1,2,4-Triazines - Products of reaction of thiocarbohydrazide and its alkyl(aryl)-substituted derivatives with 1,2-dicarbonyl compounds

Article abstract of DOI:10.1007/s10593-010-0610-2

The reaction of a series of 1,2-dicarbonyl compounds with thiocarbohydrazide and its 1- and 1,4-alkyl-(aryl)-substituted analogs has been studied. Treatment of diacetyl with the polynucleophiles indicated gives monohydrazones and/or 5-methylene-4,5-dihydr

Full text of DOI:10.1007/s10593-010-0610-2

Chemistry of Heterocyclic Compounds, Vol. 46, No. 8, 2010
1,2,4-TRIAZINES – PRODUCTS OF REACTION
OF THIOCARBOHYDRAZIDE AND ITS
ALKYL(ARYL)-SUBSTITUTED DERIVATIVES
WITH 1,2-DICARBONYL COMPOUNDS
V. V. Alekseyev1*, I. V. Lagoda2, S. I. Yakimovich3, and M. B. Yegorova1
The reaction of a series of 1,2-dicarbonyl compounds with thiocarbohydrazide and its 1- and 1,4-alkyl-
(aryl)-substituted analogs has been studied. Treatment of diacetyl with the polynucleophiles indicated
gives monohydrazones and/or 5-methylene-4,5-dihydro-2H-[1,2,4]triazine-3-thiones. Reaction of
phenylglyoxal and benzil with thiocarbohydrazide yields 5-hydroxy- or 5-alkoxy-4,5-dihydro-
2H-[1,2,4]triazine-3-thiones depending on the nature of the solvent. The products of condensation with
1,1-dimethylthiocarbohydrazide showed a thiocarbonohydrazone – 5-hydroxy-4,5-dihydro-2H-[1,2,4]tri-
azine-3-thione ring-chain type equilibrium.
Keywords: 1,2-dicarbonyl compounds, thiocarbonohydrazones, 1,2,4-triazines, ring-chain tautomerism.
Thiocarbonohydrazones of mono- and 1,3-dicarbonyl compounds show a clear trend towards ring-chain
and ring-linear-ring tautomeric conversion amongst various nitrogen- and sulfur-containing heterocycles [1].
Data regarding the structure of the condensation products of 1,2-dicarbonyl compounds and thiocarbohydrazide
and its analogs and also their tendency towards tautomeric conversion is quite contradictory [2-10].
Treatment of phenylglyoxal hydrate with thiocarbohydrazide in benzene gives the corresponding
5-hydroxy-4,5-dihydro-2H-[1,2,4]triazine-3-thione while reaction in ethanol forms the 5-ethoxy analog [11].
1-Phenylthiocarbohydrazide and diacetyl gave the 5-methylene-4,5-dihydro-2H-[1,2,4]triazine-3-thione derivative.
In continuation of these investigations we have studied the reaction of diacetyl, phenylglyoxal hydrate,
and benzil with thiocarbohydrazide and its 1-alkyl(aryl)-, 1,1-dialkyl-, and 1,1,4-trialkyl-substituted derivatives.
Reaction of diacetyl with thiocarbohydrazide under mild conditions (1:1 molar ratio of reagents,
1
methanol, cooling in ice) gives a mixture which H NMR spectroscopy shows to contain about 30% of the
monohydrazone 1 and 70% of the 5-methylene-4,5-dihydro-2H-[1,2,4]triazine-3-thione 5. The latter was
1
13
separated in the pure state by extraction with hexane and was characterized by H and C NMR spectroscopy
1
(Tables 1 and 2). The H NMR spectrum of compound 5 indicates the geminal protons on the C=C(5) bond
_______
* To whom correspondence should be addressed, e-mail: alekseyevv.v@mail.ru.
1Russian Military Medical Academy, Saint-Petersburg 194044.
2Scientific Research Test Center (Medical and Biological Defence) of the Federal State Research Test Institute
of Military Medicine, Defence Ministry of Russian Federation, Saint-Petersburg 195043, Russia; e-mail:
lagodai@peterstar.ru.
3Saint Petersburg State University, Saint Petersburg 198504, Russia; e-mail: viktoriapakalnis@mail.ru.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1202-1216, August, 2010.
Original article submitted November 18, 2009.
0009-3122/10/4608-0971©2010 Springer Science+Business Media, Inc.
971

13
appearing as two doublet signals at 4.50 and 4.95 ppm (J = 1.5 Hz). The C NMR spectrum shows resonance
signals for carbon atoms at 88.94, 132.75, and 167.39 ppm which can be rationalized as due to the CH2= group,
the carbon atom at position 5 of the heterocycle, and the C=S bond respectively. This data is practically the same
as for the model structured 5-methylene-1,2,4-triazoline compounds which are the products of reaction of
thiosemicarbazide and its substituted analogs with 1,2-dicarbonyl compounds [12, 13]. The hydrazone 1 could
not be obtained in a pure state as attempts to separate it from the reaction mixture using TLC gave samples
containing both compound 1 and a certain amount of the methylene derivative 5. Formation of this latter
compound can be explained through conversion of monohydrazone 1 to the corresponding 5-hydroxy-
2H-[1,2,4]triazoline-3-thione and its subsequent dehydration.
Me
N
NR2
CNR2N
S
R2
RR1
RR1
NNH
NH2
MeC CMe
NNHCN
S
C(Me)COMe
+
–H2O
–H2O
H2C
S
N
N
O
O
1–3
RR1
5–10
R = R1 = R2 = H
MeC CMe
–H2O
O
O
HN
MeCOC(Me)
CN
NNH
C(Me)COMe
S
4
1–3, 5–7 R= H; 8, 9 R = Me; 1, 5 R1 = H; 2, 6 R1 = i-Pr; 3, 7 R1 = Ph; 8, 9 R1 = Me;
1–3, 5–8, 10 R2 = H; 9 R2 = Me; 10 R+R1 = МеСОС(Ме)=
It should be noted that hydrazone 1 presents as a single geometric isomer, evidently with a (Z)-configura-
tion relative to the C=N bond and allowing the formation of a chelating intramolecular hydrogen bond (IHB)
involving the NH and C=O bonds.
