New method of synthesis of β,β′-spiropyrrolidinooxindoles

Full text of DOI:10.1134/S1070428009020296

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 2, pp. 306−308. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © A.A. Shvets, S.V. Kurbatov, 2009, published in Zhurnal Organicheskoi Khimii, 2010, Vol. 46, No. 2, pp. 309−310.
SHORT
COMMUNICATIONS
New Method of Synthesis of β,β'-Spiropyrrolidinooxindoles
A.A. Shvets and S. V. Kurbatov
Southern Federal University, Rostov-on-Don, 344090 Russia
e-mail: kurbatov@rsu.ru
Received August 1, 2009
DOI: 10.1134/S1070428009020296
Natural alkaloids containing spiroheterocyclic frag-
ment A (horsfiline, spirotryprostatin, pteropodin etc.)
exhibit a pronounced biological activity, in particular,
immunomodulating, antitumor, and antibacterial action
[1, 2].
[3]. Avisual criterion of the reaction completion was the
total decoloration of the reaction mixture.
Most probably compounds IVa–IVc formed as
racemic mixture of two enantiomers IVa–IVc and IV'a–
IV'c resulting from the addition of azomethine ylide from
above and from below of the plane of isatylidenes IIIa–
IIIc (Scheme 2).
N
O
'
β
β
The cycloaddition reaction proceeded absolutely
diastereoselectively as showed the absence in the NMR
spectra even minor signals of other possible
diastereomers. The bis-spiroheterocycles synthesized in
this way contain a labile hydrogen in the oxindole fragment
N
H
A
One of the promising approaches to the designing of
this β,β’-spiro joint structure is the reaction of [3+2]-di-
polar cycloaddition of azomethine ylides to 3-ylidene isatin
derivatives [2].
Scheme 1.
O
O
We developed a new method of the synthesis of
heterocycles with bis-spiro junction using as dipolaro-
philes condensation products of isatins Ia–Ic with the
methylene-active heterocycles IIa–IIc: rhodanine,
pseudothiohydantoin, and thiazolidine-2,4-dione. The
reaction proceeded at room temperature with nearly
quantitative yields. Isatin derivatives IIIa–IIIc formed
quickly as brightly colored crystals not requiring further
purification (Scheme 1).
R
R'
N
O +
S
N
H
X
IIa_IIc
Ia_Ic
R'
X
N
3'
2'
1'
4'
O
5'
MeOH, KOH
S
R
In all events formed exclusively E-stereoisomer with
the trans-location of the carbonyl groups, the signal of
the H4 proton of the isatylidene fragment suffered
a considerable downfield shift in the H NMR spectra
under the influence of the carbonyl group.
4
3
5
3a
7a
2
O
6
1
7
N
H
1
IIIa_IIIc
III, R = Cl, R' = H, X = S (a); R = OEt, R' = Ph, X = NPh (b);
R = Br, R' = H, X = O (c).
The azomethine ylide was generated in situ by the
standard method from paraformaldehyde and sarcosine
306

