Five-membered 2,3-dioxo heterocycles: LX. Reaction of 3-aroyl-1H-pyrrolo[2, 1-c][1,4]benzoxazine-1,2,4-triones with cyclic enehydrazino ketones. Crystalline and molecular structure of N-[3′-benzoyl-4′-hydroxy-1′-(2- hydroxyphenyl)-6, 6-dimethyl-2,4,5′-tri

Article abstract of DOI:10.1134/S1070428008060092

3-Aroyl-1H-pyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones react with N′-(5,5-dimethyl-3-oxocyclohex-1-en-1-yl)benzohydrazides to give the corresponding N-[3′-aroyl-4′-hydroxy-1′-(2-hydroxyphenyl)-6,6- dimethyl-2,4,5′-trioxo-1′,4,5,5′,6,7-hexahydrospiro[indo

Full text of DOI:10.1134/S1070428008060092

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 6, pp. 836–839. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © N.L. Racheva, Z.G. Aliev, A.N. Maslivets, 2008, published in Zhurnal Organicheskoi Khimii, 2008, Vol. 44, No. 6, pp. 848–851.
Five-Membered 2,3-Dioxo Heterocycles: LX.* Reaction
of 3-Aroyl-1H-pyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones
with Cyclic Enehydrazino Ketones. Crystalline and Molecular
Structure of N-[3′-Benzoyl-4′-hydroxy-1′-(2-hydroxyphenyl)-
6,6-dimethyl-2,4,5′-trioxo-1′,4,5,5′,6,7-hexahydro-
spiro[indole-3,2′-pyrrol]-1(2H)-yl]-3-nitrobenzamide
N. L. Rachevaa, Z. G. Alievb, and A. N. Maslivetsa
a Perm State University, ul. Bukireva 15, Perm, 614990 Russia
e-mail: koh2@psu.ru
b Institute of Chemical Physics Problems, Russian Academy of Sciences, Chernogolovka, Moscow oblast, Russia
Received June 25, 2007
Abstract—3-Aroyl-1H-pyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones react with N′-(5,5-dimethyl-3-oxocyclo-
hex-1-en-1-yl)benzohydrazides to give the corresponding N-[3′-aroyl-4′-hydroxy-1′-(2-hydroxyphenyl)-
6,6-dimethyl-2,4,5′-trioxo-1′,4,5,5′,6,7-hexahydrospiro[indole-3,2′-pyrrol]-1(2H)-yl]benzamides. The molec-
ular and crystalline structure of one of the products, N-[3′-benzoyl-4′-hydroxy-1′-(2-hydroxyphenyl)-
6,6-dimethyl-2,4,5′-trioxo-1′,4,5,5′,6,7-hexahydrospiro[indole-3,2′-pyrrol]-1(2H)-yl]-3-nitrobenzamide, was
determined by X-ray analysis.
DOI: 10.1134/S1070428008060092
Nucleophilic transformations of 1H-pyrrole-2,3-di-
ones, including those fused at the [a] side to various
heterocycles, by the action of O- and N-mono- and
N,N-, N,O-, and N,S-binucleophiles underlie conven-
ient methods for the synthesis of carbonyl derivatives
of five- and six-membered nitrogen-containing hetero-
cycles, ensembles of such heterocycles, and fused het-
erocyclic systems which attract interest from the view-
point of biological activity [2, 3].
reactions were alkyl 4-aroyl-3-hydroxy-1-(2-hydroxy-
phenyl)-2,6-dioxo-1,7-diazaspiro[4.4]nona-3,8-diene-
9-carboxylates [1].
In continuation of our studies on reactions of het-
areno[a]pyrrole-2,3-diones with nucleophiles, in the
present work we examined transformations of 3-aroyl-
substituted 1H-pyrrolo[2,1-c][1,4]benzoxazine-1,2,4-
triones Ia and Ib in reactions with cyclic enehydrazino
ketones. As the latter we used N′-(5,5-dimethyl-3-oxo-
cyclohex-1-en-1-yl)-2-hydroxybenzohydrazide (IIa),
2-amino-N′-(5,5-dimethyl-3-oxocyclohex-1-en-1-yl)-
benzohydrazide (IIb), and N′-(5,5-dimethyl-3-oxo-
cyclohex-1-en-1-yl)-3-nitrobenzohydrazide (IIc).
