Synthesis of bis-spirofused thiapyrrolizidinooxindoles by 1,3-dipolar cycloaddition

Article abstract of DOI:10.1007/s11172-012-0227-y

The 1,3-dipolar cycloaddition of unstabilized azomethine ylide, which is generated in situ from isatin and thiaproline, to arylidene derivatives of rhodanine affords bis-spirofused thiapyrrolizidinooxindoles. The 1,3-dipolar addition reactions under consi

Full text of DOI:10.1007/s11172-012-0227-y

Russian Chemical Bulletin, International Edition, Vol. 61, No. 8, pp. 1659—1662, August, 2012
1659
Synthesis of bisꢀspirofused thiapyrrolizidinooxindoles
by 1,3ꢀdipolar cycloaddition
A. A. Shvets,a Yu. V. Nelyubina, K. A. Lyssenko, and S. V. Kurbatov
b
b
a
aDepartment of Chemistry, Southern Federal University,
7
ul. Zorge, 344090 RostovꢀonꢀDon, Russian Federation.
Fax: +7 (863) 297 5267. Eꢀmail: shvets@sfedu.ru
b
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
8 ul. Vavilova, 119991 Moscow, Russian Federation.
2
Fax: +7 (499) 135 5085. Eꢀmail: kostya@xray.ineos.ac.ru
The 1,3ꢀdipolar cycloaddition of unstabilized azomethine ylide, which is generated in situ
from isatin and thiaproline, to arylidene derivatives of rhodanine affords bisꢀspirofused thiaꢀ
pyrrolizidinooxindoles. The 1,3ꢀdipolar addition reactions under consideration are fully regioꢀ
and diastereoselective.
Key words: isatin, thiaproline, spiroheterocycles, spirothiapyrrolizidinooxindole, azomethine
ylides, 1,3ꢀdipolar cycloaddition.
1
It is known that ꢀamino acids (for example, thiaꢀ
proline 1) react with isatin 2 to form in situ unstable azoꢀ
methine ylides 3, and the latter readily undergo addition
to C=C dipolarophiles to give thiapyrrolizidinooxindoles 4.
In recent years, the literature has seen an explosion of
interest in compounds, which contain substructure 4 (see
for the following reasons. Firstly, arylidene rhodanines
6
7
8
exhibit antiviral, antileukemic, and antidiabetic propꢀ
erties. Secondly, these compounds additionally include
two diversification points, which allows one to change the
pharmacodynamic and pharmacokinetic activity of the
target compounds by varying the substituent at the nitroꢀ
gen atom and the arylidene moiety. Earlier, arylidene and
heteroarylidene derivatives of rhodanine have been synꢀ
thesized either by heating the corresponding aldehyde and
3
3—5
Ref. 2) and exhibit antidiabetic and antituberculosis
activity.
9
rhodanine in acetic acid under prolonged reflux or under
Scheme 1
1
0
microwave radiation. The method developed in the
present study is suitable for the preparation of rhodanine
derivatives 5, without additional purification, in high yields
at room temperature within a few minutes (Scheme 2).
The heating of a mixture of compounds 1, 2, and 5
under reflux in methanol for 3 h results in the in situ forꢀ
mation of azomethine ylide 3, which undergoes addition
to the asymmetric C=C bond of compounds 5 exclusively
via the path B to form vicinally fused bisꢀspirocycles 6a—c
(
Scheme 3).
This is evidenced by the characteristic spinꢀspin interꢀ
actions between the hydrogen atoms at the C(3´a) and
C(4´) atoms. The COSY spectra of 6a—c are also indicaꢀ
tive of the vicinal positions of the spiro units in molecules
6
a—c, because they show correlations between the signal
of the proton at the C(3´a) atom observed at  4.75 and the
signals of the hydrogen atoms at the C(4´) atom and the
protons of the methylene unit C(3´)H2.
We studied for the first time the 1,3ꢀdipolar cycloaddiꢀ
tion of azomethine ylide 3 to arylidene and heteroarylidene
rhodanines 5. We chose compounds 5 as dipolarophiles
The structure of compound 6a was established by Xꢀray
diffraction (Fig. 1). It should be noted that the carbonyl
groups of the 2ꢀoxindole and rhodanine moieties are in
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1642—1645, August, 2012.
066ꢀ5285/12/6108ꢀ1659 © 2012 Springer Science+Business Media, Inc.
1