TABLE 1. 1H NMR Spectra of Compounds 1-10
Com-
pound
Chemical shifts, δ, ppm (J, Hz)*
1
2
3
4
5
6
1.94 (3Н, s, СН3C=N); 2.40 (3Н, s, СН3C=O); 4.85 (2H, s, NH2); 8.90 (1H, br. s, NHCS);
10.12 (1H, s, NHCS)
0.96 (6H, d, J = 5.9, CH(CH3)2); 1.98 (3Н, s, СН3C=N); 2.36 (3Н, s, СН3C=O);
3.2-3.6 (1H, m, CH(CH3)2); 5.05 (1H, br. s, NH); 8.50 (1Н, br. s, NHCS); 10.12 (1H, s, NHCS)
1.95 (3Н, s, СН3C=N); 2.40 (3Н, s, СН3C=O); 6.7-7.3 (5Н, m, C6H5); 7.90 (1H, s, NH);
8.75 (1Н, br. s, NHCS); 10.14 (1H, s, NHCS)
2.04 (6Н, s, СН3C=N); 2.25-2.55 (6H, br. s, CH3C=O); 10.10 (1H, s, NHCS);
10.52 (1H, s, NHCS)
2.03 (3Н, s, СН3C=N); 4.50 (1Н, d, J = 1.5, СН(Н)=C(5));
4.95 (1Н, d, J = 1.5, СН(Н)=C(5)); 5.10 (2H, s, NH2); 9.92 (1H, s, NHC=S)
0.98 (6H, d, J = 5.9, CH(CH3)2); 2.02 (3Н, s, СН3C=N); 3.2-3.6 (1H, m, CH(CH3)2);
4.45 (1Н, d, J = 0.9, СН(Н)=C(5)); 5.11 (1Н, d, J = 0.9, СН(Н)=C(5));
5.60 (1H, d, J = 6.0, NH); 9.85 (1H, s, NHC=S)
2.02 (3Н, s, СН3C=N); 4.50 (1Н, d, J = 0.8, СН(Н)=C(5)); 4.96 (1Н, d, J = 0.8, СН(Н)=C(5));
6.7-7.3 (5Н, m, C6H5); 7.40 (1H, s, NH); 9.62 (1H, s, NHC=S)
7
8
1.93 (3Н, s, СН3C=N); 2.95 (6Н, s, N(CH3)2); 4.40 (1Н, d, J = 1.0, СН(Н)=C(5));
5.08 (1Н, d, J = 1.0, СН(Н)=C(5)); 9.52 (1H, s, NHC=S)
9
1.98 (3Н, s, СН3C=N); 2.98 (6Н, s, N(CH3)2); 3.65 (3H, s, NCH3);
4.32 (1Н, d, J = 1.0, СН(Н)=C(5)); 4.92 (1Н, d, J = 1.0, СН(Н)=C(5))
10
1.86 (3Н, s, СН3C=N); 2.02 (3Н, s, СН3C=N); 2.55 (3Н, s, СН3C=O);
4.30 (1Н, d, J = 0.9, СН(Н)=C(5)); 4.46 (1Н, d, J = 0.9, СН(Н)=C(5)); 12.14 (1H, s, NHCS)
_______
Spectra recorded in CDCl3 (compounds 1-9) or DMSO-d6 (compound 10).
972

Reaction of diacetyl with thiocarbohydrazide in water in a 2:1 molar ratio gave a precipitate which
according to NMR spectroscopic (Tables 1 and 2) and mass-spectroscopic data (m/z 242 [M]+), is the product of
reaction of two molecules of diacetyl with one molecule of thiocarbohydrazide (compound 4) and most likely
with a (Z,Z)-configuration. Its NMR spectrum shows two NH signals at 10.10 and 10.52 ppm of comparable
intensity. Evidently this involves two stereoisomers with a (Z,Z)-configuration relative to the C=N bond but with
different positioning relative to the thioamide bond. The 13C NMR spectroscopic data was also in agreement
with doubling of the carbon signals (Table 2). The NMR spectrum of the reaction product obtained after
removal of solvent showed both compound 4 and also the presence of the methylene derivative 10 which arises
by loss of water from the product of intramolecular cyclization of compound 4. This is demonstrated by the
1
doublet signals for the methylene protons at 4.30 and 4.46 ppm in the H NMR spectrum of compound 10 and
also the 13C NMR signals at 90.06 (CH2=), 131.12 (C(5)), and 177.26 ppm (C=S). This data also correlates with
the spectroscopic parameters discussed above for the methylene compound 5 which is the product of reaction of
equimolar amounts of thiocarbohydrazide and diacetyl. It should additionally be noted that the 13C NMR
spectrum of compound 10 shows carbon signals for three methyl groups and for the C=N and C=O bonds.
Holding compound 4 in CDCl3 for a prolonged time showed no kind of change in its 1H NMR spectrum
but dissolving it in DMSO-d6 showed the presence of about 10% of the methylene derivative 10. The fraction of
compound 10 gradually increases and after 2 weeks reaches 50%. Holding it for longer leads to its
decomposition.
Carrying out the reaction of diacetyl with 1-phenylthiocarbohydrazide without solvent gave the
monohydrazone 3 (Table 1) as the sole product. This exists in CDCl3 solution as a singly configured isomer
which is likely to have the (Z)-configuration relative to the C=N bond for the same reason as discussed before.
1
Reaction in methanol or chloroform gives a product which H NMR spectroscopic data shows to be a
mixture of the monohydrazone 3 and 6-methyl-5-methylene-4-phenylamino-4,5-dihydro-2H-[1,2,4]triazine-
3-thione (7). Compounds 3 and 7 were separated in the pure state using TLC. The methylene structure of the
latter was identified specifically by the presence in the 1H NMR spectrum of methylene proton doublets at 4.50
and 4.96 ppm.
