Phenylglyoxal dihydrazones as unexpected products in the synthesis of 1,2,4-triazines by interaction of α-bromoacetophenones and arylhydrazides

Article abstract of DOI:10.1007/s10593-013-1336-8

On interacting α-bromoacetophenones with aromatic carboxylic acid hydrazides, the formation of two reaction products was observed in certain cases, the expected 1,2,4-triazine and the phenylglyoxal dihydrazone as an unexpected product. The effect of subst

Full text of DOI:10.1007/s10593-013-1336-8

Chemistry of Heterocyclic Compounds, Vol. 49, No. 7, October, 2013 (Russian Original Vol. 49, No. 7, July, 2013)
PHENYLGLYOXAL DIHYDRAZONES AS UNEXPECTED
PRODUCTS IN THE SYNTHESIS OF 1,2,4-TRIAZINES BY
INTERACTION OF α-BROMOACETOPHENONES AND
ARYLHYDRAZIDES
D. S. Kopchuk1,2,*, I. S. Kovalev1, G. V. Zyryanov1,2, A. F. Khasanov1,
A. S. Medvedevskikh1, V. L. Rusinov1,2, and O. N. Chupakhin1,2
On interacting α-bromoacetophenones with aromatic carboxylic acid hydrazides, the formation of two
reaction products was observed in certain cases, the expected 1,2,4-triazine and the phenylglyoxal
dihydrazone as an unexpected product. The effect of substituents in the initial substrates and of the
conditions of carrying out the synthesis on the direction of the reaction have been studied.
Keywords: aromatic acid hydrazides, α-bromoacetophenone, phenylglyoxal dihydrazone, 1,2,4-triazine,
condensation.
1,2,4-Triazines are of interest as convenient substrates in cycloaddition reactions [1-3]. In addition, they
are of interest due to their biological activity [4-6], their use as selective extractants of metal cations [7-10]
(such as the actinoids), and as ligands for cations of transition metals [11].
One of the traditional methods of obtaining 3,6-disubstituted 1,2,4-triazines is the interaction of
α-bromoacetophenones with two equivalents of carboxylic acid hydrazides [12]. We discovered that in a series
of cases of this reaction, in addition to the expected 1,2,4-triazines one further product, the phenylglyoxal
dihydrazone, was formed.
In particular, on refluxing α-bromo-3-nitroacetophenone 1a with hydrazides 2a,b in a EtOH–AcOH, 3:1
mixture under an atmosphere of argon in the presence of sodium acetate, the formation of 1,2,4-triazines 3a,b in
41-45% yield and of 3-nitrophenylglyoxal dihydrazones 4a,b in 14-16% yield was established. An effective
method of separating compounds 3a,b and 4a,b used by us was based on their different solubilities. After
carrying out the synthetic procedure, the formation was observed first of precipitates of the less soluble cyclic
1,2,4-triazines 3a,b, and only after extended delay the formation of precipitates of the more soluble hydrazones
4a,b did occur. On carrying out the reaction in air, the fraction of dihydrazones 4a,b in the reaction products
grew significantly (to 40-45%), and the yields of 1,2,4-triazines 3a,b were reduced to 10-15%.
_______
*To whom correspondence should be addressed, e-mail: dkopchuk@mail.ru.
1Ural Federal University named after the First President of Russia B. N. Yeltsin, 19 Mira St., Yekaterinburg
620002, Russia.
2I. Ya. Postovskii Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, 22
S. Kovalevskoi St.,/ 20 Akademicheskaya St., Yekaterinburg 620219, Russia; e-mail: chupakhin@ios.uran.ru.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1060-1064, July, 2013. Original
article submitted June 5, 2012; revision submitted December 26, 2012.
