Synthesis of 1,3-thiazole and 1,2,4-oxadiazole substituted spiro[3H-indole-3,2′-thiazolidine]-2,4′(1H)-diones

Article abstract of DOI:10.1002/jhet.5570450335

(Chemical Equation Presented) Some new derivatives of spiro[3H-indole-3, 2′-thiazolidine]-2,4′(1H)-dione with the heterocyclic ring such as substituted thiazole and 1,2,4-oxadiazole attached to the indolinone ring via CH₂ linkage has been synth

Full text of DOI:10.1002/jhet.5570450335

May-Jun 2008
865
Synthesis of 1,3-thiazole and 1,2,4-oxadiazole substituted spiro[3H-
indole-3,2'-thiazolidine]-2,4'(1H)-diones
Uday C. Mashelkar,* Deepak M. Rane and Rajesh S. Kenny
Organic Research Laboratory, Patkar-Varde College of Science, Goregaon (W), Mumbai 400062, India.
Email:- ucmashelkar@yahoo.com
Received November 20, 2006
O
S
N
O
O
S
S
N
O
N
N
R
S
N
O
N
O
N
R
N
R
N
O
R'
N
R'
N
O
R'
Va-j
XIIa-g
VIIIa-j
Some new derivatives of spiro[3H-indole-3,2'-thiazolidine]-2,4'(1H)-dione with the heterocyclic ring
such as substituted thiazole and 1,2,4-oxadiazole attached to the indolinone ring via CH2 linkage has been
synthesized in moderate yields. The synthesis have been carried out by making use of the reactivity of the
NH group of the indolinone moiety present in spiro[3H-indole-3,2'-thiazolidine]-2,4'(1H)-dione.
J. Heterocyclic Chem., 45, 865 (2008).
INTRODUCTION
aryl-spiro[3H-indole-3,2'-thiazolidine]-2,4'(1H)-dione-1-
ylacetonitriles IIa-b.
The chemistry of spiro[3H-indole-3,2'-thiazolidine]-
2,4'(1H)-dione in which an indolinone ring is joined to
sulfur and nitrogen containing thiazolidinone ring at the
C-3 position through a spiro carbon atom is of great
interest due to their antileukemic and anticonvulsant [1-3]
and also for biological activities [4-5]. Even the spiro[3H-
O
O
S
S
Cl
NaH, DMF
N
N
N
N
O
N
N
H
O
R
R
indole-3,2'-thiazolidine]-2,4'(1H)-diones
have
been
reported, where the phenyl ring attached to the thiazoli-
dinone ring is replaced by other heterocycles such as
coumarin [6] and 2,3-dimethyl-5-oxo-1-phenyl-3-
pyrazolin-4-yl [7] group. Some reports where the NH
group of indolinone in spiro[3H-indole-3,2'-thiazolidine]-
2,4'(1H)-diones is subjected to Mannich reaction and
acetylation is cited [8-9]. We in our earlier work have
described the synthesis of spiro[3H-indole-3,2'-thiazol-
idine]-2,4'(1H)diones substituted with phenyl-1,3,4-
oxadiazoles at the indolinone ring [10]. Owing to the
paucity of work reported and by making use of the
reactivity of NH the group, we have synthesized various
thiazole and 1,2,4-oxadiazole substituted spiro[3H-indole-
Ia,b: - R = H, OMe
IIa,b: - R = H, OMe
S
HCl
DMF
NH2
Br
O
R'
O
S
S
O
N
IVa-e
N
N
O
AcOH / H2O
N
O
NH2
R
R
S
N
S
IIIa,b: - R = H, OMe
Va: - R = R' = H
3,2'-thiazolidine]-2,4'(1H)-diones.
The
synthesized
Vb: - R = H, R' = Me
Vc: - R = H, R' = OMe
Vd: - R = H, R' = Br
Ve: - R = H, R' = Cl
Vf: - R = OMe, R' = H
compounds may be expected to possess biological
activity.
The title compounds 5-phenylthiazolyl methyl-3'-aryl-
R'
Vg: - R = OMe, R' = Me
Vh: - R = OMe, R' = OMe
Vi: - R = OMe, R' = Br
Vj: - R = OMe, R' = Cl
spiro[3H-indole-3,2'-thiazolidine]-2,4'(1H)diones
Va-j
were synthesized as per the method depicted in Scheme 1.
3'-Aryl-spiro[3H-indole-3,2'-thiazolidine]-2,4'(1H)diones
Ia-b were reacted with chloroacetonitrile in the presence
of sodium hydride under nitrogen atmosphere to give 3'-
Scheme 1. Synthesis of 5-phenylthiazolyl methyl-3'-aryl-spiro[3H-
indole-3,2'-thiazolidine]-2,4'(1H)diones Va-j.

