Adduct of dimedone and 1,2-dibenzoylethene in reactions with nitrogen binucleophiles

Article abstract of DOI:10.1134/S1070428012050090

Dimedone adduct with 1,2-dibenzoylethene in reaction with p-phenylenediamine formed a bispyrrole derivative, and with benzidine and ethylenediamine afforded the corresponding monopyrroles. The reaction of the initial adduct with tryptamine results in a product containing a pyrrole and an indole fragments. Both versions of N-heterocyclization proceed in the reaction with urea yielding derivatives of tetrahydroindole and pyrrole. In the reaction with hydrazine hydrate a substituted pyridazine was obtained as a result of a dimedone molecule elimination from the intermediate cyclization product.

Full text of DOI:10.1134/S1070428012050090

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2012, Vol. 48, No. 5, pp. 686−689. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © V.A. Vertkova, A.N. Andin, 2012, published in Zhurnal Organicheskoi Khimii, 2012, Vol. 48, No. 5, pp. 689−692.
Adduct of Dimedone and 1,2-Dibenzoylethene
in Reactions with Nitrogen Binucleophiles
V. A. Vertkova and A. N. Andin
Far-Eastern Federal University, Vladivostok, 690950 Russia
e-mail: andin@chem.dvgu.ru
Received December 2, 2011
Abstract—Dimedone adduct with 1,2-dibenzoylethene in reaction with p-phenylenediamine formed a bispyrrole
derivative, and with benzidine and ethylenediamine afforded the corresponding monopyrroles. The reaction of
the initial adduct with tryptamine results in a product containing a pyrrole and an indole fragments. Both versions
of N-heterocyclization proceed in the reaction with urea yielding derivatives of tetrahydroindole and pyrrole. In
the reaction with hydrazine hydrate a substituted pyridazine was obtained as a result of a dimedone molecule
elimination from the intermediate cyclization product.
DOI: 10.1134/S1070428012050090
Polycarbonyl compounds prepared from cyclic
1,3-diketones and acceptor 1,2-disubstituted ethenes
contain in their structure 1,3-, 1,4-, and 1,5-dicarbonyl
fragments. Polyfunctional character of this type com-
pounds gives wide opportunities for the molecular design
providing a possibility of virtually one-stage synthesis of
versatile heterocyclic systems, in particular, of nitrogen
heterocycles: pyrroles, pyridines, pyridazines and their
fused analogs, and also more complex fused systems,
pyrrolo[4,3,2-d,e]quinolines, pyrrolo[3,4-c]quinolines,
and some others. The obtained heterocyclic systems due
to the potential biological action may be of interest for
the medical chemistry in the study of the mechanism of
the pharmacological action and also for the pharmaceuti-
cal industry. The data on the analgesic activity of certain
pyrrole derivatives are published in [1]. Substituted
polyarylpyrroles exhibit versatile biological actions, they
are promising for the selection of antiarthritic druge [2],
the medicinals for diabetes and atherosclerosis treatment
[3], and also for the Alzheimer disease [4].
and its modifications for increasing the yield of the tar-
get products specific catalysts are widely used, in par-
ticular, salts of heavy metals [Bi(NO3)3, ZrCl4] [5, 6] or
Montmorillonite clays as solid-phase carriers [7]; these
reactions carried out under the microwave irradiation are
also described [8, 9].
We formerly demonstrated that the heterocyclization
of adduct of dimedone with 1,2-dibenzoylethene I under
the treatment with some N-nucleophiles provided poly-
substituted pyrroles [10]. We also studied the reactions
of the dimedone adducts to β-benzoylacrylic acid and
1,1-diacetyl-2-benzoylethene with a series of nitrogen
mono- and binucleophiles, and the obtained nitrogen het-
erocycles were characterized: derivatives of quinolines,
pyrrolo[3,4-с]quinoline, pyrrolo[4,3,2-d,e]-quinoline,
pyridazine [11–14].
In this research we extended the heterocyclization
of the adduct of dimedone and 1,2-dibenzoylethene I to
nitrogen binucleophiles. We selected among the latter p-
phenylenediamine, benzidine, ethylediamine, tryptamine,
urea, and hydrazine hydrate. The goal of the study was
the investigation of the regiospecificity of the N-hetero-
cyclization in the reaction with the said binucleophiles.
The heterocyclization of the simplest 1,4-diketones,
in particular, from the aliphatic-aromatic series, by the
reaction with N-nucleophiles (Paal–Knorr reaction)
was studied to the end of the nineteenth century; quite
a number of investigations were published later includ-
ing the syntheses of polysubstituted pyrroles of more
complex structure.
The reactions with p-phenylenediamine and
benzidine were carried out in boiling acetic acid, with
ethylenediamine and tryptamine, in ethanol at room
temperature. The molar ratio subtrate–reagent was for
In the nowadays studies of the Paal–Knorr reaction
686

