Reaction of 2-substituted 7,7-dimethyl-5-oxo-5,6,7,8-tetrahydroquinoline-4- carboxylic acids with hydrazine. Synthesis of 5-substituted 8,8-dimethyl-3,7,8, 9-tetrahydro-2H-pyrido-[4,3,2-de]cinnolin-3-ones

Article abstract of DOI:10.1007/s10593-013-1167-7

The reaction of 2-substituted 7,7-dimethyl-5-oxo-5,6,7,8- tetrahydroquinoline-4-carboxylic acids with hydrazine was studied. This reaction gave 5-substituted 8,8-dimethyl-3,7,8,9-tetrahydro-2H-pyrido-[4,3,2-de] cinnolin-3-ones in good yields. A possible reaction mechanism was discussed using nonempirical quantum-chemical calculations.

Full text of DOI:10.1007/s10593-013-1167-7

Chemistry of Heterocyclic Compounds, Vol. 48, No. 10, January 2013 (Russian Original Vol. 48, No. 10, October, 2012)
REACTION OF 2-SUBSTITUTED 7,7-DIMETHYL-5-OXO-
5,6,7,8-TETRAHYDROQUINOLINE-4-CARBOXYLIC ACIDS
WITH HYDRAZINE. SYNTHESIS OF 5-SUBSTITUTED
8,8-DIMETHYL-3,7,8,9-TETRAHYDRO-2H-PYRIDO-
[4,3,2-de]CINNOLIN-3-ONES
D. A. Rudenko1, S. N. Shurov1*, M. I. Vakhrin1, V. I. Karmanov2, and Yu. A. Shchurov1
The reaction of 2-substituted 7,7-dimethyl-5-oxo-5,6,7,8-tetrahydroquinoline-4-carboxylic acids with
hydrazine was studied. This reaction gave 5-substituted 8,8-dimethyl-3,7,8,9-tetrahydro-2H-pyrido-
[4,3,2-de]cinnolin-3-ones in good yields. A possible reaction mechanism was discussed using
nonempirical quantum-chemical calculations.
Keywords: 7,7-dimethyl-5-oxo-5,6,7,8-tetrahydroquinoline-4-carboxylic acids, 8,8-dimethyl-3,7,8,9-tetra-
hydro-2H-pyrido[4,3,2-de]cinnolin-3-ones, hydrazine.
The reaction of 1,4-dicarbonyl compounds with hydrazines is a convenient method for the construction
of pyridazine ring [1]. If the dicarbonyl fragment is a part of a cyclic system as, for example, in alkyl 5-oxo-
5,6,7,8-tetrahydroquinoline-4-carboxylates, the reactions with hydrazines may give fused heterocyclic
compounds containing a pyridazine ring [2].
Heating equimolar amounts of 2-substituted 7,7-dimethyl-5-oxo-5,6,7,8-tetrahydroquinoline-4-carb-
oxylic acids 1a-g [3] with hydrazine in ethanol at reflux gives the corresponding 5-alkyl- or 5-aryl-8,8-di-
methyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]cinnolin-3-ones 7a-g. These products are colorless or slightly
colored crystalline compounds with high melting points, soluble in hot DMF and DMSO, and poorly soluble in
acetonitrile, ethanol, acetone, and water.
The yields, melting points, and elemental analysis results for 2H-pyrido[4,3,2-de]cinnolin-3-ones 7a-g
1
13
are given in Table 1. The structures of these derivatives were established using IR, H NMR, and C NMR
spectroscopy (Tables 2 and 3). The assignment of the signals in the 1H and 13C NMR spectra was carried out by
means of heteronuclear 2D 1H-13C gHSQC and gHMBC experiments.
In particular, C-3 atoms in the 2D gHMBC spectra give cross peaks with the pyridine ring protons, while
_______
*To whom correspondence should be addressed, e-mail: seshurov@yandex.ru.
1Perm State National Research University, 15 Bukireva St., 614990 Perm, Russia.
2Institute of Technical Chemistry, Ural Branch, Russian Academy of Sciences, 3 Akademika Koroleva St.,
614013 Perm, Russia; e-mail: karmanovvi@rambler.ru.
________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1634-1638, October, 2012.
Original article submitted September 16, 2011; revision submitted June 25, 2012.
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0009-3122/13/4810-1522©2013 Springer Science+Business Media New York