1
660
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 8, August, 2012
Shvets et al.
Scheme 2
a transoid configuration. This is apparently due to the
intramolecular O(14)...S(1´) interaction accompanied by
the charge transfer from the lone pair of the oxygen atom
to the * orbital of the S(1´)—C(2´) bond (S...O, 3.060(2) Å;
C—S—O, 148.9(1)). The cycloaddition results in the forꢀ
mation of four chiral centers, thus indicating that formally
1
6 stereoisomers of compound 6 can be formed. However,
since the addition of azomethine ylide 3 takes place via
the equally probable attack from above or below of the
enantiotropic plane of dipolarophile 5 accompanied by
the formation of spiro units, only two stereoisomers (enanꢀ
tiomers) are produced, and they were isolated from the
reaction as a racemate. The absence of even trace amounts
Compound
R
R´
5
a
1
of other possible stereoisomers in the H NMR spectra
confirms the full diastereoselectivity of the cycloaddition.
According to the Xꢀray diffraction data, molecules 6a in
5
5
b
c
Bn
Bn
Ph
a
C(12´)
Scheme 3
C(11´)
C(13´)
N(10´)
C(8´)
O(16)
C(9´)
C(4´)
C(4)
N(3)
C(2)
C(6)
C(7)
O(11)
C(3´)
C(3´A)
C(5´)
S(15)
S(1)
C(6´)
N(7)
C(10)
C(9)
S(2´)
C(1´)
C(4)
C(8)
C(2)
O(14)
N(1) C(3A)
C(5)
C(6)
C(7A)
C(7)
b
S(2´A)
S(15)
N(10A)
N(1)
O(16A)
O(14a)
S(1)
6
a
R
R´
S(1A)
O(14)
O(16)
N(10)
N(1A)
S(15A)
S(2´)
b
c
Bn
Bn
Fig. 1. Molecular structure of compound 6a with thermal ellipꢀ
soids (p = 50%) (a) and the centrosymmetric dimer in the crystal
structure (b) (hydrogen atoms, except for H(1N), are not shown).
Ph

Synthesis of thiapyrrolizidinooxindoles
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 8, August, 2012
1661
1
the crystal structure are packed as a racemic mixture (space
C, 61.51; H, 3.87; N, 8.97. H NMR (CDCl3), : 5.32 (s, 2 H,
H(6)); 7.26—7.52 (m, 6 H, Ph, H(18)); 7.70 (s, 1 H, =CH); 7.75
group P2 /c) through the N(1)—H(1N)...N(10´) hydroꢀ
1
(
dd, 1 H, H(19), J = 8.1 Hz, J = 2.2 Hz); 8.63 (dd, 1 H, H(17),
J = 4.7 Hz, J = 1.6 Hz); 8.76 (d, 1 H, H(15), J = 2.2 Hz).
ꢀBenzylꢀ5ꢀbenzylideneꢀ2ꢀthioxoꢀ1,3ꢀthiazolidinꢀ4ꢀone (5c).
Yield 63%, m.p. 155 C (cf. lit. data : m.p. 157—159 C).
Found (%): C, 64.93; H, 4.80; N, 4.39. C H NOS . Calculatꢀ
gen bond (N...N, 2.825(2) Å; N—H—N, 165) and the
intermolecular O(14)...S(1´) interaction (S...O, 3.279(2)
Å; C—S—O, 132.7(1)), resulting in the formation of cenꢀ
trosymmetric dimers (see Fig. 1). The supramolecular asꢀ
sociates are linked to each other by a number of weak
contacts (C—H...S, C—H...O, C=S..., and C—H...) to
form a threeꢀdimensional framework.
3
1
2
.
.
17
13
2
1
ed (%): C, 65.57; H, 4.21; N, 4.50. H NMR (CDCl ), : 5.32
(s, 2 H, H(6)); 7.26 (m, 3 H, Bn); 7.42—7.58 (m, 7 H, Bn, Ph);
3
7.74 (s, 1 H, =CH).
Therefore, due to the full regioꢀ and diastereoselectiviꢀ
ty combined with the possibility of varying substituents
both in the oxindole core and the rhodanine moiety, these
methods can be used for the synthesis of wide series of
potent biologically active bisꢀspirofused heterocycles.
Synthesis of bisꢀspirothiapyrrolizidinooxindoles 6a—c (generꢀ
al procedure). A mixture of dipolarophile 5 (1 mmol), isatin 6
(1 mmol, 147 mg), and thiaproline 1 (1 mmol, 133 mg) was
suspended in methanol (30 mL). The reaction mixture was reꢀ
fluxed for 3 h. The course of the reaction was monitored by TLC
on Silufol 245 plates in AcOEt; the spots were visualized with
iodine vapor. The reaction mixture was cooled, methanol was
distilled off under reduced pressure, and the residue was recrysꢀ
tallized from methanol.
3ꢀ(2ꢀFurylmethyl)ꢀ4´Іꢀ(pyridinꢀ3ꢀyl)ꢀ2ꢀthioxoꢀ4´,3a´ꢀdiꢀ
hydroꢀ3´H,4Hꢀdispiro[indoleꢀ3,6´ꢀpyrrolo[1,2ꢀc][1,3]thiazoleꢀ
5´,5ꢀ[1,3]thiazolidine]ꢀ2,4(1H)ꢀdione (6a). Paleꢀyellow crysꢀ
Experimental
1
The H NMR spectra were recorded on a Bruker DPXꢀ250
instrument (250 MHz, 60 MHz) in CDCl and DMSOꢀd using
3
6
Me Si as the internal standard. Single crystals of compound 6a
4
were obtained by the crystallization from methanol.
tals. Yield 40%, m.p. 190 C (MeOH). Found (%): C, 57.83;
.
Xꢀray diffraction study. Crystals of 6a (C25H20N O S ,
H, 3.99; N, 10.65. C H N O S . Calculated (%): C, 57.67;
4
3
3
25 20
4
3 3
1
M = 520.63) are monoclinic, space group P2 /c at 120 K:
H, 3.87; N, 10.76. H NMR (CDCl ), : 2.88 (dd, 1 H, C(3´)H ,
1
3
2
a = 12.9604(8) Å, b = 17.8710(11) Å, c = 10.0603(7) Å,
J = 9.6 Hz, J = 7.0 Hz); 3.01 (dd, 1 H, C(3´)H , J = 9.6 Hz,
2
3