TABLE 2. 13C NMR Spectra of Compounds 4-6, 8-11, 13, 15-17
Com-
pound
Chemical shifts, δ, ppm*
4
9.14 (CH3С=N); 9.42 (CH3C=N); 24.37 (2CH3C=O); 146.87 (C=N); 151.29 (C=N);
176.00 (C=S); 195.55 (C=O); 197.46 (C=O)
5
6
18.76 (СН3C=N); 88.94 (СН2=); 132.75 (C-5); 145.75 (C=N); 167.39 (C=S)
18.82 (СН3C=N); 19.24 (CH(СН3)(CH3)); 19.59 (CH(СН3)(CH3)); 48.10 (CH(CH3)2);
89.90 (СН2=); 134.19 (C-5); 146.45 (C=N); 170.21 (C=S)
8
18.80 (СН3C=N); 40.03 (N(CH3)2); 90.16 (СН2=); 135.09 (C-5); 146.49 (C=N);
170.31 (C=S)
9
18.74 (СН3C=N); 39.66 (N(CH3)2); 44.03 (NCH3); 90.10 (СН2=); 134.82 (C-5);
146.43 (C=N); 170.87 (C=S)
10
13.90 (СН3C=N); 18.59 (СН3C=N); 25.82 (СН3C=O); 90.06 (СН2=); 131.12 (C-5);
145.59 (C=N); 164.09 (C=N); 177.26 (C=S); 197.33 (C=O)
11
13
15
16
80.39 (C-5); 126.0-140.8 (C6H5); 140.34 (C=N); 170.71 (C=S)
78.85 (C-5); 125.7-134.4 (C6H5); 140.81 (C=N); 172.79 (C=S)
51.01 (CH3О); 88.12 (C-5); 126.5–133.6 (C6H5); 142.36 (C=N); 170.85 (C=S)
14.56 (CH3); 59.13 (CH2); 87.36 (C-5); 126.5–133.6 (C6H5); 142.71 (C=N);
170.35 (C=S)
17
42.48 (N(СН3)(CH3)); 43.23 (N(СН3)(CH3)); 50.81 (CH3O); 90.69 (C-5);
126.5-133.6 (C6H5); 142.64 (C=N); 170.81 (C=S)
_______
* Spectra recorded in a mixture of the solvents CDCl3–DMSO-d6 (2:1)
(compound 4) or DMSO-d6 (compounds 5, 6, 8-11, 13, 15-17).
973

TABLE 3. 1H NMR Spectra of Compounds 11-17
Com- Configuration,
Configuration,
%
δ, ppm, CDCl3
δ, ppm, DMSO-d6
pound
%
1
2
3
4
5
11
12
В, 100
4.66 (2Н, s, NH2);
5.61 (1H, s, OH);
6.81 (1Н, s, НС=N);
7.3-7.9 (5H, m, С6Н5);
9.45 (1H, s, NH)
В, 100
5.03 (2Н, s, NH2);
6.80 (1Н, s, НС=N);
7.2-7.5 (5H, m, С6Н5);
7.58 (1H, s, OH);
11.60 (1H, s, NH)
(Z,Е')-А, 49
(Z,Z')-А, 22
(E,E')-А, 20
(E,Z')-А, 9
B, 0
2.70 (6Н, s, N(СН3)2);
7.4-8.0 (5H, m, С6Н5);
8.12 (1H, s, НС=N);
8.17 (1H, s, NH);
(Z,E')-А, 7
(Z,Z')-А, 3
(E,E')-А, 35
(E,Z')-А, 13
B, 42
2.60 (6Н, s, N(СН3)2);
7.3-7.9 (5H, m, С6Н5);
8.01 (1H, s, NH);
8.27 (1H, s, НС=N);
14.61 (1H, s, NH)
14.31 (1H, s, NH)
2.73 (6Н, s, N(СН3)2);
7.4-8.0 (5H, m, С6Н5);
7.65 (1H, s, NH);
8.36 (1H, s, НС=N);
13.56 (1H, s, NH)
2.63 (6Н, s, N(СН3)2);
7.3-7.9 (5H, m, С6Н5);
14.32 (1H, s, NH)
2.68 (6Н, s, N(СН3)2);
7.4-8.2 (5H, m, С6Н5);
7.92 (1H, s, НС=N);
8.09 (1H, s, NH);
2.56 (6Н, s, N(СН3)2);
7.3-8.4 (5H, m, С6Н5);
8.24 (1H, s, НС=N);
9.79 (1H, s, NH);
10.84 (1H, s, NH)
11.84 (1H, s, NH)
2.64 (6Н, s, N(СН3)2);
7.4-8.2 (5H, m, С6Н5);
7.69 (1H, s, NH);
7.82 (1H, s, НС=N);
10.57 (1H, s, NH)
2.56 (6Н, s, N(СН3)2);
7.3-8.4 (5H, m, С6Н5);
7.99 (1H, s, НС=N);
8.97 (1H, s, NH);
11.87 (1H, s, NH)
—
2.40 (3Н, s, N(СН3)(CH3));
3.01 (3Н, s, N(СН3)(CH3));
6.79 (1H, s, HС=N);
7.3-7.9 (5H, m, С6Н5);
7.32 (1H, s, OH);
11.42 (1H, s, NH)
13
14
В, 100
4.57 (2Н, s, NH2);
6.01 (1H, s, OH);
7.1-7.6 (10H, m, С6Н5);
9.52 (1H, s, NH)
В, 100
5.05 (2Н, s, NH2);
7.0-7.6 (10H, m, С6Н5);
8.02 (1H, s, OH);
11.89 (1H, s, NH)
(Z,E')-А, 21
(Z,Z')-А, 17
(E,E')-А, 10
(E,Z')-А, 22
B, 30
2.56 (6Н, s, N(СН3)2);
7.1-7.9 (10H, m, С6Н5);
7.97 (1H, s, NH);
(Z,E')-А, 0
(Z,Z')-А, 0
(E,E')-А, 0
(E,Z')-А, 0
—
—
—
—
10.82 (1H, s, NH)
2.32 (6Н, s, N(СН3)2);
7.1-7.9 (10H, m, С6Н5);
8.40 (1H, s, NH);
10.57 (1H, s, NH)
2.71 (6Н, s, N(СН3)2);
7.1-7.9 (10H, m, С6Н5);
8.22 (1H, s, NH);
9.23 (1H, s, NH)
2.28 (6Н, s, N(СН3)2);
7.1-7.9 (10H, m, С6Н5);
7.86 (1H, s, NH);
8.90 (1H, s, NH)
2.38 (3Н, s, N(СН3)(CH3)); B, 100
3.08 (3Н, s, N(СН3)(CH3));
6.47 (1H, s, OH);
7.1-7.6 (10H, m, С6Н5);
9.83 (1H, s, NH)
2.24 (3Н, s, N(СН3)(CH3));
3.05 (3Н, s, N(СН3)(CH3));
7.1-7.6 (10H, m, С6Н5);
7.91 (1H, s, OH);
11.78 (1H, s, NH)
15
В, 100
3.38 (3Н, s, СН3О);
4.58 (2Н, s, NH2);
7.1-7.7 (10H, m, С6Н5);
9.90 (1H, s, NH)
В, 100
3.27 (3Н, s, СН3О);
4.95 (2Н, s, NH2);
7.1-7.6 (10H, m, C6H5);
12.17 (1Н, s, NH)
974

TABLE 3 (continued)
1
2
3
4
5
16
В, 100
1.31 (3Н, t,
J = 6.9, СН3СН2);
3.49 (2Н, q,
В, 100
1.28 (3Н, t, J = 6.9, СН3СН2);
3.36 (1Н, q,
J = 6.9, СН3СН2);
J = 6.9, СН3СН2);
4.52 (2Н, s, NH2);
7.1-7.6 (10H, m, C6H5);
10.22 (1Н, s, NH)
3.47 (1Н, q, J = 6.9, СН3СН2);
4.90 (2Н, s, NH2);
7.1-7.6 (10H, m, C6H5);
12.05 (1Н, s, NH)
17
В, 100
2.32 (3Н, s, N(СН3)(CH3));
3.07 (3Н, s, N(СН3)(CH3));
3.40 (3Н, s, СН3O);
В, 100
2.25 (3Н, s, N(СН3)(CH3));
3.08 (3Н, s, N(СН3)(CH3));
3.31 (3Н, s, СН3O);
7.1-7.6 (10H, m, C6H5);
9.98 (1Н, s, NH)
