Five-membered 2,3-dioxo heterocycles: LXII. Reaction of 3-aroyl-1H-pyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones with N,N′-dihydroxycyclohexane-1,2-diamine. Unusual rearrangement in the spiro[quinoxaline-2,2′-pyrrole] system

Article abstract of DOI:10.1134/S1070428008080149

3-Aroyl-1H-pyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones reacted with N,N′-dihydroxycyclohexane-1,2-diamine to give 3-aroyl-1′,4,4′- trihydroxy-1-(2-hydroxyphenyl)-4a′,5′,6′,7′,8′, 8a′-hexahydro-1′H-spiro[pyrrole-2,2′-quinoxaline]-3′, 5(1H,4′H)-diones whic

Full text of DOI:10.1134/S1070428008080149

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 8, pp. 1189–1193. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © I.V. Mashevskaya, Z.G. Aliev, D.G. Mazhukin, S.A. Popov, A.Ya. Tikhonov, A.N. Maslivets, 2008, published in Zhurnal Organicheskoi
Khimii, 2008, Vol. 44, No. 8, pp. 1202–1206.
Five-Membered 2,3-Dioxo Heterocycles: LXII.* Reaction
of 3-Aroyl-1H-pyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones
with N,N′-Dihydroxycyclohexane-1,2-diamine. Unusual
Rearrangement in the Spiro[quinoxaline-2,2′-pyrrole] System
I. V. Mashevskayaa, Z. G. Alievb, D. G. Mazhukinc, S. A. Popovc,
A. Ya. Tikhonovc, 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 Siciences, Chernogolovka, Moscow oblast, Russia
c Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Division, Russian Academy of Sciences,
pr. Akademika Lavrent’eva 9, Novosibirsk, 630090 Russia
Received February 13, 2008
Abstract—3-Aroyl-1H-pyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones reacted with N,N′-dihydroxycyclohexane-
1,2-diamine to give 3-aroyl-1′,4,4′-trihydroxy-1-(2-hydroxyphenyl)-4a′,5′,6′,7′,8′,8a′-hexahydro-1′H-spiro[pyr-
role-2,2′-quinoxaline]-3′,5(1H,4′H)-diones which underwent rearrangement into 1′-aroyloxy-4,4′-dihydroxy-
1-(2-hydroxyphenyl)-4a′,5′,6′,7′,8′,8a′-hexahydro-1′H-spiro[pyrrolidine-2,2′-quinoxaline]-3′,4,5(4′H)-triones
via [1,4]-migration of the aroyl group. The product structure was proved by X-ray analysis.
DOI: 10.1134/S1070428008080149
2,3-Dihydro-1H-pyrrole-2,3-diones fused at the [a]
side to various heterocycles react with difunctional
nucleophiles to give polyoxo heterocyclic systems that
are difficult to obtain by other methods [2]. We previ-
ously found that reactions of 3-aroyl-1H-pyrrolo-
[2,1-c][1,4]benzoxazine-1,2,4-triones I with o-phenyl-
enediamine and o-aminobenzenethiol [3, 4] under mild
conditions lead to recyclization products as a result of
successive attacks by the two nucleophilic centers on
the C3a and C4 atoms in compound I and opening of
the oxazine ring at the C4–O5 bond and pyrrole ring at
the C3a–N10 bond. It was interesting to involve in these
reactions another type of nitrogen-centered binucle-
ophiles, N,N′-dihydroxy-1,2-diamines. It is known that
reactions of the latter with polycarbonyl compounds
and enones underlie convenient procedures for the
synthesis of functionally substituted derivatives of
N-hydroxypyrazine [5] and N-hydroxy-1,4-diazepine
[6] or the corresponding N-oxides.
cyclohexane-1,2-diamine [7] at a ratio of 1:1 (boiling
anhydrous acetonitrile, 2–3 min [3, 4]) we obtained
compounds IIa–IIc whose spectral parameters did not
allow us to unambiguously determine their structure.