= 95.0370(10), V = 2321.1(3) Å , Z = 4 (Z´ = 1), d
=
J = 7.0 Hz); 3.63 (d, 1 H, C(1´)H , J = 6.0 Hz); 4.02 (d, 1 H,
calc
2
–
3
–1
=
1.490 g cm , (MoK) = 3.57 cm , F(000) = 1080. The
C(1´)H , J = 6.0 Hz); 4.21 (d, 1 H, H(4´), J = 9.6 Hz); 4.81—5.07
2
intensities of 14973 reflections were measured on a Bruker
(m, 3 H, H(3´a), NC(6)H Furyl); 6.10 (d, 1 H, H(8),
2
SMART 1000 CCD diffractometer ((MoK) = 0.71072 Å,
J = 3.5 Hz); 6.22 (dd, 1 H, H(9), J = 3.5 Hz, J = 2.8 Hz); 6.70
(d, 1 H, H(7), J = 7.9 Hz); 6.90 (dd, 1 H, H(1), J = 7.9 Hz,
J = 7.9 Hz); 7.18—7.24 (m, 1 H, H(10)); 7.23—7.29 (m, 1 H,
H(5)); 7.32 (dd, 1 H, H(12´), J = 7.9 Hz, J = 4.7 Hz); 7.39 (d, 1 H,
H(4), J = 7.9 Hz); 7.88 (d, 1 H, H(13´), J = 7.9 Hz); 7.96 (s, 1 H,
N(1)H); 8.43 (d, 1 H, H(9´), J = 1.2 Hz); 8.56 (dd, 1 H, H(11´),
J = 4.7, J = 1.2 Hz).
ꢀscanning technique, 2 < 58), and 6131 unique reflections
(
Rint = 0.0217) were used in the subsequent refinement. The
structure was solved by direct methods and refined by the fullꢀ
2
matrix leastꢀsquares method based on F with anisotropic and
isotropic displacement parameters. The hydrogen atoms were
positioned geometrically and refined isotropically using a riding
model. The final R factors for compound 6a were wR = 0.1187,
3ꢀBenzylꢀ(4´ꢀpyridinꢀ3ꢀyl)ꢀ2ꢀthioxoꢀ4´,3a´ꢀdihydroꢀ3´H,
4Hꢀdispiro[indoleꢀ3,6´ꢀpyrrolo[1,2ꢀc][1,3]thiazoleꢀ5´,5ꢀ[1,3]ꢀ
thiazolidine]ꢀ2,4(1H)ꢀdione (6b). Paleꢀyellow crystals. Yield
2
GOOF = 1.018 for all unique reflections (R = 0.0484 was calꢀ
1
culated based on F for 4611 observed reflections with I > 2(I)).
All calculations were carried out using the SHELXTL PLUS 5.0
program package.11
NꢀBenzylrhodanine12 and Nꢀfurfurylrhodanine9 were synꢀ
thesized according to known procedures.
45%, m.p. 195 C (MeOH). Found (%):C, 61.05; H, 4.26;
.
