Recyclization of dimedone adduct with 2-(2-oxo-2-phenylethylidene) propanedinitrile in the reaction with N-nucleophiles

Article abstract of DOI:10.1134/S107042801307018X

Three-component condensation of dimedone with phenylglyoxal hydrate and malononitrile gave a polyfunctional 5,6,7,8-tetrahydro-4H-chromene derivative, 2-amino-4-benzoyl-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3- carbonitrile, which reacted with ammonium acetate to produce pyrrolo[3,4-c]quinoline ring system. Reactions of the condensation product with primary and secondary amines and hydroxylamine hydrochloride afforded polysubstituted pyrroles, whereas the reaction with hydrazine hydrate led to 3-amino-6-phenylpyridazine-4-carbonitrile.

Full text of DOI:10.1134/S107042801307018X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2013, Vol. 49, No. 7, pp. 1067–1071. © Pleiades Publishing, Ltd., 2013.
Original Russian Text © V.V. Ovchinnikova, A.N. Andin, 2013, published in Zhurnal Organicheskoi Khimii, 2013, Vol. 49, No. 7, pp. 1082–1085.
Recyclization of Dimedone Adduct
with 2-(2-Oxo-2-phenylethylidene)propanedinitrile
in the Reaction with N-Nucleophiles
V. V. Ovchinnikova and A. N. Andin
Far Eastern Federal University, ul. Oktyabr'skaya 27, Vladivostok, 690950 Russia
e-mail: andin@chem.dvgu.ru
Received November 10, 2012
Abstract—Three-component condensation of dimedone with phenylglyoxal hydrate and malononitrile gave
a polyfunctional 5,6,7,8-tetrahydro-4H-chromene derivative, 2-amino-4-benzoyl-7,7-dimethyl-5-oxo-5,6,7,8-
tetrahydro-4H-chromene-3-carbonitrile, which reacted with ammonium acetate to produce pyrrolo[3,4-c]quino-
line ring system. Reactions of the condensation product with primary and secondary amines and hydroxylamine
hydrochloride afforded polysubstituted pyrroles, whereas the reaction with hydrazine hydrate led to 3-amino-6-
phenylpyridazine-4-carbonitrile.
DOI: 10.1134/S107042801307018X
Numerous publications deal with Michael adducts
derived from α,β-unsaturated components containing
one or several cyano groups. In particular, adducts of
cyclic 1,3-diketones with substituted benzylidene-
malononitriles or their analogs are well known.
These adducts are derivatives of 2-amino-5-oxo-
5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile, and
they can be synthesized by both reaction of the two
above listed compounds [1–4] and unsymmetrical
three-component condensation of a cyclic 1,3-diketone
with aromatic aldehyde (or ketone) and malononitrile,
bypassing the isolation of unsaturated nitrile [5–10].
The resulting polyfunctional compounds attract inter-
est from the viewpoint of their biological activity; for
example, there are published data on their antibacterial
effect [11].
with participation of reactive amino and cyano groups.
Recyclization into quinoline derivatives by the action
of ammonium acetate [2] and isocyanates [14], as well
as via Dimroth rearrangement [15], was also reported.
We previously studied N-heterocyclization of dime-
done adducts with 1,1-diacetyl-2-benzoylethene [16],
β-benzoylacrylic acid [17], and 1,2-dibenzoylethene
[18]. The goal of the present study was to elucidate the
direction of recyclization of dimedone adduct with
2-(2-oxo-2-phenylethylidene)propanedinitrile (com-
pound I) in reactions with N-nucleophiles under dif-
ferent conditions. As nucleophiles we used ammonium
acetate in acetic acid, primary amines (methylamine
and benzylamine), secondary amines (morpholine and
piperidine), and difunctional nucleophiles (hydroxyl-
amine amine hydrochloride and hydrazine hydrate).
A number of studies have been concerned with
N-heterocyclizations of the aforesaid tetrahydro-4H-
chromene derivatives; these heterocyclizations involve
mainly fusion of pyridine [12] or pyrimidine ring [13]
Initial tetrahydrochromene I was synthesized in
66% yield by three-component condensation of dime-
done with equimolar amounts of phenylglyoxal hy-
drate and malononitrile. The condensation was carried
Scheme 1.
O
Ph
O
O
O
CN
NaOH, EtOH
OH
+
+
NC
CN
Ph
Me
Me
Me
Me
OH
OH
O
NH2
I
1067

OVCHINNIKOVA, ANDIN
1068
Scheme 2.
