Synthesis of aminovinyl derivatives of quinoline- and isoquinoline-5,8- diones

Article abstract of DOI:10.1007/s10593-012-1071-6

Aminovinyl derivatives of quinoline-5,8-dione and isoquinoline-5,8-dione were obtained. The structure of (E)-6-chloro-7-[2-(N,N-diethylamino)vinyl] quinoline-5,8-dione was confirmed by X-ray structural analysis.

Full text of DOI:10.1007/s10593-012-1071-6

Chemistry of Heterocyclic Compounds, Vol. 48, No. 6, September, 2012 (Russian Original Vol. 48, No. 6, June, 2012)
SYNTHESIS OF AMINOVINYL DERIVATIVES OF
QUINOLINE- AND ISOQUINOLINE-5,8-DIONES*
N. Batenko1**, O. Popova1, S. Belyakov2, and R. Valters1
Aminovinyl derivatives of quinoline-5,8-dione and isoquinoline-5,8-dione were obtained. The structure
of (E)-6-chloro-7-[2-(N,N-diethylamino)vinyl]quinoline-5,8-dione was confirmed by X-ray structural
analysis.
Keywords: aminovinyl derivatives, isoquinoline-5,8-dione, quinoline-5,8-dione.
One of the most important problems in the development of anticancer preparations is to produce
selectively acting substances with minimal side effects. Various nitrogen-containing heterocyclic quinones have
exhibited high antitumor activity [1]. Of particular interest are compounds containing a quinoline fragment since
they are selective inhibitors of the growth of certain types of tumor cells [1, 2]. However, the effect of
substituents and the mechanism of inhibition are not yet entirely clear. It is known that compounds containing a
substituent at position 7 of quinoline-5,8-dione are significantly more pharmacologically active than the
6-substituted analogs [2].
On the basis of the data mentioned above and of our long-standing interest in the chemistry of
heterocyclic quinones [3-5], it was decided to produce aminovinyl derivatives of quinoline- and isoquinoline-
5,8-diones.
O
Cl
Y
R1
O
O
Et2N
Et2N
X
X
Cl
Cl
O
O
3a,b
Et2NH
NaClO3
MeCHO
Y
Y
X
X
R
1a,b
2a,b
Y
Cl
4a,b
O
1 a R = OH, R1 = H; b R = H, R1 = OH; 1–4 a X = N, Y = CH; b X = CH, Y = N
_______
*Dedicated to Prof. Ivars Kalvinsh, talented chemist, brilliant leader, in honor of his birthday.
**To whom correspondence should be addressed, e-mail: Nelli.Batenko@rtu.lv.
1Riga Technical University, 14/24 Azenes St., Riga LV-1048, Latvia.
2Latvian Institute of Organic Synthesis, 21 Aizkraukles St., Riga LV-1006, Latvia; e-mail: serg@osi.lv.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 955-959, June, 2012. Original
article submitted February 16, 2012.
888
0009-3122/12/4806-0888©2012 Springer Science+Business Media New York

