Five-membered 2,3-dioxoheterocycles: XC. Reaction of 4,5- bis(methoxycarbonyl)-1H-pyrrole-2,3-diones with enaminoesters. crystal and molecular structure of 4-methyl 9-ethyl 7-benzyl-3-hydroxy-8-methyl-1-(4- methoxyphenyl)-2,6-dioxo-1,7-diazaspiro[4.4]nona

Article abstract of DOI:10.1134/S107042801211005X

1-Aryl-4,5-bis(methoxycarbonyl)-1H-pyrrole-2,3-diones react with ethyl 3-(benzylamino)but-2-enoate and ethyl 3-(benzylamino)-3-phenylacrylate giving 4-methyl 9-ethyl 1-aryl-7-benzyl-3-hydroxy-8-methyl- and 4-methyl 9-ethyl 1-aryl-7-benzyl-3-hydroxy-8-phen

Full text of DOI:10.1134/S107042801211005X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2012, Vol. 48, No. 11, pp. 1435−1438. © Pleiades Publishing, Ltd., 2012.
Original English Text © P.S. Silaichev, M.A. Chudinova, P.A. Slepukhin, A.N. Maslivets, 2012, published in Zhurnal Organicheskoi Khimii, 2012, Vol. 48,
No. 11, pp. 1445−1448.
Five-Membered 2,3-Dioxoheterocycles: XC.*
Reaction of 4,5-Bis(methoxycarbonyl)-1H-pyrrole-2,3-diones
with Enaminoesters. Crystal and Molecular Structure
of 4-Methyl 9-Ethyl 7-Benzyl-3-hydroxy-8-methyl-1-(4-
methoxyphenyl)-2,6-dioxo-1,7-diazaspiro[4.4]nona-3,8-
diene-4,9-dicarboxylate
P. S. Silaicheva, M. A. Chudinovab, P. A. Slepukhinc, and A. N. Maslivetsa,b
aInstitute of Natural Sciences at Perm State National Research University, Perm, 614990 Russia
e-mail: kohb@psu.ru
bPerm State National Research University, Perm, Russia
cPostovskii Institute of Organic Synthesis, Ural Branch, Russian Academy of Sciences, Ekaterinburg, Russia
Received October 12, 2011
Abstract—1-Aryl-4,5-bis(methoxycarbonyl)-1H-pyrrole-2,3-diones react with ethyl 3-(benzylamino)but-2-enoate
and ethyl 3-(benzylamino)-3-phenylacrylate giving 4-methyl 9-ethyl 1-aryl-7-benzyl-3-hydroxy-8-methyl- and
4-methyl 9-ethyl 1-aryl-7-benzyl-3-hydroxy-8-phenyl-2,6-dioxo-1,7-diazaspiro[4.4]nona-3,8-diene-4,9-
dicarboxylates.
DOI: 10.1134/S107042801211005X
Substituted 1H-pyrrole-2,3-diones (5-phenyl-4-eth-
oxycarbonyl-, 4-isopropoxallyl-5-phenyl-, and 4-aroyl-
5-methoxycarbonyl-1H-pyrrole-2,3-diones) react with
carbocyclic enamines affording spiro[acridine-9,3'-pyr-
roles] [2, 3], spiro[furan-2,3'-indoles] [4], spiro[indole-
3,2'-pyrroles], or spiro[furan-2,3'-indoles] [5] depending
on the structure of the substituents in the positions 4 and
5 of the pyrrolediones.
the carbocyclic enamines exist in the form of Z-isomers
with an intramolecular hydrogen bond of an H-chelate
type preventing their reactions in the role of binucleo-
philes, therefore it is expectable that they may react in
another way.
The reaction of 1-aryl-4,5-bis(methoxycarbonyl)-1H-
pyrrole-2,3-diones Ia–Id with ethyl 3-(benzyl-amino)
but-2-enoate (IIa) and ethyl 3-(benzylamino)-3-phen-
ylacrylate (IIb) in a ratio 1 : 1 carried out by boiling
in anhydrous toluene within 3–4 h furnished in good
yields 4-methyl 9-ethyl 1-aryl-7-benzyl-3-hydroxy-8-
methyl-2,6-dioxo-1,7-diazaspiro[4.4]nona-3,8-diene-
4,9-dicarboxylates IIIa–IIId and 4-methyl 9-ethyl
1-aryl-7-benzyl-3-hydroxy-8-phenyl-2,6-dioxo-1,7-
diazaspiro[4.4]-nona-3,8-diene-4,9-dicarboxylates IIIe,
IIIf whose structure was proved by XRD analysis by the
example of compound IIIc.