988
0009-3122/13/4907-0988©2013 Springer Science+Business Media New York

R1
R1
R1
H
N
N
2 ArCONHNH2
R
2a–c
O
N
N
Ar
+
R
R
N
AcONa
EtOH, AcOH
, 12 h
O
N
Ar
NH
Br
Ar
1a–d
3a,b
O
4a–f
1 a R = NO2, b–d R = H; a,c R1 = H, b R1 = NO2, d R1 = OMe; 2 a Ar = Ph, b Ar = 4-MeOC6H4,
c Ar = 6-methoxycarbonylpyridin-2-yl; 3 a R = NO2, R1 = H, Ar = Ph, b R = NO2, R1 = H,
Ar = 4-MeOC6H4; 4 a R = NO2, R1 = H, Ar = Ph, b R = NO2, R1 = H, Ar = 4-MeOC6H4, c R = H,
R1 = NO2, Ar = Ph, d R = H, R1 = NO2, Ar = 4-MeOC6H4, e R = R1 = H, Ar = 6-methoxcarbonylpyridin-2-yl
f R = H, R1 = OMe, Ar = 6-methoxycarbonylpyridin-2-yl
In the case of using α-bromo-4-nitroacetophenone 1b, the formation of exclusively 4-nitro-
phenylglyoxal dihydrazones 4c,d in 36-42% was observed. The expected 1,2,4-triazines were formed in only
trace amounts even on carrying out the reaction under an argon atmosphere.
It was shown previously [13] that on interacting 6-methoxycarbonylpyridine-2-carboxylic acid
hydrazide (2c) with α-bromo-4-methoxyacetophenone 1d in a EtOHAcOH, 4:1 mixture, the corresponding
triazine may be obtained in moderate yield. However, when using a different ratio of solvents (EtOHAcOH,
1:3), the sole isolated reaction products were dihydrazones 4e,f. Carrying out the reaction under an argon
atmosphere in this case did not lead to any significant change.
It is evident that compounds 4 are the products of oxidation of the intermediate compounds A by
oxygen of the air. Compounds A are formed as a result of alkylation of acid hydrazide 2 by bromoacetophenone
1 (alternative reaction route). It should be mentioned that compounds 4 may no longer be converted into
triazines 3.
Structures similar to compounds 4 have previously been described only in the sole publication [14], and
the procedure for separation and isolation of the reaction products was more complex than that proposed within
the present work.
The structures of the compounds obtained were confirmed by data of IR, 1H and 13C NMR spectra, mass
spectroscopy, and elemental analysis. In the NMR spectra, the presence of two fragments of carboxylic acid
hydrazide was noted unequivocally. In addition, the one-proton singlet of the azomethine hydrogen atom at
8.65-8.85 ppm and the two broadened singlets for protons of the NH group were characteristic. The IR
R1
O
3
–ArCONH2
–H2O
N
R
N
Ar
AcONa
H
H
+
1
2
EtOH, AcOH
NH
HN
H
, 12 h
[O]
Ar
4
O
A
spectra contained bands corresponding to the stretching vibrations of the carbonyl groups, and also to the NH
groups. In the 13C NMR spectra, the downfield signals of the carbonyl groups in the 160-165 ppm region should
be mentioned. Signals of the aliphatic methylene group at 4.00-4.50 ppm were absent which enables the product
to be assigned the structure 4 but not A.
989

1
In the case of dihydrazones 4c,d in the H NMR spectra the presence was noted of two signals of the
NH groups, and in the spectrum of compound 4c two signals were also observed for the azomethine proton (the
ratio of the intensities of the signals was close to 1:1). This may be explained by the presence of two geometric
isomers (cis and anti) of the given compounds. The 13C NMR spectra contained a larger set of carbon signals
than expected if one isomer was present, which also confirms this hypothesis. It should be noted that a such
effect was established only for compounds 4c,d, other dihydrazones showed the presence of only one isomer.
When obtaining 3,6-disubstituted 1,2,4-triazines by the interaction of α-bromoacetophenone with two
equivalents of carboxylic acid hydrazides it is therefore necessary to take into account the possibility of the
formation of noncyclic secondary products – dihydrazones of glyoxal derivatives. The extent of forming these
products depends on the nature of the substituents in the starting compounds, a series of particular cases was
considered in the present work. Thus, in the case of using α-bromo-4-nitroacetophenone, the arylglyoxal
dihydrazones are the dominant reaction product, carrying out the interaction under an atmosphere of argon does
not introduce significant changes. A different rule was noted on using α-bromo-3-nitroacetophenone, in this
case on carrying out the reaction under an argon atmosphere the main products were 1,2,4-triazines, the
arylglyoxal dihydrazones were formed to a significantly lesser extent. However, carrying out the reaction in the
air changes the ratio of products to the opposite, the dihydrazone becomes the main product. Consequently in
this case, on account of the change in the nature of the atmosphere it is possible to direct this reaction on the
necessary route. On using 6-methoxycarbonylpyridine-2-carboxylic acid hydrazide the key role in directing the
reaction is played by the solvent. An increase in the proportion of ethanol directs the reaction along the route of
forming the triazine, an increase in the proportion of acetic acid directs along the route of forming dihydrazone.