866
U. C. Mashelkar, D. M. Rane and R. S. Kenny
Vol 45
These acetonitrile derivatives IIa-b underwent
aminehydrochloride in the presence of sodium carbonate
rearrangement when treated with thioacetamide and dry
hydrogen chloride gas to give 3'-aryl-spiro[3H-indole-
3,2'-thiazolidine]-2,4'(1H)dione-1-yl-thioacetamides IIIa-
b. The synthetic methodology used for the conversion of a
nitrile into thioacetamides using above methodology is
reported in the literature [11]. The thioacetamides IIIa-b
on refluxing with α-bromoacetophenones IVa-e in acetic
acid and water mixture to give 5-phenylthiazolyl methyl-
3'-aryl-spiro[3H-indole-3,2'-thiazolidine]-2,4'(1H)diones
Va-j in 43-76 percent yields.
In the 1H nmr spectra of acetonitriles IIa-b, thio-
acetamides IIIa-b and 3'-aryl-[2-(5-phenylthiazole)-
methyl]spiro[3H-indole-3,2'-thiazolidine]-2,4'(1H)diones
Va-j the SCH2 group showed AB splitting between δ 3.9
to δ 4.3 except for the compound IIIb which showed AX
splitting. The NCH2 group which appeared as a singlet
between δ 4.8 to δ 5.0 in acetonitriles IIa-b showed AB
splitting for thioacetamides IIIa-b and 3'-aryl-[2-(5-
phenylthiazole)methyl]spiro[3H-indole-3,2'-thiazolidine]-
2,4'(1H)diones Va-j between δ 4.2 to δ 5.5, except for the
compound IIIb which showed AX splitting. The AB or
AX splitting of NCH2 and SCH2 group was due to
geminal coupling.
as base give N-hydroxy-3'-aryl-spiro[3H-indole-3,2'-
thiazolidine]-2,4'(1H)dione-1-yl-acetamidines
VIa-b.
Heating acetamidines VIa-b with various aliphatic and
aromatic acid chlorides VIIa-e in the absence of any
solvent at 100 °C resulted in the formation of 5-aryl/alkyl-
[1,2,4]oxadiazolyl
methyl-3'-aryl-spiro[3H-indole-3,2'-
1
thiazolidine]-2,4'(1H)dione VIIIa-j. The H nmr spectra
of the N-hydroxy acetamidines VIa,b and 5-aryl/alkyl-
[1,2,4]oxadiazolyl
methyl-3'-aryl-spiro[3H-indole-3,2'-
thiazolidine]-2,4'(1H)diones VIIIa-j showed AB splitting
between δ 3.9 to δ 5.5 for SCH2 and NCH2 group due to
geminal coupling.
O
O
O
S
S
Cl
N
N
aq. NaOH
OEt
Ia,b
N
O
N
O
NaH, DMF
OH
OEt
R
R = H, OMe
R
O
O
Xa,b:- R = H, OMe
IXa,b:- R = H, OMe
O
S
1) SOCl2
N
NH2
OH
N
O
2)
XIIa:- R = H, R' = H
XIIb:- R = H, R' = 3-Me
XIIc:- R = H, R' = 4-Cl
XIId:- R = OMe, R' = H
XIIe:- R = OMe, R' = 3-Me
XIIf:- R = OMe, R' = 4-Cl
XIIg:- R = OMe, R' = 4-Ph
R'
N
R
N
O
XIa-d
R'
Cl
O
O
N
S
R'
N
VIIa-e
NH2OH.HCl
NH2OH.HCl
N
O
IIa,b
Scheme 3. Synthesis of 3-phenyl-1,2,4-oxadiazolyl methyl-3'-aryl-
spiro[3H-indole-3,2'-thiazolidine]-2,4'(1H)diones XIIa-g.