On the basis of the X-ray diffraction data for com-
pound IIa (Fig. 1) the products were assigned the
structure of 1′-aroyloxy-4′-hydroxy-1-(2-hydroxy-
phenyl)hexahydro-1′H-spiro[pyrrolidine-2,2′-quinoxa-
line]-3′,4,5(4′H)-triones (Scheme 1).
Compounds IIa–IIc are colorless high-melting
(with decomposition) crystalline substances which are
readily soluble in dimethylformamide and dimethyl
sulfoxide, poorly soluble in common organic solvents,
and insoluble in saturated hydrocarbons and water;
they show a positive test (dark cherry color) for phe-
nolic hydroxy group on treatment with an alcoholic
solution of iron(III) chloride.
Compounds IIa–IIc displayed in the IR spectra
absorption bands belonging to stretching vibrations of
OH group (broad bands in the regions 3360–3410 and
3100–3320 cm–1), OCOAr ester carbonyl group (1770–
1780 cm–1), C5=O lactam carbonyl group (1740–
By reactions of 3-aroyl-1H-pyrrolo[2,1-c][1,4]-
benzoxazine-1,2,4-triones Ia–Ic with N,N′-dihydroxy-
* For communication LXI, see [1].
1189

MASHEVSKAYA et al.
1190
Scheme 1.
OH
HN
R
O
N
O
O
R
O
N
O
NHOH
NHOH
O
N
OH
COAr
+
Ar
O
O
OH
Ia–Ic
R
R
HO
HO
N
O
N
O
N
N
N
N
HO
HO
O
OH
COAr
O
O
Ar
HO
OH
OH
IIIa–IIIc
IV
R
R
HO
HO
N
N
4'
O
O
3'
2'
1'
N
N
N1
5
2
3
N
HO
HO
4
OCOAr
OCOAr
O
O
OH
O
IIa–IIc
R = H, Ar = Ph (a), 4-MeC6H4 (b); R = Me, Ar = 4-MeC6H4 (c).
1760 cm–1), C4=O (1730–1740 cm–1), and C3′=O lac-
other five atoms. The N1 atom has almost planar con-
figuration (the sum of the bond angles at N1 is 359.4°)
which is stabilized by intramolecular hydrogen bond
O1–H1···O2 [2.635(5) Å]. The N2 atom is pyramidal;
the sum of the bond angles at that atom is 320.7°. The
planar benzoyl group on N2 occupies bisector position
relative to the pyrazine ring, and the C18=O6 bond is
directed toward the unshared electron pair on the nitro-
gen atom. Molecules duplicated by the glide reflection
plane n are linked through intermolecular hydrogen
bond O1–H1 ···O4 [2.872(6) Å] so that the O1–H1
hydroxy group is involved in bifurcate hydrogen bond
(intra- and intermolecular). The hydrogen bond
O1–H1···O2 is characterized by the following param-
eters: D–H 1.06(7), H···A 2.17(6), D···A 2.635(5) Å;
∠DHA 104(4)° (here, D and A stand for the donor and
acceptor atoms, respectively). The solvate acetone
molecule is linked to molecule IIa by the hydrogen
bond O7–H7 ···O8 [2.887(7) Å]. No other shortened
intermolecular contacts were found in the crystalline
structure of compound IIa.
1
tam carbonyl groups (1650–1690 cm–1). The H NMR
spectra of IIa–IIc in DMSO-d6 contained signals from
aromatic protons, methyl protons in tolyl groups, 5′-H–
8′-H methylene protons (δ 1.62–1.65 ppm, m, 8H), 3-H
(δ 3.06–3.77 ppm, d.d, AB system), 4a-H and 8a-H
(δ 3.64–3.85 ppm), OH (δ 8.65–8.83 ppm, s), and
N–OH (δ 10.51–10.54 ppm, s). In the 13C NMR spec-
trum of compound IIb in DMSO-d6 the following
signals were present, δC, ppm: 195.0 (C4), 170.3 (C3′),
162.9 (OCO), 158.5 (C5), 153.4 (C2″), 144.7 (C4′′′),
122.8 (C1″), 129.5–116.2 (Carom), 85.2 (Cspiro), 59.7
(C8a), 59.3 (C4a), 40.1 (C3), 39.1 (C8′), 38.9 (C5′), 25.7
(C6′), 21.9 (C7′), 20.7 (Me).
