Reaction of pyrrolo[2,1-a]isoquinoline-2,3-diones with carbon-centered nucleophiles

Article abstract of DOI:10.1134/S1070428008060110

Knoevenagel condensations of 5,5-dimethyl-2,3,5,6-tetrahydropyrrolo[2,1-a] isoquinoline-2,3-diones with malononitrile, ethyl cyanoacetate, indan-1,3-dione, and Drotaverine base involved the ketone carbonyl group in the former with formation of deeply colored dark blue substances. The lactam ring in the products can be opened by the action of nitrogen-centered nucleophiles, e.g., p-toluidine. The reaction of 5,5-dimethyl-2,3,5,6-tetrahydropyrrolo[2,1-a] isoquinoline-2,3-dione with methyl magnesium iodide gave 2-hydroxy-2,5,5- trimethyl-2,3,5,6-tetrahydropyrrolo[2,1-a]isoquinolin-3-one.

Full text of DOI:10.1134/S1070428008060110

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 6, pp. 845–848. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © O.V. Surikova, A.G. Mikhailovskii, N.N. Polygalova, M.I. Vakhrin, 2008, published in Zhurnal Organicheskoi Khimii, 2008,
Vol. 44, No. 6, pp. 856–858.
Reaction of Pyrrolo[2,1-a]isoquinoline-2,3-diones
with Carbon-Centered Nucleophiles
O. V. Surikova, A. G. Mikhailovskii, N. N. Polygalova, and M. I. Vakhrin
Perm State Pharmaceutical Academy, ul. Lenina 48, Perm, 614990 Russia
e-mail: perm@pfa.ru
Received July 27, 2007
Abstract—Knoevenagel condensations of 5,5-dimethyl-2,3,5,6-tetrahydropyrrolo[2,1-a]isoquinoline-2,3-di-
ones with malononitrile, ethyl cyanoacetate, indan-1,3-dione, and Drotaverine base involved the ketone
carbonyl group in the former with formation of deeply colored dark blue substances. The lactam ring in the
products can be opened by the action of nitrogen-centered nucleophiles, e.g., p-toluidine. The reaction of
5,5-dimethyl-2,3,5,6-tetrahydropyrrolo[2,1-a]isoquinoline-2,3-dione with methyl magnesium iodide gave
2-hydroxy-2,5,5-trimethyl-2,3,5,6-tetrahydropyrrolo[2,1-a]isoquinolin-3-one.
DOI: 10.1134/S1070428008060110
The chemistry of pyrrolo[2,1-a]isoquinolin-2,3-di-
ones is versatile [1–7]. However, reactions of these
compounds with carbon-centered nucleophiles have
not been studied. Therefore, the goal of the present
work was to examine reactions of pyrrolo[2,1-a]iso-
quinolin-2,3-diones I with CH acids and Grignard
compounds. The reactions with CH acids were carried
out according to Knoevenagel using malononitrile,
ethyl cyanoacetate, and indan-1,3-dione as active
methylene component. The condensations readily
occurred in the presence of piperidinium acetate as
catalyst [8], and the products were the corresponding
lactams IIa–IIc and III (Scheme 1). Cyanoacetamides
failed to react with pyrrolo[2,1-a]isoquinolin-2,3-di-
ones Ia and Ib, presumably because of weaker elec-
tron-withdrawing effect of the amide group.
Enamines can also be regarded as CH acids. As
an example, we tried to use Drotaverine base as
an active methylene compound in the Knoevenagel
condensation with compound Ia. The reaction in the
presence of p-toluenesulfonic acid gave compound IV,
whereas no reaction occurred with the use of piperi-
dinium acetate as catalyst. The reaction of lactam III
with p-toluidine was accompanied by opening of the
pyrrole ring with formation of amide V. 5,5-Dimethyl-
2,3,5,6-tetrahydropyrrolo[2,1-a]isoquinoline-2,3-dione
(Ia) reacted with methyl magnesium iodide to give
2-hydroxy-2,5,5-trimethyl-2,3,5,6-tetrahydropyrrolo-
[2,1-a]isoquinolin-3-one (VI) (Scheme 2).