N, 10.43. C H N O S . Calculated (%): C, 61.11; H, 4.18;
2
7
22
4
2 3
1
N, 10.56. H NMR (CDCl ), : 2.91 (dd, 1 H, C(3´)H , J = 9.5 Hz,
3
2
J = 7.0 Hz); 3.04 (dd, 1 H, C(3´)H , J = 9.5 Hz, J = 7.0 Hz);
2
Synthesis of arylidene or heteroarylidene derivatives of rhodaꢀ
nine 5a—c (general procedure). A 40% KOH aqueous solution
3.66 (d, 1 H, C(1´)H , J = 6.0 Hz); 4.05 (d, 1 H, C(1´)H ,
J = 6.0 Hz); 4.24 (d, 1 H, H(4´), J = 9.2 Hz); 4.83—5.23 (m, 3 H,
2
2
(
0.1 mL) was added to a solution of equimolar amounts of the
corresponding aldehyde (1 mol) and Nꢀsubstituted rhodanine
1 mol) in methanol (30 mL). After 20 min, the precipitate that
formed was filtered off and washed with methanol.
ꢀ(Furanꢀ2ꢀylmethyl)ꢀ5ꢀ(pyridinꢀ3ꢀylmethylene)ꢀ2ꢀthioxoꢀ
H(3´a), NCH Ph); 6.75 (dd, 1 H, H(6), J = 7.6 Hz, J = 7.6 Hz);
2
6.84 (d, 1 H, H(7), J = 7.6 Hz); 7.00—7.12 (m, 2 H, H(4), H(5));
7.16—7.35 (m, 5 H, Ph); 7.40 (dd, 1 H, H(12´), J = 7.6 Hz,
J = 4.7 Hz); 7.90 (d, 1 H, H(13´), J = 7.9 Hz); 8.51 (s, 1 H, 1ꢀNH);
(
13
3
8.55—8.80 (m, 2 H, H(9´), H(11´)). C NMR (DMSOꢀd ),
6
1
,3ꢀthiazolidinꢀ4ꢀone (5a). Yellow crystals. Yield 82%, m.p..
: 38.1 (C (3´)), 47.0 (C(6)), 47.5 (C(4´)), 55.2 (C(3´a)), 69.9
(C(1´)), 75.6 (C(5´)), 76.1 (C(6´)), 110.5 (C(7)), 121.5 (C(3a)),
122.5 (C(5)), 123.7 (C(12´)), 127.1 (C(8), C(12), Bn), 127.4
(C(4)), 127.5 (C(10)), 128.4(C(9), C(11), Bn), 130.9 (C(6)),
131.7 (C(8´)), 134.1 (C(7)), 137.3 (C(13´)), 143.1 (C(7a)), 149.3
(C(9´)), 150.2 (C(11)), 175.8 (C(2)), 175.9(C(4)), 197.7
(C(2)).
3ꢀBenzylꢀ4´ꢀphenylꢀ2ꢀthioxoꢀ4´,3a´ꢀdihydroꢀ3´H,4Hꢀ
dispiro[indoleꢀ3,6´ꢀpyrrolo[1,2ꢀc][1,3]thiazoleꢀ5´,5ꢀ[1,3]thiꢀ
azolidine]ꢀ2,4(1H)ꢀdione (6c). Paleꢀyellow crystals. Yield 44%,
1
79 C. Found (%): C, 55.59; H, 3.45; N, 8.95. C H N O S .
14
10
2
2 2
1
Calculated (%): C, 55.61; H, 3.33; N, 9.26. H NMR (CDCl ),
3