Figure 1 shows the structure of molecule IIa as
determined by X-ray analysis (hydrogen atoms are not
shown). All bond lengths conform to the corresponding
standard values. The pyrazine ring adopts a weakly
distorted envelope conformation. The bend angle along
the N2···C12 line is 53.2°, and the C13 atom deviates by
0.71 Å from the mean-square plane formed by the
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 8 2008

FIVE-MEMBERED 2,3-DIOXO HETEROCYCLES: LXII.
1191
C9
C8
O7
Presumably, the primary recyclization products,
O1
N1
spiro compounds III, are formed according to
a scheme analogous to that described by us previously
[3, 4], i.e., via successive nucleophilic attacks by the
NH groups of N,N′-dihydroxycyclohexane-1,2-diamine
on the C3a and C4 atoms in Ia–Ic and opening of the
oxazine ring at the C4–O5 bond. We succeeded in
isolating one intermediate product, compound IIIc, as
individual substance; it underwent rearrangement to
IIc upon attempted recrystallization.
C10
O2
C11
C17
C7
C16
C1
C2
C3
C12
C13
C6
N3
C15
C14
C5
O3
C4
O4
O6
O5
C18
Compound IIIc is a light yellow crystalline sub-
stance which is readily soluble in common organic
solvents and insoluble in unsaturated hydrocarbons and
water. The presence of enolic and phenolic hydroxy
groups in molecule IIIc was confirmed by positive
color test (cherry color) with an alcoholic solution of
iron(III) chloride. The spectral parameters of IIIc are
very consistent with those reported by us previously
for structurally related spiro[indole-3,2′-pyrroles] [8]
whose structure was proved by X-ray analysis.
C19
C20
C24
C21
C23
C22
Compounds III are unstable, and their rearrange-
ment into final products IIa–IIc is likely to involve
intramolecular addition of the 1′-OH group at the car-
bonyl carbon atom in the aroyl group with formation
of intermediate tricyclic isoxazolidine derivatives IV
[9]; cleavage of the C4–C5 bond in the isoxazolidine
ring yields compounds II. Thus initially formed spiro
compounds III are stabilized via unexpected [1, 4]
C→O migration of the aroyl group rather than via
opening of the pyrrole ring as described in [3, 4].
Fig. 1. Structure of the molecule of 1′-benzoyloxy-4′-hy-
droxy-1-(2-hydroxyphenyl)hexahydro-1′H-spiro[pyrrolidine-
2,2′-quinoxaline]-3′,4,5(4′H)-trione (IIa) according to the
X-ray diffraction data.
ylsilane as internal reference. The purity of the prod-
ucts was checked by thin-layer chromatography on
Silufol plates using ethyl acetate or ethyl acetate–ben-
zene (1:5) as eluent; the chromatograms were devel-
oped by treatment with iodine vapor.
1′-Benzoyloxy-4′-hydroxy-1-(2-hydroxyphenyl)-
hexahydro-1′H-spiro[pyrrolidine-2,2′-quinoxaline]-
With a view to elucidate whether the above rear-
rangement is possible we compared the thermodynam-
ic stabilities of the ketone and enol tautomers of inter-
mediate and final compounds IIIa and IIa on the basis
of the results of ab initio calculations [10]. Conforma-
tional analysis of each tautomer using STO-3G basis
set gave a structure corresponding to the global mini-
mum on the potential energy surface (Fig. 2, see table).
As followed from the calculated ab initio [6-31G(d)]
energies of formation of the most stable conformers,
the ketone tautomer of II is more thermodynamically
stable, the energy difference being 16.3 kcal/mol.
EXPERIMENTAL
The IR spectra were recorded on an FSM-1201
spectrometer from samples dispersed in mineral oil.
