 h. The solvent was removed from the mother liquor in vacuum. The
residue was recrystallized from 1:4 benzene–hexane mixture and dried in vacuum to give 0.275 g (93%) of
triazinone 6a.
4-Amino-5-ethoxy-5,6-diphenyl-4,5-dihydro-2H-[1,2,4]triazin-3-one (6b). A solution of carbo-
hydrazide (0.180 g, 2 mmol) and benzil (0.420 g, 2 mmol) in ethanol (20 ml) was heated at reflux for 15 h with
a catalytic amount of trifluoroacetic acid. The precipitate (0.110 g) was separated. The solvent was removed
from the mother liquor in vacuum. The residues was combined with the precipitate and recrystallized from 1:3
benzene–hexane mixture. The product was dried in vacuum to give 0.305 g (49%) of triazinone 6b (Rf 0.60, 1:1
benzene–acetone as eluent).
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