ADDUCT OF DIMEDONE AND 1,2-DIBENZOYLETHENE
687
p-phenylenediamine 2:1, benzidine 1:2, ethylenediamine
1:3, tryptamine 1:1. As a result the corresponding sub-
stituted pyrroles II–IV were isolated in 42–63% yields,
and the heterocylization with benzidine was accompa-
nied with the N-acetylation of one amino group of the
benzidine fragment.
HO
R(NH2)2
AcOH
O
Ph
Ph
N
R
2
II
HO
O
Ph
O
(H2N R
AcOH
)
2
O
Ph
Ph
N
O
Ph
R R NHAc
OH
III
I
HO
R'(CH2)2NH2
EtOH
O
Ph
Ph
N
(CH2)2R'
IVa, IVb
II, III, R = n-C6H4; IV, R’ = NH2 (a), 3-indolyl (b).
In reactions with ethylenediamine and benzidine even
at the excess of the tetraketone we succeeded to isolate
from the reaction mixture only the corresponding mono-
pyrroles apparently due to the presence of stabilizing
intermolecular hydrogen bonds in compounds III and
IVа. Bispyrrole II was obtained only in the reaction of
the initial adduct with p-phenylenediamine.
The reaction of adduct I with urea was carried out in
boiling acetic acid, and urea was taken in the four-fold
excess because of its reduced nucleophilicity as com-
pared with amines. As a result we isolated a mixture of
two isomeric products: derivative of tetrahydroindole V
and pyrrole VI in the molar ratio 3 : 1 and the overall
yield 84%. The mixture was separated into individual
HO
O
CH2COPh
Ph
NH2CONH2
+
I
AcOH
O
Ph
N
Ph
H
N
H
V
VI
components by preparative TLC on silica gel. Compound
V was described in [15].
the corresponding intermediate N-carbamoyl derivatives
whose subsequent acidolysis affords the final products
V, VI.
The described reaction evidently proceeds through
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 5 2012