Initial pyrrolo[2,1-a]isoquinoline-2,3-diones Ia and
Ib are red substances. Condensation products II–IV
are dark blue crystalline substances. Opening of the
Scheme 1.
O
Me
Me
N
Me
Me
Me
Me
O
O
R'CH2CN
O
N
N
O
O
R
R
O
CN
O
R'
IIa–IIc
Ia, Ib
III
I, R = H (a), piperidinocarbonyl (b); II, R = H, R′ = CN (a), EtOCO (b), R = piperidinocarbonyl, R′ = CN (c).
845

SURIKOVA et al.
846
Me
Me
Me
Me
N
NH
Me
OEt
O
O
OEt
EtO
O
O
N
EtO
IV
V
pyrrole ring in the reaction leading to compound V
was accompanied by change of the color to yellow.
Compound VI is a colorless substance.
EXPERIMENTAL
The IR spectra were recorded on a Specord M-80
instrument from samples dispersed in mineral oil. The
1H NMR spectra were measured on a Bruker DRX-300
spectrometer at 300 MHz from solutions in CDCl3
using hexamethyldisiloxane as internal reference
(δ 0.05 ppm). The mass spectra (electron impact,
70 eV) were obtained on a Varian MAT-311 mass spec-
trometer. The progress of reactions and the purity of
products were monitored by TLC on Silufol UV-254
plates using acetone–propan-2-ol–chloroform (1:3:6);
all products, except for compound VI, are colored.
Compound IV was recrystallized from hexane, com-
pound VI, from acetonitrile, and the others, from iso-
propyl alcohol.
Scheme 2.
Me
Me
MeMgI
N
Ia
O
Me
OH
VI
The product structure was confirmed by the IR,
1H NMR, and mass spectra. The IR spectra of IIa–IIc
contained absorption bands typical of cyano group
(2200 cm–1) and lactam carbonyl (1710–1730 cm–1)
[9]. Lactam carbonyl band was also present in the
spectra of compounds III and IV (1720 and 1725 cm–1,
respectively). Ester IIb, amide IIc, and ketone III dis-
played in the IR spectra the corresponding carbonyl
absorption bands at 1710, 1640, and 1680 cm–1. In the
spectrum of V we observed absorption bands at 3120
and 3250 cm–1 due to stretching vibrations of the endo-
cyclic and amide NH groups. The hydroxy group in
compound VI gave rise to absorption at 3350 cm–1.
Initial pyrrolo[2,1-a]isoquinoline-2,3-diones Ia and
Ib were synthesized according to the procedures
described in [10, 11].
2-(5,5-Dimethyl-3-oxo-2,3,5,6-tetrahydropyrrolo-
[2,1-a]isoquinolin-2-ylidene)malononitrile (IIa).
Compound Ia, 2.27 g (0.01 mol), was dissolved in
30 ml of benzene, and 0.6 ml (0.01 mol) of malono-
nitrile, 0.1 ml (1 mmol) of piperidine, and 0.06 ml
(1 mmol) of acetic acid were added. The mixture was
heated for 5 min under reflux, and it turned dark blue.
It was then cooled to 20°C and diluted with 100 ml of
hexane, and the precipitate was filtered off, dried, and
recrystallized. Yield 1.4 g (38%), dark blue crystals,
1
The H NMR spectrum of IIb contained signals
from protons in the ethoxy group, and signals corre-
sponding to the Drotaverine residue were present in the
spectrum of IV. The NH proton signals appeared in
the 1H NMR spectrum of V as singlets at δ 11.95 and
8.10 ppm, respectively.
