Five-membered 2,3-dioxo heterocycles: CII. Spiro heterocyclization of 3-aroylpyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones by the action of tetrahydroquinoline

Article abstract of DOI:10.1134/S1070428014060141

3-Aroylpyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones reacted with 1,2,3,4-tetrahydroquinoline to give 3-aroyl-4-hydroxy-1-(2-hydroxyphenyl)-5,6- dihydrospiro[pyrrole-2,1-pyrrolo[3,2,1-ij]quinoline]-2,5(1H,4H)-diones.

Full text of DOI:10.1134/S1070428014060141

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 6, pp. 840–842. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © N.M. Tutynina, V.A. Maslivets, A.N. Maslivets, 2014, published in Zhurnal Organicheskoi Khimii, 2014, Vol. 50, No. 6,
pp. 857–859.
Five-Membered 2,3-Dioxo Heterocycles:
CII.* Spiro Heterocyclization of 3-Aroylpyrrolo[2,1-c][1,4]benz-
oxazine-1,2,4-triones by the Action of Tetrahydroquinoline
N. M. Tutynina, V. A. Maslivets, and A. N. Maslivets
Perm State National Research University, ul. Bukireva 15, Perm, 614990 Russia
e-mail: koh2@psu.ru
Received March 27, 2013
Abstract—3-Aroylpyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones reacted with 1,2,3,4-tetrahydroquinoline to
give 3-aroyl-4-hydroxy-1-(2-hydroxyphenyl)-5′,6′-dihydrospiro[pyrrole-2,1′-pyrrolo[3,2,1-ij]quinoline]-
2′,5(1H,4′H)-diones.
DOI: 10.1134/S1070428014060141
Nucleophilic heterocyclizations and recyclizations
of 1H-pyrrole-2,3-diones fused at the N1–C5 bond to
heterocyclic systems in reactions with binucleophiles
provide a convenient synthetic route to various five-,
six-, and seven-membered aza heterocycles and fused,
bridged, and spiro heterocyclic systems [2, 3]. Recy-
clizations of 3-acylpyrrolo[2,1-c][1,4]benzoxazine-
1,2,4-triones by the action of 1,4-N,N- [4, 5], 1,4-S,N-
[6], and 1,3-C,N- binucleophiles [7] follow a common
scheme including successive nucleophilic attacks on
the 3a-carbon atom and carbonyl carbon atom in posi-
tion 4 of pyrrolobenzoxazinetrione. The reactions with
N,N- and S,N-binucleophiles are accompanied by
opening of the oxazine and pyrrole rings at the C4–O5
and N10–C3a bonds, respectively. In continuation of our
studies on nucleophilic recyclizations of pyrrolobenz-
oxazinetriones in the present article we report on their
reaction with 1,2,3,4-tetrahydroquinoline.
Scheme 1.
HN
O
O
O
O
O
+
C(O)Ar
R
C(O)Ar
N
R
H
O
O
OH
Ia–Ig
II
A
R
N
O
N
C(O)Ar
OH
O
OH
IIIa–IIIg
Ar = Ph (a, g), 4-BrC6H4 (b), 4-FC6H4 (c), 4-O2NC6H4 (d), 4-MeOC6H4 (e), 4-EtOC6H4 (f); R = H (a–f), Cl (g).
* For communication CI, see [1].
840

