Ionic liquid-catalyzed and microwave-assisted syntheses of pyrrolizine-and indolizinedione derivatives

Article abstract of DOI:10.1134/S1070428012060073

3H-Pyrrolo[2,1-a]isoindole-2,5-diones and isoindolo[2,1-a]quinoline-5,11- diones were synthesized by intramolecular cyclization of N-[2-oxo-3-(triphenyl- λ⁵-phosphanylidene)propyl]-and N-[2-(triphenyl- λ⁵-phosphanylidene)acetyl]phthalimides, respectively, in the presence of ionic liquid ([bmim][BF₄], 10 mol %) as catalyst or under microwave irradiation.

Full text of DOI:10.1134/S1070428012060073

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2012, Vol. 48, No. 6, pp. 788–792. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © I.M. Sakhautdinov, I.R. Batyrshin, N.A. Sergeeva, F.Z. Galin, M.S. Yunusov, 2012, published in Zhurnal Organicheskoi Khimii,
2012, Vol. 48, No. 6, pp. 792–796.
Ionic Liquid-Catalyzed and Microwave-Assisted Syntheses
of Pyrrolizine- and Indolizinedione Derivatives
I. M. Sakhautdinova, I. R. Batyrshina, N. A. Sergeevab, F. Z. Galina, b, and M. S. Yunusova
a Institute of Organic Chemistry, Ufa Research Center, Russian Academy of Sciences,
pr. Oktyabrya 71, Ufa, 450054 Bashkortostan, Russia
e-mail: ims@anrb.ru
b Bashkir State University, Ufa, Bashkortostan, Russia
Received May 5, 2011
Abstract—3H-Pyrrolo[2,1-a]isoindole-2,5-diones and isoindolo[2,1-a]quinoline-5,11-diones were synthesized
by intramolecular cyclization of N-[2-oxo-3-(triphenyl-λ5-phosphanylidene)propyl]- and N-[2-(triphenyl-λ5-
phosphanylidene)acetyl]phthalimides, respectively, in the presence of ionic liquid ([bmim][BF4], 10 mol %) as
catalyst or under microwave irradiation.
DOI: 10.1134/S1070428012060073
Pyrrolizidine and indolizidine alkaloids constitute
a class of pharmacologically important compounds
[1–3] isolated from natural sources. Pyrrolizidine- and
indolizidinedione derivatives have found versatile
applications in medicine, primarily as CNS stimulators
and antidiabetic, antiviral, antimicrobial, and antitumor
drugs [4–7]. Recent studies have shown that natural
alkaloids of the pyrrolizidine and indolizidine series
(mappicine and mappicine ketone) exhibit high anti-
retroviral activity, so that they can be used as efficient
drugs in a new line of AIDS chemotherapy [8]. In-
creased interest in pyrrolizidine- and indolizidinedione
derivatives stimulates search for and development of
new simple, inexpensive, and general methods for their
preparation.
We previously showed [9–13] that keto-stabilized
sulfonium and phosphonium ylides derived from
N-substituted α- and β-amino acids undergo intra-
molecular cyclization. We synthesized compounds
having pyrrolizine and indolizine fragments from
phosphorus ylides I and II which were obtained by
acylation of simple alkylidenephosphoranes with
N-phthaloyl amino acids III and IV (transylidation),
which allowed us to considerably reduce the number of
Scheme 1.
O
O
O
O
O
PPh3
R
(1) SOCl2
(2) RCH=PPh3
OH
N
N
N
O
O
O
R
III
Ia–Ic
Va, Vb
O
O
O
(1) SOCl2
(2) RCH=PPh3
N
N
N
O
COOH
O
O
O
R
PPh3
R
IV
IIa–IIc
VIa, VIb
R = H (a), Me (b), MeOC(O) (c).