R
O
Ph
Ph
N
NH
O
O
NH4OAc, AcOH
or RNH2, AcOH
O
O
I
Me
Me
Me
Me
N
R
N
O
H
III
II
R = Me, PhCH2.
out by heating the reactants in boiling ethanol for 4 h
in the presence of sodium hydroxide (Scheme 1).
Obviously, the reaction begins with formation of inter-
mediate (2-oxo-2-phenylethylidene)propanedinitrile
from phenylglyoxal hydrate and malononitrile, and the
subsequent addition of dimedone and intramolecular
cyclization involving the enolic hydroxy group in the
dimedone fragment and one cyano group in the
malononitrile fragment yield the final product.
involve unsubstituted nitrogen atom in intermediate
amidine.
Different results were obtained when the reactions
were carried out in a large excess of amine, i.e., when
benzylamine, piperidine, or morpholine was used as
solvent. By heating compound I in these amines at 85–
90°C over a period of 2 h we obtained the correspond-
ing substituted pyrroles IVa–IVc in 20–26% yield
(Scheme 4).
Structural features of compound I imply the pos-
sibility for building up pyrrolo[3,4-c]quinoline system
via closure of pyridine and pyrrole rings in one syn-
thetic step in the reaction with ammonia. By heating
compound I with ammonium acetate in boiling acetic
acid (reaction time 1 h) we obtained 56% of pyrrolo-
[3,4-c]quinoline derivative II (Scheme 2).
We initially presumed that reactions of I with
primary amines (aqueous methylamine and benzyl-
amine) would lead to the corresponding N,N′-disubsti-
tuted derivatives III. However, these reactions in
boiling acetic acid afforded the same product (~40%)
as that isolated in the reaction with ammonium acetate,
pyrrolo[3,4-c]quinoline II. Compound II was also
formed when nitrile I reacted with secondary amines,
piperidine and morpholine. These findings may be ra-
tionalized assuming a mechanism shown in Scheme 3,
according to which both N-heterocyclization steps
Obviously, under these conditions the process stops
at the step of recyclization of initial adduct I to pyrrole
derivative. The low yields of IVa–IVc are likely to be
determined by their donor character which favors
tarring. We failed to improve the yield of IVa–IVc by
varying the reaction conditions.
The reaction of I with hydroxylamine hydro-
chloride in ethanol followed a similar pattern, and the
product was compound V which was obtained in
a fairly good yield (67%); the product was isolated as
solvate with one ethanol molecule (Scheme 4).
A different recyclization was observed in the reac-
tion of I with hydrazine hydrate. Heating of the reac-
tants at a I–N2H4·H2O ratio of 1:1.2 in boiling ethanol
afforded previously described [19] pyridazine deriva-
tive VI (Scheme 5). Presumably, the reaction involves
successive opening of the 4H-pyran ring, cyclization
Scheme 3.
Ph
O
Ph
Ph
O
NH
N
R
O
O
NH
O
N
RNH2
CN
··
NHR
I
–H2O
··
··
NH2R
Me
Me
NH2
Me
Me
CN
Me
Me
O
OH
OH
NHR
Ph
NH
O
R
H2O
N
R
I
–H2O
Me
Me
N
H
N
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 7 2013

RECYCLIZATION OF DIMEDONE ADDUCT
1069
Scheme 4.
Me
Me
Me
Me
OH
OH
CN
NH
CN
NH
NH2OH·HCl, EtOH
HNRR'
· EtOH
I
NHOH
NRR'
O
O
Ph
Ph
IVa–IVc
V
R = PhCH2, R′ = H (a); RR′N = piperidin-1-yl (b), morpholin-4-yl (c).
with participation of the fatty–aromatic carbonyl group
and second nitrogen atom of hydrazine, and elimina-
tion of dimedone molecule with formation of aromatic
pyridazine system.
C 71.02; H 5.78; N 8.81. C19H18N2O3. Calculated, %:
C 70.79; H 5.63; N 8.69. M 322.36.
7,7-Dimethyl-1-phenyl-3,3a,4,5,6,7,8,9-octa-
hydro-2H-pyrrolo[3,4-c]quinoline-3,4,9-trione (II).