H
H
=
NH2
OH
O
N
O
COOH
HN
COOH
HN
N2H4
OH
OH
EtOH, 
Me
Me
Me
Me
Me
Me
N
R
N
R
N
R
1a–g
2a–g
3a–g
H
N
OH
OH
N
Me
Me
H
N
H
OH
OH
N
R
N
O
HN
5a–g
or
N
OH
–H2O
–H2O
R
Me
Me
Me
Me
H
N
OH
O
N
R
N
HN
4a–g
7a–g
Me
Me
N
R
6a–g
a R = t-Bu, b R = Ph, c R = 4-MeC6H4, d R = 4-MeOC6H4, e R = 4-BrC6H4,
f R = 2,4,5-Me3C6H2, g R = 1-naphthyl
C-5 atoms give cross peaks with protons of the R substituents. In turn, C-9b atoms are coupled with H-4, H-7,
and H-9 protons, while C-9a atoms are coupled with H-4 and H-7 protons. The signals for C-7 and C-9 atoms
were assigned using the 2D gHSQC spectra according to the direct spin-spin coupling constants of bound
hydrogen and carbon atoms.
A possible scheme for the formation of cinnolinones 7a-g assumes an attack on the ketone carbonyl
group of acids 1a-g by a hydrazine nitrogen atom and cyclization of the resultant intermediates 2a-g due to
reaction of the primary amino group and carboxyl carbon atom, to give intermediates 4a-g. The tricyclic
intermediates 4a-g then undergo dehydration to yield the reaction products 7a-g.
TABLE 1. Physicochemical Characteristics of the Synthesized Compounds 7a-g
Found, %
——————
Com-
pound
Empirical
formula
Mp, °С
Yield, %
Calculated, %
C
H
N
C16H21N3O
C18H17N3O
C19H19N3O
C19H19N3O2
C18H16 BrN3O
C21H23N3O
C22H19N3O
70.49
70.82
74.08
74.21
7.75
7.80
5.73
5.88
6.20
6.27
5.85
5.96
4.17
4.36
6.93
6.95
5.51
5.61
15.39
15.48
14.24
14.42
13.57
13.76
12.90
13.07
11.43
11.35
12.54
12.60
12.18
12.31
212-213
282-284
280-281
261-262
316-318
231-232
233-234
74
71
99
94
90
92
84
7a
7b
7c
7d
7e
7f
74.61
74.73
70.97
71.01
58.40
58.39
75.67
75.65
77.29
77.40
7g
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TABLE 2. IR and 1H NMR Spectra of Cinnolinones 7a-g
Com-
pound
IR spectrum,
1Н NMR spectrum, δ, ppm (J, Hz)
Н-4 7-СН2 8-СН3 9-СН2
ν, cm-1
2-NH
12.46
R
3156 (N-H),
1666 (C=O),
1596 (С=S, С=N)
7.84 2.97
8.34 3.05
8.26 3.03
8.22 3.01
1.04
1.11
1.06
1.06
2.69 1.39 (9Н, s, C(CH3)3)
7a
7b
7c
7d
3152 (N-H),
1668 (C=O),
1592 (С=S, С=N)
12.60
12.52
12.49
2.76 7.51-7.57 (3Н, m, H Ph);
8.21-8.23 (2Н, m, H Ph)
3156 (N-H),
1668 C=O),
1596 (С=S, С=N)
2.72 2.38 (3Н, s, 4'-СН3);
7.34 (2Н, d, J = 8.4, H Ar);
8.09 (2Н, d, J = 8.4, H Ar)
3153 (N-H),
1666 (C=O),
1589 (С=S, С=N)
3156 (N-H),
1668 (C=O),
2.71 3.85 (3Н, s, ОСН3);
7.07 (2Н, d, J = 9.0, H Ar);
8.16 (2Н, d, J = 9.0, H Ar)
12.57
12.56
8.35 3.07
7.89 3.00
1.07
1.06
2.76 7.73 (2Н, d, J = 8.4, H Ar);
8.18 (2Н, d, J = 8.4, H Ar)
7e
7f
1590 (С=S, С=N)
3162 (N-H),
1657 (C=O),
1587 (С=S, С=N)
2.72 2.25 (6Н, s, 4',5'-СН3);
2.31 (3Н, s, 2'-СН3);
7.07 (1Н, s, H-3');
7.29 (1Н, s, H-6')
3147 (N-H),
1654 (C=O),
12.63
8.06 3.07
1.11
2.78 7.74-7.50 (4Н, m, H Ar);
8.11-8.01 (3Н, m, H Ar)
7g
1589 (С=S, С=N)
In order to discover the fine details of the reaction of acids 1a-g with hydrazine, we carried out
nonempirical quantum-chemical calculations for the total energy (Etot), bond lengths, atomic charges, and bond
orders in the intermediates 2b and 4b-6b, activated complex 3b, and cinnolinone 7b by the LCAO MO SCF
method in the 6-31G(d) basis. These calculations indicate that the distance between the reaction sites (lN···C), the
amino group nitrogen atom and the carboxyl carbon atom in compound 2b is 2.711 Å, while the distance
between an NH2 group hydrogen atom and the carbonyl oxygen atom of the carboxyl group (lH···O) is 2.779 Å.
The decrease in the lN···C interatomic distance is accompanied by an increase in the N–H bond length and
decrease in the corresponding lH···O interatomic distance. The lN···C distance in activated complex 3b is contracted
to 1.538 Å, the N–H bond length is extended from 1.002 Å in intermediate 2b to 1.231 Å, while the lH···O
interatomic distance is 1.311 Å. Further approach of the nitrogen and carbon atoms leads to cleavage of the N–
H bond, i.e., proton transfer from the nitrogen atom to the oxygen atom with formation of a stable intermediate 4b.
The subsequent transformation of intermediate 4b into the reaction product 7b may proceed either through
intermediates 5b or 6b. Calculations indicate that the intermediate 5b has lower total energy (Etot = -1005.7685 a.u.)
than intermediate 6b (Etot = -1005.7585 a.u.). Thus, the formation of intermediate 5b is more likely and,
correspondingly, our quantum-chemical calculations are in accord with the proposed reaction scheme.
Hence, the reaction studied is a convenient and efficient method for the preparation of fused tricyclic
heterocyclic compounds containing a pyridazine fragment, by means of the reaction of 2-substituted
7,7-dimethyl-5-oxo-5,6,7,8-tetrahydroquinoline-4-carboxylic acids with hydrazine.
EXPERIMENTAL
1
13
The IR spectra were recorded on a Bruker IFS 66ps spectrometer for vaseline mulls. The H and C
NMR spectra were recorded in DMSO-d6 solution with HMDS as internal standard (δ 0.059 ppm) on a Varian
Mercury 300 plus spectrometer at 300 and 75 MHz, respectively. Elemental analysis was carried out on a LECO
CHNS-932 analyzer. The melting points were determined on a PTP instrument. The purity of the products was
1524