Pyrrolobenzoxazinetriones Ia and Ib reacted with
substituted benzohydrazides IIa–IIc at a ratio of 1:1
on heating in boiling anhydrous m-xylene to give in 8–
15 min the corresponding N-[3′-aroyl-4′-hydroxy-1′-
(2-hydroxyphenyl)-6,6-dimethyl-2,4,5′-trioxo-
1′,4,5,5′,6,7-hexahydrospiro[indole-3,2′-pyrrol]-1(2H)-
yl]benzamides IIIa–IIIe (Scheme 1) whose structure
was confirmed by X-ray analysis of compound IIIe**
We previously showed that 4-acyl-2,3-dihydro-1H-
pyrrole-2,3-diones fused to a 1,4-benzoxazine frag-
ment, namely 3-aroyl-1H-pyrrolo[2,1-c][1,4]benzoxa-
zine-1,2,4-triones Ia and Ib, react with substituted
alkyl 3-aminoprop-2-enoates (β-enamino esters), as
well as with 1,3-C,N-binucleophiles, via addition of
the activated β-CH group in the enamino fragment at
the C3a carbon atom of pyrrolobenzoxazine I, followed
by pyrrole ring closure as a result of intramolecular
attack by the side-chain amino group on the lactone
carbonyl carbon atom in the benzoxazine fragment and
cleavage of the C4–O5 bond. The products of these
* For communication LIX, see [1].
** For preliminary communication, see [4].
836

FIVE-MEMBERED 2,3-DIOXO HETEROCYCLES: LX.
837
Scheme 1.
Me
Me
RCONHNH
O
N
O
O
O
O
O
+
COAr
COAr
O
N
Me
Me
NHNHCOR
IIa–IIc
O
O
OH
O
Ia, Ib
R
NHCOR
N
Me
Me
N
NH
O
O
O
Me
Me
N
N
HO
HO
O
O
O
COAr
COAr
HO
HO
IIIa–IIIe
A
I, Ar = Ph (a), 4-BrC6H4 (b); II, R = 2-HOC6H4 (a), 2-H2NC6H4 (b), 3-O2NC6H4 (c); III, R = 2-HOC6H4, Ar = Ph (a), 4-BrC6H4 (b);
R = 2-H2NC6H4, Ar = Ph (c), 4-BrC6H4 (d); Ar = Ph, R = 3-O2NC6H4 (e).
(Fig. 1). Compounds IIIa–IIIe are light yellow crystal-
line substances which melt with decomposition at
a high temperature; they are readily soluble in DMF
and DMSO, poorly soluble in common organic sol-
vents, and insoluble in saturated hydrocarbons and
water. The presence of enolic and phenolic hydroxy
groups in their molecules was confirmed by a positive
color test (cherry color) with an alcoholic solution of
iron(III) chloride.
(Carom); 67.61 [C3(C2′)], 50.59 (C5); 48.57 (C7), 33.59
(C6); 27.57 (CH3).
According to the X-ray diffraction data, compound
IIIe crystallizes as solvate with methanol at a ratio of
1:1.5. One methanol molecule is located in the general
position. The oxygen atom in the second methanol
O9
O8
N4
C31
C32
The IR spectra of spiro compounds IIIa–IIIe con-
tained absorption bands belonging to stretching vibra-
tions of the OH and NH groups (a broad band in the
region 3165–3458 cm–1), two lactam carbonyl groups
(two peaks at 1698–1778 cm–1), and ArC=O,
NHCOC6H4, and C4=O groups (1605–1666 cm–1);
also, amide II band was present at 1524–1578 cm–1.
