Nitrogen-containing heterocycles based on tetracarbonyl compounds and their analogs. 2. Reactions of 2-(4,4-dimethyl-2,6-dioxocyclohexyl)-4-oxo-4-phenylbutanoic acid with N-nucleophiles

Article abstract of DOI:10.1023/A:1013279716591

The adduct of dimedone and β-benzoylacrylic acid is shown to form quinoline derivatives in reactions with primary amines.

Full text of DOI:10.1023/A:1013279716591

Chemistry of Heterocyclic Compounds, Vol. 37, No. 9, 2001
NITROGEN-CONTAINING HETEROCYCLES
BASED ON TETRACARBONYL COMPOUNDS
AND THEIR ANALOGS. 2.* REACTIONS OF
2-(4,4-DIMETHYL-2,6-DIOXOCYCLOHEXYL)-
4-OXO-4-PHENYLBUTANOIC ACID
WITH N-NUCLEOPHILES
A. N. Andin, V. A. Kaminski, and S. V. Dubovitskii
The adduct of dimedone and -benzoylacrylic acid is shown to form quinoline derivatives in reactions
β
with primary amines.
Keywords: -benzoylacrylic acid, dimedone, 1,4,5,6,7,8-hexahydroquinolines, Michael reaction.
β
Earlier we have shown that the adduct of dimedone and trans-1,2-dibenzoylethylene forms pyrrole
derivatives in reactions with ammonia and primary amines [1]. We also established that the adduct of dimedone
and -benzoylacrylic acid, when treated with ammonia, forms pyrrolo[4,3,2-d,e]quinoline structure that appears
β
within the composition of some marine alkaloids [2].
With the objective of determining the prospects for synthesis of N-substituted pyrrolo[4,3,2-d,e]-
quinolines, we thought it was advisable to study the characteristic features of the behavior of this triketo acid in
reactions with various N-nucleophiles.
We carried out the reactions of 2-(4,4-dimethyl-2,6-dioxocyclohexyl)-4-oxo-4-phenylbutanoic acid with
ammonium acetate, methylamine, benzylamine, and p-toluidine. We obtained only quinoline derivatives as a result.
As the model N-nucleophiles, we selected aliphatic, aliphatic-aromatic, and aromatic amines. Reactions
with these amines in acetic acid lead to formation of compounds of type 2a-c.
H
O
O
O
COOH
O
RNH2
AcOH
O
Ph
N
R
Ph
OH
2a–c
1
2a R = Me, b R = PhCH2–, c R = 4-MeC6H4–
_______
* For Communication 1, see [1].
__________________________________________________________________________________________
Far-East State University, Vladivostok 690600, Russia; e-mail: sdubov@chem.dvgu.ru. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 9, 1211-1213, September, 2001. Original article submitted
November 17, 1999.
0009-3122/01/3709-1111$25.00©2001 Plenum Publishing Corporation
1111

In the IR spectra of the indicated compounds, we observe an intense absorption band in the 1600 cm-1 region
-1
-1
+
(hydrogen-bonded carboxyl) and the 2350-2250 cm region (C=O –H), and also in the 1640 cm region (C=O).
For the 1H NMR spectra of these compounds, two doublet signals are typical in the 5-6 ppm and 8 ppm region
1
(4-H and 3-H respectively). In the H NMR spectrum of compound 2b, the signals from protons of the CH2Ph
group appear as two doublets with Jgem = 15.5 Hz and
= 1.42 ppm, which indicates a fixed conformation at
∆δ
the N–CH2– bond, where one of the protons of the –CH2– group falls within the deshielding cone of the phenyl
substituent in the position 2.
In the reaction of triketo acid 1 with ammonium acetate, also carried out in acetic acid, the pyridine ring
is closed; furthermore, decarboxylation occurs and the previously described compound 3 is formed [3].
O
AcONH4
AcOH
1
N
Ph
3
Oxidation of dihydropyridine ring of compounds 2a-c could lead to formation of betaines, which could
act as lipophilic membrane stabilizers. But on oxidation of compound 2b by chromic anhydride in pyridine, we
obtained compound 4.
–
CH2Ph
N
O
COO
Ph
2b
COOH
N
Ph
+
O
O
CH2Ph
COOH
Ph
N
CH2Ph
4
1
In the H NMR spectrum of the compound obtained, there are no signals from protons in the positions
4, 4'. The position of the other signals is similar to what is observed in the spectrum of the starting compound.
The absorption bands in the IR spectrum are also similar to the starting data. The mass spectrum does not give
molecular ion, showing only the molecular degradation products.
EXPERIMENTAL
The IR spectra were recorded on a Perkin Elmer Spectrum BX in KBr. The mass spectra were
determined on an HP 5972 MSD/HP chromatographic/mass spectrometric system with ionizing electron energy
1
of 70 eV. The H NMR spectra were obtained on a Bruker WM-250 spectrometer in CDCl3 (internal standard
TMS). The course of the reactions and the purity of the compounds obtained were monitored by TLC on Silufol
UV-254 and Sorbfil plates, and also by gas chromatography.
1,7,7-Trimethyl-5-oxo-2-phenyl-1,4,5,6,7,8-hexahydroquinoline-4-carboxylic Acid (2a). Mixture of
compound 1 (0.40 g, 1.3 mmol) and 25% aqueous methylamine (2 ml) in acetic acid (5 ml) was boiled for
30 min and then poured into ice water; the precipitating oil was triturated. A solid residue that was obtained was
filtered, washed with water, and dried. Compound 2a was obtained, yield 0.21 g (53%); mp 130-132°C
1
(ethanol). IR spectrum (KBr), , cm-1: 2266, 1892, 1640, 1609, 1563. H NMR spectrum (CDCl3), , ppm,
ν
δ
1112