FIVE-MEMBERED 2,3-DIOXO HETEROCYCLES: CII.
The reactions of 3-aroylpyrrolo[2,1-c][1,4]benzox-
EXPERIMENTAL
841
azine-1,2,4-triones Ia–Ig with 1,2,3,4-tetrahydroquino-
line (II) were carried out with equimolar amounts of
the reactants which were heated in boiling benzene
(79–80°C) for 30–60 min, the progress of the reaction
being monitored by HPLC. As a result, we isolated
3-aroyl-4-hydroxy-1-(2-hydroxyphenyl)-5′,6′-dihydro-
spiro[pyrrole-2,1′-pyrrolo[3,2,1-ij]quinoline]-
2′,5(1H,4′H)-diones IIIa–IIIg [8] as colorless high-
melting (with decomposition) crystalline substances
which were readily soluble in DMF and DMSO,
poorly soluble in alcohols and chlorinated hydro-
carbons, and insoluble in alkanes and water. The prod-
ucts showed a positive color test (cherry color) for
enolic and phenolic hydroxy groups on treatment with
an alcoholic solution of iron(III) chloride.
The IR spectra were recorded on a Perkin Elmer
Spectrum Two spectrometer from samples dispersed in
1
mineral oil. The H and 13C NMR spectra were
obtained on a Bruker WP-400 spectrometer at 400 and
100 MHz, respectively, using DMSO-d6 as solvent and
tetramethylsilane as internal reference. The reactions
conditions were optimized using a Waters Acquity
UPLC I Class instrument (BEH C18 column, grain
size 1.7 μm; eluents methanol–water and acetonitrile–
water, flow rate 0.3–0.5 mL/s; ESI MS Xevo TQD
detector). The purity of the products was checked by
UPLC and TLC (Silufol plates; benzene, ethyl acetate–
benzene, 1:5; development with iodine vapor).
3-Benzoyl-4-hydroxy-1-(2-hydroxyphenyl)-5′,6′-
dihydrospiro[pyrrole-2,1′-pyrrolo[3,2,1-ij]quino-
line]-2′,5(1H,4′H)-dione (IIIa). A solution of
3.1 mmol of compound Ia and 3.1 mmol of 1,2,3,4-
tetrahydroquinoline (II) in 40 mL of anhydrous ben-
zene was heated for 30 min under reflux (HPLC moni-
toring). The mixture was cooled, and the precipitate
was filtered off. Yield 84%, mp 260–262°C (decomp.,
from benzene). IR spectrum, ν, cm–1: 3325 br (OH),
The IR spectra of IIIa–IIIg contained absorption
bands typical of stretching vibrations of phenolic and
enolic hydroxy groups (one broadened band in the
region 3325–3177 cm–1), lactam carbonyl groups (one
or two bands in the region 1720– 1687 cm–1), and
ketone carbonyl group (3-C=O, 1637–1626 cm–1). In
1
the H NMR spectra of IIIa–IIIg in DMSO-d6 we ob-
served signals from protons in the aromatic rings and
substituents therein, three multiplets from methylene
protons in the tetrahydroquinoline fragment at δ 1.73–
1.91, 2.60–2.64, and 3.64–3.68 ppm (5′-H, 6′-H, and
4′-H, respectively), a singlet from the phenolic OH
proton at δ 9.42–9.61 ppm, and a broadened singlet
from the enolic hydroxy proton at δ 12.00–12.67 ppm.
1
1716, 1698 (C5=O, C2′=O), 1630 (COPh). H NMR
spectrum, δ, ppm: 1.75 m and 1.91 m (2H, 5′-H),
2.62 m (2H, 6′-H), 3.68 m (2H, 4′-H), 6.67–7.73 m
(12H, Harom), 9.59 s (1H, 2″-OH), 12.00 br.s (1H,
4-OH). Found, %: C 71.75; H 4.44; N 6.12.
C27H20N2O5. Calculated, %: C 71.67; H 4.46; N 6.19.
Compounds IIIb–IIIg were synthesized in a similar
way.
Presumably, in the first step addition of the activat-
ed C8H group of tetrahydroquinoline II to the carbon
atom in position 3a of pyrrolobenzoxazinetrione I
yields intermediate A, and the subsequent intramolec-
ular attack by the NH group of the tetrahydroquinoline
on the lactone carbonyl carbon atom of the oxazine
ring is accompanied by cleavage of the latter at the
C4–O5 bond and closure of a new pyrrole ring
(Scheme 1).
3-(4-Bromobenzoyl)-4-hydroxy-1-(2-hydroxy-
phenyl)-5′,6′-dihydrospiro[pyrrole-2,1′-pyrrolo-
[3,2,1-ij]quinoline]-2′,5(1H,4′H)-dione (IIIb). Yield
76%, mp 264–267°C (decomp., from benzene). IR
spectrum, ν, cm–1: 3262 br (OH), 1711 (C5=O, C2′=O),
1637 (3-C=O). 1H NMR spectrum, δ, ppm: 1.73 m and
1.90 m (2H, 5′-H), 2.60 m (2H, 6′-H), 3.67 m (2H,
4′-H), 6.66–7.72 m (11H, Harom), 9.58 s (1H, 2″-OH),
12.67 br.s (1H, 4-OH). Found, %: C 60.56; H 3.52;
Br 15.07; N 5.37. C27H19BrN2O5. Calculated, %:
C 61.03; H 3.60; Br 15.04; N 5.27.
The described reaction is an example of regio-
selective synthesis of difficultly accessible spiro[pyr-
role-2,1′-pyrrolo[3,2,1-ij]quinoline] system. Molecules
IIIa–IIIg contain a fused heterocyclic lilolidine system
(pyrrolo[3,2,1-ij]quinoline) which rarely occurs in
nature and constitutes the base fragment of hippadine
[9, 10] and lycorine alkaloids [11]. These alkaloids
exhibit antitumor activity and are also active toward
cardiovascular system. Thus, the described reaction
may be regarded as a new synthetic approach to
lilolidine derivatives.
3-(4-Fluorobenzoyl)-4-hydroxy-1-(2-hydroxy-
phenyl)-5′,6′-dihydrospiro[pyrrole-2,1′-pirrolo-
[3,2,1-ij]quinoline]-2′,5(1H,4′H)-dione (IIIc). Yield
81%, mp 274–276°C (decomp., from benzene). IR
spectrum, ν, cm–1: 3265 br (OH), 1709 (C5=O, C2′=O),
1635 (3-C=O). 1H NMR spectrum, δ, ppm: 1.74 m and
1.90 m (2H, 5′-H), 2.62 m (2H, 6′-H), 3.67 m (2H,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 6 2014

