Reactions of dimedone-β-benzoylacrylic acid adduct with nitrogen-containing binucleophiles

Article abstract of DOI:10.1134/S1070428011030146

2-(2-Hydroxy-4,4-dimethyl-6-oxocyclohex-1-en-1-yl)-4-oxo-4-phenylbutanoic acid (dimedone adduct with β-benzoylacrylic acid) reacted with ethylenediamine and benzidine to give bis-quinoline derivatives. In the reaction with tryptamine a product containing

Full text of DOI:10.1134/S1070428011030146

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2011, Vol. 47, No. 3, pp. 408–411. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © N.A. Vatolina, A.N. Andin, 2011, published in Zhurnal Organicheskoi Khimii, 2011, Vol. 47, No. 3, pp. 415–418.
Reactions of Dimedone–β-Benzoylacrylic Acid Adduct
with Nitrogen-Containing Binucleophiles
N. A. Vatolina and A. N. Andin
Far East State University, ul. Oktyabr’skaya 27, Vladivostok, 690950 Russia
e-mail: andin@chem.dvgu.ru
Received March 29, 2009
Abstract—2-(2-Hydroxy-4,4-dimethyl-6-oxocyclohex-1-en-1-yl)-4-oxo-4-phenylbutanoic acid (dimedone
adduct with β-benzoylacrylic acid) reacted with ethylenediamine and benzidine to give bis-quinoline deriva-
tives. In the reaction with tryptamine a product containing hexahydroquinoline and indole fragments was
obtained, while the reaction with phenylhydrazine hydrochloride afforded pyridazine derivative. The reactions
with o- and p-phenylenediamines involved retro-Michael decomposition of the initial adduct and formation of
enamino derivatives of dimedone.
DOI: 10.1134/S1070428011030146
Polycarbonyl compounds derived from cyclic
1,3-diketones and electron-deficient 1,2-disubstituted
ethylenes possess 1,3-, 1,4-, or 1,5-dicarbonyl frag-
ment and are convenient model structures for various
heterocyclizations, e.g., in reactions with nitrogen-
centered nucleophiles. These reactions could lead to
the formation of heterocyclic compounds belonging to
the pyrrole, quinoline, pyrroloquinoline, and pyrida-
zine series, and they attract much interest from the
viewpoint of molecular design. Some products ob-
tained as a result of the above heterocyclization are
important as potential physiologically active sub-
stances. For example, data on the use of tetra- and
hexahydroquinoline derivatives as analgesic, antial-
lergic, antiphlogistic, and antipyretic agents have been
reported [1–3].
[4,3,2-de]quinoline derivative [4] and that hexahydro-
quinoline derivatives are formed in reactions of I
with primary amines [5]. N-Heterocyclizations of other
polycarbonyl compounds, products of Michael addi-
tion of dimedone to 1,2-dibenzoylethylene [6] and
1,1-diacetyl-2-benzoylethylene [7], were also studied,
and the resulting nitrogen-containing heterocycles
were identified as pyrrole, quinoline, and pyrrolo-
[3,4-c]quinoline derivatives.
In the present work we examined reactions of
adduct I with some nitrogen-centered binucleophiles,
in particular ethylenediamine, benzidine, phenylhydra-
zine hydrochloride, o- and p-phenylenediamines, and
a biogenic amine, tryptamine, with a view to determine
their regioselectivity. The reactions with ethylenedi-
amine and benzidine were carried out by heating the
reactants in boiling acetic acid; the substrate–diamine
molar ratio was 1:1.5 for ethylenediamine and 2:1 for
benzidine. As a result, we obtained the corresponding
bis-quinoline derivatives IIa and IIb (Scheme 1);
It was shown previously that 2-(2-hydroxy-4,4-di-
methyl-6-oxocyclohex-1-en-1-yl)-4-oxo-4-phenylbuta-
noic acid (I, Michael adduct of dimedone and β-ben-
zoylacrylic acid) reacts with ammonia to give pyrrolo-
Scheme 1.
Ph
Ph
HOCO
O
COOH
O
COOH
O
N
N
H2N–X–NH2, AcOH
X
Ph
Me
Me
O
OH
Me
Me
Me
Me
I
IIa, IIb
X = CH2CH2 (a), p-C6H4C6H4-p′ (b).
408