1
mp 266–267°C. H NMR spectrum, δ, ppm: 1.52 s
(6H, CH3), 2.91 s (2H, 4-H), 6.30 s (1H, CH=), 7.12–
7.72 (4H, Harom). Mass spectrum, m/z (Irel, %): 275 (62)
[M]+, 260 (100) [M – CH3]+. Found, %: C 74.07;
H 4.68; N 15.37. C17H13N3O. Calculated, %: C 74.16;
H 4.76; N 15.26. M 275.31.
In the mass spectrum of nitrile IIa, the base peak
was that belonging to the [M – Me]+ ion. The most
abundant ion in the mass spectrum of ester IIb resulted
from elimination of methyl and ethoxy groups from the
molecular ion, m/z 261 (Irel = 100%). The most intense
peak in the mass spectrum of IIc had an m/z value of
274 (87%) [M – CON(CH2)5]+.
Ethyl cyano(5,5-dimethyl-3-oxo-2,3,5,6-tetra-
hydropyrrolo[2,1-a]isoquinolin-2-ylidene)acetate
(IIb) was synthesized in a similar way from 1.1 ml
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 6 2008

REACTION OF PYRROLO[2,1-a]ISOQUINOLINE-2,3-DIONES
847
(0.01 mol) of ethyl cyanoacetate. Yield 1.65 g (47%),
dark blue crystals, mp 146–147°C. 1H NMR spectrum,
δ, ppm: 1.48 s (6H, CH3), 2.88 s (2H, 4-H), 6.18 s (1H,
CH=), 7.15–7.74 m (4H, Harom), 1.35 t (3H, CH3CH2),
4.32 q (2H, CH2O). Mass spectrum, m/z (Irel, %): 322
(88) [M]+, 307 (28) [M – CH3]+, 261 (100) [M – CH3 –
OC2H5]+. Found, %: C 70.56; H 5.47; N 8.62.
C19H18N2O3. Calculated, %: C 70.79; H 5.63; N 8.69.
M 322.36.
3-(3,3-Dimethyl-1,2,3,4-dihydroisoquinolin-1-
ylidene)-2-(1,3-dioxo-2,3-dihydro-1H-inden-2-yli-
dene)-N-(4-methylphenyl)propanamide (V). A mix-
ture of 3.56 g (0.01 mol) of diketone III and 0.13 g
(0.012 mol) of p-toluidine in 20 ml of glacial acetic
acid was heated for 30 min under reflux. The mixture
was cooled to 20°C and diluted with 100 ml of water,
and the precipitate was filtered off, thoroughly washed
on a filter with a 10% solution of ammonia and water,
dried, and recrystallized from propan-2-ol. Yield 2.9 g
2-(5,5-Dimethyl-3-oxo-1-piperidinocarbonyl-
2,3,5,6-tetrahydropyrrolo[2,1-a]isoquinolin-2-yli-
dene)malononitrile (IIc) was synthesized in a similar
way from 3.38 g (0.01 mol) of compound Ib and
0.6 ml (0.01 mol) of malononitrile. Yield 2.4 g (62%),
dark blue crystals, mp 203–204°C. 1H NMR spectrum,
δ, ppm: 1.54 s (6H, CH3), 2.90 s (2H, 4-H), 7.13–
7.76 m (4H, Harom), 1.45–2.08 m (6H, CH2), 3.02–
3.76 m (4H, CH2N). Mass spectrum, m/z (Irel, %): 386
(47) [M]+, 274 (87) [M – CON(CH2)5]+. Found, %:
C 71.35; H 5.66; N 14.66. C23H22N4O2. Calculated, %:
C 71.48; H 5.74; N 14.50. M 386.45.
1
(60%), black crystals, mp 96–98°C. H NMR spec-
trum, δ, ppm: 1.68 s (6H, CH3), 2.93 s (2H, 4-H),
6.23 s (1H, CH=), 7.00–7.76 m (8H, Harom), 2.34 s (3H,
CH3C6H4), 8.10 s (1H, NHCO), 11.95 s (NH). Found,
%: C 77.78; H 5.47; N 6.15. C30H26N2O3. Calculated,
%: C 77.89; H 5.66; N 6.05.