After assessment of the published methods for the synthesis of quinoline- and isoquinoline-5,8-diones,
the method [6] was selected, which in spite of low yields makes it possible to easily obtain compounds 2a,b
from readily available starting compounds 1a,b.
In the reaction of the quinones 2a,b, diethylamine, and acetaldehyde, in which the C-nucleophile is
N,N-diethyl-N-vinylamine [3], a mixture of 7- and 6-diethylaminovinyl derivatives 3a,b and 4a,b, respectively,
is formed. The different biological activity of the isomers makes it important to determine the position of
substitution. Analysis of the published data showed that the mechanism of nucleophilic substitution of the
halogen atoms and the factors influencing the regioselectivity of the reaction are not clear. There are reports that
nucleophilic substitution of the halogen atoms by various amino derivatives takes place predominantly at the
position 7 [1, 6, 7]. Other authors have attested the preferential formation of the 6-substituted isomer [8, 9]. In
the study [8], the effect of the medium and of the activity of the nucleophilic reagent on the regioselectivity of
the reaction was assessed; with protic solvents such as ethanol and methanol, a mixture of isomers with a
preponderance of the C-6 isomer is formed. The use of aprotic solvents leads to the formation of a mixture with
a larger content of the C-7 isomer.
We conducted the reaction of quinoline-5,8-dione 2a with the enamine in CH2Cl2 and obtained a
mixture of compounds 3a and 4a with the isomer ratio of 0.7:1.0 (determined from the 1H NMR spectrum of the
reaction mixture), i.e., more of the 6-substituted isomer is formed in aprotic solvent.
In the 1H NMR spectra of compounds 3a and 4a, there is a significant difference in the positions of the
signals of the proton H-4: whereas the signal of 6-aminovinyl-substituted compound 4a appears at 8.33 ppm, the
signal of the 7-aminovinyl-substituted compound 3a is shifted downfield to 8.48 ppm. The difference in the
shifts of the proton H-2 signals is less significant, and the signals appear at 8.92 (compound 3a) and 8.99 ppm
(compound 4a). It can be supposed that the shift of the H-4 signal is affected by the presence or absence of the
chlorine atom at carbon C-6. The downfield shift of the signal for the C-7 isomer agrees with data in [9]. In all
probability the position of the H-4 signal can be used in the assignment of the compound to the 6- or
7-substituted isomer.
It was possible to separate the mixture of isomers by column chromatography. The structure of the
isomer 3a was confirmed by X-ray structural analysis.
Fig. 1. The molecular structure of compound 3a with the atoms represented by thermal
vibration ellipsoids with 50% probability.
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A spatial molecular model of the compound 3a is shown in Figure 1. As can be seen, the
diethylaminovinyl substituent has the E-configuration. All atoms in the molecule of compound 3a lie in one
plane, except for the methyl groups and the protons at the C(16) and C(18) atoms. Analysis of the bond lengths
indicates that there are no classical double and single bonds in the molecule of compound 3a, i.e., the
conjugation includes nearly the whole molecule. In the crystal structure, quite strong intermolecular π–π
interaction is observed in the stacks of molecules: the parallel planes of the molecules, linked by an inversion
center, are separated from each other by only 3.372(5) Å.
Resonance structures for compound 2b were proposed in [6, 7], where the positive charge is localized at the
C-7 atom, and the substitution reactions accordingly take place with the preferential formation of the 7-substituted
isomer. Unfortunately, we were unable to separate the mixture of isoquinoline-5,8-dione derivatives 3b and 4b. In
the 1H NMR spectrum of the mixture of compounds 3b and 4b, there are signals of both isomers with an intensity
ratio of 1:2. Here the signal of the proton at the C-4 atom appears as a broad singlet at 8.08 ppm, common to both
isomers. The signal of H-1 proton is observed at 9.23 ppm (major isomer) and 9.36 ppm (minor isomer). In view of
the shift of the signals for the quinoline-5,8-dione derivatives, it can be assumed that the signal of the
6-aminovinyl-substituted derivative 4b appears in the downfield region (9.36 ppm) from the signal of the C-7
isomer 3b, and the reaction accordingly takes place with the preferential formation of the C-7 product. However, it
is not possible to prove with certainty at which of the atoms, C-6 or C-7, the reaction occurs preferentially.
The quinones 3a,b and 4a,b are intensely colored compounds. In the UV spectra of compounds 3a and
4a, there is a band for intramolecular charge transfer at 596 and 598 nm, respectively. Earlier we synthesized
(E)-2-(2-N,N-dialkylaminothiazol-5-yl)-3,6-dichloro-5-(N,N-diethylaminovinyl)-1,4-benzoquinones, UV spectra
of which contained an intramolecular charge transfer band in the region of 557-566 nm [5].
As a result of this work, the products from the reaction of 6,7-dichloroquinoline- and 6,7-di-
chloroisoquinoline-5,8-diones with the C-nucleophile N,N-diethyl-N-vinylamine were obtained. The obtained
compounds can be used as the basis for the construction of potentially biologically active quinoline-substituted
heterocycles.
EXPERIMENTAL
The IR spectra were recorded in pellets with KBr on a Thermo Electron Nicolet 5700 instrument. The UV
1
spectra were recorded in CHCl3 on a Perkin Elmer Lambda 35 instrument. The H NMR spectra were obtained in
CDCl3 on a Bruker Avance 300 spectrometer (300 MHz) with HMDS as internal standard (δ 0.05 ppm). Elemental
analysis was performed on a Carlo Erba IEA1108 elemental analyzer. X-ray structural analysis was performed
on a Nonius Kappa CCD instrument. The melting points were determined on Kruess KSP 11 Melting Point
Analyzer. The reactions and the purity of the products were monitored by TLC on Merck F254 plates with UV
visualization. Compounds 2a,b were obtained by the method in [6].
(E)-6-Chloro-7-[2-(N,N-diethylamino)vinyl]quinoline-5,8-dione (3a) and (E)-7-Chloro-6-[2-(N,N-di-
ethylamino)vinyl]quinoline-5,8-dione (4a). 6,7-Dichloroquinoline-5,8-dione (2a) (2.00 g, 8.8 mmol) was
dissolved in CH2Cl2 (50 ml). Acetaldehyde (0.43 ml, 8.8 mmol) was added to the solution at room temperature, and
Et2NH (1.82 ml, 17.6 mmol) was then added dropwise over 10 min. The mixture was stirred for 30 min. The
precipitated Et2NH·HCl was filtered off, the solvent was distilled in vacuo to a residual volume of 15 ml, which was
heated, and hot hexane (15 ml) was added. It was left to crystallize in a dark place at room temperature for 24 h, and
the precipitate that formed was filtered off, washed with hexane, and dried at room temperature. Yield 1.38 g (54%);
dark-purple crystals. The mixture of isomers 3a and 4a was separated by column chromatography (eluent MeCN).
Compound 3a. Yield 0.46 g (18%). Rf 0.65 (MeCN); mp 137-139°C (decomp., MeCN). UV spectrum,
1
3
λ
max, nm (log ε): 305 (4.20), 365 (4.19), 596 (4.07). H NMR spectrum, δ, ppm (J, Hz): 1.34 (6Н, t, J = 7.2,
3
3
2СН3СН2); 3.47 (4Н, q, J = 7.2, 2СН3СН2); 5.80 (1Н, d, J = 12.9, NCН=CH); 7.63-7.67 (1Н, m, Н-3); 8.48
(1Н, d, 3J = 7.2, Н-4); 8.52 (1Н, d, 3J = 12.9, NCH=CН); 8.92 (1Н, d, 3J = 3.1, Н-2).
890