A solution of 0.2 g (0.62 mmol) of compound I and
0.2 g (2.6 mmol) of ammonium acetate in 5 ml of
acetic acid was heated for 1 h under reflux. The mix-
ture was poured into 100 ml of water and extracted
with ethyl acetate (2×20 ml), the combined extracts
were washed with water (2×20 ml) and dried over an-
hydrous sodium sulfate, the solvent was distilled off,
and the residue was purified by express chromatog-
raphy on silica gel using diethyl ether as eluent. Yield
0.112 g (56%), colorless crystals, mp 144–145°C. IR
spectrum, ν, cm–1: 3390 (NH), 3356 (NH), 1707
Scheme 5.
N
NH2
CN
NH2NH2·H2O, EtOH
N
I
Ph
VI
EXPERIMENTAL
The IR spectra were recorded in KBr on a Perkin
1
Elmer Spectrum BX spectrometer. The H NMR spec-
1
tra were measured on a Bruker AC-400 instrument at
400 MHz using tetramethylsilane as internal reference.
The mass spectra were obtained on an Agilent 1200
Series LC/MSD instrument (Zorbax XDB C18 col-
umn, 2.1×150 mm, 3.5 μm; eluent acetonitrile–water,
85:15; detector temperature 50°C). The progress of re-
actions was monitored by TLC on Sorbfil plates using
chloroform as eluent; spots were visualized by treat-
ment with iodine vapor.
(C=O), 1670 (C=O). H NMR spectrum (CDCl3), δ,
ppm: 1.17 s (3H, CH3), 1.20 s (3H, CH3), 2.45 d and
2.53 d (1H each, CH2, J = 16.2 Hz), 2.82 d and 2.87 d
(1H each, CH2, J = 17.5 Hz), 5.00 s (1H, 3a-H),
5.56 br.s (1H, NH), 7.42–7.52 m (3H, Harom), 7.80 d
(2H, Harom, J = 7.1 Hz), 7.95 br.s (1H, NH). Mass spec-
trum: m/z 323 [M + H]+. Found, %: C 70.97; H 5.53;
N 8.84. C19H18N2O3. Calculated, %: C 70.79; H 5.63;
N 8.69. M 322.36.
2-Amino-4-benzoyl-7,7-dimethyl-5-oxo-5,6,7,8-
tetrahydro-4H-chromene-3-carbonitrile (I). A solu-
tion of 1.4 g (10 mmol) of dimedone, 1.52 g
(10 mmol) of phenylglyoxal hydrate, 0.66 g (10 mmol)
of malononitrile, and 50 mg (1.25 mmol) of sodium
hydroxide in 50 ml of ethanol was heated for 4 h under
reflux. After cooling, the precipitate was filtered off,
washed with ethanol and diethyl ether, and dried in air.
Yield 2.14 g (66%), colorless crystals, mp 204–206°C.
IR spectrum, ν, cm–1: 3400, 3321 (NH2), 2193 (CN),
1689 (C=O), 1655 (C=O), 1594 (C=C). 1H NMR spec-
trum (CDCl3), δ, ppm: 1.12 s (3H, CH3), 1.17 s (3H,
CH3), 2.28 s (2H, CH2), 2.47 s (2H, CH2), 4.68 s (2H,
NH2), 5.03 s (1H, 4-H), 7.49 t (2H, Harom, J = 7.4 Hz),
7.59 t (1H, Harom, J = 7.4 Hz), 8.07 d (2H, Harom, J =
7.3 Hz). Mass spectrum: m/z 323 [M + H]+. Found, %:
2-Benzylamino-4-(4,4-dimethyl-2,6-dioxocyclo-
hexyl)-5-phenyl-1H-pyrrole-3-carbonitrile (IVa).
A solution of 0.2 g (0.62 mmol) of compound I in 3 ml
of benzylamine was heated for 2 h at 85°C. The mix-
ture was poured into 100 ml of water, 3 ml of con-
centrated aqueous HCl was added, and the precipitate
was filtered off, washed with water, dried in air, and
washed with cold methylene chloride. Yield 50 mg
(20%), light yellow crystals, mp 150–152°C. IR spec-
trum, ν, cm–1: 3414, 3258 (NH); 2620 (OH), 2196
1
(CN), 1639 (C=O), 1597 (C=C). H NMR spectrum
(CDCl3), δ, ppm: 1.11 s (3H, CH3), 1.19 s (3H, CH3),
2.35 d and 2.47 d (2H each, CH2, J = 16.8 Hz), 4.39 s
(2H, CH2NH), 4.73 s (1H, NH), 6.87–7.11 m (5H,
Harom), 7.23–7.45 m (5H, Harom), 9.09 s (1H, NH).