J (Hz): 15.44 (1H, s, OH); 8.13 (1H, d, J = 2.0, 3-H); 7.10-7.40 (5H, m, Ph); 5.10 (1H, d, J = 2.0, 4-H); 2.90
(3H, s, CH3); 2.48 (2H, s, CH2); 2.31 (2H, s, CH2); 1.07 (6H, s, 2 CH3). Mass spectrum: 311 [M]+. Found, %:
C 73.05; H 6.96; N 4.68. C19H21NO3. Calculated, %: C 73.29; H 6.80; N 4.50.
1-Benzyl-7,7-dimethyl-5-oxo-2-phenyl-1,4,5,6,7,8-hexahydroquinoline-4-carboxylic Acid (2b).
The acid was obtained according to similar procedure from compound 1 (0.40 g, 1.3 mmol) and benzylamine
(1 ml, 9.2 mmol), yield 0.45 g (92%); mp 154-156°C (ethanol). IR spectrum (KBr), , cm-1: 2337, 1889, 1638,
ν
1601, 1566. 1H NMR spectrum (CDCl3), , ppm, J (Hz): 15.37 (1H, s, OH); 8.12 (1H, d, J = 2.0, 3-H); 7.28-7.38
δ
(5H, m, Ph); 7.05-7.14 (5H, m, Ph); 5.16 (1H, d, J = 15.5, CH2N); 5.02 (1H, d, J = 2.0, 4-H); 3.74 (1H, d,
J = 15.5, CH2–N); 2.50 (2H, s, CH2); 2.31 (2H, s, CH2); 1.08 (6H, s, 2CH3). Mass spectrum: 387 [M]+.
Found, %: C 77.75; H 6.28; N 3.88. C25H25NO3. Calculated, %: C 77.49; H 6.50; N 3.61.
7,7-Dimethyl-1-(4-methylphenyl)-5-oxo-2-phenyl-1,4,5,6,7,8-hexahydroquinoline-4-carboxylic Acid
(2c). The acid was obtained similarly from compound 1 (0.40 g, 1.3 mmol) and p-toluidine (0.14 g, 1.3 mmol).
Yield 0.20 g (41%); mp 156-158°C (ethanol). The material was purified by express chromatography on Al2O3
(eluent CH2Cl2). IR spectrum (KBr), , cm-1: 2389, 2303, 1895, 1641, 1607, 1573. 1H NMR spectrum (CDCl3),
ν
, ppm, J (Hz): 14.97 (1H, s, OH); 8.24 (1H, d, J = 2.5, 3-H); 7.07-7.28 (9H, m, Harom); 5.75 (1H, d, J = 2.5,
δ
4-H); 2.50 (2H, s, CH2); 2.33 (2H, s, CH2); 2.28 (3H, s, CH3); 1.09 (6H, s, 2CH3). Mass spectrum: 387 [M]+.
Found, %: C 77.66; H 6.38; N 3.42. C25H25NO3. Calculated, %: C 77.49; H 6.50; N 3.61.
7,7-Dimethyl-2-phenyl-5,6,7,8-tetrahydroquinolin-5-one (3). Mixture of compound 1 (0.40 g,
1.3 mmol) and ammonium acetate (1.00 g, 13 mmol) in acetic acid (5 ml) was boiled for 2 h, poured into ice
water, the precipitated crystals were filtered off, washed with water, and dried. Yield 0.05 g (16%); mp 70-72°C
1
(ethanol–water). Lit. mp 71.5-73°C [3]. The IR and H NMR data correspond to the literature values. Mass
spectrum: 251 [M]+. Found, %: C 81.47; H 6.96; N 5.28. C17H17NO. Calculated, %: C 81.24; H 6.82; N 5.57.
Bis(1-benzyl-7,7-dimethyl-5-oxo-2-phenyl-1,4,5,6,7,8-hexahydro-4-quinolyl)-4,4'-dicarboxylic Acid
(4). Solution of compound 2b (0.20 g, 0.52 mmol) was added to solution of chromic anhydride (0.02 g,
0.2 mmol) in pyridine (5 ml); this was held for 1 h at room temperature. The mixture was poured into water and
extracted with methylene chloride. The extract was dried, the solvent was evaporated down, and the residue was
triturated with acetone. Yield 0.10 g (50%); mp 177-179°C (acetone). IR spectrum (KBr), , cm-1: 2249, 1899,
ν
1610, 1568. 1H NMR spectrum (CDCl3), , ppm, J (Hz): 15.14 (1H, s, OH); 7.95 (1H, s, 3-H); 7.27-7.38 (5H, m,
δ
Ph); 7.18 -7.25 (5H, m, Ph); 4.62 (1H, d, J = 15, CH2N); 4.15 (1H, d, J = 15, CH2N); 2.44 (2H, s, CH2); 2.20
(2H, s, CH2); 1.01 (6H, s, 2CH3). Mass spectrum: 281 [M/2 - Ph - CO]+; 105 [Ph - CO]+. Found, %: C 77.92;
H 6.15; N 3.48. C50H48N2O6. Calculated, %: C 77.70; H 6.26; N 3.62.
This research was done with the financial support of the Russian Foundation for Basic Research (grant
No. 98-03-32891) and the US Civilian Research and Development Foundation (CRDF)/Ministry of Education
(grant No. REC-003).
REFERENCES
1.
2.
3.
A. N. Andin, V. A. Kaminski, S. V. Dubovitskii, Khim. Geterotsikl. Soedin., 1497 (1999).
S. V. Dubovitskii and V. A. Kaminski, Zh. Org. Khim., 33, 1118 (1997).
T. D. Kazarinova, L. I. Markova, and V. G. Kharchenko, Khim. Geterotsikl. Soedin., 647 (1994).
1113