Five-membered 2,3-dioxoheterocycles: LVIII. Reaction of methyl 1-aryl-3-aroyl-4,5-dioxo-4,5-dihydro-1H-pyrrol-2-carboxylates with substituted 1-methyl-3,4-dihydroisoquinolines. New approach to the synthesis of steroid 13-azaanalogs

Article abstract of DOI:10.1134/S1070428008050102

Methyl 1-aryl-3-aroyl-4,5-dioxo-4,5-dihydro-1H-pyrrole-2-carboxylates reacted with substituted 1-methyl-3,4-dihydroisoquinolines with the formation of substituted 3-oxo-2,3,5,6-tetra-hydropyrrolo[2,1-a]-isoquinoline-2-spiro- 2′-(1-aryl-3-aroyl-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrroles). A new approach was developed to the synthesis of 13-azagonanes, substituted benzo[f]pyrrolo[2,1-a]isoquinoline-9-spiro-2′-pyrroles.

Full text of DOI:10.1134/S1070428008050102

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 5, pp. 697−700. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © Yu.N. Bannikova, Yu.S. Rozhkova, Yu.V. Shklyaev, A.N. Maslivets, 2008, published in Zhurnal Organicheskoi Khimii, 2008, Vol.
44, No. 5, pp. 706−709.
Five-Membered 2,3-Dioxoheterocycles: LVIII.* Reaction
of Methyl 1-Aryl-3-aroyl-4,5-dioxo-4,5-dihydro-1H-pyrrol-2-
carboxylates with Substituted 1-Methyl-3,4-dihydroisoquinolines.
New Approach to the Synthesis of Steroid 13-Azaanalogs
Yu. N. Bannikovaa, Yu. S. Rozhkovab, Yu. V. Shklyaevb, and A. N. Maslivetsa
aPerm State University, Perm, 614990 Russia
e-mail: koh2@psu.ru
bInstitute of Problems of Chemical Physics, Russian Academy of Sciences, Chernogolovka, Russia
Received May 16, 2006
Abstract—Methyl 1-aryl-3-aroyl-4,5-dioxo-4,5-dihydro-1H-pyrrole-2-carboxylates reacted with substituted
1-methyl-3,4-dihydroisoquinolines with the formation of substituted 3-oxo-2,3,5,6-tetra-hydropyrrolo[2,1-a]-
isoquinoline-2-spiro-2'-(1-aryl-3-aroyl-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrroles).Anew approach was developed
to the synthesis of 13-azagonanes, substituted benzo[f]pyrrolo[2,1-a]isoquinoline-9-spiro-2'-pyrroles.
DOI: 10.1134/S1070428008050102
We formerly described the reaction of monocyclic 1H-
pyrrole-2,3-diones (methyl 1-aryl-3-aroyl-4,5-dioxo-4,5-
dihydro-1H-pyrrole-2-carboxylates) with cyclic enamino-
ketones (3-alkylamino- and 3-anilino-5,5-dimethyl-2-
cyclohexen-1-ones) leading to the formation of substitut-
ed 6,6-dimethyl-2,4-dioxo-2,3,4,5,6,7-hexahydro-1H-
indole-3-spiro-2'-(1-aryl-3-aroyl-4-hydroxy-5-oxo-2,3-
dihydro-1H-pyrroles) whose structure was confirmed by
XRD analysis [2]. The reaction proceeds through succes-
sive attacks by two nucleophilic sites (β-CH and NH
groups) on the enamino fragment of the cyclic enamino-
ketone at the carbon atom in position 5 and carbonyl
carbon of the methoxycarbonyl substituent in position 5
of 1H-pyrrole-2,3-diones with methanol elimination.
attack on highly electrophilic 2,3-dioxoheterocycles both
by NH [3] and β-CH [4] groups of this fragment. The
direction of the primary nucleophilic attack of one of
these groups on one among the several electrophilic
centers of compounds Ia−If (atoms C4, C5, MeOCO)
would have decided the structure of products obtained.