The recyclizations of 4,5-bis(methoxycarbonyl)-1H-
pyrrole-2,3-diones at the treatment with enamines are
poorly studied. A reaction is described of 1-aryl-4,5-bis-
(methoxycarbonyl)-1H-pyrrole-2,3-diones with carbo-
cyclic enamines proceeding as an addition of the β-CH
group of enamines to the atom C5 of the pyrrolediones
followed by the intramolecular cyclization involving the
amino group of the enamines and the methoxycarbonyl
substituent in the position 5 of the pyrrolediones [6, 7].
The reactions of these pyrrolediones with acyclic en-
Compounds IIIa–IIIf are colorless crystalline
substances of high melting points, readily soluble in
DMF and DMSO, sparingly soluble in methanol, ethanol,
amines were not described. The latter enamines unlike
______________
* For Communication LXXXIX, see [1].
1435

SILAICHEV et al.
1436
H
Bn
N
R
COOEt
H
MeO
O
O
MeO
O
O
MeOOC
MeOOC
O
MeO
OH
Bn
R
OH
IIа, IIb
N
Bn NH
_MeOH
O
N
N
N
O
O
Ar
R
Ar
Ar
OEt
O
O
OEt
IIIа_IIIf
Iа_Id
I, Ar = Ph (a), C6H4Me-4 (b), C6H4OMe-4 (c), C6H4Cl-4 (d); II, R = Me (a), Ph (b); III, R = Me, Ar = Ph (a), C6H4Me-4
(b), C6H4OMe-4 (c), C6H4Cl-4 (d); R = Ph, Ar = Ph (e), C6H4Me-4 (f).
acetone and other solvents, insoluble in alkanes and
water, exhibiting a positive reaction (cherry color) for
the presence of the enol hydroxy group with the alcoholic
solution of iron(III) chloride.
oxycarbonyl substituent (0.83–1.12 and 3.82–4.07 ppm
respectively), two doublets of the methylene group of
the benzyl substituent with a characteristic coupling
constant (2JHH 16.0–16.4 Hz) (4.28–4.87 ppm), a singlet
of the methyl protons in the position 8 (2.25–2.30 ppm
in the spectra of compounds IIIa–IIId), and a broad-
ened singlet of the proton of the enol hydroxy group
(12.32–12.57 ppm) were observed.
In the 13C NMR spectra of compound IIIf along with
the carbon signals of the aromatic and aliphatic sub-
stituents and the ethylene fragments of the heterocyclic
system the signals of the carbon atoms are present from
two lactam and two ester carbonyl groups in the region
158.69–165.17 ppm, and also a signal of the spiro carbon
atom at 70.10 ppm.
IR spectra of compounds IIIa–IIIf contain the char-
acteristic bands of the stretching vibrations of the enol
hydroxy group (3167–3335 cm–1), of lactam carbonyl
groups C6=O (1732–1740 cm–1), and of C2=O (1705–
1723 cm–1), of the carbonyl groups of the ethoxycarbonyl
(1676–1698 cm–1) and methoxycarbonyl substituents; the
latter is involved in the formation of the intramolecular
hydrogen bond and has an absorption band in the region
1628–1653 cm–1.
In the 1H NMR spectra of compounds IIIa–IIIf along-
side the proton signals of the aromatic substituents and the
groups attached to them the singlet appears of the protons
of the methoxycarbonyl group (3.65–3.71 ppm); a triplet
of a methyl and a quartet of a methylene group of the eth-
To prove the structure of obtained compounds IIIa–
IIIf and to establish the special features of their spatial
structure we carried out the XRD analysis of a single
crystal of compound IIIc whose general appearance is
shown in the figure.
According to the data of XRD analysis the pyrroline
rings of the spiro-system are flat (in one of them the
deviation of the atoms from the mean-square plane does
not exceed 0.01 Å, in another, 0.02 Å), and they are
turned with respect to each other by an angle of 89.4°.
The distribution of the bond lengths in the rings may be
regarded as common for the conjugated diene systems.