7.1-7.6 (10H, m, C6H5);
11.99 (1Н, s, NH)
Exchanging the aromatic for an aliphatic substituent (changing to the 1-isopropylthiocarbohydrazide)
and carrying out the reaction of diacetyl either without solvent or in methanol or chloroform gives a mixture of
the monohydrazone 2 and 4-isopropylamino-6-methyl-5-methylene-4,5-dihydro-2H-[1,2,4]triazine-3-thione (6).
Both compounds were separated in a pure state using TLC. The methylene structure of compound 6 was also
confirmed by the presence in the 13C NMR spectrum of characteristic carbon atom resonance signals for the
CH2= group at 89.90 ppm (Table 2) [12, 13]. If the hydrazone 2 is held for a week in methanol it is fully
converted to the corresponding methylene 6.
The reaction of diacetyl with 1,1-dimethyl- and 1,1,4-trimethylthiocarbohydrazides gave only the
corresponding methylene derivatives 8 and 9. Recording of even intermediate appearance of the
monohydrazones was not successful and is possibly related to the following circumstances. The appearance of
the methylene derivatives is preceded by reversible cyclization of hydrazones to 5-hydroxy-4,5-dihydro-2H-
[1,2,4]triazine-3-thiones. Exchange of the amino group on the nitrogen atom at position 4 of this heterocycle for
a dimethylamino group leads to an increase in the steric interactions with the methyl and hydroxyl group
substituents bonded to the carbon atom at position 5. Changing to the methylene derivative removes this strain
thus accelerating the dehydration process. The initial monohydrazone is rapidly converted to the methylene
derivative.
As for the compounds 5-7, conclusions regarding the structure of derivatives 8 and 9 can be made on the
basis of the presence in their 1H NMR spectra of two doublets in the region 4.30-5.10 ppm corresponding to the
methylene protons and of resonance signals for methylene group carbon atoms in the region of 90 ppm in the
13C NMR spectra.
Reaction of phenylglyoxal hydrate with thiocarbohydrazide in water and benzene (molar ratio 1:1) gave
the 5-hydroxy-4,5-dihydro-2H-[1,2,4]triazine-3-thione (11B). This was deduced from mass-spectrometric data
1
13
(m/z 222 [M]+) and H and C NMR spectra (Tables 2 and 3). The spectroscopic parameters for compound 11
are virtually the same as those for 5-hydroxy-4,5-dihydro-2H-[1,2,4]triazine-3-thiones obtained by treating
phenylglyoxal with 4-mono- and 2,4-disubstituted thiosemicarbazides [13]. The latter are characterized by the
presence of the heterocycle C(5) atom signal at 80-85 ppm in the 13C NMR spectrum (for compound 11 in
DMSO-d6 solution the signal occurs at 80.39 ppm).
R1
Ph
HO
N
R1
Ph
R2O
N
NH R2OH
NH
CR1
O
CR1COPh
NNHCNHNH2
S
R2
NNH
PhC
O
R2
CNHN
S
+
–H2O
–H2O
S
N
N
S
A
11–14
NR2
NR2
B
15–17
11, 13, 15, 16 R = H; 12, 14, 17 R = Ме; 11, 12 R1 = H; 13–17 R1 = Ph; 15, 17 R2 = Ме; 16 R2 = Et
975

TABLE 4. 13C NMR Spectra of Compounds 12, 14
Com- Configuration,
Chemical shifts, δ, ppm
pound
%
in CDCl3
in DMSO-d6
12
(Z,E')-А
46.98 (N(СН3)2); 128.5-136.1(C6H5); 45.83 (N(СН3)2);
134.06(C=N); 180.32 (C=S);
127.9-135.8 (C6H5); 134.36 (C=N);
186.49 (C=О)
179.27 (C=S); 186.40 (C=О)
(Z,Z')-А
(E,E')-А
(E,Z')-А
B
46.98 (N(СН3)2);
124.8-136.2 (C6H5); 133.03 (C=N);
176.24 (C=S); 186.09 (C=О)
—*
47.09 (N(СН3)2);
128.5-136.1 (C6H5); 133.29 (C=N);
176.29 (C=S); 188.10 (C=О)
46.64 (N(СН3)2);
126.7-143.9 (C6H5); 133.12 (C=N);
178.53 (C=S); 189.09 (C=О)
128.5-136.1 (C6H5); 176.20 (C=S);
45.54 (N(СН3)2);
126.7-143.9 (C6H5); 133.35 (C=N);
176.52 (C=S); 188.61 (C=О)
187.25 (C=О)*2
—
43.10 (N(СН3)(CH3));
44.94 (N(СН3)(CH3)); 82.69 (C-5);
126.7-143.9 (C6H5); 141.01 (C=N);
171.32 (C=S)
14
(Z,E')-А
(Z,Z')-А
(E,E')-А
(E,Z')-А
B
47.21 (N(СН3)2);
126.9-136.9 (C6H5); 144.94 (C=N);
175.93 (C=S); 194.93 (C=О)
—
—
—
—
46.59 (N(СН3)2);
126.9-136.9 (C6H5); 151.43 (C=N);
178.02 (C=S); 189.91 (C=О)
47.25 (N(СН3)2);
126.9-136.9 (C6H5); 145.89 (C=N);
178.02 (C=S); 193.43 (C=О)
46.65 (N(СН3)2);
126.9-136.9 (C6H5); 150.97 (C=N);
178.22 (C=S); 189.93 (C=О)
43.54 (N(СН3)(CH3));
42.58 (N(СН3)(CH3));
44.97 (N(СН3)(CH3)); 85.04 (C-5);
126.0-141.3 (C6H5); 147.36 (C=N);
169.65 (C=S)
44.89 (N(СН3)(CH3)); 85.18 (C-5);
126.9-141.5 (C6H5); 146.22 (C=N);
169.32 (C=S)
_______
* Signals of the configuration not observed.