C33
C18
C19
C17
C28
O7
C27
N1
C16
C15
O5
C30
O3
C14
C1
C29
O1
C3
N3
C2
O4
N2
C7
C6
C12
C11
1
Compounds IIIa–IIIe showed in the H NMR spectra
C4
C9
(DMSO-d6) signals from protons in the aromatic rings
and substituents therein, two singlets from the methyl
groups in the cyclohexenone fragment (δ 0.78–
0.86 ppm), signals from two methylene groups in the
cyclohexenone fragment (δ 2.01–2.42 ppm), a singlet
from the phenolic hydroxy proton (δ 9.20–9.35 ppm),
a singlet from the exocyclic amide NH proton (δ 11.33–
12.03 ppm) and a broadened singlet from the enolic
C5
C20
C10
O2
C8
O6
C13
C21
C26
C25
C22
C23
C24
13
hydroxy proton (δ 12.40–12.60 ppm). The C NMR
Structure of the molecule of N-[3′-benzoyl-4′-hydroxy-1′-(2-
hydroxyphenyl)-6,6-dimethyl-2,4,5′-trioxo-1′,4,5,5′,6,7-
hexahydrospiro[indole-3,2′-pyrrol]-1(2H)-yl]-3-nitrobenza-
mide (IIIe) according to the X-ray diffraction data (hydrogen
atoms are not shown).
spectrum of IIIb in DMSO-d6 contained the following
signals, δC, ppm: 190.26 (C4); 187.92 (COC6H4);
172.57, 167.58, 165.79, 165.21 (C2O, C7a, C5′, C4′);
158.92 (NHCOC6H4); 153.23 (C3′); 136.69–107.91
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 6 2008

RACHEVA et al.
838
Parameters of hydrogen bonds D–H···A in the crystalline structure of N-[3′-benzoyl-4′-hydroxy-1′-(2-hydroxyphenyl)-6,6-
dimethyl-2,4,5′-trioxo-1′,4,5,5′,6,7-hexahydrospiro[indole-3,2′-pyrrol]-1(2H)-yl]-3-nitrobenzamide (IIIe).
D–H
O5–H5
O5–H5
N1–H1
O10–H10
O2–H2
d(D–H), Å
1.016
d(H···A), Å
2.036
∠DHA, deg
133.97
d(D···A), Å
2.838
A
O4
N3
1.016
2.138
124.94
2.844
0.836
2.084
176.29
2.918
O3 [x + 1, y, z]
O6
O10 [x – 1, y, z]
1.076
1.687
170.64
2.754
1.019
1.644
144.06
2.540
molecule occupies the symmetry center, its carbon
atom is statistically disordered by two positions, and
the molecule is characterized by large thermal vibra-
tions. All bond lengths and bond angles in molecule
IIIe conform to the corresponding standard values.
The planes of the benzene rings in the hydroxyphenyl
and benzoyl fragments are almost parallel (the corre-
sponding dihedral angle is 178.1°) and are turned
through dihedral angles close to 60° (62.6 and 61.2°,
respectively) with respect to the pyrrole ring plane.
The benzoyl fragment is not planar: the torsion angle
O6C20C21C22 is equal to –40.9°. The benzoyl oxygen
atom deviates from the benzene ring plane by 0.83 Å,
and from the pyrrole ring plane, by 0.58 Å. The orien-
tation of the benzoylamino group is characterized by
the torsion angles C1N2N1C27 84.8, N2N1C27O7 13.3,
and N1C27C28C29 25.1°. The bend along the C9···C11
line is 45.3° toward the hydroxyphenyl group on N3.
The hydroxy proton in the hydroxyphenyl fragment is
likely to be involved in intramolecular hydrogen bond
with O4 and N3 (bifurcate bond). The molecule of
methanol occupying the general crystallographic posi-
tion forms hydrogen bonds O10–H10 ···O6 and O2–
H2···O10 with molecules IIIe, giving rise to an infinite
chain along the a axis. Molecules IIIe in that chain are
also linked through intramolecular hydrogen bonds
N1–H1 ···O3; however, the H1 ···O3 distance suggests
that this bond is relatively weak. The hydrogen bond
parameters are given in table.
The described reaction is a rare example of syn-
thesis of a difficultly accessible spiro[indole-3,2′-pyr-
role] heterocyclic system with various substituents in
both heterocyclic fragments.