Compound 4a. Yield 0.72 g (28%). Rf 0.38 (MeCN); mp 139-141°С (decomp., MeCN). IR spectrum, ν,
cm-1: 1462, 1518, 1578, 1598, 1655, 2929. UV spectrum, λmax, nm (log ε): 307 (4.20), 360 (4.08), 598 (4.05). 1H
NMR spectrum, δ, ppm (J, Hz): 1.33 (6Н, t, 3J = 7.2, 2СН3СН2); 3.49 (4Н, q, 3J = 7.2, 2СН3СН2); 5.76 (1Н, d,
3J = 13.0, NCН=CH); 7.56 (1Н, dd, 3J = 7.7, 3J = 4.7, Н-3); 8.33 (1Н, d, 3J = 7.7, Н-4); 8.49 (1Н, d, 3J = 13.0,
NCH=CН); 8.99 (1Н, d, 3J = 4.7, Н-2). Found, %: С 61.46; Н 4.99; N 9.40. C15H15C1N2O2. Found, %: С 61.97;
Н 5.20; N 9.63.
(E)-6-Chloro-7-[2-(N,N-diethylamino)vinyl]isoquinoline-5,8-dione (3b) and (E)-7-Chloro-6-[2-(N,N-di-
ethylamino)vinyl]isoquinoline-5,8-dione (4b). 6,7-Dichloroisoquinoline-5,8-dione (2b) (2 g, 8.8 mmol) was
dissolved in CH2Cl2 (50 ml). At room temperature, acetaldehyde (0.43 ml, 8.8 mmol) was added to the solution.
Then Et2NH (1.82 ml, 17.6 mmol) was added dropwise over 10 min. The reaction mixture was then treated
similarly to the method used for the preparation of compounds 3a and 4a. Yield 1.45 g (57%). The mixture of
isomers could not be separated. Rf 0.68 (both isomers, MeCN). 1H NMR spectrum (mixture of isomers, 2:1), δ,
ppm (J, Hz): 1.24-1.36 (6Н, m, 2СН3СН2 (both isomers)); 3.50 (2.67Н, q, 3J = 7.2, 2СН3СН2 (major isomer));
3.68 (1.33Н, q, 3J = 7.2, 2СН3СН2 (minor isomer)); 5.75 (0.33Н, d, 3J = 12.5, NCН=CH (minor isomer)); 5.85
(0.67Н, d, 3J = 12.8, NCН=CH (major isomer)); 8.08 (1Н, br. s, Н-4 (both isomers)); 8.50 (0.33Н, d, 3J = 12.5,
3
3
NCH=CН (minor isomer)); 8.60 (0.67Н, d, J = 12.8, NCH=CН (major isomer)); 8.96 (1Н, d, J = 5.2, Н-3
(both isomers)); 9.23 (0.67Н, br. s, Н-1 (major isomer)); 9.36 (0.33Н, br. s, Н-1 (minor isomer)). Found, %:
С 61.97; Н 5.08; N 9.52. C15H15C1N2O2. Calculated, %: С 61.97; Н 5.20; N 9.63.
X-ray Structural Analysis of Compound 3a. The single crystals of compound 3a, obtained by
crystallization from MeCN, are monoclinic. Crystal lattice parameters: a 7.9517(2), b 19.2140(6), c 9.5620(3)
Å; β 112.185(1)°, V 1352.77(7) Å3; F(000) 608; μ 0.285 mm-1; dcalc 1.428 g·cm-3; Z = 4; space group P21/c. The
intensities of 3231 independent reflections were measured to 2θmax = 56° at -80°C. In the calculations, 2235
reflections with I > 2σ(I) were used. The structure was interpreted with SHELXS97 software [10] and refined
with the least-squares method in full-matrix anisotropic approximation with the SHELXL97 software [10]. The
final probability factor was R 0.0983. All information on the crystal structure has been deposited at the
Cambridge Crystallographic Data Center (deposition CCDC 865657).
The work was carried out with financial support from the Latvian Council of Science (grant 09/1617)
and the European Regional Development Fund (2DP/2.1.1.2.0/10/APIA/VIAA/003).
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