The bond lengths C–COOR equal ~1.45 Å indicating
that the electrons of their carbonyl groups are involved
in the system of the conjugated bonds of the heterocyclic
rings. The hydroxy group takes part in the formation of
an intramolecular hydrogen bond with the carbonyl group
of the methoxycarbonyl substituent (O7–H···O2). The
molecules are packed in the crystals by layers parallel to
the [001] plane with the alteration of the zones of het-
General view of the molecule of 4-methyl 9-ethyl 7-benzyl-3-
hydroxy-8-methyl-1-(4-methoxyphenyl)-2,6-dioxo-1,7-diaza-
spiro[4.4]nona-3,8-diene-4,9-dicarboxylate (IIIc) according
to XRD data shown as a ball-rod model (hydrogen atoms are
omitted to facilitate the image perception).
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FIVE-MEMBERED 2,3-DIOXOHETEROCYCLES: XC.
1437
phenyl-2,6-dioxo-1,7-diazaspiro[4.4]nona-3,8-diene-
4,9-dicarboxylate (IIIa). A solution of 1.0 mmol of
pyrroledione Ia and 1.0 mmol of enaminoester IIa in 20
ml of anhydrous toluene was boiled for 4 h (TLC monitor-
ing), the mixture was cooled, the separated precipitate was
filtered off and recrystallized from toluene. Yield 73%,
mp 161–162°C. IR spectrum, ν, cm–1: 3310 (OH), 1736
(C6=O), 1723 (C2=O), 1690 (COOEt), 1649 (COOMe).
1H NMR spectrum, δ, ppm: 1.12 t (3H, CH3CH2,
J 7.0 Hz), 2.26 s (3H, Me), 3.65 s (3H, COOMe), 4.06 q
(2H, OCH2, J 7.0 Hz), 4.74 d (1H, CH2Ph, J 16.4 Hz),
4.87 d (1H, CH2Ph, J 16.4 Hz), 6.90–7.41 group of sig-
nals (10H, 2Ph), 12.40 (1H, OH). Found, %: C 65.48;
H 5.06; N 5.89. C26H24N2O7. Calculated, %: C 65.54;
H 5.08; N 5.88.
erocyclic and aromatic fragments. The phenyl ring of the
benzyl substituent and the methoxyphenyl substituent are
disordered by two positions with the population factors
0.5 (the second disordered components are designated
in the figure by an additional index “A”). It is difficult to
make a conclusion on the nature of the disordering, but
for the molecule (and within the monomolecular layer) the
coordinated positions of the disorder should be retained
to avoid the appearance of inadmissibly short interatomic
contacts CAr–H···CAr (up to ~1.9 Å) and CAr···CAr (up to
~2.5 Å). The appearance of such unfavorable contacts can
be avoided if in the limits of a monomolecular layer the
alternation occurs of the molecules with different disorder
components probably capable to the synchronized varia-
tions provided by the thermal oscillations.
Compounds IIIb–IIIf were analogously synthesized.
The formation of compounds IIIa–IIIf proceeds evi-
dently as a result of the initial addition of the activated
β-CH group of the enamine fragment of compounds IIa,
IIb to the carbon atom in the position 5 of pyrroledio-
nes Ia–Id followed by the subsequent intramolecular
closure of the pyrrolone ring due to the nucleophilic at-
tack of the amino group of the enamine fragment on the
carbonyl group of the ester substituent in the position 5
of pyrrolediones accompanied by the methanol elimina-
tion according to the scheme earlier described in [5–7].
Therewith the existence of the reagent in the unfavorable
form of the Z-isomer affects the reaction rate by increas-
ing the time required for the completion of the reaction.
This reaction is one more example of the direct spiro-
bis-heterocyclization of monocyclic pyrrolediones under
the action of enamines with the building up a difficultly
available heterocylic system of 1,7-diazaspiro[4.4]nona-
3,8-diene and with the possibility to vary substituents in
several positions.
4-Methyl 9-ethyl 7-benzyl-3-hydroxy-8-methyl-
1-(4-methylphenyl)-2,6-dioxo-1,7-diazaspiro[4.4]-
nona-3,8-diene-4,9-dicarboxylate (IIIb). Yield 78%,
mp 158–160°C (toluene). IR spectrum, ν, cm–1: 3170
(OH), 1740 ( C6=O), 1705 (C2=O), 1690 (COOEt),
1630 (COOMe). 1H NMR spectrum, δ, ppm: 1.12 t (3H,
CH3CH2, J 7.0 Hz), 2.25 s (3H, Me), 2.34 s (3H, Me),
3.65 s (3H, COOMe), 4.05 q (2H, OCH2, J 7.0 Hz),
4.73 d (1H, CH2Ph, J 16.4 Hz), 4.86 d (1H, CH2Ph,
J 16.4 Hz), 6.84–7.27 group of signals (9H, Ph + C6H4),
12.35 br.s (1H, OH). Found, %: C 66.05; H 5.35; N 5.69.