IIIa
IIa
1
The H and 13C NMR spectra were measured on
a Bruker AM-400 instrument at 400.13 and 100.2 MHz,
respectively, using DMSO-d6 as solvent and tetrameth-
Fig. 2. Conformations of molecules IIIa (ketone) and IIa
(ketone) simulated by HF/6-31G(d) calculations.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 8 2008

MASHEVSKAYA et al.
1192
Energies of formation (a.u.) of structures IIa and IIIa, cal-
culated ab initio using STO-3G and 6-31G(d) basis sets
Found, %: C 63.25; H 5.48; N 8.49. C26N27N3O7. Cal-
culated, %: C 63.28; H 5.52; N 8.51.
1′,4,4′-Trihydroxy-1-(2-hydroxy-4-methyl-
phenyl)-3-(4-methylbenzoyl)-4a′,5′,6′,7′,8′,8a′-hexa-
hydro-1′H-spiro[pyrrole-2,2′-quinoxaline]-
3′,5(1H,4′H)-dione (IIIc). A solution of 1.0 mmol of
N,N′-dihydroxycyclohexane-1,2-diamine in 30 ml of
anhydrous acetonitrile was added dropwise to a solu-
tion of 1.0 mmol of compound Ic in 30 ml of anhy-
drous acetonitrile. The precipitate was filtered off and
reprecipitated from 5 ml of dioxane with 1 ml of hex-
ane. Yield 67%, mp 112–113°C (decomp.). IR spec-
trum, ν, cm–1: 3410, 3100 br (OH), 1750 (C5=O), 1695
Compound no.
STO-3G
6-31G(d)
IIa (ketone)
–1589.22841
–1589.20091
–1589.19190
–1589.18807
–1608.84735
–1608.82142
IIIa (ketone, R)
IIIa (ketone, S)
IIIa (enol)
3′,4,5(4′H)-trione (IIa). A solution of 1.0 mmol of
N,N′-dihydroxycyclohexane-1,2-diamine in 30 ml of
anhydrous acetonitrile was added dropwise to a solu-
tion of 1.0 mmol of compound Ia in 30 ml of anhy-
drous acetonitrile. The mixture was heated for 2–3 min
at 60°C and cooled, and the precipitate was filtered off.
Yield 78%, mp 210–212°C (decomp., from acetone).
IR spectrum, ν, cm–1: 3410, 3320 br (OH); 1780
(OCO); 1760 (C5=O); 1740 (C4=O); 1690 (C3′=O).
1H NMR spectrum, δ, ppm: 1.65 m (8H, 5′-H, 6′-H,
7′-H, 8′-H), 3.65 m (1H, 8a′-H), 3.85 m (1H, 4a′-H),
3.10 d.d and 3.66 d.d (1H each, 3-H, AB system, J =
15.3 Hz), 7.27 m (9H, Harom), 8.83 s (1H, 2″-OH),
10.54 s (1H, 4′-OH). Found (after drying at 90–95°C
under reduced pressure), %: C 61.86; H 4.98; N 8.95.
C24H23N3O7. Calculated, %: C 61.93; H 4.97; N 9.03.
1
(C3′=O), 1680 (COC6H4Me-p). H NMR spectrum, δ,
ppm: 1.46 m (8H, 5′-H, 6′-H, 7′-H, 8′-H), 2.27 s (3H,
Me), 2.38 s (3H, Me), 3.56 m (2H, 8a′-H, 4a′-H),
7.30 m (7H, Harom), 8.09 s (1H, 4′-OH), 9.20 s (1H,
1′-OH), 10.30 s (1H, 2″-OH), 11.65 s (1H, 4-OH).
13C NMR spectrum, δC, ppm: 191.1 (3-CO), 164.9
(C3′), 159.5 (C5), 154.3 (C4), 151.7 (C2″), 143.3 (C4″),
131.3 (C4′′′), 130.25 (C3), 128.8–117.3 (Carom), 88.6
(Cspiro), 59.3 (C8a′), 54.2 (C4a′), 39.9 (C4′), 39.1 (C8′),
26.9 (C5′), 23.6 (C6′), 21.3 (C7′), 21.1 and 20.9 (Me).