Mass spectrum: m/z 412 [M + H]+. Found, %: C 75.64;
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 7 2013

OVCHINNIKOVA, ANDIN
1070
H 5.98; N 10.30. C26H25N3O2. Calculated, %: C 75.89;
H 6.12; N 10.21. M 411.50.
0.16 g (67%), light yellow crystals, mp 166–168°C. IR
spectrum, ν, cm–1: 3456 (NH), 3335 (OH), 3175 (OH),
3134 (NH), 2640 (OH), 2208 (CN), 1641 (C=O), 1613
4-(4,4-Dimethyl-2,6-dioxocyclohexyl)-5-phenyl-
2-(piperidin-1-yl)-1H-pyrrole-3-carbonitrile (IVb).
A solution of 0.2 g (0.62 mmol) of compound I in 3 ml
of piperidine was heated for 2 h at 90°C. The mixture
was poured into 100 ml of water, 4 ml of concentrated
aqueous HCl was added, and the precipitate was
filtered off, washed with water, dried in air, and puri-
fied by express chromatography on neutral aluminum
oxide using methylene chloride as eluent. Yield 50 mg
(21%), yellow crystals, decomposition point >180°C.
IR spectrum, ν, cm–1: 3150 (NH), 2650 (OH), 2217
1
(C=C). H NMR spectrum (DMSO-d6), δ, ppm: 1.05 s
(3H, CH3), 1.07 s (3H, CH3), 1.36 t (3H, CH3CH2, J =
7.1 Hz), 2.11–2.26 m (2H, CH2), 2.36–2.50 m (2H,
CH2), 4.36 q (2H, CH2CH3, J = 7.1 Hz), 7.13 t (1H,
Harom, J = 7.2 Hz), 7.20–7.36 m (4H, Harom), 10.56 br.s
(1H, NH), 11.58 s (1H, OH). Mass spectrum: m/z 338
[M – C2H5OH + H]+. Found, %: C 65.46; H 6.43;
N 11.06. C19H19N3O3 · C2H5OH. Calculated, %:
C 65.78; H 6.57; N 10.96. M 383.44.
3-Amino-6-phenylpyridazine-4-carbonitrile (VI).
A solution of 0.2 g (0.62 mmol) of compound I and
37 mg (0.74 mmol) of hydrazine hydrate in 2 ml of
ethanol was heated for 0.5 h under reflux, 1 ml of
water was added, the mixture was cooled, and the pre-
cipitate was filtered off and washed with cold ethanol.
Yield 65 mg (53%), light yellow crystals. The spectral
parameters of the product were consistent with pub-
lished data [19]. Found, %: C 67.55; H 4.22; N 28.40.
C11H8N4. Calculated, %: C 67.34; H 4.11; N 28.55.
1
(CN), 1644 (C=C). H NMR spectrum (CDCl3), δ,
ppm: 0.77 s (6H, CH3), 1.65–1.95 m (6H, CH2), 2.16 s
(2H, CH2), 2.19 s (2H, CH2); 3.38–3.55 m, 3.59–
3.76 m, 3.88–4.04 m, and 4.37–4.53 m (1H each,
CH2N); 7.10–7.30 m (5H, Harom), 8.42 br.s (1H, NH),
11.59 s (1H, OH). Mass spectrum: m/z 390 [M + H]+.
Found, %: C 73.60; H 7.07; N 10.88. C24H27N3O2. Cal-
culated, %: C 74.01; H 6.99; N 10.79. M 389.49.
4-(4,4-Dimethyl-2,6-dioxocyclohexyl)-2-(mor-
pholin-4-yl)-5-phenyl-1H-pyrrole-3-carbonitrile
(IVc). A solution of 0.2 g (0.62 mmol) of compound I
in 3 ml of morpholine was heated for 2 h at 90°C. The
mixture was poured into 100 ml of water, 4 ml of con-
centrated aqueous HCl was added, and the precipitate
was filtered off, washed with water, dried in air, and
washed with cold methylene chloride. Yield 64 mg
(26%), light yellow crystals, decomposition point
>260°C. IR spectrum, ν, cm–1: 3238 (NH), 2630 (OH),
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