*2 Signals for the carbon atoms of the dimethylamino groups and C=N
bond hidden by the signals of the main configuration.
Data for ring-linear-ring tautomerism in thiocarbonohydrazones of monocarbonyl compounds infers the
possible existence of compound 11 in the tetrahydro-1,2,4,5-tetrazine (signal for atom C(6) at 60-65) and/or
1,2,4-triazolidine form (signal for atom C(5) at 80-85 ppm) [1]. However, the presence of a resonance signal for the
carbon atom of the C=N bond (140-150) and the absence of a signal for a C=O group in the region 185-195 ppm
unambiguously shows that the cyclic form of compound 11 is 4-amino-5-hydroxy-4,5-dihydro-2H-[1,2,4]triazine-
3-thione (B).
Carrying out the reaction of phenylglyoxal hydrate with 1,1-dimethylthiocarbohydrazide in chloroform
and partial evaporation of the solvent gives a crystalline precipitate. The 1H NMR spectrum of the crystalline mass
in CDCl3, which was separated from the solution by filtration, immediately showed a second set of resonance
signals corresponding to the spatially isomeric hydrazone 12A in the ratio 3:1. The predominant isomer includes
singlet signals at 2.70 (methyl groups on nitrogen), 8.12 (proton at C=N bond), 8.17 (N(4)H bond), and 14.31 ppm
(N(2)H) bond. The corresponding signals for the minor stereoisomer occur at 2.73, 8.36, 7.65, and 13.56 ppm.
The low field position of the N(2)H signals supports a (Z)-configuration of the substituent relative to the C=N
bond in which a strong, chelating IHB is formed.
976

Scheme 1
Ph
N
Ph
Ph
Ph
R
R
R
N
R
N
O
H
O
H
O
O
N
S
N
H
S
N
S
H
N
N
H
H
H
H
N
N
N
N
N
N
S
N
N
Me
Me
Me
Me
Me
Me
Me
Me
Z, E'
E, E'
Z, Z'
E, Z'
12, 14
12 R = H, 14 R = Ph
The existence of two stereoisomers at the (Z)-configured double bond is evidently associated with slow
rotation relative to the thioamide N(2)–C=S bond. The predominant isomer most likely has a (Z,E')-spatial
structure (Z,E')-12 and the minor a (Z,Z')-structure (Z,Z'-12). The predominance of the first stereoisomer is
possibly connected not only with a difference in spatial interactions but also the possible formation of an
additional IHB between the proton of the N(4)H bond and the C=N nitrogen atom as shown in Scheme 1.The
lower field position of the N(4)H signal for the predominant stereoisomer (8.17 versus 7.65 ppm, Table 3) also
indicates the formation of such a bond.
1
When a solution of compound 12 is held its H NMR spectrum gradually changes and shows a second
set of resonance signals corresponding to a stereoisomer with an (E)-configuration relative to the C=N bond.
The signals for the N(2)H protons are found at 10.84 and 10.57 ppm (Table 3). Most likely this is a question of
the (E,E')- and (E,Z')-hydrazone structures (E,E'-12) and (E,Z'-12). After some time the spectrum stops changing
and becomes an equilibrium including all four of the indicated stereoisomers of compound 12: (Z,E') (49), (Z,Z')
(22), (E,E') (20), and (E,Z') (9%). The shift of the equilibrium towards the (Z,E')- and (Z,Z')-stereoisomers may
again be connected to formation of a chelating IHB. The (E')-configured structure predominates amongst the
geometric isomers.
In the basically dipolar solvent DMSO-d6 a five-component ring-chain equilibrium is established in
which the set of hydrazone stereoisomers conflicts with a cyclic 5-hydroxy-4,5-dihydro-2H-[1,2,4]triazine-
3-thione form 12B (Tables 3 and 4). When equilibrium is achieved its fraction is 42%. It should be noted that, in
the 13C NMR spectrum, the resonance signal for the carbon atom at position 5 of the heterocycle (as for
compound 11) is found in the region 80-85 ppm (82.69 ppm, Table 4) [13]. Within the linear hydrazone forms
there occurs a redistribution of stereoisomers and the isomer with an (E)-configuration predominates. This is
associated with the much higher polarity of the (E)-configured isomers (E,E')-12 and (E,Z')-12 which implies a
more marked nonspecific solvation by the dipolar solvent and also additional stabilization of these forms thanks
to formation of intermolecular hydrogen bonds between the DMSO and the N(2)H bond.
By treatment of phenylglyoxal hydrate with 1,1-dimethylthiocarbohydrazide in methanol the reaction
1
product 12A separates as the hydrazone with an (E)-configuration. The H NMR spectrum of the compound in
CDCl3 immediately after solution showed two sets of signals for the two stereoisomers (E,E')-12 and (E,Z')-12.