REACTIONS OF DIMEDONE–β-BENZOYLACRYLIC ACID ADDUCT
409
Scheme 2.
HOCO
Ph
NH2
AcOH
O
N
I
+
N
NH
H
Me Me
III
compound IIa was formed as a mixture of atrop-
isomers at a ratio of 1:2. The poor yield of IIa (9%)
may be rationalized assuming that the main process is
retro-Michael decomposition of initial adduct I and
subsequent formation of water-soluble enamines from
dimedone; in this case, the expected heterocyclization
of I to compound IIa is a minor process. We failed to
improve the yield of IIa by varying the reaction
conditions.
VI and VIII (Scheme 4) which were reported previ-
ously [9–11]. Obviously, compounds VI and VIII were
formed via retro-Michael decomposition of initial
adduct I and subsequent reaction of dimedone with
o- and p-phenylenediamines. The latter are likely to act
as bases which catalyze retro-Michael reaction.
The structure of the isolated compounds was
proved by the IR, NMR, and mass spectra (HPLC–
MS data).
By reaction of adduct I with an equimolar amount
of tryptamine in acetic acid we obtained 65% of com-
pound III possessing both hexahydroquinoline and
indole fragments (Scheme 2). We can conclude that
adduct I in the above reactions acts as 1,5-diketone
whose N-heterocyclization gives rise to compounds
with a 1,4-dihydropyridine fragment.
EXPERIMENTAL
The IR spectra were recorded in KBr on a Perkin–
Elmer Spectrum BX spectrometer. The H NMR spec-
1
tra were measured on a Bruker AC-400 spectrometer
(400 MHz) from solutions in CDCl3 and DMSO-d6
using tetramethylsilane as internal reference. The mass
spectra were obtained on an Agilent 1200 Series
LC/MSD instrument; Zorbax XDB C18 column, 2.1×
150 mm, grain size 3.5 μm, eluent methanol–water
(70:30), detector temperature 50°C. The progress of
reactions was monitored by TLC on Sorbfil plates
using ethyl acetate–ethanol (10:1) as eluent; develop-
ment with iodine vapor.
A different regioselectivity was observed in the
reaction of adduct I with phenylhydrazine hydro-
chloride. Heating of equimolar amounts of the reac-
tants in boiling acetic acid led to the formation of pyr-
idazine derivative IV in which the dimedone fragment
remained unchanged (Scheme 3). The synthesis of
simpler pyridazinones from γ-keto acids is well
known [8].
1,1′-(Ethane-1,2-diyl)bis(7,7-dimethyl-5-oxo-2-
phenyl-1,4,5,6,7,8-hexahydroquinoline-4-carboxylic
acid) (IIa). A solution of 0.2 g (0.63 mmol) of adduct I
and 0.114 g (0.95 mmol) of 50% aqueous ethylene-
diamine in 5 ml of acetic acid was heated for 20 min
under reflux. The mixture was poured into 100 ml of
a dilute aqueous solution of sodium chloride, and the
precipitate was filtered off, washed with water, dried in
air, and ground with diethyl ether. Yield 18 mg (9%),
colorless crystals, mp 225–227°C. IR spectrum, ν, cm–1:
Scheme 3.
Ph
PhNHNH2 ·HCl
AcOH
O
N
N
I
Ph
Me
Me
O
OH
IV
2300 br (OH, assoc.), 1606 (C=O in CO2–). H NMR
1
As nitrogen-containing binucleophiles we also used
o- and p-phenylenediamines. The reaction with
o-phenylenediamine was expected to give compound
V as double cyclization product, whereas p-phenylene-
diamine was presumed to produce bis-quinoline VII.
However, contrary to the expectations, the products of
the above reactions were the corresponding enamines
spectrum (CDCl3), δ, ppm: atropisomer A: 1.10 s
(12H, CH3), 2.31 s (4H, CH2), 2.47 s (4H, CH2), 2.84 d
and 3.96 d (2H each, NCH2, J = 9.8 Hz), 5.32 d (2H,
4-H, J = 1.5 Hz), 7.14 t (4H, Harom, J = 7 Hz), 7.29–
7.38 m (6H, Harom), 8.18 d (2H, 3-H, J = 1.5 Hz),
14.92 s (2H, OH); atropisomer B: 1.10 s (12H, CH3),
2.32 s (4H, CH2), 2.48 s (4H, CH2), 3.07 d and 3.76 d
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 3 2011