788

IONIC LIQUID-CATALYZED AND MICROWAVE-ASSISTED SYNTHESES
789
Intramolecular cyclization of phosphorus ylides Ia–Ic and IIa–IIc under different conditions (argon atmosphere)
Yield, %
Reaction conditions
Reaction time, h
Va
Vb
VIa
VIb
PhCO2H, PhMe
56
40
53
61
72
85
55
67
77
89
15
32
39
58
27
36
78
81
[bmim][BF4], PhMe
MW, 450 W, THF
MW, 750 W, PhMe
01
0.00.5
1
steps as compared to salt and carbene procedures used
previously. In the present work we examined specific
effects of a ionic liquid and microwave irradiation on
the rate of intramolecular cyclization of keto-stabilized
phosphorus ylides.
data [19]. The H NMR spectra of Va, Vb, VIa, and
Vb displayed symmetry violation for two multiplet
signals from four protons in the phthaloyl fragment in
the region δ 7.46–8.32 (Vb), 7.49–9.15 (VIa), and
7.07–9.18 ppm (VIb), a singlet from protons in the
methyl group was observed at δ 1.58 (Vb) and
2.55 ppm (VIb), and the 12-H proton in VIa resonated
as a singlet at δ 6.76 ppm. Signals from the double-
bonded carbon atom were located in the 13C NMR
spectra at δC 103.57 (Vb, C1), 106.58 (VIa, C12), and
104.25 ppm (VIb, C12), while methyl carbon atoms
gave signals at δC 12.43 (Vb) and 10.58 ppm (VIb).
Keto-stabilized phosphorus ylides Ia, Ib, IIa, and
IIb were synthesized from phthalimidoglycine (III)
and o-phthalimidobenzoic acid (IV) which were pre-
pared by fusion of phthalic anhydride with the corre-
sponding amino acids according to Reese [14]. Acids
III and IV were then treated with SOCl2 to obtain the
corresponding acid chlorides, and the latter (without
isolation) were brought into reaction with 2 equiv of
alkylidenephosphorane prepared by dehydrohalo-
genation of phosphonium salts with butyllithium
(Scheme 1). Heating of ylides Ia, Ib, IIa, and IIb in
toluene in the presence of benzoic acid as catalyst gave
cyclic products Va, Vb, VIa, and VIb having pyr-
rolizine- and indolizinedione fragments. Doubly
stabilized ylides Ic and IIc did not undergo intra-
molecular cyclization under the same conditions and
were recovered from the reaction mixtures.
Taking into account that the synthesized com-
pounds are promising as biologically active sub-
stances, they were subjected to computer-assisted
screening for biological activity using PASS program.
The results showed a probability of more than 70% for
immunomodulatory and anti-inflammatory activity of
the cyclic products.
To conclude, we have synthesized compounds with
pyrroloisoindoledione and isoindoloquinolinedione
structures from phosphorus ylides. The use of ionic
liquid ([bmim][BF4]) and microwave irradiation con-
siderably increases the yield in intramolecular cycliza-
tion and shortens the reaction time. Electron-acceptor
substituents on the ylide carbon atom hamper the
cyclization process.
With a view to improve the yield of intramolecular
cyclization products we carried out the reaction in
ionic liquid and under microwave irradiation [15–18].
Ionic liquids are widely used in organic synthesis. It is
known that the use of 1-butyl-3-methylimidazolium
tetrafluoroborate [bmim][BF4] considerably increases
the yield of the Wittig reaction [15]. In fact, the yields
of compounds Va, Vb, VIa, and VIb increased when
phosphorus ylides Ia, Ib, IIa, and IIb were heated in
toluene in the presence of [bmim][BF4] as catalyst.
Moreover, multimode microwave irradiation not only
considerably increased the yield of the cyclization
products but also appreciably shortened the reaction
time (see table). However, no heterocyclic products
were obtained from ylides Ic and IIc in the presence of
ionic liquid or under microwave irradiation.
EXPERIMENTAL
The IR spectra were recorded on a Specord M-80
instrument from thin films or mineral oil mulls. The 1H
and 13C NMR spectra were obtained on a Bruker AM-
300 spectrometer at 300.13 and 75.25 MHz, respec-
tively, using tetramethylsilane as internal reference.
The progress of reactions was monitored by thin-layer
chromatography on Sorbfil PTSKh-AF-A plates; spots
were detected under UV light, by treatment with iodine
vapor, or by spraying with a ninhydrin reagent or
a solution of 4-methoxybenzaldehyde with subse-
quent heating to 100–120°C. The mass spectra (atmos-
The structure of compounds Va, Vb, VIa, and Vb
was confirmed by spectral methods; the physicochem-
ical parameters of Va were consistent with published
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SAKHAUTDINOV et al.