When held, an equilibrium was established in the solution involving four isomers having the same quantitative
composition as achieved with a sample separated after carrying out the reaction in chloroform.
Hence variation of the conditions for carrying out the reaction of phenylglyoxal hydrate with 1,1-di-
methylthiocarbohydrazide can give two modifications of the condensation product of the hydrazone structure
with (Z)- and (E)-configurations. In solutions a partial configurational change occurs to give a multicomponent
ring-chain equilibrium.
977

TABLE 5. Characterictics of Compounds 2-9 and 11-17
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °C
Yield, %
С
Н
N
2
C8H16N4OS
C11H14N4OS
C9H14N4O2S
C5H8N4S
44.42
44.28
52.78
52.86
44.61
44.56
38.45
38.33
48.46
48.52
56.87
56.75
45.63
45.76
48.46
48.36
48.63
48.66
52.78
52.86
52.78
52.89
60.38
60.46
62.55
62.56
61.52
61.63
62.55
62.46
63.50
63.59
7.46
7.56
5.64
5.54
5.82
5.74
5.16
5.24
7.12
7.20
5.21
5.24
6.56
6.44
7.12
7.14
4.53
4.44
5.64
5.69
5.64
5.54
4.73
4.79
5.56
5.48
5.16
5.22
5.56
5.49
5.92
5.84
25.90
25.99
22.38
22.50
23.12
23.20
35.87
35.77
28.25
28.40
24.12
24.20
30.41
30.50
28.25
28.30
25.21
25.30
22.38
22.30
22.38
22.29
18.78
18.66
17.16
17.30
17.93
17.85
17.16
17.30
16.46
16.35
Oil
31
62
72
22
65
38
69
60
72
70
64
21
58
33
34
54
3
130-131
118-119
90-91
4
5
6
C8H14N4S
C11H12N4S
C7H12N4S
C8H14N4S
C9H10N4OS
98-99
7
Oil
8
124-125
94-95
9
11
148-149
178-179
146-147
176-178
177-179
180-181
115-117
189-190
(Z)-12А C11H14N4OS
(E)-12A C11H14N4OS
13
14
15
16
17
C15H14N4OS
C17H18N4OS
C16H16N4OS
C17H18N4OS
C18H20N4OS
Reaction of benzil with thiocarbohydrazide and 1,1-dimethylthiocarbohydrazide in benzene gives
compounds 13 and 14 (R2 = Ph, Tables 2-4) having many structural similarities with compounds prepared by
reaction with phenylglyoxal hydrate.
The reaction of thiocarbohydrazide with benzil is complicated by the fact that, in benzene solution, the
reaction mixture forms a precipitate which most likely exists as an oligomer. It is poorly soluble in various
1
solvents and shows only aromatic proton signals in the H NMR spectrum. The mother liquor shows the
presence of a low yield (15-20%) of the 4-amino-5-hydroxy-5,6-diphenyl-4,5-dihydro-2H-[1,2,4]triazine-
3-thione (13).
Alcohols have been used as solvent in the formation of the corresponding derivatives 15 and 16 (Tables
2 and 3). The 5-alkoxy-4,5-dihydro-2H-[1,2,4]triazine structure of these compounds has been confirmed from
the NMR spectroscopic data (in particular, in the 13C NMR spectrum a signal for the C(5) atom is seen at 87-89
ppm) and also in the mass spectra (m/z 312 [M]+ and 326 [M]+ respectively) which is markedly similar to the
corresponding data for the 5-alkoxy derivatives formed by reacting benzil with thiosemicarbazide [8]. When
compounds 15 and 16 are held for several days in DMSO their hydrolysis products accumulate, i.e. 5-hydroxy-
4,5-dihydro-2H-[1,2,4]triazine-3-thione 13 together with methanol or ethanol respectively.
Reaction of benzil with 1,1-dimethylthiocarbohydrazide in benzene with different variants of the synthesis
1
does not go to completion as indicated by the H NMR spectra of the crystalline materials separated from the
reaction mixture. The reaction product at the unsubstituted amino group (molar ratio 1:1, compound 14) occurs
partially as a precipitate (about 35%) and the rest was separated from the mother liquor by TLC (23%).
978

In solution in CDCl3 the product of condensation occurs as an equilibrium involving four hydrazone
structure stereoisomers 14A: (Z,E')-, (Z,Z')-, (E,E')- and (E,Z)- and also the cyclic tautomer 4-dimethylamino-
5-hydroxy-5,6-diphenyl-4,5-dihydro-2H-[1,2,4]triazine-3-thione (14B). When changing to DMSO-d6 as solvent
the equilibrium is fully shifted to the cyclic form 14B. The 13C NMR spectrum (Table 4) of the cyclic form
shows the presence of a signal at 85.04 due to the carbon atom at position 5 of the heterocycle and the 1H NMR
spectrum a signal at 6.47 ppm which can be assigned to the proton of the OH bond (Table 3).
Reaction of 1,1-dimethylthiocarbohydrazide with benzil in methanol gives the 4-dimethylamino-
5-methoxy-5,6-diphenyl-4,5-dihydro-2H-[1,2,4]triazine-3-thione (17) whose structure was confirmed by 1H and
13C NMR spectroscopy (Tables 2 and 3). Hence the 13C NMR spectrum shows a signal for the carbon at position
5 at 90.69 and a signal for the C=S carbon at 170.81 ppm.
We can conclude that reaction of 1,2-dicarbonyl compounds with thiocarbohydrazide and its substituted
analogs depends not only on the structure of the reacting materials but also on the conditions of carrying out the
reaction and leads to a rather broad range of condensation products of linear and cyclic structure tending to
configurational conversions in solutions with ring-chain conversion in a number of cases.
EXPERIMENTAL
13
1H and C NMR spectra were obtained on a JEOL JNM-A-500 (500 and 125 MHz respectively) and
Bruker AM-300 spectrometer (300 and 75 MHz respectively) using DMSO-d6 or CDCl3 using HMDS as
internal standard at 0.05 ppm. Mass spectra were recorded on a Finnigan MAT 95 mass spectrometer using the
EI method (electron ionization energy 70 eV). Elemental analysis was carried out on a Carlo Erba
Strumentazione model 1106 analyzer. Monitoring of the reaction course and the purity of the compounds
prepared was carried out by TLC on Silufol UV-254 grade plates. The characteristics of the synthesized
compounds 1-17 are given in Table 5.