VATOLINA, ANDIN
410
Scheme 4.
O
COOH
N
Ph
Ph
COOH
O
HOCO
O
N
N
X
Me
Me
Ph
HN
Me
Me
Me
Me
V
VII
I
O
O
H
N
Me
Me
o-(H2N)2C6H4
PhH, TsOH
p-(H2N)2C6H4
AcOH, TsOH
Me
Me
Me
Me
N
N
H
H
NH2
O
VI
VIII
X = p-C6H4.
(2H each, NCH2, J = 9.8 Hz), 5.10 d (2H, 4-H, J =
1.5 Hz), 7.04 t (4H, Harom, J = 7 Hz), 7.29–7.38 m (6H,
poured into 100 ml of ice water, and the precipitate
was filtered off, washed with water, dried in air, and
recrystallized from chloroform. Yield 0.182 g (65%),
colorless crystals, mp 283–284°C (decomp.). IR spec-
trum, ν, cm–1: 3290 (NH), 2750 br (OH, assoc.), 1637
Harom), 8.33 d (2H, 3-H, J = 1.5 Hz), 15.00 s (2H, OH).
Mass spectrum: m/z 621 [M + H]+. Found, %: C 73.25;
H 6.64; N 4.60. C38H40N2O6. Calculated, %: C 73.53;
H 6.50; N 4.51. M 620.
(C=O), 1616 (C=O in CO2–). H NMR spectrum
1
(DMSO-d6), δ, ppm: 0.98 s (6H, CH3), 2.20 s (4H,
CH2), 2.63 t (1H, NCH2, J = 9.5 Hz), 2.72–2.79 m (2H,
CH2), 2.89 d (1H, 4-H, J = 11.9 Hz), 3.92 t (1H, NCH2,
J = 9.5 Hz), 4.29 d (1H, 3-H, J = 11.9 Hz), 7.00 d (1H,
1,1′-(Biphenyl-4,4′-diyl)bis(7,7-dimethyl-5-oxo-
2-phenyl-1,4,5,6,7,8-hexahydroquinoline-4-carbox-
ylic acid) (IIb). A solution of 0.4 g (1.27 mmol) of
adduct I and 0.117 g (0.63 mmol) of benzidine in 5 ml
of acetic acid was heated for 1 h under reflux. The
mixture was poured into ice water, and the precipitate
was filtered off, washed with water, dried in air, and
purified by express chromatography on silica gel using
ethyl acetate as eluent. Yield 0.25 g (53%), light
yellow crystals, mp 187–188°C. IR spectrum, ν, cm–1:
2400 br (OH, assoc.), 1640 (C=O), 1619 (C=O in
Harom, J = 7.6 Hz), 7.09 t (1H, Harom, J = 7.6 Hz), 7.34–
7.40 m (8H, Harom), 10.84 s (1H, NH), 11.31 s (1H,
OH). Mass spectrum: m/z 441 [M + H]+. Found, %:
C 76.13; H 6.63; N 6.47. C28H28N2O3. Calculated, %:
C 76.34; H 6.41; N 6.36. M 440.
4-(4,4-Dimethyl-2,6-dioxocyclohexyl)-2,6-di-
phenyl-2,3,4,5-tetrahydropyridazin-3-one (IV).
A solution of 0.2 g (0.63 mmol) of adduct I and 92 mg
(0.63 mmol) of phenylhydrazine hydrochloride in 5 ml
of acetic acid was heated for 30 min under reflux. The
mixture was poured into 100 ml of a dilute aqueous
solution of sodium chloride, and the precipitate was
filtered off, washed with water, dried in air, and ground
with diethyl ether. Yield 73 mg (30%), Colorless
crystals, mp 215–216°C. IR spectrum, ν, cm–1: 2600 br
CO2–). H NMR spectrum (DMSO-d6), δ, ppm: 1.05 s
1
(12H, CH3), 2.05 s (4H, CH2), 2.40 s (4H, CH2), 6.22 d
(2H, 4-H, J = 1 Hz), 7.17–7.37 m (10H, Harom), 7.41 d
(2H, 3-H, J = 1 Hz), 7.56 d (4H, Harom, J = 8 Hz),
7.63 d (4H, Harom, J = 8 Hz), 12.29 s (2H, OH). Mass
spectrum: m/z 745 [M + H]+. Found, %: C 77.07;
H 6.12; N 3.88. C48H44N2O6. Calculated, %: C 77.40;
H 5.95; N 3.76. M 744.
1
(OH, enol), 1637 (NC=O). H NMR spectrum
1-[2-(1H-Indol-3-yl)ethyl]-7,7-dimethyl-5-oxo-2-
phenyl-1,4,5,6,7,8-hexahydroquinoline-4-carboxylic
acid (III). A solution of 0.2 g (0.63 mmol) of adduct I
and 0.1 g (0.63 mmol) of tryptamine in 5 ml of acetic
acid was heated for 1 h under reflux. The mixture was
(DMSO-d6), δ, ppm: 1.03 s (6H, CH3), 2.28 s (4H,
CH2), 3.06 d.d (1H, 5-H, J = 16.8, 7.6 Hz), 3.24 d.d
(1H, 5-H, J = 13.0, 16.8 Hz), 3.98 d.d (1H, 4-H, J =
7.6, 13.0 Hz), 7.26 t (1H, Harom, J = 7.4 Hz), 7.34–
7.47 m (5H, Harom), 7.53 d (2H, Harom, J = 7.7 Hz),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 3 2011

REACTIONS OF DIMEDONE–β-BENZOYLACRYLIC ACID ADDUCT
411
7.80 d (2H, Harom, J = 7.3 Hz), 11.02 s (1H, OH). Mass
spectrum: m/z 389 [M + H]+. Found, %: C 74.35;
H 6.39; N 7.32. C24H24N2O3. Calculated, %: C 74.21;
H 6.23; N 7.21. M 388.
data [11]. Mass spectrum: m/z 353 [M + H]+. Found,
%: C 74.70; H 8.20; N 8.09. C22H28N2O2. Calculated,
%: C 74.97; H 8.01; N 7.95. M 352.
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2-en-1-one (VI). Benzene, 10 ml, was added to a mix-
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mp 176–177°C; published data [10]: mp 178–179°C.
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H 8.08; N 12.33. C14H18N2O. Calculated, %: C 73.01;
H 7.88; N 12.16. M 230.
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 3 2011