C27H26N2O7. Calculated, %: C 66.11; H 5.34; N 5.71.
4-Methyl 9-ethyl 7-benzyl-3-hydroxy-8-methyl-
1-(4-methoxyphenyl)-2,6-dioxo-1,7-diazaspiro[4.4]-
nona-3,8-diene-4,9-dicarboxylate (IIIc). Yield 77%,
mp 174–175°C (toluene). IR spectrum, ν, cm–1: 3174
(OH), 1738 (C6=O), 1721 (C2=O), 1698 (COOEt),
1640 (COOMe). 1H NMR spectrum, δ, ppm: 1.13 t (3H,
CH3CH2, J 7.0 Hz), 2.26 s (3H, Me), 3.65 s (3H, COOMe),
3.78 s (3H, OMe), 4.07 q (2H, OCH2, J 7.0 Hz), 4.70 d
(1H, CH2Ph, J 16.4 Hz), 4.87 d (1H, CH2Ph, J 16.4 Hz),
6.85–7.27 group of signals (9H, Ph + C6H4), 12.32 br.s
(1H). Found, %: C 63.98; H 5.14; N 5.50. C27H26N2O8.
Calculated, %: C 64.03; H 5.17; N 5.53.
EXPERIMENTAL
IR spectra of compounds synthesized were recorded
on a spectrophotometer FSM-1201 from mulls in mineral
oil. 1H and 13C NMR spectra were registered on a spec-
trometer Bruker AM-400 [operating frequencies 400
(1H) and 100 MHz (13C)] from solutions in DMSO-d6,
internal reference TMS. The homogeneity of compounds
synthesized was checked and the reaction progress was
monitored by TLC on Silufol plates, eluents benzene–
ethyl acetate, 5:1, and ethylacetate, development in iodine
vapor and at heating.
XRD structural analysis of compound IIIc. The unit
cell parameters and the array of the experimental reflec-
tions of compound with empirical formula C27H26N2O8
were measured on an automatic four-circle diffractometer
equipped with a CCD-detector Xcalibur 3 (Oxford Dif-
fraction) by the method of ω/2θ-scanning using the mono-
chromatic MOKα-radiation in the range of angles 2.79 <
θ < 26.37. Crystals triclinic: a 8.8556(13), b 11.4626(12),
4-Methyl 9-ethyl 7-benzyl-3-hydroxy-8-methyl-1-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 11 2012

SILAICHEV et al.
1438
c 13.0462(11) Å, α 94.294(8), β 93.286(8), γ 109.262(7)°,
V 1241.9(2) Å3, M 506.50, dcalc 1.354 g/cm3, Z 2, space
group P-1. The total number of 7707 rflections was mea-
sured, among them 5033 independent (Rint 0.0235), 2195
with I > 2σ(I). The completeness of the experiment at
the angle θ 26.37O was 99.3%. No correction for extinc-
tion was introduced (μ 0.101 mm–1). The structure was
solved by the direct statistical method and was refined
by full-matrix root-mean-square method with respect to
F2 in the anisotropic approximation for all nonhydro-
gen atoms. Hydrogen atoms of OH group were solved
directly and refined independently, the other hydrogen
atoms were placed in the geometrically calculated posi-
tions. All calculations were carried out using SHELX 97
software [8]. The final results of refining are as follows:
R1 0.0396, wR2 0.0866 for reflections with I > 2σ(I), R1
0.1018, wR2 0.0925 (for all reflections), S 1.001. Maximal
and minimal peaks of the residual electron density are
0.157 and –0.157 ēÅ–3.
group of signals (15H, 3Ph), 12.57 br.s (1H, OH). Found,
%: C 69.10; H 4.90; N 5.17. C31H26N2O7. Calculated, %:
C 69.14; H 4.87; N 5.20.
4-Methyl 9-ethyl 7-benzyl-3-hydroxy-1-(4-methyl-
phenyl)-8-phenyl-2,6-dioxo-1,7-diazaspiro[4.4]nona-
3,8-diene-4,9-dicarboxylate (IIIf). Yield 67%, mp 225–
227°C (toluene). IR spectrum, ν, cm–1: 3335 (OH), 1740
(C6=O), 1713 (C2=O), 1680 (COOEt), 1651 (COOMe).