790
pheric pressure chemical ionization) were obtained on
a Shimadzu LCMS-2010EV instrument. Microwave
assisted reactions were carried out in a modified SAM-
OM75S-(31) multimode microwave cavity (2.45×
109 Hz, 750 W) using a 50-ml quartz reactor equipped
with a mechanical stirrer and reflux condenser; the
stirrer drive and the condenser were placed out of the
irradiation zone.
to lower frequencies (~1550 cm–1) due to the presence
of neighboring carbanionic center. Compounds Ia–Ic
and IIc were isolated by extraction with chloroform
and were dried over calcined potassium carbonate.
2-[2-Oxo-3-(triphenyl-λ5-phosphanylidene)-
propyl]-1H-isoindole-1,3(2H)-dione (Ia). Yield
4.21 g (91%), red oily substance. IR spectrum ν, cm–1:
1717, 1623, 1579. 1H NMR spectrum (CDCl3), δ, ppm:
4.43 s (2H, CH2), 3.36 d (1H, CH), 7.31–7.96 m
(19H, Harom). Found, %: C 75.04; H 4.63; N 2.96;
P 6.59. C29H22NO3P. Calculated, %: C 75.15; H 4.78;
N 3.02; P 6.68.
Acetone, methylene chloride, and ethyl acetate
were distilled over P2O5. Toluene, tetrahydrofuran, and
petroleum ether were heated under reflux over metallic
sodium and then distilled. Thionyl chloride of analyt-
ical grade was used without additional purification.
1-Butyl-3-methyl-1H-imidazolium tetrafluoroborate
[bmim][BF4] was prepared in two steps starting from
1-methylimidazole (Acros, purity ≥ 99.2%). The
reaction of 1-methylimidazole with butyl chloride gave
59% of 1-butyl-3-methylimidazolium chloride, and the
latter was treated with KBF4 according to [20] to
obtain [bmim][BF4]. Commercial 2,5 M butyllithium
in hexane was used. Compounds Va, Vb, VIa, and
VIb were isolated by column chromatography on silica
gel (40–100, 100–160 μm). N-Phthaloylglycine (III)
and 2-phthalimidobenzoic acid (IV) were prepared as
described in [14].
2-[2-Oxo-3-(triphenyl-λ5-phosphanylidene)-
butyl]-1H-isoindole-1,3(2H)-dione (Ib) . Yield 4.48 g
(94%), red oily substance. IR spectrum, ν, cm–1: 1714,
1
1617, 1583. H NMR spectrum (CDCl3), δ, ppm:
1.93 s (3H, CH3), 4.79 s (2H, CH2), 7.37–8.10 m
(19H, Harom). Found, %: C 75.61; H 5.00; N 2.88;
P 6.25. C30H24NO3P. Calculated, %: C 75.46; H 5.07;
N 2.93; P 6.49.
2-{2-[1-Oxo-2-(triphenyl-λ5-phosphanylidene)-
ethyl]phenyl}-1H-isoindole-1,3(2H)-dione (IIa). IR
spectrum, ν, cm–1: 1721, 1613, 1569.
2-{2-[1-Oxo-2-(triphenyl-λ5-phosphanylidene)-
propyl]phenyl}-1H-isoindole-1,3(2H)-dione (IIb). IR
spectrum, ν, cm–1: 1725, 1629, 1567.