NH2
R
N
OH
In our third attempt we became interested in the synthesis
of spiro[3H-indole-3,2'-thiazolidine]-2,4'(1H)diones with 3-
phenyl-1,2,4-oxadiazol-5-yl methyl moiety. The schematic
representation for the synthesis of 3-phenyl-1,2,4-oxa-
diazolyl methyl-3'-aryl-spiro[3H-indole-3,2'-thiazolidine]-
2,4'(1H)diones XIIa-g is depicted in Scheme 3. The
starting material ethyl-3'-aryl-spiro[3H-indole-3,2'-thiazol-
idine]-2,4'(1H)-dione-1-yl-acetates IXa-b required for the
synthesis were synthesized as per the method reported by
us [12]. The ester derivatives were hydrolyzed using 2% aq.
sodium hydroxide solution to give the corresponding 3'-
aryl-spiro[3H-indole-3,2'-thiazolidine]-2,4'(1H)-dione-1-yl-
acetic acids Xa-b. The compounds Xa-b were then
converted into acid chlorides using thionyl chloride and
reacted in situ with N-hydroxy phenylamidines XIa-d in
acetic acid at reflux temperature to give the desired
VIa,b: -R = H, OMe
O
S
N
VIIIa: - R = H, R' = CH2Cl
VIIIb: - R = H, R' = CHCl2
VIIIc: - R = H, R' = Ph
N
O
VIIId: - R = H, R' = 4-ClPh
VIIIe: - R = H, R' = 4-O2NPh
VIIIf: - R = OMe, R' = CH2Cl
VIIIg: - R = OMe, R' = CHCl2
VIIIh: - R = OMe, R' = Ph
VIIIi: - R = OMe, R' = 4-ClPh
VIIIj: - R = OMe, R' = 4-O2NPh
R
N
N
R'
O
Scheme 2. Synthesis of 3-Aryl/alkyl[1,2,4]oxadiazolyl methyl-3'-aryl-
spiro[3H-indole-3,2'-thiazolidine]-2,4'(1H)diones VIIIa-j.
After successfully synthesizing various 5-phenyl-
thiazole substituted spiro[3H-indole-3,2'-thiazol-idine]-
2,4'(1H)dione Va-j, we utilized the spiroaceto-nitrile
derivatives IIa-b for the synthesis of 5-aryl/alkyl-
1
molecules XIIa-g. Even the H nmr spectra of 3-phenyl-
1,2,4-oxadiazolyl methyl-3'-aryl-spiro[3H-indole-3,2'-thia-
zolidine]-2,4'(1H)diones XIIa-g showed AB splitting
between δ 3.9 to δ 5.5 for SCH2 and NCH2 group as
observed in earlier cases, except for the compound XIIa-b
which showed AX splitting.
[1,2,4]oxadiazolyl
methyl-3'-aryl-spiro[3H-indole-3,2'-
thiazolidine]-2,4'(1H)dione VIIIa-j as exemplified in
Scheme 2. Compounds IIa-b on refluxing with hydroxyl

May-Jun 2008
Synthesis of 1,3-thiazole and 1,2,4-oxadiazole substituted
867
spiro[3H-indole-3,2'-thiazolidine]-2,4'(1H)-diones
J = 8.5 Hz, 2H), 7.03 (t, J = 7.1 Hz, 1H), 7.24 (t, J = 7.2 Hz,
1H), 7.53 (d, J = 7.2 Hz, 1H), 9.39 (s, Br, 1H, CSNH2), 9.72 (s,
Br, 1H, CSNH2). Microanalysis calculated for C18H15N3O2S2
(%): C, 58.52; H, 4.09; N, 11.37; S, 17.36. Found (%): C, 58.49;
H, 3.95; N, 11.51; S, 17.19.
EXPERIMENTAL
3'-Aryl-spiro[3H-indole-3,2'-thiazolidine]-2,4'(1H)
diones
Ia-b required for the synthesis were prepared as per the method
reported in the literature [8-9]. The α-bromoacetophenones
IVa-e and various aliphatic as well as aromatic acid chlorides
VIIa-e were purchased from Aldrich or Lanchester chemical
companies. The N-hydroxy phenylamidines XIa-c were
synthesized as per the reported method [13-14]. Melting points
are uncorrected. Ir spectra (νmax in cm-1) were recorded in KBr
on a Shimadzu 8201 PC FTIR spectrophotometer. 1H nmr
spectra were recorded on Varian AX400 spectrophotometer at
400MHz using DMSO-d6 or CDCl3 as a solvent (chemical shifts
in δ ppm).