EXPERIMENTAL
The IR spectra were recorded on a Bruker Alpha Fourier spectrometer with a NPVO (ZnSe) attachment.
1
The H and 13C NMR spectra were recorded on a Bruker DRX-400 spectrometer (400 and 100 MHz,
respectively) in DMSO-d6, standard was TMS. Mass spectra (ionization by electrospray) were recorded on a
MicrOTOF-Q II mass spectrometer (Bruker Daltonics). Elemental analysis was carried out on a Perkin-Elmer
PE 2400 CHN analyzer, series II. Melting points were determined on a Boetius hot stage apparatus. TLC was
carried out on Merck silica gel 60F254 plates, eluent was EtOAc, visualization in UV light.
Preparation of 1,2,4-Triazines 3a,b and Dihydrazones 4a-d (General Method). A mixture of
nitroacetophenone 1a,b (8.20 mmol), carboxylic acid hydrazide 2a,b (16.40 mmol), and NaOAc (0.81 g,
9.84 mmol) was refluxed with stirring in a EtOHAcOH, 3:1, mixture (150 ml) for 12 h under an argon
atmosphere. The reaction mixture was cooled to room temperature and maintained for 30 min. In the case of
α-bromo-3-nitroacetophenone 1a, the precipitated solid (1,2,4-triazines 3a,b) was filtered off, washed with
EtOH, and dried. The filtrate was stored at room temperature for 12 h, the precipitated solid (dihydrazones 4a,b)
was filtered off, washed with EtOH, and dried. An analytical sample was recrystallized from EtOH. In the case
of α-bromo-4-nitroacetophenone 1b, the formation of solid 1,2,4-triazine did not occur, after maintaining the
reaction mixture for 30 min the solid dihydrazones 4c,d were filtered off, washed with EtOH, and dried.
6-(3-Nitrophenyl)-3-phenyl-1,2,4-triazine (3a). Yield 1.03 g (45%), yellow crystals, mp 226-228°C.
1Н NMR spectrum, δ, ppm (J, Hz): 7.59-7.63 (3Н, m, Н Ph); 7.91 (1Н, dd, 3J = 8.0, 3J = 8.0, Н-5 Ar); 8.40-8.44 (1H,
m, Н-6 Ar); 8.52-8.56 (2Н, m, Н Ph); 8.70-8.74 (1Н, m, Н-4 Ar); 9.11 (1Н, dd, 4J = 2.0, 4J = 2.0, Н-2 Ar); 9.62 (1Н,
s, Н-5). Found, %: С 64.55; Н 3.49; N 20.05. C15H10N4O2. Calculated, %: С 64.74; Н 3.62; N 20.13.
3-(4-Methoxyphenyl)-6-(3-nitrophenyl)-1,2,4-triazine (3b). Yield 1.06 g (42%), yellow crystals, mp
1
215-217°C. Н NMR spectrum, δ, ppm (J, Hz): 3.90 (3Н, s, OСН3); 7.06-7.10 (2Н, m, Н ArOMe); 7.88 (1Н,
3
3
dd, J = 8.0, J = 8.0, Н-5 ArNO2); 8.37-8.41 (1H, m, Н-6 ArNO2); 8.46-8.50 (2Н, m, Н ArOMe); 8.66-8.70
4
4
(1Н, m, Н-4 ArNO2); 9.08 (1Н, dd, J = 2.0, J = 2.0, Н-2 ArNO2); 9.49 (1Н, s, Н-5). Found, %: С 62.21;
Н 3.77; N 17.94. C16H12N4O3. Calculated, %: С 62.34; Н 3.92; N 18.17.