1H NMR spectrum, δ, ppm: 0.83 t (3H, CH3CH2,
J 7.0 Hz), 2.39 s (3H, Me), 3.71 s (3H, COOMe), 3.83 m
(2H, OCH2), 4.28 d (1H, CH2Ph, J 16.0 Hz), 4.63 d (1H,
CH2Ph, J 16.0 Hz), 6.45–7.42 group of signals (14H,
2Ph + C6H4), 12.52 br.s (1H, OH). 13C NMR spectrum,
δ, ppm: 13.46 (CH2CH3), 20.76 (Me), 43.97 (CH2Ph),
51.48 (COOCH3), 59.20 (OCH2), 70.10 (C5), 104.89 (C9),
107.84 (C4), 125.27–138.27, 155.73 (C8), 158.69 (C6),
160.86 (COOEt), 161.85 (COOMe), 165.17 (C2), 173.66
(C3). Found, %: C 69.63; H 5.06; N 5.05; C32H28N2O7.
Calculated, %: C 69.56; H 5.11; N 5.07.
The results of the structural research were deposited
to the Cambridge Crystallographic Data Center, CCDC
901415. The data can be obtained free at the address
http://www.ccdc.cam.ac.uk.
ACKNOWLEDGMENTS
The study was carried out under the financial support
of the Russian Foundation for Basic Research (grants
nos. 12-03-31157, 12-03-00696) and of the Ministry of
Education and Science of the Russian Federation (project
no. 2.19.10).
4-Methyl 9-ethyl 7-benzyl-3-hydroxy-8-methyl-1-
(4-chlorophenyl)-2,6-dioxo-1,7-diazaspiro[4.4]nona-
3,8-diene-4,9-dicarboxylate (IIId). Yield 69%, mp 174–
176°C (toluene). IR spectrum, ν, cm–1: 3180 (OH), 1732
(C6=O), 1713 (C2=O), 1676 (COOEt), 1653 (COOMe).
1H NMR spectrum, δ, ppm: 1.12 t (3H, CH3CH2,
J 7.0 Hz), 2.30 s (3H, Me), 3.65 s (3H, COOMe), 4.06 q
(2H, OCH2, J 7.0 Hz), 4.76 d (1H, CH2Ph, J 16.1 Hz),
4.86 d (1H, CH2Ph, J 16.1 Hz), 6.92–7.47 group of signals
(9H, Ph + C6H4), 12.48 br.s (1H, OH). Found, %: C 61.16;
H 4.51; Cl 6.90; N 5.43. C26H23ClN2O7. Calculated, %:
C 61.12; H 4.54; Cl 6.94; N 5.48.
REFERENCES
1. Silaichev, P.S., Filimonov, V.O., Slepukhin, P.A., and
Maslivets, A.N., Zh. Org. Khim., 2012, vol. 48, p. 1334.
2. Silaichev, P.S., Aliev, Z.G., and Maslivets, A.N., Zh. Org.
Khim., 2009, vol. 45, p. 1125.
3. Silaichev, P.S., Dmitriev, M.V., Aliev, Z.G., and Masliv-
ets, A.N., Zh. Org. Khim., 2010, vol. 46, p. 1173.
4. Silaichev, P.S., Aliev, Z.G., and Maslivets, A.N., Zh. Org.
Khim., 2009, vol. 45, p. 130.
5. Denislamova, E.S. and Maslivets, A.N., Zh. Org. Khim.,
2010, vol. 46, p. 396.
6. Silaichev, P.S., Chudinova, M.A., and Maslivets,A.N., Zh.
Org. Khim., 2011, vol. 47, p. 1570.
4-Methyl 9-ethyl 7-benzyl-3-hydroxy-1,8-diphenyl-
2,6-dioxo-1,7-diazaspiro[4.4]nona-3,8-diene-4,9-dicar-
boxylate (IIIe). Yield 71%, mp 198–199°C (toluene).
IR spectrum, ν, cm–1: 3167 (OH), 1732 (C6=O), 1709
1
(C2=O), 1682 (COOEt), 1628 (COOMe). H NMR
spectrum, δ, ppm: 0.83 t (3H, CH3CH2, J 7.2 Hz), 3.71 s
(3H, COOMe), 3.82 m (2H, OCH2), 4.31 d (1H, CH2Ph,
J 16.0 Hz), 4.62 d (1H, CH2Ph, J 16.0 Hz), 6.48–7.83
7. Silaichev, P.S., Chudinova, M.A., Slepukhin, P.A., and
Maslivets, A.N., Zh. Org. Khim., 2011, vol. 47, p. 1682.
8. Sheldrick, G.M., Acta Cryst., 2008, vol. A64, p. 112.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 11 2012