EXPERIMENTAL
The IR spectra were recorded in mineral oil on
1
an FSM-1201 spectrometer. The H and 13C NMR
spectra were measured on a Bruker AM-400 spec-
trometer at 400 MHz for 1H using DMSO-d6 as solvent
and TMS as internal reference. The purity of the prod-
ucts was checked by TLC on Silufol plates using ethyl
acetate and ethyl acetate–benzene (1:5) as eluents;
spots were visualized by treatment with iodine vapor.
N-[3′-Benzoyl-4′-hydroxy-1′-(2-hydroxyphenyl)-
6,6-dimethyl-2,4,5′-trioxo-1′,4,5,5′,6,7-hexahydro-
spiro[indole-3,2′-pyrrol]-1(2H)-yl]-2-hydroxybenz-
amide (IIIa). A solution of 1.0 mmol of compound Ia
and 1.0 mmol of cyclic enehydrazine IIa in 10 ml of
anhydrous m-xylene was heated for 10 min under
reflux. The mixture was cooled, and the precipitate
was filtered off. Yield 86%, mp 205–206°C (from
methanol). IR spectrum, ν, cm–1: 3450, 3264 br (NH,
OH); 1762, 1715 (C2=O, C5′=O); 1650 (1-NHC=O),
1
1625 (C4=O, 3′-C=O), 1578 (δNH). H NMR spec-
trum, δ, ppm: 0.78 s (3H, Me), 0.86 s (3H, Me),
2.04 d.d and 2.12 d.d (1H each, 7-H, J = 16.0 Hz),
2.23 d.d and 2.40 d.d (1H each, 5-H, J = 18.3 Hz),
6.73–7.93 m (13H, Harom), 9.32 s (1H, OH), 11.33 s
(1H, NH), 11.46 s (1H, OH), 12.40 br.s (1H, 4′-OH).
Found, %: C 64.60; H 3.48; N 6.06. C33H27N3O8. Cal-
culated, %: C 66.77; H 4.58; N 7.08.
Presumably, the process involves addition of the
β-CH group of cyclic enehydrazino ketone II at the C3a
atom of the pyrrolobenzoxazine system (as in reactions
of compounds I with mononucleophiles) [2, 3], fol-
lowed by nucleophilic attack by the NH group on the
lactone carbonyl carbon atom (C4) and cleavage of the
C4–O5 bond. Closure of pyridazine ring with formation
of structure A does not occur, presumably because of
lower nucleophilicity of the NH group adjacent to the
benzoyl carbonyl group.
Compounds IIIb–IIIe were synthesized in a similar
way.
N-[3′-(4-Bromobenzoyl)-4′-hydroxy-1′-(2-hy-
droxyphenyl)-6,6-dimethyl-2,4,5′-trioxo-1′,4,5,5′,-
6,7-hexahydrospiro[indole-3,2′-pyrrol]-1(2H)-yl]-2-
hydroxybenzamide (IIIb). Yield 85%, mp 239–240°C
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 6 2008

FIVE-MEMBERED 2,3-DIOXO HETEROCYCLES: LX.
839
(from methanol). IR spectrum, ν, cm–1: 3455, 3233 br
NH2), 9.20 s (1H, OH), 11.33 s (1H, NH), 12.40 br.s
(1H, 4′-OH). Found, %: C 60.03; H 3.75; Br 10.92;
N 8.50. C33H27BrN4O7. Calculated, %: C 59.03;
H 4.05; Br 11.90; N 8.34.
(NH, OH); 1762, 1708 (C2=O, C5′=O); 1650, 1624
1
(C4=O, 3′-C=O, 1-NHC=O), 1541 (δNH). H NMR
spectrum, δ, ppm: 0.79 s (3H, Me), 0.86 s (3H, Me),
2.04 d.d and 2.09 d.d (1H each, 7-H, J = 15.9 Hz),
2.24 d.d and 2.41 d.d (1H each, 5-H, J = 18.2 Hz),
6.79–7.90 m (12H, Harom), 9.39 s (1H, OH), 11.34 s
(1H, NH), 11.43 s (1H, OH), 12.60 br.s (1H, 4′-OH).