3'-Phenyl-spiro[3H-indole-3,2'-thiazolidine]-2,4'(1H)-dione-
1-yl acetonitriles IIa. Sodium hydride (50% in mineral oil) (4.8
g, 0.11mole) was added to suspension of 3'-phenyl-spiro[3H-
indole-3,2'-thiazolidine]-2,4'(1H)-dione 1a (29.6 g, 0.10 mole)
taken in 250 mL dry DMF at 0–5 °C under an inert atmosphere
3'-(4-Methoxyphenyl)-spiro[3H-indole-3,2'-thiazolidine]-
2,4'(1H)dione-1-yl-thioacetamide IIIb. Similarly was
synthesized IIIb from IIb (15.0 g, 0.041 mole) in 75% yield,
mp.183-85°C. Ir (KBr): 3413, 3294, 1720, 1691, 1610, 1510,
1
1361, 1249, 1031,937, 783 and 752 cm.-1; H nmr (CHCl3) δ =
3.71 (s, 3H), 3.91 (AX splitting, 1H, SCH2), 4.30 (AX splitting,
1H, SCH2), 4.52 (AX splitting, 1H, NCH2), 4.79 (AX splitting,
1H, NCH2), 6.41 (s, Br, 1H, CSNH2), 6.74 (d, J = 9.0 Hz, 2H),
7.82 (d, J = 7.5 Hz, 1H), 6.92 (d, J = 9.0 Hz, 2H), 7.07 (s, Br,
1H, CSNH2), 7.21 (t, J = 7.2 Hz, 1H), 7.33 (t, J = 7.2 Hz, 1H),
7.61 (d, J = 7.5 Hz, 1H). Microanalysis calculated for
C19H17N3O3S2 (%) C, 57.13; H, 4.29; N, 10.52; S, 16.05. Found:
C, 57.28; H, 4.18; N, 10.67; S, 15.93.
Procedure A: General procedure for the synthesis of
(un)substituted 5-phenylthiazolemethyl-3'-aryl-spiro[3H-
indole-3,2'-thiazolidine]-2,4'(1H)diones Va-j.
of nitrogen. After the mixture was stirred for
1 h,
chloroacetonitrile (8.25 g, 0.11mole) was added drop wise at
such a rate that the temperature of the reaction is maintained
below 10 °C. The reaction was stirred at 5–10 °C for 30 min and
at room temperature for 2.5 h. The reaction mixture was poured
into ice water. The solid obtained was collected by filtration,
washed with water and dried. It was further recrystallized from
methanol. Yield: 25.0g (75%), mp 206 - 08 °C. Ir (KBr): 2925,
2382, 1732, 1691, 1608, 1475, 1353, 1253, 1105, 902, 833 and
5-Phenylthiazolyl methyl-3'-phenyl-spiro[3H-indole-3,2'-
thiazolidine]-2,4'(1H)dione Va. The synthesis of Va is
representative. A mixture of IIIa (1.11 g, 0.003 moles) and α-
bromoacetophenone IVa (0.6 g, 0.003 moles) was taken in 25
mL acetic acid/water (3:1) and heated to reflux for 45 min. The
reaction mixture was cooled in ice-water at 5–10 °C. The
precipitated solid was collected by filtration, washed with
aqueous solution of Na2CO3 followed by water and dried. The
crude product on crystallization from ethanol afforded 0.92 g
(66% yield) of Va, mp. = 238-40 °C. Ir (KBr): 3058, 1730,
1697, 1610, 1510, 1492, 1350, 1249, 1029, 831 and 752 cm-1, 1H
nmr (DMSO-d6) δ = 4.14 (center of AB quartet, 2H, SCH2),
5.30 (center of AB quartet, 2H, NCH2), 6.95-7.90 (m, 4H), 7.14-
7.22 (m, 3H), 7.25-7.35 (m, 2H), 7.42 (t, J = 7.8 Hz, 2H), 7.60
(d, J = 7.3 Hz, 1H), 7.89 (d, J = 7.3 Hz, 2H), 8.03 (s, 1H, Th H),
ms: m/z 470(M+1). Microanalysis calculated for C26H19N3O2S2
(%): C, 66.50; H, 4.08; N, 8.95; S, 13.66. Found (%): C, 66.36;
H, 4.17; N, 8.80; S, 13.82.
5-(4-methylphenyl)thiazolyl methyl-3'-phenyl-spiro[3H-
indole-3,2'-thiazolidine]-2,4'(1H)dione Vb. Following general
procedure A was synthesized Vb from IIIa (1.1 g, 0.003 mole)
and α-bromo-4-methylacetophenone IVb (0.64 g, 0.003 moles)