The reaction of compounds Ia−If with equimolar
amount of isoquinolines IIa−IIc at boiling in anhydrous
benzene for 0.5-2 min provided in practically quantitative
yield substituted 5,5-dimethyl-3-oxo-2,3,5,6-tetrahydro-
pyrrolo[2,1-a]isoquinoline-2-spiro-2c-(1-aryl-3-aroyl-4-
hydroxy-5-oxo-2,5-dihydro-1H-pyrroles) IIIa−IIIi; the
structure of compound IIIb was proved by XRD analysis
[5].
In extension of research on recyclization and hetero-
cyclization of acyl-substituted 1H-pyrrole-2,3-diones
under the action of CH,NH-binucleophilic reagents we
studied reactions of methyl 1-aryl-3-aroyl-4,5-dioxo-4,5-
dihydro-1H-pyrrole-2-carboxylates Ia−If with substituted
1-methyl-3,4-dihydroisoquinolines IIa−IIc. 1-Methyl-
3,4-dihydroisoquinolines in the tautomeric form of 1-
methylene-1,2,3,4-tetrahydroisoquinolines contain
an enamino fragment with two nearly equivalent nucleo-
philic groups, and they give products of nucleophilic
Compounds IIIa-IIIi are colorless or light-yellow
crystalline substances melting at high temperature,
sparingly soluble in common organic solvents, readily
soluble in DMF and DMSO, insoluble in alkanes and
water, positive test with iron(III) chloride on the presence
of enol hydroxy group (cherry-red coloration).
The IR spectra of spiro-compounds IIIa–IIIi record-
ed from mulls in mineral oil contain the bands of
the stretching vibrations of enol OH group as a broad
peak in the region 3180−3220 cm−1, of two lactam
carbonyl groups as one or two peaks in the region
* For communication LVII, see [1].
697

BANNIKOVA et al.
p-XC6H4CO
698
O
O
MeOCO
N
C6H4Y-p
Ia−If
Ia If
R1
Me
N
Me
R1
R2
R3
Me
Me
R2
R3
Me
Me
H
N
MeOCO
N
R1
R2
N
H
CH
p-YC6H4
−
IIa IIb
CH2
II -
IIa−IIf
Me
O
R3
COC6H4X-p
OH
R1
Me
R2
R3
Me
O
N
p-YC6H4
N
-MeOH
III -
O
COC6H4X-p
IIIa−IIIi
OH
IIIa IIIi
−
1688–1730 cm–1, of aroyl carbonyl in the region 1625−
The described reaction is a rare example of building
up a difficultly accessible spiro-bis-heterocyclic system
containing purposefully variable functional substituents
in several positions of both heterocycles.
1636 cm−1.
1
In the H NMR spectra of solutions of compounds
IIIa–IIIi in DMSO-d6 alongside the signals of aromatic
rings protons appear two singlets of methyl groups in
the region 1.01−1.61 ppm, signals from two protons of
CH2 group of the isoquinoline fragment in the form of
doublet of doublets (AB-system) in the region 3.12−
3.63 ppm split due to the nonequivalence because of
adjacent chiral center, and a signal of vinyl CH proton
in the region 6.01−6.98 ppm.
It should be stressed that substituted benzo[f]pyr-
rolo[2,1-a]isoquinoline-9-spiro-2'-pyrroles IIIb, IIIh,
and IIIi are 13-azagonanes, heterocyclic analogs of
steroids containing a spiro-heterocyclic substituent in the
position 16 of the tetracyclic system, and the described
reaction constitutes the new approach to their synthesis.
EXPERIMENTAL
Evidently in the first stage of the reaction the activated
β-CH group of the tautomeric enamino form of
isoquinolines IIa−IIc adds to the carbon atom in the
position 5 of compounds Ia−If followed by the closure
of the pyrrole ring through an intramolecular attack of
the amino group of the enamino form of isoquinolines
on the ester carbonyl of the substituent in the position
5 of pyrrolediones and by methanol elimination.