990

3-Nitrophenylglyoxal Bisbenzoylhydrazone (4a). Yield 0.46 g (14%), light-yellow crystals, mp
1
246-248°C. IR spectrum, ν, сm-1: 1705 (СО), 3061 (NH), 3198 (NH), 3309 (NH). Н NMR spectrum, δ, ppm
3
3
(J, Hz): 7.54-7.68 (6Н, m, Н Ph); 7.80 (1Н, dd, J = 8.0, J = 8.0, Н-5 Ar); 8.01-8.06 (2H, m, H Ph); 8.27-8.34
4
4
(2Н, m, H-4,6 Ar); 8.35-8.42 (2Н, m, H Ph); 8.60 (1Н, dd, J = 2.0, J = 2.0, Н-2 Ar); 8.84 (1H, s, CH=N);
12.42 (1Н, br. s, NH); 14.66 (1Н, br. s, NH). 13C NMR spectrum, δ, ppm: 121.3; 124.3; 128.3; 128.4; 128.6;
129.2; 129.4; 129.7; 130.9; 132.6; 133.1; 133.2; 133.3; 133.9; 138.6; 148.5; 163.9; 164.0. Mass spectrum, m/z
(Irel, %): 416.13 [M+Н]+ (100). Found, %: С 63.40; Н 4.04; N 16.90. C22H17N5O4. Calculated, %: С 63.61;
Н 4.12; N 16.86.
3-Nitrophenylglyoxal Bis(4-methoxybenzoyl)hydrazone (4b). Yield 0.60 g (16%), light-yellow
1
crystals, mp 158-160°C. IR spectrum, ν, сm-1: 1676 (СО), 3149 (NH), 3406 (NH). Н NMR spectrum, δ, ppm
(J, Hz): 3.89 (3Н, s, OСН3); 3.91 (3Н, s, OСН3); 7.02-7.09 (4Н, m, Н ArOMe); 7.78 (1H, dd, 3J = 8.0, 3J = 8.0,
Н-5 ArNO2); 8.00-8.07 (2H, m, H ArOMe); 8.26-8.32 (2Н, m, H-4,6 ArNO2); 8.32-8.38 (2Н, m, H ArOMe);
8.58 (1Н, dd, 4J = 2.0, 4J = 2.0, Н-2 ArNO2); 8.83 (1Н, s, CH=N); 12.27 (1Н, br. s, NH); 14.58 (1Н, br. s, NH).
13C NMR spectrum, δ, ppm: 55.5; 55.6; 113.4; 114.0; 114.1; 120.8; 123.7; 123.8; 124.1; 129.4; 130.0; 130.3;
130.4; 132.6; 138.1; 138.4; 141.2; 148.1; 162.7; 162.8. Mass spectrum, m/z (Irel, %): 476.15 [M+Н]+ (100).
Found, %: С 60.39; Н 4.27; N 14.71. C24H21N5O6. Calculated, %: С 60.63; Н 4.45; N 14.73.
4-Nitrophenylglyoxal Bisbenzoylhydrazone (4c). Yield 1.23 g (36 %), light-yellow crystals, mp
>250°C. IR spectrum, ν, сm-1: 1659 (СО), 1690 (CO), 3059 (NH), 3213 (NH). 1Н NMR spectrum, δ, ppm (J, Hz):
7.51-7.68 (6Н, m, H Ph); 7.93-8.08 (4Н, m, H Ph, H ArNO2); 8.27-8.32 (2Н, m, H Ph); 8.33-8.45 (2Н, m,
H ArNO2); 8.82 (0.5Н, s) and 8.84 (0.5H, s, CH=N); 12.38 (0.5Н, s), 12.42 (0.5H, s), 14.64 (0.5Н, s) and 14.68
13
(0.5Н, s, 2NН). C NMR spectrum, δ, ppm: 123.1; 125.9; 127.4; 127.8; 128.1; 128.4; 128.6; 128.7; 128.9; 129.1;
129.2; 132.6; 132.7; 132.8; 132.9; 133.0; 138.2; 140.0; 140.4; 140.7; 142.4; 142.6; 144.6; 148.4; 164.3 (br.). Mass
spectrum, m/z (Irel, %): 416.14 [M+Н]+ (100). Found, %: С 63.39; Н 3.92; N 16.65. C22H17N5O4. Calculated, %:
С 63.61; Н 4.12; N 16.86.