: 5.32 (s, 2 H, H(6)): 6.31 (dd, 1 H, H(9), J = 3.2 Hz, J = 1.9 Hz);
.43 (d, 1 H, H(8), J = 3.2 Hz); 7.34 (dd, 1 H, H(10), J = 1.9 Hz,
J = 0.9 Hz); 7.43 (dd, 1 H, H(17), J = 8.1 Hz, J = 4.9 Hz); 7.72
s, 1 H, =CH); 7.76 (m, 1 H, H(18)); 8.63 (dd, 1 H, H(16),
J = 4.9 Hz, J = 1.5 Hz); 8.76 (d, 1 H, H(14), J = 2.1 Hz).
ꢀBenzylꢀ5ꢀ(pyridinꢀ3ꢀylmethylene)ꢀ2ꢀthioxoꢀ1,3ꢀthiazolꢀ
6
(
3
idinꢀ4ꢀone (5b). Yellow crystals. Yield 76%, m.p. 182 C. Found (%):
.
C, 61.38; H, 3.71; N, 9.17. C H N OS . Calculated (%):
m.p. 172 C (MeOH). Found (%): C, 63.55; H, 4.33; N, 7.91.
1
6
12
2
2
.

1
662
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 8, August, 2012
Shvets et al.
C H N O S . Calculated (%): C, 63.49; H, 4.38; N, 7.93.
3. K. Atul, M. R. Awatar, S. A. Kumar, S. A. Bahadur, T. A.
Kumar, Ind. Pat. Appl., 2011, 48, 20110114.
2
8
23
3
2 3
1
H NMR (CDCl ), : 2.84 (dd, 1 H, C(3´)H , J = 9.6 Hz,
3
2
J = 7.1 Hz); 3.02 (dd, 1 H, C(3´)H , J = 9.6 Hz, J = 7.1 Hz);
4. M. S. Uma, B. Kamaraj, P. Subbu, Y. Perumal, S. Dharmaꢀ
rajan, Bioorg. Med. Chem. Lett., 2010, 20, 7278.
2
3
.62 (d, 1 H, C(1´)H , J = 6.0 Hz); 3.97 (d, 1 H, C(1´)H ,
2
2
J = 6.0 Hz); 4.19 (d, 1 H, H(4´), J = 9.6 Hz); 4.85—5.09 (m, 3 H,
5. P. Pitchaimani, B. Kamaraj, P. Subbu, Y. Perumal, S. Dharꢀ
marajan, Eur. J. Med. Chem., 2010, 45, 5653.
6. R. Marco, B. Maurizio, F. Federico, M. Giovanni, B. Fausꢀ
to, P. Stefania, PCT Int. Appl., 2011, 187, 20110407.
7. S. Ravi, K. K. Chiruvella, K. Rajesh, V. Prabhu, S. C. Raghaꢀ
van, Eur. J. Med. Chem., 2010, 45, 2748.
8. R. Murugan, S. Anbazhagan, S. S. Narayanan, Eur. J. Med.
Chem., 2010, 45, 3518.
9. E. L. Tarasevichyus, Farmatsevtichnii Zhurnal (Kiev), 1966,
21, 11; Chem. Abstr., 1967, 66, 104946.
H(3´a), CH Ph); 6.65—6.85 (m, 2 H, H(7), H(6)); 6.95—7.40
2
1
2
13
(
(
(
m, 12 H, H(4), H(5), Ph , Ph ); 7.78 (s, 1 H, N(1)H). C NMR
DMSOꢀd ), : 38.8 (C (3´)), 47.0 (C(6)), 47.3 (C(4´)), 57.9
C(3´a)), 69.7 (C(1´)), 75.6 (C(5´)), 76.9 (C(6´)), 110.4 (C(7)),
6
1
21.9 (C(3a)), 122.4 (C(5)), 126.9 (C(8), C(12), Bn), 127.3
C(4)), 127.5 (C(10)), 128.2 (C(11)), 128.4 (C(9), C(11),
Bn), 128.9 (C(9´), C(13´), Ph), 129.6 (C(12´), C(10´), Ph), 130.9
C(6)), 134.1 (C(7), 135.5 (C(8´)), 143.1 (C(7a)), 175.7 (C(2)),
(
(
1
76.2 (C(4)), 198.4 (C(2)).
1
1
0. M. Radi, L. Botta, G. Casaluce, M. Bernardini, M. Botta,
J. Comb. Chem., 2010, 12, 200.
1. G. M. Sheldrick, SHELXTL v. 5.10, Structure Determination
Software Suit, Bruker AXS, Madison, Wisconsin (USA), 1998.
This study was financially supported by the Russian
Foundation for Basic Research (Project No. 09ꢀ03ꢀ00726ꢀa),
the Foundation for Facilitation of Development of Small
Businesses in the Field of Science and Technology (Project
No. 9653/10), and the Ministry of Education and Sciꢀ
ence of the Russian Federation (Project AVTsP RNP
VSh 3.6.11).
12. Yu. M. Pashkevich, Farmatsevtichnii Zhurnal (Kiev), 1961,
16, 10; Chem. Abstr., 1962, 56, 38460.
References
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. C. Najera, J. M. Sansano, Curr. Org. Chem., 2003, 7, 1105.
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Received August 18, 2011;
in revised form April 9, 2012