IR spectra of compounds synthesized were recorded
on a spectrophotometer UR-20 from mills in mineral oil.
1H and 13C NMR spectra were registered on a spectrom-
eter Bruker AM-400 (operating frequency 400 MHz)
from solutions in DMSO-d6, internal reference TMS.
Mass spectra were measured on a MKh-1320, instrument,
energy of ionizing electrons 70 eV. The homogeneity of
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 5 2008

FIVE-MEMBERED 2,3-DIOXOHETEROCYCLES: LVIII.
699
compounds synthesized was checked by TLC on Silufol
plates, eluents ethyl acetate–benzene, 1:5, ethyl acetate,
development in iodine vapor.
dichloroethane). IR spectrum, cm−1: 3198 br (OH), 1731,
1705 (C3=O, C5=O), 1639 (COPh). 1H NMR spectrum,
δ, ppm: 1.26 s (3H, Me); 1.53 s (3H, Me); 2.25 s (3H,
C6H4Me-4); 2.66, 2.86 d.d (2H, H6 , J 15.9 Hz); 5.88 s
5,5-Dimethyl-8,9-dimethoxy-3-oxo-2,3,5,6-
tetrahydropyrrolo[2,1-a]isoquinoline-2-spiro-2'-(3-
benzoyl-4-hydroxy-5-oxo-1-phenyl-2,5-dihydro-1H-
pyrrole) (IIIa). A solution of 1.0 mmol of compound Ia
and 1.0 mmol of enamine IIa in 10 ml of anhydrous
benzene was boiled for 1 min, cooled, the separated
precipitate was filtered off. Yield 72%, mp 220−223°C
(decomp., from ethyl acetate). IR spectrum, cm−1:
3205 br (OH), 1730, 1702 (C3=O, C5=O), 1635 (COPh).
1H NMR spectrum, δ, ppm: 1.25 s (3H, Me), 1.52 s (3H,
Me), 2.61,2.77 d.d (2H, H62, J 15.7 Hz), 3.72 s (3H,
OMe), 3.75 s (3H, OMe), 5.76 s (1H, H1), 6.76−
7.77 group of signals (12H, 2Ph + H7,10), 12.20 br.s (1H,
OH). Found, %: C 71.61; H 5.18; N 5.31. C32H28N2O6.
Calculated, %: C 71.63; H 5.26; N 5.22.
2
(1H, H1); 6.98-7.75 group of signals (13H, Ph + 2C6H4);
12.30 br.s (1H, OH).Found, %: C 76.09; H 5.46; N 5.74.
C31H26N2O4. Calculated, %: C 75.90; H 5.34; N 5.71.
5,5-Dimethyl-8,9-dimethoxy-3-oxo-2,3,5,6-tetra-
hydropyrrolo[2,1-a]isoquinoline-2-spiro-2'-[4-hy-
droxy-3-benzoyl-5-oxo-1-(p-tolyl)-2,5-di-hydro-1H-
pyrrole] (IIIe). Yield 58%, mp 160−161°C (decomp.,
from ethyl acetate). IR spectrum, cm−1: 3208 br (OH),
1726, 1701 (C3=O, C5=O), 1634 (COPh). 1H NMR spec-
trum, δ, ppm: 1.19 s (3H, Me), 1.51 s (3H, Me), 2.35 s
(3H, C6H4Me-4); 2.62,2.77 d.d (2H, H62, J 15.6 Hz),
3.72 s (3H, OMe), 3.75 s (3H, OMe), 5.73 s (1H, H1),
6.77−7.76 group of signals (11H, Ph+C6H4 + H7,10),
12.24 br.s (1H, OH). Found, %: C 71.87; H 5.41; N 5.11.
C33H30N2O6. Calculated, %: C 71.99; H 5.49; N 5.09.
Compounds IIIb–IIIi were similarly synthesized.