The substituted thiocarbohydrazides were prepared according to the method reported in [14].
Reaction of Thiocarbohydrazide with Diacetyl. A. Thiocarbohydrazide (0.212 g, 2 mmol) and
diacetyl (0.17 g, 0.18 ml, 2 mmol) were mixed with cooling in ice. The mixture was allowed to stand for 1 day
in a fridge and the precipitate was filtered off.
B. A solution of diacetyl (0.17 g, 0.18 ml, 2 mmol) in water (5 ml) was added to a suspension of
thiocarbohydrazide (0.212 g, 2 mmol) in water (10 ml) and heated for 3 h at 80ºC. The mixture was left for
1 day and the precipitate was filtered off.
C. A solution of diacetyl (0.17 g, 0.18 ml, 2 mmol) in methanol (5 ml) was added to a suspension of
thiocarbohydrazide (0.212 g, 2 mmol) in methanol (20 ml), stirred at room temperature for 2 days, and the
precipitate was filtered off.
1
According to H NMR spectroscopic data, the mother liquor in all cases contained a mixture of the di-
acetyl thiocarbonohydrazone (1) and 4-amino-6-methyl-5-methylene-4,5-dihydro-2H-[1,2,4]triazine-3-thione (5).
Diacetyl Bisthiocarbonohydrazone (4). A solution of diacetyl (0.34 g, 0.35 ml, 4 mmol) in water
(5 ml) was added to a suspension of thiocarbohydrazide (0.212 g, 2 mmol) in water (10 ml). The mixture was
allowed to stand for 3 days and the precipitate was filtered off and washed with methanol and ether to give
compound 4 (0.36 g, 72%).
4-Amino-6-methyl-5-methylene-4,5-dihydro-2H-[1,2,4]triazine-3-thione (5). A. A suspension of
thiocarbohydrazide (0.212 g, 2 mmol) in methanol (10 ml) was mixed with a solution of diacetyl (0.17 g, 0.18 ml,
2 mmol) in methanol (5 ml) with cooling in ice. The mixture was left at this temperature for 1 day and the
precipitate was filtered off. The mother liquor was evaporated in vacuo and the residue was extracted with
hexane (3×20 ml). The extracts were combined, solvent removed in vacuo, and the residue was recrystallized
from pentane to give compound 5 (0.085 g, 22%).
979

B. Solvent was removed from the mother liquors of the reaction of thiocarbohydrazide with diacetyl by
methods A-C to give a solid residue (0.10-0.15 g). The residue was chromatographed on a silica gel column (100 g)
using the system ether–hexane (4:3). Evaporation of solvent gave compound 5 (0.02-0.04 g, 5-11%) with Rf 0.45.
Reaction of Diacetyl with 1-Isopropylthiocarbohydrazide. A. 1-Isopropylthiocarbohydrazide
(0.296 g, 2 mmol) in chloroform (10 ml) was mixed with a solution of diacetyl (0.18 g, 0.19 ml, 2.1 mmol) in
chloroform (5 ml). The mixture was held at room temperature for 1 day and solvent was removed in vacuo to
give 0.42 g of a mixture of 5-diacetyl isopropylthiocarbonohydrazone (2) (Rf 0.40, ether–hexane, 4:3) and
4-isopropylamino-6-methyl-5-methylene-4,5-dihydro-2H-[1,2,4]triazine-3-thione (6) (Rf 0.95) in a molar
ratio of about 1:1 (according to 1H NMR spectroscopic data). When the mixture was held for a week the ratio of
reaction products was virtually unchanged. Solvent was removed and the residue was chromatographed on a
silica gel column (100 g) in the system ether–hexane (4:3). Removal of solvent gave compound 2 (0.14 g, 31%)
and compound 6 (0.19 g, 44%).
Treatment of 1-isopropylthiocarbohydrazide with diacetyl by method A in methanol gave a mixture of
hydrazone 2 and methylene 6 which was converted over a week in solution to pure 4-isopropylamino-6-methyl-
5-methylene-4,5-dihydro-2H-[1,2,4]triazine-3-thione (6).
B. 1-Isopropylthiocarbohydrazide (0.296 g, 2 mmol) was mixed with diacetyl (0.18 g, 0.19 ml,
2.1 mmol). The product was held at room temperature for a week, excess diacetyl was removed in vacuo and the
residue was recrystallized from hexane to give compound 6 (0.28 g, 65%).
Reaction of Diacetyl with 1-Phenylthiocarbohydrazide. A. A solution of 1-phenylthiocarbohydrazide
(0.364 g, 2 mmol) in chloroform (10 ml) was mixed with a solution of diacetyl (0.18 g, 0.19 ml, 2.1 mmol) in
chloroform (5 ml). The mixture was held for a week at room temperature. Solvent was removed in vacuo to give
0.48 g of a mixture of diacetyl 5-phenylthiocarbonohydrazone (3) and 6-methyl-5-methylene-4-phenyl-
1
amino-4,5-dihydro-2H-[1,2,4]triazine-3-thione (7) in the molar ratio of about 1:1 (according to H NMR
spectroscopic data). Chromatography of the reaction mixture on silica gel plates (ether–hexane, 4:3) gave
compound 3 (0.21 g, 41%, Rf 0.40) and compound 7 (0.19 g, 38%, Rf 0.60).
B. A solution of 1-phenylthiocarbohydrazide (0.364 g, 2 mmol) in methanol (10 ml) was mixed with a
solution of diacetyl (0.18 g, 0.19 ml, 2.1 mmol) in methanol (5 ml) and refluxed for 5 h. Solvent and excess
diacetyl were removed in vacuo to give, as in the case of the reaction in chloroform, a mixture of diacetyl
5-phenylthiocarbonohydrazone (3) and 6-methyl-5-methylene-4-phenylamino-4,5-dihydro-2H-[1,2,4]triazine-
3-thione (7). The mixture was chromatographed on silica gel plates (ether–hexane, 4:3) to give compound 3
(0.19 g, 37%) and compound 7 (0.16 g, 32%).