Phosphorus ylides Ia–Ic and IIa–IIc (general
procedure). Fused acid III or IV, 10 mmol, was
dispersed in 30 ml of anhydrous benzene, 50 mmol of
thionyl chloride was added, and the mixture was
heated under reflux until gaseous products no longer
evolved (~3 h). The mixture was evaporated, and the
residue (the corresponding acid chloride) was used
without additional purification. In the next step it was
necessary to use 2 equiv of alkylidenephosphorane to
ensure deprotonation of the initially formed phos-
phonium salt with the second ylide molecule. Methyl
(triphenyl)phosphonium iodide or ethyl(triphenyl)-
phosphonium bromide, 20 mmol, was dispersed in
tetrahydrofuran, 20 mmol of 2.5 M butyllithium in
hexane was added dropwise using a syringe under
stirring, the mixture was stirred for 1 h, a solution of
the corresponding acid chloride in tetrahydrofuran was
slowly added, and the mixture was stirred for 3 h. The
precipitate was filtered off, and the solvent was
distilled off. Ylides IIa and IIb were subjected to intra-
molecular cyclization without additional purification,
for they rapidly decomposed even at room tempera-
ture. We failed to obtain spectra of pure ylides IIa and
IIb, but their formation was confirmed by displace-
ment of the carbonyl absorption band in the IR spectra
Methyl 4-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-
yl)-3-oxo-2-(triphenyl-λ5-phosphanylidene)butano-
ate (Ic). Yield 4.95 g (95%), yellow oily substance. IR
1
spectrum, ν, cm–1: 1724, 1539, 1458. H NMR spec-
trum (CDCl3), δ, ppm: 3.32 s (3H, CH3), 5.11 s (2H,
13
CH2), 7.41–7.81 m (19H, Harom). C NMR spectrum
(CDCl3), δC, ppm: 46.29 (CH2), 49.64 (CH3), 69.55
(Cylide), 122.93 (CHarom), 124.86 (Carom), 128.38
(CHarom), 128.56 (CHarom), 131.77 (CHarom), 132.58
(Carom), 133.32 (CHarom), 168.11 (C=O), 168.37 (C=O),
187.98 (C=O). Found, %: C 71.23; H 4.76; N 2.89;
P 6.21. C30H24NO3P. Calculated, %: C 71.40; H 4.64;
N 2.69; P 5.94.
Methyl 3-[2-(1,3-dioxo-2,3-dihydro-1H-isoindol-
2-yl)phenyl]-3-oxo-2-(triphenyl-λ5-phosphanyli-
dene)propanoate (IIc). Yield 5.72 g (98%), yellow
oily substance. IR spectrum, ν, cm–1: 1714, 1533,
1485. 1H NMR spectrum (CDCl3), δ, ppm: 3.16 s (3H,
13
CH3), 7.26–7.96 m (19H, Harom). C NMR spectrum
(CDCl3), δC, ppm: 49.96 (CH3), 77.16 (Cylide), 115.39
(CHarom), 120.73 (Carom), 121.59 (Carom), 123.53
(CHarom), 123.92 (Carom), 125.21 (Carom), 126.44
(CHarom), 128.51 (CHarom), 128.92 (CHarom), 130.84
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IONIC LIQUID-CATALYZED AND MICROWAVE-ASSISTED SYNTHESES
791
(Carom), 131.95 (CHarom), 132.06 (CHarom), 133.27
(CHarom), 133.41 (CHarom), 134.35 (CHarom), 134.87
(Carom), 141.27 (Carom), 167.03 (C=O), 167.50 (C=O),
190.11 (C=O). Found, %: C 74.13; H 4.69; N 2.52;
P 5.27. C36H26NO5P. Calculated, %: C 74.09; H 4.49;
N 2.40; P 5.31.
(C=C), 198.31 (C=O). Mass spectrum, m/z: 200
[M + H]+, 199 [M]–. Found, %: C 72.53; H 4.63;
N 7.07. C12H9NO2. Calculated, %: C 72.35; H 4.55;
N 7.03. Calculated: M 199.2.
Isoindolo[2,1-a]quinoline-5,11-dione (VIa).
Eluent ethyl acetate–petroleum ether (1 :4). Yield
37 mg (15%) (a), 79 mg (32%) (b), 96 mg (39%) (c),
143 mg (58%) (d); yellow crystals, mp 198–200°C. IR
Intramolecular Wittig reaction (general proce-
dures). a. Phosphorus ylide I or II, 1 mmol, was dis-
persed in 30 ml of anhydrous toluene, a catalytic
amount (5 mol %) of benzoic acid was added, and the
mixture was heated for 56 h under reflux in an argon
atmosphere. The solvent was distilled off, and the
product was isolated by column chromatography on
silica gel.