6,6-Dimethyl-8-oxo-5,6,8,9-tetrahydro-benzo-
[f]pyrrolo[2,1-a]isoquinoline-9-spiro-2'-(3-benzoyl-4-
hydroxy-5-oxo-1-phenyl-2,5-dihydro-1H-pyrrole)
(IIIb) Yield 86%, mp 255-257°C (decomp., from ethyl
acetate-dichloroethane). IR spectrum, cm-1: 3220 br
(OH), 1728, 1703 (C5=O, C8=O), 1638 (COPh). 1H NMR
spectrum, δ, ppm: 1.28 s (3H, Me), 1.63 s (3H, Me), 3.14,
5,5-Dimethyl-3-oxo-2,3,5,6-tetrahydropyrrolo[2,1-
a]isoquinoline-2-spiro-2'-[3-benzoyl-4-hydroxy-5-
oxo-1-(p-chlorophenyl)-2,5-dihydro-1H-pyrrole]
(IIIf). Yield 58%, mp 280-281°C (decomp., from ethyl
acetate). IR spectrum, cm−1: 3215 br (OH), 1724, 1698
(C3=O, C5=O), 1638 (COPh). 1H NMR spectrum, δ,
ppm: 1.23 s (3H, Me); 1.52 s (3H, Me); 2.73, 2.86 d.d
3.28 d.d (2H, H5 , J 16.5 Hz), 6.05 s (1H, H10), 7.27−
2
(2H, H6 , J 16.0 Hz); 5.87 s (1H, H1); 7.24−7.76 group
8.12 group of signals (16H, 2Ph + H1-4,11,12), 12.22 br.s
(1H, OH). Mass spectrum, m/z (Irel, %): 526 (50) [M+.],
421 (18), 407 (58), 406 (100), 379 (15), 105 (96)
[PhCO]+, 77 (35) [Ph]+. Found, %: C 77.38; H 4.93;
N 5.40. C34H26N2O4. Calculated, %: C 77.55; H 4.98;
N 5.32.
2
of signals (13H, Ph + 2C6H4); 12.27 br.s (1H, OH).Found,
%: C 70.62; H 4.57; Cl 7.03; N 5.56. C30H23ClN2O4.
Calculated, %: C 70.52; H 4.54; Cl 6.94; N 5.48.
5,5-Dimethyl-8,9-dimethoxy-3-oxo-2,3,5,6-
tetrahydropyrrolo[2,1-a]isoquinoline-2-spiro-2'-[3-
benzoyl-4-hydroxy-5-oxo-1-(p-chlorophenyl)-2,5-
dihydro-1H-pyrrole] (IIIg). Yield 58%, mp 225-227°C
(decomp., from ethyl acetate). IR spectrum, cm-1: 3218
5,5-Dimethyl-8,9-dimethoxy-3-oxo-2,3,5,6-
tetrahydropyrrolo[2,1-a]isoquinoline-2-spiro-2'-[4-
hydroxy-3-(p-nitrobenzoyl)-5-oxo-1-phenyl-2,5-
dihydro-1H-pyrrole] (IIIc). Yield 58%, mp 234-236°C
(decomp., from ethyl acetate). IR spectrum, cm-1: 3190
1
br (OH), 1733, 1682 (C3=O, C5=O), 1628 (COPh). H
NMR spectrum, δ, ppm: 1.29 s (3H, Me), 1.53 s (3H,
Me), 2.67,2.79 d.d (2H, H6 , J 16.1 Hz), 3.72 s (3H,
1
br (OH), 1725, 1686 (C3=O, C5=O), 1640 (COAr). H
2
OMe), 3.76 s (3H, OMe), 5.76 s (1H, H1), 6.80-7.77 group
of signals (11H, Ph + C6H4 + H7,10), 12.28 br.s (1H, OH).
Found, %: C 67.44; H 4.72; Cl 6.25; N 4.83.