VERTKOVA, ANDIN
688
The reaction of tetraketone I with the double molar
6.89 s (4Нarom), 6.80–7.30 m (20Нarom), 9.95 br.s (2Н,
2ОН). Found, %: С 81.92; H 6.28; N 3.63. C54H48N2O4.
Calculated, %: С 82.21; H 6.13; N 3.55.
excess of hydrazine hydrate occurred at boiling in etha-
nol. As a result we isolated in 97% yield already known
pyridazine VII [16]. Apparently the process proceeds
through an intermediate dihydropyridazine А formed at
the hydrazine attack on two aliphatic-aromatic carbonyls;
further the intermediate suffers the elimination of the
dimedone molecule with the simultaneous aromatization
of the heterocyclic ring. Evidently the latter factor governs
the regioselectivity of the reaction.
N-1-{4’-[3-(4,4-Dimethyl-2,6-dioxocyclohexyl)-
2,5-diphenyl-1Н-pyrrol-1-yl]biphenyl-4-yl}acetamide
(III). A solution of 100 mg (0.27 mmol) of adduct I and
100 mg (0.54 mmol) of benzidine in 5 ml of acetic acid
was boiled for 30 min. On cooling the separated precipi-
tate was filtered off, washed with acetic acid and ethyl
ether. Yield 80 mg (53%). Light-red crystals, mp 234–
235°С. IR spectrum, ν, cm–1: 3418 (NH), 2625 br (ОН
enol), 1668 (C=O amide), 1601, 1572, 1501 (aromatic
rings). 1Н NMR spectrum (DMSO-d6), δ, ppm: 0.90 s
(6H, 2СН3), 2.01 s (3Н, СН3), 2.09 s (2Н, СН2), 2.26 s
(2Н, СН2), 5.23 s (1Н, Н4), 6.17 d (1Нarom, J 5.1 Hz),
6.56 d (1Нarom, J 8.1 Hz), 6.85–7.20 m (11Нarom), 7.32 d
(1Нarom, J 7.8 Hz), 7.42 d (1Нarom, J 7.9 Hz), 7.50–7.62 m
(3Нarom), 9.93 br.s (1Н, ОН), 9.99 s (1Н, NH). Mass
spectrum, m/z: 567 [M + H]+. Found, %: С 80.30; H 6.15;
N 4.88. C38H34N2O3. Calculated, %: С 80.54; H 6.05;
N 4.94. M 566.69.
Ph
Ph
N
O
N
.
N
N
NH2NH2 H2O
I
Ph
EtOH
OH
Ph
VII
A
Thus in all reactions under study adduct I behaves
as 1,4-diketone and in the most cases the N-heterocycli-
zation proceeds at the expense of the aliphatic-aromatic
carbonyl groups, only with urea both versions of N-
heterocyclization take place, involving both aliphatic-
aromatic carbonyl groups and also one aliphatic-aromatic
carbonyl group and a carbonyl of the dimedone fragment.
1-(2-Aminoethyl)-3-(4,4-dimethyl-2,6-dioxo-
cyclohexyl)-2,5-diphenyl-1Н-pyrrole (IVа). A solution
of 200 mg (0.53 mmol) of adduct I and 200 mg
(3.33 mmol) of 50% aqueous ethylenediamine in 4 ml
of ethanol was maintained for 24 h at room temperature.
Ethanol was evaporated, the residue was repeatedly
triturated with ethyl ether, then it was dissolved in 4 ml
of 25% aqueous ethanol and kept at 0°С for 24 h. The
separated precipitate was filtered off, washed with ethyl
ether. Yield 88 mg (42%). Light-yellow crystals, mp
143–144°С. IR spectrum, ν, cm–1: 3361, 3136 (NH2),
EXPERIMENTAL
IR spectra were recorded on a spectrophotom-
eter Perkin Elmer Spectrum BX from pellets with KBr.
1Н NMR spectra were registered on a spectrometer Bruker
AC-400 (operating frequency 400 MHz). Internal refer-
ence TMS. Mass spectra were measured on an instrument
Agilent 1200 Series LC/MSD, column Zorbax XDB
C18 (2.1 × 150 mm), grains of sorbent 3.5 μm, eluent
acetonitrile–water, 85 : 15, detector temperature 50°С.
The reaction progress was monitored by TLC on Sorbfil,
eluent dichloromethane, development in iodine vapor.
1
2650 br (ОН enol), 1603, 1530 (aromatic rings). Н NMR
spectrum (CDCl3), δ, ppm: 0.96 s (6H, 2СН3), 2.27 br.s
(4Н, 2СН2), 2.45 t (2Н, СН2NH2, J 6.2 Hz), 4.08 t (2Н,
СН2N, J 6.2 Hz), 6.12 s (1Н, Н4), 7.28–7.37 m (6Нarom),
7.40 t (2Нarom, J 7.1, 7.6 Hz), 7.46 d (2Нarom, J 7.5 Hz).
Mass spectrum: m/z 401 [M + H]+. Found, %: С 78.15;
H 7.17; N 6.92. C26H28N2O2. Calculated, %: С 77.97;
H 7.05; N 6.99. M 400.52.
1,1'-(1,4-Phenylene)bis[3-(4,4-dimethyl-2,6-
dioxocyclohexyl)-2,5-diphenyl-1Н-pyrrole] (II).
Asolution of 200 mg (0.53 mmol) of adduct I and 30 mg
(0.27 mmol) of p-phenylenediamine in 5 ml of acetic
acid was boiled for 30 min. On cooling the separated
precipitate was filtered off, washed with acetic acid and
ethyl ether. Yield 132 mg (63%). Light-red crystals, mp
>350°С (decomp.). IR spectrum, ν, cm–1: 2620 br (ОН
enol), 1601, 1571, 1516 (aromatic rings). 1Н NMR
spectrum (DMSO-d6), δ, ppm: 0.90 s (12H, 4СН3),
2.07 s (4Н, 2СН2), 2.25 s (4Н, 2СН2), 6.14 s (2Н, Н4,4'),
1-[2-(3-Indolyl)ethyl]-3-(4,4-dimethyl-2,6-dioxo-
cyclohexyl)-2,5-diphenyl-1Н-pyrrole (IVb). Asolution
of 100 mg (0.27 mmol) of adduct I and 43 mg (0.27 mmol)
of tryptamine in 5 ml of ethanol was maintained for 24 h
at room temperature. The precipitated crystals were
filtered off, washed in succession with cold ethanol and
ethyl ether. Yield 70 mg (54%). Light-brown crystals,
mp 247–248°С. IR spectrum, ν, cm–1: 3308 (NH), 2650 br
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 5 2012