13C NMR spectrum (DMSO-d6), δC, ppm: 190.26
(C4=O); 187.92 (COC6H4); 172.57, 167.58, 165.79,
165.21 (C2, C7a, C5′, C4′); 158.92 (NHCO); 153.23
(C3′); 136.69–107.91 (Carom); 67.61 (Cspiro); 50.59 (C5);
48.57 (C7); 33.59 (C6); 27.57 (CH3). Found, %:
C 57.60; H 3.90; Br 12.70; N 5.25. C33H26BrN3O3.
Calculated, %: C 58.94; H 3.90; Br 11.88; N 6.25.
N-[3′-Benzoyl-4′-hydroxy-1′-(2-hydroxyphenyl)-
6,6-dimethyl-2,4,5′-trioxo-1′,4,5,5′,6,7-hexahydro-
spiro[indole-3,2′-pyrrol]-1(2H)-yl]-3-nitrobenzam-
ide (IIIe). Yield 87%, mp 230–232°C (from metha-
nol). IR spectrum, ν, cm–1: 3377 br, 3214 br (NH, OH);
1771, 1698 (C2=O, C5′=O); 1655, 1620, 1605 (3′-C=O,
1
C4=O, 1-NHC=O); 1524 (δNH). H NMR spectrum, δ,
ppm: 0.80 s (3H, Me), 0.86 s (3H, Me), 2.03 d.d and
2.14 d.d (1H each, 7-H, J = 15.9 Hz), 2.26 d.d and
2.42 d.d (1H each, 5-H, J = 18.5 Hz), 6.76–8.51 m
(13H, Harom), 9.35 s (1H, OH), 12.03 s (1H, NH),
12.40 br.s (1H, 4′-OH). Found, %: C 62.57; H 4.01;
N 9.50. C33H26N4O9. Calculated, %: C 63.66; H 4.21;
N 9.00.
2-Amino-N-[3′-benzoyl-4′-hydroxy-1′-(2-hy-
droxyphenyl)-6,6-dimethyl-2,4,5′-trioxo-1′,4,5,5′,-
6,7-hexahydrospiro[indole-3,2′-pyrrol]-1(2H)-yl]-
benzamide (IIIc). Yield 91%, mp 202–204°C (from
methanol). IR spectrum, ν, cm–1: 3457, 3165 br (NH,
OH); 1778, 1715 (C2=O, C5′=O); 1666, 1613 (C4=O,
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 07-03-96036).
1
3′-C=O, 1-NHCO), 1561 (δNH). H NMR spectrum, δ,
ppm: 0.81 s (3H, Me), 0.85 s (3H, Me), 2.01 d.d and
2.13 d.d (1H each, 7-H, J = 15.7 Hz), 2.17 d.d and
2.37 d.d (1H each, 5-H, J = 18.1 Hz), 6.53–7.75 m
(13H, Harom), 7.76 br.s (2H, NH2), 9.21 s (1H, OH),
11.34 s (1H, NH), 12.40 br.s (1H, 4′-OH). Found, %:
C 66.88; H 3.99; N 9.01. C33H28N4O7. Calculated, %:
C 66.88; H 4.76; N 9.45.
REFERENCES
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(2-hydroxyphenyl)-6,6-dimethyl-2,4,5′-trioxo-1′,4,-
5,5′,6,7-hexahydrospiro[indole-3,2′-pyrrol]-1(2H)-
yl]benzamide (IIId). Yield 89%, mp 227–230°C
(from methanol). IR spectrum, ν, cm–1: 3458, 3168 br
(NH, OH); 1775, 1711 (C2=O, C5′=O); 1658, 1619,
1608 (C4=O, 3′-C=O, 1-NHC=O); 1556 (δ NH).
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(3H, Me), 2.02 d.d and 2.09 d.d (1H each, 7-H, J =
15.7 Hz), 2.19 d.d and 2.31 d.d (1H each, 5-H, J =
18.1 Hz), 6.52–7.73 m (12H, Harom), 7.75 br.s (2H,
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 6 2008