Found, %: C 63.29; H 5.46; N 8.43. C26H27N3O7. Cal-
culated, %: C 63.28; H 5.52; N 8.51.
Compounds IIb and IIc were synthesized in a simi-
lar way.
X-Ray diffraction data for compound IIa. Mono-
clinic crystals, C24H23N3O7·(CH3)2CO; unit cell param-
eters: a = 13.706(3), b = 11.437(2), c = 17.046(3) Å;
β = 108.50(3), γ = 104.32(3)°; V = 2589.0(9) Å3;
M 523.53; dcalc = 1.343 g/cm3; Z = 2; space group
4′-Hydroxy-1-(2-hydroxyphenyl)-1′-(4-methyl-
benzoyloxy)-hexahydro-1′H-spiro[pyrrolidine-2,2′-
quinoxaline]-3′,4,5(4′H)-trione (IIb). Yield 80%,
mp 161–162°C (decomp., from acetone). IR spectrum,
ν, cm–1: 3360, 3100 br (OH); 1770 (OCO); 1740
P2(1)/n. Total of 5027 independent reflections (Rint
=
0.0688) were measured on a KM-4 Kuma Diffraction
automatic four-circle diffractometer (χ geometry,
monochromatized CuKα irradiation, ω/2Θ scanning,
2Θ ≤ 160.48°). No correction for absorption was intro-
duced (μ = 0.834 mm–1). The structure was solved by
the direct method using SIR92 program [11] with sub-
sequent calculation of electron density maps. Hydro-
gen atoms in the hydroxy groups were visualized
objectively by difference synthesis of electron density,
and positions of the other hydrogen atoms were set on
the basis of geometry considerations. The positions of
non-hydrogen atoms were refined by the least-squares
procedure in full-matrix anisotropic approximation
using SHELXL-97 software package [12]. The final
divergence factor was R1 = 0.0872 [19384 reflections
with I ≥ 2σ(I)]; goodness of fit 0.919.
1
(C5=O); 1730 (C4=O); 1650 (C3′=O). H NMR spec-
trum, δ, ppm: 1.64 m (8H, 5′-H, 6′-H, 7′-H, 8′-H), 2.38 s
(3H, Me), 3.09 d.d and 3.77 d.d (1H each, 3-H, AB
system, J = 15.3 Hz), 3.64 m (1H, 8a′-H), 3.85 m (1H,
4a′-H), 7.29 m (7H, Harom), 8.81 s (1H, 2″-OH), 10.52 s
(1H, 4′-OH). Found, %: C 62.59; H 5.21; N 8.71.
C25H25N3O7. Calculated, %: C 62.62; H 5.26; N 8.76.
4′-Hydroxy-1-(2-hydroxy-4-methylphenyl)-1′-(4-
methylbenzoyloxy)-hexahydro-1′H-spiro[pyrroli-
dine-2,2′-quinoxaline]-3′,4,5(4′H)-trione (IIc). Yield
79%, mp 199–200°C (decomp., from acetone). IR spec-
trum, ν, cm–1: 3360, 3250 (OH); 1780 (OCO); 1760
1
(C5=O); 1740 (C4=O); 1670 (C3′=O). H NMR spec-
trum, δ, ppm: 1.62 m (8H, 5′-H, 6′-H, 7′-H, 8′-H),
2.28 s (3H, Me), 2.49 s (3H, Me), 3.06 d.d and
3.75 d.d (1H each, 3-H, AB system, J = 15.3 Hz),
3.64 m (1H, 8a′-H), 3.84 m (1H, 4a′-H), 7.19 m (7H,
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 07-03-96036).
H
arom), 8.65 s (1H, 2″-OH), 10.51 s (1H, 4′-OH).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 8 2008

FIVE-MEMBERED 2,3-DIOXO HETEROCYCLES: LXII.
1193
and Gatilov, Yu.V., Izv. Ross. Akad. Nauk, Ser. Khim.,
1993, p. 896.
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