C32H27ClN2O6. Calculated, %: C 67.31; H 4.77; Cl 6.21;
N 4.91.
NMR spectrum, δ, ppm: 1.27 s (3H, Mε); 1.50 s (3H,
Mε); 2.62, 2.78 d.d (2H, H62, J 15.9 Hz); 3.73 s (3H,
OMe), 3.76 c (3H, OMe), 5.78 c (1H, H1); 6.79−8.34
group of signals (11H, Ph + C6H4 + H7,10); 12.28 br.s
(1H, OH). Found, %: C 66.13; H 4.66; N 7.37.
C32H27N3O8. Calculated, %: C 66.09; H 4.68; N 7.23.
6,6-Dimethyl-8-oxo-5,6,8,9-tetrahydrobenzo-
[f]pyrrolo[2,1-a]isoquinoline-9-spiro-2'-[4-hydroxy-5-
oxo-1-(p-tolyl)-3-(p-ethoxybenzoyl)-2,5-dihydro-1H-
pyrrole] (IIIh). Yield 86%, mp 200-202°C (decomp.,
from ethyl acetate−dichloroethane). IR spectrum cm−1:
5,5-Dimethyl-3-oxo-2,3,5,6-tetrahydropyrrolo[2,1-
a]isoquinoline-2-spiro-2'-[4-hydroxy-3-benzoyl-5-
oxo-1-(p-tolyl)-2,5-dihydro-1H-pyrrole] (IIId). Yield
75%, mp 249-251°C (decomp., from ethyl acetate-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 5 2008

BANNIKOVA et al.
700
98.88–143.36 (Ar), 152.94 (C4OH), 165.38 (C5), 173.82
(C8), 187.30 (COAr). Found, %: C 73.06; H 4.79; Cl 6.22;
N 4.79. C35H27ClN2O4. Calculated, %: C 73.10; H 4.73;
Cl 6.16; N 4.87.
3210 br (OH), 1730 (C5=O, C8=O), 1641 (COPh).
1H NMR spectrum, δ, ppm: 1.05 s (3H, Me), 1.28 t (3H,
CH3CH2O), 1.59 s (3H, Me), 2.39 s (3H, C6H4Me-4),
2.96,3.18 d.d (2H, H5 , J 16.2 Hz), 3.84 q (2H,
2
CH3CH2O), 6.32 s (1H, H10), 7.20-8.23 group of signals
(14H, 2C6H4 + H1-4,11,12), 12.45 br.s (1H, OH). Found,
%: C 76.13; H 5.55; N 4.78. C37H32N2O5. Calculated,
%: C 76.01; H 5.52; N 4.79.
The study was carried out under financial support of
the Russian Foundation for Basic Research (grants
nos. 07-03-96036, 04-03-96045).
REFERENCES
6,6-Dimethyl-8-oxo-5,6,8,9-tetrahydrobenzo-
[f]pyrrolo[2,1-a]isoquinoline-2-spiro-2'-[4-hydroxy-5-
oxo-1-(p-tolyl)-3-(p-chlorobenzoyl)-2,5-dihydro-1H-
pyrrole] (IIIi). Yield 95%, mp 257−259°C (decomp.,
from ethyl acetate-dichloroýtaνa). IR spectrum, cm−1,:
3180 br (OH), 1722, 1688 (C5=O, C8=O), 1636 (COAr).
1H NMR spectrum, δ, ppm: 1.34 s (3H, Me), 1.61 s (3H,
Me), 2.22 s (3H, C6H4Me-4), 3.12, 3.28 d.d (2H, H25,
J 16.3 Hz), 6.01 s (1H, H10), 7.16-8.14 group of signals
(14H, 2C6H4 + H1-4,11,12), 12.20 br.s (1H, OH). 13C NMR
spectrum, δC, ppm: 20.53 (Me-p), 25.92, 26.20 (2Me
isoquinoline), 39.50 (C5), 53.43 (C spiro), 72.19 (C6),
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 5 2008