NEW METHOD OF SYNTHESIS OF β,β'-SPIROPYRROLIDINOOXINDOLES
307
Scheme 2.
R'
R'
N
R'
R
O
X
N
N
S
X
O
3''
2''
1''
4''
5''
O
N
O
X
_
N+
C6H5CH3
heating
S
S
5'
4'
3'
+
N
O
+
1'
R
R
2'
4
3
5
3a
7a
2
N
O
6
1
7
H
N
N
H
H
IIIa_IIIc
IV'a_IV'c
IVa_IVc
8.44 d (1H, H4, J 2.5 Hz), 11.00 br.s (1H, NH1). Found,
%: C 68.19; H 4.43; N 9.89. C25H19N3O3S. Calculated,
%: C 68.01; H 4.34; N 9.52.
and can be subjected to further functionalization by
alkylation, acylation, and aminomethylation.
The successful replacement of heterocycles at the
2-oxindolin-3-ylidene fragment makes it possible to state
that the described approach can be applied to sufficiently
numerous sterically overloaded systems analogous to
compounds IIIa–IIIc, and this opens wide opportunities
for the preparation of new bis-spirooxindole derivatives.
(5Z)-5-(5-Bromo-2-oxo-1,2-dihydro-3H-indol-3-
ylidene)-1,3-thiazolidin-2,4-dione (IIIc). Yield 93%,
1
mp 406°C (decomp.). H NMR spectrum, δ, ppm:
6.90 d (1H, H7, J 8.8 Hz), 7.55 d.d (1H, H6, J 8.8,
J 2.3 Hz), 8.92 d (1H, H4, J 2.3 Hz), 11.35 s (1H, NH1),
12.91 br.s (1H, NH3). Found, %: C 40.87; H 1.61; Br 24.61;
N 8.59. C11H5BrN2O3S. Calculated, %: C 40.64; H 1.55;
Br 24.58; N 8.62.
Dipolarophiles IIIa–IIIc. To a solution of equimolar
amounts (0.01 mol each) of isatin and an appropriate
methylene-active heterocycle in 30 ml of methanol was
added 0.001 ml of 40% aqueous KOH. After 20 min the
separated precipitate was filtered off and washed with
methanol.
1'-Methyl-2"-thioxo-5-chloro-4"H-dispiro-
[indole-3,3'-pyrrolidine-4',5'-[1,3]thiazolidine]-
1
2,4"(1H)-dione (IVa). Yield 10%, mp 328°C. H NMR
spectrum, δ, ppm: 2.72 s (3H, NCH3), 3.46 d (1H, H2',
J 10.2 Hz), 3.80 d (1H, H5', J 10.6 Hz), 3.89 d (1H, H2',
J 10.2 Hz), 4.18 d (1H, H5', J 10.6 Hz), 6.96 d (1H, H7,
J 8.3 Hz), 7.14–7.25 m (1H, H6), 7.74 s (1H, H4), 12.43
(1H, NH1). Found, %: C 47.73; H 3.51; Cl 9.68; N 11.84.
C14H12ClN3O2S2. Calculated, %: C 47.52; H 3.42;
Cl 10.02; N 11.88.
Bisspirooxindoles IVa–IVc. In 40 ml of toluene was
dispersed an appropriate dipolarophile, sarcosine, and
paraform aldehyde in the molar ratio 1:4:4. The reaction
mixture was boiled for 7 h. After 30–40 min the reaction
mixture started to loose color and completely decolorized
to the end of the process. The reaction mixture was
cooled, toluene was distilled off at a reduced pressure,
and the residue was recrystallized from methanol (IVa,
IVb) or butanol (IVc).
1'-Methyl-3"-phenyl-2"-(phenylimino)-5-ethoxy-
4"H-dispiro[indole-3,3'-pyrrolidine-4',5"-
[1,3]thiazolidine]-2,4"(1H)-dione (IVb). Yield 50%,
(3Z)-3-(4-Oxo-2-thioxo-1,3-thiazolidin-5-ylid-
ene)-5-chloro-1,3-dihydro-2H-indol-2-one (IIIa).
Yield 91%, mp 344°C (decomp.). 1H NMR spectrum, δ,
ppm: 6.89 s (1H, H7, J 7.9 Hz), 7.37 m (1H, H6), 8.71 C
(1H, H4), 11.30 s (1H, NH1), 14.02 br.s (1H, NH3). Found,
%: C 44.62; H 1.64; Cl 11.67; N 9.30. C11H5ClN2O2S2.
Calculated, %: C 44.52; H 1.70; Cl 11.95; N 9.44.
1
mp 166°C. H NMR spectrum, δ, ppm: 1.40 t (3H,
OCH2CH3, J 6.8 Hz), 3.38 d (1H, H2', J 10.4 Hz), 3.55–
3.72 m (2H, H2', H5'), 3.75–3.97 m (2H, OCH2CH3),
4.01 d (1H, H5', J 10.9 Hz), 6.65–8.82 m (2H), 6.83–
7.00 m (3H), 7.02–7.15 m (1Harom), 7.18–7.37 m (4Harom),
7.40–7.65 m (3Harom), 8.44 s (1H, NH1). Found, %:
C 67.53; H 5.31; N 11.12. C28H26N4O3S. Calculated, %:
C 67.45; H 5.26; N 11.24.
(3Z)-3-[(2Ε)-4-Oxo-3-phenyl-2-(phenylimino)-5-
ethoxy-1,3-thiazolidin-5-ylidene]-1,3-dihydro-2H-
1
5-Bromo-1'-methyl-2"H,4"H-dispiro[indole-3,3'-
pyrrolidine-4',5"-[1,3]thiazolidine]-2,2",4"(1H)-
indol-2-one (IIIb). Yield 90%, mp 314°C. H NMR
spectrum, δ, ppm: 1.28 t (3H, OCH2CH3, J 7.0 Hz),
3.93 q (2H, OCH2CH3, J 7.0 Hz), 6.82 d (1H, H7,
J 8.8 Hz), 6.90–7.00 m (3Harom, H6), 7.10–7.25 m
(1Harom), 7.30–7.45 m (2Harom), 7.45–7.7 m (5Harom),
1
trione (IVc). Yield 12%, mp 320°C. H NMR spectrum,
δ, ppm: 2.71 s (3H, NCH3), 3.44 d (1H, H2', J 10.1 Hz),
3.79 d (1H, H5', J 10.7 Hz), 3.86 d (1H, H2', J 10.1 Hz),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 2 2010

SHVETS, KURBATOV
308
4.21 d (1H, H5', J 10.7 Hz), 6.98 d (1H, H7, J 8.5 Hz),
7.41 d (1H, H6, J 8.5 Hz), 7.86 s (1H, H4), 12.47 s (1H,
NH1). Found, %: C 43.81; H 3.07; Br 20.65; N 11.15.
C14H12BrN3O3S. Calculated, %: C 43.99; H 3.16;
Br 20.90; N 10.99.
1H NMR spectra were registered on spectrometers
Bruker DPX-250 (250 MHz) and Varian Unity VXR-
300 (300 MHz) in DMSO-d6 and pyridine-d5 with respect
to TMS.
of the Russian Foundation for Basic Research (grant no.
09-03-00726-a) and project RNP 2.2.1.1/2348.
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p. 8748.
3. Nair V., Sheela K.C., and Rath N.P., Chem. Lett. 2000, vol. 29,
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The study was carried out under a financial support
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 2 2010