TUTYNINA et al.
842
4′-H), 6.67–7.89 m (11H, Harom), 9.57 s (1H, 2″-OH),
12.53 br.s (1H, 4-OH). Found, %: C 68.75; H 4.14;
F 3.9; N 6.08. C27H19FN2O5. Calculated, %: C 68.93;
H 4.07; F 4.04; N 5.95.
(1H, 2″-OH), 12.51 br.s (1H, 4-OH). 13C NMR spec-
trum (DMSO-d6), δC, ppm: 188.69 (3-C=O); 171.53,
165.29, 153.14 (C4, C2′, C5); 140.41–117.80 (Carom),
71.23 (Cspiro), 31.10 (C4′), 23.66 (C6′), 20.69 (C5′).
Found, %: C 66.78; H 4.11; Cl 7.32; N 5.73.
C27H19ClN2O5. Calculated, %: C 66.60; H 3.93;
Cl 7.28; N 5.75.
4-Hydroxy-1-(2-hydroxyphenyl)-3-(4-nitroben-
zoyl)-5′,6′-dihydrospiro[pyrrole-2,1′-pyrrolo-
[3,2,1-ij]quinoline]-2′,5(1H,4′H)-dione (IIId). Yield
74%, mp 256–257°C (decomp., from benzene). IR
spectrum, ν, cm–1: 3318 br (OH), 1707, 1687 (C5=O,
This study was performed under financial support
by the Ministry of Education and Science of the
Russian Federation, by the Ministry of Education of
Perm Krai (International Research Teams Competi-
tion), and by the Russian Foundation for Basic
Research (project nos. 12-03-00696, 13-03-96009).
1
C2′=O), 1636 (3-C=O). H NMR spectrum, δ, ppm:
1.75 m and 1.91 m (2H, 5′-H), 2.64 m (2H, 6′-H),
3.67 m (2H, 4′-H), 6.67–8.32 m (11H, Harom), 9.61 s
(1H, 2″-OH), 12.10 br.s (1H, 4-OH). Found, %:
C 65.21; H 3.79; N 8.51. C27H19N3O7. Calculated, %:
C 65.19; H 3.85; N 8.45.
REFERENCES
4-Hydroxy-1-(2-hydroxyphenyl)-3-(4-methoxy-
benzoyl)-5′,6′-dihydrospiro[pyrrole-2,1′-pyrrolo-
[3,2,1-ij]quinoline]-2′,5(1H,4′H)-dione (IIIe). Yield
82%, mp 269–271°C (decomp., from benzene). IR
spectrum, ν, cm–1: 3182 br (OH), 1708 (C5=O, C2′=O),
1626 (3-C=O). 1H NMR spectrum, δ, ppm: 1.74 m and
1.90 m (2H, 5′-H), 2.62 m (2H, 6′-H), 3.67 m (2H,
4′-H), 3.83 s (3H, OMe), 6.66–7.74 m (11H, Harom),
9.56 s (1H, 2″-OH), 12.15 br.s (1H, 4-OH). Found, %:
C 69.87; H 4.54; N 5.99. C28H22N2O6. Calculated, %:
C 69.70; H 4.60; N 5.81.
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phenyl)-5′,6′-dihydrospiro[pyrrole-2,1′-pyrrolo-
[3,2,1-ij]quinoline]-2′,5(1H,4′H)-dione (IIIf). Yield
79%, mp 204–206°C (decomp., from benzene). IR
spectrum, ν, cm–1: 3230 br (OH), 1709 (C5=O, C2′=O),
1634 (3-C=O). 1H NMR spectrum, δ, ppm: 1.33 t (3H,
CH2CH3), 1.73 m and 1.90 m (2H, 5′-H), 2.60 m (2H,
6′-H), 3.64 m (2H, 4′-H), 4.11 q (2H, OCH2), 6.63–
7.21 m (11H, Harom), 9.42 s (1H, 2″-OH), 12.02 br.s
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3-Benzoyl-1-(5-chloro-2-hydroxyphenyl)-4-hy-
droxy-5′,6′-dihydrospiro[pyrrole-2,1′-pyrrolo-
[3,2,1-ij]quinoline]-2′,5(1H,4′H)-dione (IIIg). Yield
77%, mp 274–276°C (decomp., from benzene). IR
spectrum, ν, cm–1: 3177 br (OH), 1720 and 1696
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1
(C5=O, C2′=O), 1632 (3-C=O). H NMR spectrum, δ,
ppm: 1.75 m and 1.94 m (2H, 5′-H), 2.65 m (2H, 6′-H),
3.70 m (2H, 4′-H), 6.67–7.73 m (11H, Harom), 10.02 s
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 6 2014