C. 1-Phenylthiocarbohydrazide (0.364 g, 2 mmol) was mixed with diacetyl (0.18 g, 0.19 ml, 2.1 mmol).
After 1 day the excess diacetyl was removed in vacuo. The residue was recrystallized from a mixture of hexane–
benzene (1:1) to give compound 3 (0.32 g, 62%).
Reaction of Diacetyl with 1,1-Dimethylthiocarbohydrazide. 1,1-Dimethylthiocarbohydrazide
(0.268 g, 2 mmol) was mixed with diacetyl (0.8 g, 0.19 ml, 2.1 mmol). After 1 day the excess diacetyl was
removed in vacuo and the residue was recrystallized from hexane to give 4-Dimethylamino-6-methyl-
5-methylene-4,5-dihydro-2H-[1,2,4]triazine-3-thione (8) (0.28 g, 69%, Rf 0.60, ether–hexane, 4:3).
Carrying out the reaction in chloroform and methanol also gave only compound 8.
Reaction of Diacetyl with 1,1,4-Trimethylthiocarbohydrazide. 1,1,4-Trimethylthiocarbohydrazide
(0.296 g, 2 mmol) was mixed with diacetyl (0.18 g, 0.19 ml, 2.1 mmol). After 1 day the excess diacetyl was
removed in vacuo and the residue was recrystallized from hexane to give 2,6-dimethyl-4-dimethylamino-
5-methylene-4,5-dihydro-2H-[1,2,4]triazine-3-thione (9) (0.26 g, 60%, Rf 0.70, ether–hexane, 4:3).
Carrying out the reaction in chloroform or methanol also gave only compound 9.
4-Amino-5-hydroxy-5-phenyl-4,5-dihydro-2H-[1,2,4]triazine-3-thione (11).
A
suspension of
thiocarbohydrazide (0.212 g, 2 mmol) in water (10 ml) was mixed with a solution of phenylglyoxal hydrate
980

(0.304 g, 2 mmol) in water (5 ml) with cooling in ice. The mixture was allowed to stand for 7 days and the
precipitate was filtered off and washed with water and ether to give compound 11 (0.32 g, 72%).
Phenylglyoxal 5,5-Dimethylthiocarbonohydrazone (12). A. 1,1-Dimethylthiocarbohydrazide
(0.268 g, 2 mmol) was mixed with a solution of phenylglyoxal hydrate (0.304 g, 2 mmol) in chloroform (20 ml)
and allowed to stand at room temperature for 1 day. Solvent was evaporated in vacuo and the residue was
recrystallized from a mixture of hexane and benzene (1:1) to give the (Z)-isomer of phenylglyoxal
5,5-dimethylthiocarbonohydrazone (Z)-12A (0.35 g, 70%).
B. 1,1-Dimethylthiocarbohydrazide (0.268 g, 2 mmol) was mixed with a solution of phenylglyoxal
hydrate (0.304 g, 2 mmol) in methanol (20 ml) and refluxed for 2 h. Solvent was evaporated in vacuo and the
residue was washed with a mixture of hexane and benzene (1:1) and ether to give the (E)-isomer of
phenylglyoxal 5,5-dimethylthiocarbonohydrazone (E)-12A (0.32 g, 64%).
4-Amino-5-hydroxy-5,6-diphenyl-4,5-dihydro-2H-[1,2,4]triazine-3-thione (13).
A
solution of
thiocarbohydrazide (0.212 g, 2 mmol) and benzil (0.420 g, 2 mmol) in benzene (20 ml) was refluxed for 10 h
1
with the addition of a catalytic amount of trifluoroacetic acid. The precipitate (0.25 g) was separated. The H
NMR spectroscopic data showed that the compound contained just aromatic proton signals. Solvent was
removed from the mother liquor in vacuo. The residue was recrystallized from a mixture of benzene–hexane
(1:5) to give compound 13 (0.126 g, 21%).
5-Hydroxy-4-dimethylamino-5,6-diphenyl-4,5-dihydro-2H-[1,2,4]triazine-3-thione (14). A solution
of 1,1-dimethylthiocarbohydrazide (0.268 g, 2 mmol) and benzil (0.420 g, 2 mmol) in benzene (20 ml) was
refluxed for 10 h with the addition of a catalytic amount of trifluoroacetic acid. The precipitate (0.245 g) was
separated and washed with benzene and hexane. Solvent was removed from the mother liquor in vacuo. The
residue was chromatographed on a silica gel column (100 g) using the system benzene–acetone (2:1). Removal
of solvent gave a solid residue (0.145 g, Rf 0.45, benzene–acetone, 2:1) which was washed with cold chloroform
and benzene to give compound 14 (0.135 g). The overall yield of compound 14 is 0.38 g (58%).
4-Amino-5-methoxy-5,6-diphenyl-4,5-dihydro-2H-[1,2,4]triazine-3-thione (15). A solution of
thiocarbohydrazide (0.212 g, 2 mmol) and benzil (0.420 g, 2 mmol) in methanol (20 ml) was refluxed for 10 h
with the addition of a catalytic amount of trifluoroacetic acid. The precipitate separated (0.15 g) showed only
1
aromatic proton signals in the H NMR spectrum. Solvent was removed from the mother liquor in vacuo. The
residue was dried in vacuo at 90ºC and recrystallized from a mixture of benzene–hexane (1:1) to give compound
15 (0.209 g, 33%).
4-Amino-5-ethoxy-5,6-diphenyl-4,5-dihydro-2H-[1,2,4]triazine-3-thione (16) was obtained from
thiocarbohydrazide and benzil in ethanol similarly to compound 15 to give compound 16 (0.218 g, 34%).
4-Dimethylamino-5-methoxy-5,6-diphenyl-4,5-dihydro-2H-[1,2,4]triazine-3-thione (17). A solution
of 1,1-dimethylthiocarbohydrazide (0.268 g, 2 mmol) and benzil (0.420 g, 2 mmol) in methanol (20 ml) and
refluxed for 10 h with the addition of a catalytic amount of trifluoroacetic acid. Solvent was removed in vacuo.
The residue was washed with a small volume of cold methanol and recrystallized from a mixture of benzene and
hexane (1:1) to give compound 17 (0.37 g, 54%).
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