1
spectrum, ν, cm–1: 1768, 1704, 1665. H NMR spec-
trum (CDCl3), δ, ppm: 6.76 s (1H, CH), 7.49–9.15 m
13
(4H, C6H4), 7.61–7.67 m (4H, C6H4). C NMR spec-
trum (CDCl3), δC, ppm: 106.85 (C=C), 117.71
(CHarom), 119.90 (CHarom), 121.87 (CHarom), 125.27
(CHarom), 129.12 (CHarom), 129.29 (CHarom), 132.64
(Carom), 132.76 (Carom), 132.91 (CHarom), 134.35
(CHarom), 140.08 (Carom), 141.05 (Carom), 145.93 (C=C),
166.01 (C=O), 179.96 (C=O). Mass spectrum, m/z:
248 [M + H]+, 247 [M]–. Found, %: C 77.79; H 3.54;
N 5.69. C16H9NO2. Calculated, %: C 77.72; H 3.67;
N 5.67. M 247.2.
b. Phosphorus ylide I or II, 1 mmol, was dispersed
in 30 ml of anhydrous toluene, a catalytic amount
(10 mol %) of [bmim][BF4] was added, and the mix-
ture was heated for 40 h under reflux in an argon
atmosphere. The solution was separated by decanting,
the solvent was distilled off, and the product was
isolated by column chromatography on silica gel.
6-Methylisoindolo[2,1-a]quinoline-5,11-dione
(VIb). Eluent ethyl acetate–petroleum ether (1:4).
Yield 70 mg (27%) (a), 94 mg (36%) (b), 204 mg
(78%) (c), 211 mg (81%) (d); yellow crystals, mp 215–
217°C. IR spectrum, ν, cm–1: 1715, 1634, 1603.
1H NMR spectrum (CDCl3), δ, ppm: 2.55 s (3H, CH3),
c. Phosphorus ylide I or II, 1 mmol, was dispersed
in 30 ml of anhydrous tetrahydrofuran, and the mixture
was subjected to microwave irradiation over a period
of 1 h. The solution was separated by decanting, the
solvent was distilled off, and the product was isolated
by column chromatography on silica gel.
13
7.07–9.18 m (8H, Harom). C NMR spectrum (CDCl3),
δC, ppm: 10.58 (CH3), 104.25 (C=C), 117.71 (CHarom),
123.89 (CHarom), 125.30 (CHarom), 125.46 (CHarom),
127.07 (CHarom), 129.53 (Carom), 129.74 (Carom), 131.14
(CHarom), 134.12 (CHarom), 134.38 (CHarom), 137.81
(Carom), 138.02 (Carom), 152.89 (C=C), 164.37 (C=O),
180.13 (C=O). Mass spectrum, m/z: 262 [M + H]+, 261
[M]–. Found, %: C 78.1; H 4.3; N 5.3. C17H11NO2. Cal-
culated, %: C 78.15; H 4.24; N 5.36. M 261.3.
d. Phosphorus ylide I or II, 1 mmol, was dispersed
in 30 ml of anhydrous toluene, and the mixture was
subjected to microwave irradiation over a period of
0.5 h. The solution was separated by decanting, the
solvent was distilled off, and the product was isolated
by column chromatography on silica gel.
3H-Pyrrolo[2,1-a]isoindole-2,5-dione (Va). Eluent
ethyl acetate–petroleum ether (1:3). Yield 98 mg
(53%) (a), 113 mg (61%) (b), 133 mg (72%) (c),
157 mg (85%) (d). The physicochemical parameters of
Va were consistent with published data [19].
This study was performed under financial support
by the President of the Russian Federation (Program
for Support of Leading Scientific Schools, project
no. NSh-3756.2010.3) and by the Federal Special-
Purpose Program “Scientific and Scientific–Pedagog-
ical Staff of Innovation Russia 2009-2013” (state
contract no. 14.740.11.0367).
1-Methyl-3H-pyrrolo[2,1-a]isoindole-2,5-dione
(Vb). Eluent ethyl acetate–petroleum ether (1:3). Yield
109 mg (55%) (a), 133 mg (67%) (b), 153 mg (77%)
(c), 177 mg (89%) (d); yellow crystals, mp 185–
187°C. IR spectrum, ν, cm–1: 1720, 1697, 1572.
1H NMR spectrum (CDCl3), δC, ppm: 1.58 s (3H,
CH3), 7.46–8.32 m (4H, C6H4), 4.43–4.55 d.d (2H,
CH2). 13C NMR spectrum (CDCl3), δC, ppm: 12.43
(CH3), 40.16 (CH2), 103.57 (C=C), 116.75 (CHarom),
123.35 (CHarom), 128.35 (Carom), 130.22 (CHarom),
131.88 (CHarom), 133.98 (Carom), 159.63 (C=O), 165.13
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