2-Hydroxy-2,5,5-trimethyl-2,3,5,6-tetrahydro-
pyrrolo[2,1-a]isoquinolin-3-one (VI). Compound Ia,
2.27 g (0.01 mol), was added in portions to a solution
of methylmagnesium iodide prepared from 0.29 g
(0.012 mol) of magnesium and 0.75 ml (0.012 mol) of
methyl iodide in 100 ml of diethyl ether. The originally
red color intrinsic to compound Ia disappeared. The
resulting suspension was stirred for 2 h on heating
under reflux and was then quenched by adding 30 ml
of 10% hydrochloric acid. The organic phase was sepa-
rated and washed with a saturated solution of sodium
hydrogen carbonate and water, the aqueous phase was
neutralized with a saturated solution of NaHCO3 and
extracted with diethyl ether (2×15 ml), and the ex-
tracts were combined with the organic phase, dried
over potassium carbonate, and evaporated. The residue
was treated with 100 ml of hexane, and the precipitate
was filtered off, dried, and recrystallized from aceto-
nitrile. Yield 0.9 g (28%), colorless crystals, mp 193–
2-(5,5-Dimethyl-3-oxo-2,3,5,6-tetrahydropyrrolo-
[2,1-a]isoquinolin-2-ylidene)-2H-indene-1,3-dione
(III) was synthesized in a similar way from 2.27 g
(0.01 mol) of compound Ia and 1.46 g (0.01 mol) of
indan-1,3-dione. Yield 2.5 g (85%), violet crystals,
1
mp 210–212°C. H NMR spectrum, δ, ppm: 1.61 s
(6H, CH3), 2.94 s (2H, 4-H), 6.40 s (1H, CH=), 7.17–
7.89 (8H, Harom). Mass spectrum: m/z 355 (Irel = 67%)
[M]+. Found, %: C 77.53; H 4.73; N 3.88. C23H17NO3.
Calculated, %: C 77.72; H 4.82; N 3.94. M 355.39.
2-[(6,7-Diethoxy-3,4-dihydroisoquinolin-1-yl)(3,4-
diethoxyphenyl)methylidene]-5,5-dimethyl-2,3,5,6-
tetrahydropyrrolo[2,1-a]isoquinolin-3-one (IV).
Compound Ia, 2.27 g (0.01 mol), was dissolved in
30 ml of benzene, 3.57 g (0.01 mol) of 6,7-diethoxy-1-
(3,4-diethoxybenzyl)-3,4-dihydroisoquinoline was
added, and 10 mg (1–2 crystals) of p-toluenesulfonic
acid was then added. The mixture was heated for
30 min under reflux (it turned dark blue) and treated
as described above in the synthesis of compound IIa.
Yield 2.85 g (80%), dark red crystals, mp 188–190°C.
1H NMR spectrum, δ, ppm: 1.55 s (6H, CH3), 6.64–
7.74 m (9H, Harom), 1.26–1.53 m (12H, CH3CH2),
2.80–3.05 m (4H, 4-H, 4′-H), 3.85–4.13 m (10H,
CH2O, CH2N); the CH= singlet was overlapped by
the aromatic multiplet. Found, %: C 75.08; H 6.85;
N 4.72. C38H42N2O5. Calculated, %: C 75.21; H 6.97;
N 4.61.
1
195°C. H NMR spectrum, δ, ppm: 1.44 s (6H, CH3),
2.73 s (2H, 4-H), 6.19 s (1H, CH=), 6.92–7.63 (4H,
Harom), 1.13 s (3H, 2-CH3); the OH singlet was over-
lapped by the aromatic multiplet. Found, %: C 73.87;
H 6.85; N 5.83. C15H17NO2. Calculated, %: C 74.05;
H 7.04; N 5.75.
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