1525

products was checked by HPLC on an Agilent 1260 chromatograph equipped with a 2504.6 mm Zorbax
Eclipse XDB-C18 column (5 μm particle size) using gradient elution with 50-100% acetonitrile in water over 20
min at 30°C. The flow rate was 1 ml/sec. Detection was carried out at 254 and 300 nm.
The quantum-chemical calculations were carried out using the Firefly software suite [14] adapted for a
Toshiba Portege M400 personal computer.
5-Substituted 8,8-dimethyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]cinnolin-3-ones 7a-g (General
Method). A mixture of corresponding quinolinecarboxylic acid 1a-g (6 mmol) and 64% hydrazine hydrate (0.6 g,
12 mmol) was heated at reflux in ethanol (30 ml) for 2 h. The reaction mixture was cooled. The precipitate
formed was filtered off and washed on the filter with hot ethanol.
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2.
J. A. Joule and K. Mills, Heterocyclic Chemistry [Russian translation], Mir, Moscow (2009), p. 284.
T. Mulamba, R. El Boukili-Garré, D. Séraphin, E. Noé, C. Charlet-Fagnère, J. Hénin, J. Laronze,
J. Sapi, R. Barret, J.-Y. Laronze, and J. Lévy, Heterocycles, 41, 29 (1995).
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4.
S. N. Shurov, D. A. Rudenko, A. S. Shurov, Yu. A. Shchurov, O. V. Vinokurova, M. P. Kolobova, and
L. A. Shurova, in: Proceedings of the International Conference on Innovation Potential of Natural
Sciences [in Russian], Vol. 1, Izd. Permsk. Univ., Perm, Russia (2006), p. 236.
A. A. Granovsky, Firefly Version 7.1.G. URL: http://classic.chem.msu.su/gran/firefly/index.html
(29.02.2012).
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