4-Nitrophenylglyoxal Bis(4-methoxybenzoyl)hydrazone (4d). Yield 1.64 g (42%), light-yellow
crystals, mp >250°C. IR spectrum, ν, сm-1: 1667 (СО), 1701 (CO), 3168 (NH), 3406 (NH). 1Н NMR spectrum,
δ, ppm (J, Hz): 3.89 (3Н, s, ОСН3); 3.90 (3Н, s, ОСН3); 7.01-7.10 (4Н, m, H ArOMe); 7.93-8.08 (4Н, m,
H ArOMe, H ArNO2); 8.24-8.42 (4Н, m, H ArMeO, H ArNO2); 8.86 (1Н, s, CH=N); 12.24 (0.5Н, s), 12.28
(0.5H, s), 14.55 (0.5H, s) and 14.57 (0.5H, s, 2NH). 13C NMR spectrum, δ, ppm: 56.0; 56.1; 114.5; 114.6;
115.2; 122.9; 124.3; 124.6; 124.8; 124.9; 125.9; 127.2; 127.6; 128.0; 128.3; 130.3; 130.5; 130.7; 130.8; 138.3;
139.2; 139.6; 140.8; 141.8; 142.0; 144.4; 148.2; 163.2; 163.3; 163.5 (br.). Mass spectrum, m/z (Irel, %): 476.16
[M+Н]+ (100). Found, %: С 60.33; Н 4.36; N 14.64. C24H21N5O6. Calculated, %: С 60.63; Н 4.45; N 14.73.
Preparation of Dihydrazones 4e,f (General Method). A mixture of phenacyl bromide 1c,d (5 mmol),
6-methoxycarbonylpyridine-2-carboxylic acid hydrazide (2c) (1.95 g, 10 mmol), and NaOAc (0.49 g, 6 mmol)
in a mixture of EtOH–AcOH, 1:3 (100 ml) was refluxed for 12 h. The solvent was distilled off at reduced
pressure, and the residue treated with EtOH. The precipitated solid was filtered off, washed with EtOH, and
dried. Analytical samples of compounds 4e,f were obtained by recrystallization from MeCN.
Phenylglyoxal Bis[(6-methoxycarbonylpyridin-2-yl)carbonyl]hydrazone (4e). Yield 0.73 g (30%),
light-yellow crystals, mp 173-175°C. IR spectrum, ν, сm-1: 1699 (СО), 1723 (CO), 3292 (NH), 3504 (NH),
1
3593 (NH). Н NMR spectrum, δ, ppm (J, Hz): 3.82 (3Н, s, СООСН3); 3.97 (3Н, s, СООСН3); 7.45-7.49 (2Н,
m, Н Ph); 7.66-7.80 (3Н, m, Н Ph); 8.20-8.35 (6Н, m, Н Py); 8.68 (1Н, s, CH=N); 11.26 (1Н, s, NН); 12.22
(1Н, s, NН). 13C NMR spectrum, δ, ppm: 53.1; 53.2; 126.1; 126.7; 128.1; 128.4; 129.0; 129.4; 129.8; 130.4;
140.0; 140.6; 146.6; 147.4; 148.6; 150.2; 150.6; 154.3; 158.7; 161.0; 164.5; 165.2. Mass spectrum, m/z (Irel, %):
489.15 [M+Н]+ (100). Found, %: С 58.88; Н 3.96; N 16.94. C24H20N6O6. Calculated, %: С 59.02; Н 4.13;
N 17.21.
4-Methoxyphenylglyoxal Bis[(6-methoxycarbonylpyridin-2-yl)carbonyl]hydrazone (4e). Yield 0.74 g
(29%), light-yellow crystals, mp 181-183°C. 1Н NMR spectrum, δ, ppm (J, Hz): 3.81 (3Н, s, СООСН3); 3.93 (3Н,
s, ArОСН3); 3.97 (3Н, s, СООСН3); 7.21-7.26 (2Н, m, H Ar); 7.43-7.47 (2Н, m, H Ar); 8.20-8.37 (6Н, m,
991

H Py); 8.65 (1Н, s, CH=N); 11.33 (1Н, s, NН); 12.27 (1Н, s, NН). Mass spectrum, m/z (Irel, %): 519.16
[M+Н]+(100). Found, %: С 57.69; Н 4.17; N 16.01. C25H22N6O7. Calculated, %: С 57.91; Н 4.28; N 16.21.
The work was carried out with the support of the Ministry of Education and Science of the Russian
Federation (State contracts # 14.740.11.1020 and 14.A18.21.0817), the Russian Foundation for Basic Research
(grant 12-03-31726) and the Grants Council of the President of the Russian Federation (grant MK-
1511.2013.3).
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