ADDUCT OF DIMEDONE AND 1,2-DIBENZOYLETHENE
689
1
(ОН enol), 1602, 1581, 1555 (aromatic rings). Н NMR
spectrum (CDCl3), δ, ppm: 0.98 s (6H, 2СН3), 2.27 s (2Н,
СН2), 2.30 s (2Н, СН2), 2.64 t (2Н, СН2, J 7.4 Hz), 4.26 t
(2Н, СН2N, J 7.4 Hz), 6.11 br.s (1Н, ОН), 6.12 s (1Н,
Н4), 6.59 d (1Нarom, J 2.1 Hz), 6.73 d (1Нarom, J 8 Hz),
6.88 t (1Нarom, J 7.2, 8 Hz), 7.10 t (1Нarom, J 7.2, 7.5 Hz),
7.14–7.20 m (2Нarom), 7.23–7.47 m (9Нarom), 7.91 br.s
(1Н, NH). Mass spectrum: m/z 501 [M + H]+. Found,
%: С 81.45; H 6.34; N 5.65. C34H32N2O2. Calculated,
%: С 81.57; H 6.44; N 5.60. M 500.64.
cooling the precipitated sparkling crystals were filtered
off and washed with cold ethanol. Yield 120 mg (97%).
Light-yellow crystals, mp 220–221°С (219–220°С [16]).
The spectral findings are consistent with the published
data [16]. Mass spectrum: m/z 233 [M + H]+. M 232.28.
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6,6-Dimethyl-3-phenacyl-2-phenyl-4,5,6,7-
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dioxo-cyclohexyl)-2,5-diphenyl-1Н-pyrrole (VI).
Asolution of 100 mg (0.27 mmol) of adduct I and 64 mg
(1 mmol) of urea in 5 ml of acetic acid was boiled for
30 min. The reaction mixture was poured into 100 ml
of dilute NaCl solution. The separated precipitate was
filtered off, washed with water, and dried in air. Overall
yield of the mixture of isomeric compounds V, VI at-
tained 80 mg (84%) [63% (V), 21% (VI)]. The separation
was carried out by preparative TLC on silica gel (eluent
dichloromethane–ethyl ether, 3 : 1).
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Compound VI. White crystals, t.decomp. >200°С.
IR spectrum, ν, cm–1: 3400 (NH), 2600 br (ОН enol),
1565 (aromatic rings). 1Н NMR spectrum (СDCl3), δ,
ppm: 1.18 s (6Н, 2СН3), 2.43 s (2Н, СН2), 2.47 s (2Н,
12. Andin,A.N., Kaminskii, V.A., and Dubovitskii, S.V., Khim.
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СН2), 6.19 br.s (1Н, NH), 6.60 s (1Н, Н4), 7.27 t (2Нarom
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J 7.4 Hz), 7.31–7.42 m (4Нarom), 7.62 d (2Нarom, J 7.5 Hz),
7.70 d (2Нarom, J 7.6 Hz). Mass spectrum: m/z 358 [M +
H]+. Found, %: С 80.48; H 6.38; N 3.97. C24H23NO2.
Calculated, %: С 80.64; H 6.49; N 3.92. M 357.45.
3,6-Diphenylpyridazine (VII). Asolution of 200 mg
(0.53 mmol) of adduct I and 50 mg (1 mmol) of hydrazine
hydrate in 5 ml of ethanol was boiled for 10 min. On
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 5 2012