by heating in acetic acid/water mixture. The crude product on
crystallization from ethanol afforded 0.92 g (64% yield) of Vb
as colourless crystals, mp = 210-12 °C. Ir (KBr): 3066, 1733,
1692, 1615, 1513, 1473, 1345, 1233, 1052, 830 and 732 cm-1, 1H
nmr (DMSO-d6) δ = 2.31 (s, 3H, CH3), 4.14 (center of AB
quartet, 2H, SCH2), 5.29 (center of AB quartet, 2H, NCH2),
6.98-7.10 (m, 4H), 7.15-7.30 (m, 6H), 7.60 (d, J = 7.4 Hz, 1H),
7.78 (d, J = 8.2 Hz, 2H), 7.94 (s, 1H, Th H). Microanalysis
calculated for C27H21N3O2S2 (%) C, 67.06; H, 4.38; N, 8.69; S,
13.26. Found: C, 67.23; H, 4.19; N, 8.55; S, 13.03.
765 cm-1; H nmr (CDCl3): δ = 4.09 (center of AB quartet, 2H,
1
SCH2), 4.89 (s, 2H, NCH2), 6.85-7.08 (m, 3H), 7.14-7.32 (m,
4H), 7.39 (t, J = 6.2 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H);
Microanalysis calculated for C18H13N3O2S (%): C, 64.46; H,
3.91; N, 12.53; S, 9.56. Found: C, 64.31; H, 4.11; N, 12.76; S,
9.43.
3'-(4-Methoxyphenyl)-spiro[3H-indole-3,2'-thiazolidine]-
2,4'(1H)-dione-1-yl acetonitriles IIb. Similarly was
synthesized IIb from 3'-(4-methoxyphenyl)-spiro[3H-indole-
3,2'-thiazolidine]-2,4'(1H)-dione Ib (32.6g, 0.1mole) and
chloroacetonitrile (8.25 g, 0.11mole) in 78 % yield using sodium
hydride as base,mp 238-40°C. Ir (KBr): 2947, 2382, 1731, 1693,
1610, 1510, 1467,1363, 1249, 1180, 1031, 937, 900, 835 and
752 cm-1; H nmr (DMSO-d6): δ = 3.64 (s, 3H), 4.10 (center of
1
AB quartet, 2H, SCH2), 4.97 (s, 2H, NCH2), 6.78 (d, J = 8.9 Hz,
2H), 6.88 (d, J = 8.9 Hz, 2H), 7.14-7.20 (m, 2H), 7.39 (t, J = 6.2
Hz & J = 6.2 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H); Microanalysis
calculated for C19H15N3O3S (%) C, 62.45; H, 4.14; N, 11.50; S,
8.77. Found (%): C, 62.21; H, 4.41; N, 11.23; S, 8.93.
3'-Phenyl-spiro[3H-indole-3,2'-thiazolidine]-2,4'(1H)dione-
1-yl-thioacetamide IIIa. A flask containing a mixture of IIa
(15.0 g, 0.044 moles) and thioacetamide (9.9 g, 0.13 moles)
dissolved in 75 mL of DMF was immersed in an ice bath and
cooled to 0-5 °C. Freshly generated dry hydrogen chloride gas
was bubbled into it for 1.5 h maintaining the reaction mixture at
0-5 °C. The cold solution was poured into ice-water mixture and
the solid product was collected by filtration. It was further
washed with 200 mL of ice-cold water and dried in air. Crude
product was crystallized from methanol and afforded 16.2 g
(85% yield) of IIIa as colourless crystals, mp. 212-14 °C. Ir
(KBr): 3554, 3292, 3195, 1720, 1670, 1612, 1490, 1363, 1263,
5-(4'-Methoxyphenyl)thiazolyl methyl-3'-phenyl-spiro[3H-
indole-3,2'-thiazolidine]-2,4'(1H)dione Vc. Following general
procedure A was synthesized Vc from IIIa (1.1 g, 0.003 mole)
and α-bromo-4-methoxyacetophenone IVc (0.69 g, 0.003
moles) by heating in acetic acid/water mixture. The crude
product on crystallization from ethanol afforded 0.93 g (64%
yield) of Vc as colourless crystals, mp = 193-95 °C. Ir (KBr);
3059, 1722, 1697, 1509, 1345, 1278, 1027, 973, 832, 747 cm-1.
1
1178, 910, 817 and 756 cm-1; H nmr (DMSO d6) δ = 4.14
(center of AB quartet, 2H, SCH2), 4.45 (center of AB quartet,
2H, NCH2), 6.73-6.81 (m, 3H), 6.88 (d, J = 7.2 Hz, 1H), 6.95 (d,

868
U. C. Mashelkar, D. M. Rane and R. S. Kenny
Vol 45
1H nmr (DMSO-d6) δ = 3.8 (s, 3H, OCH3), 4.11 (center of AB
quartet, 2H, SCH2), 5.30 (center of AB quartet, 2H, NCH2),
6.96-7.10 (m, 6H), 7.15-7.20 (m, 3H), 7.28 (t, J = 7.1 Hz, 1H),
7.59 (d, J = 7.5 Hz, 1H), 7.82 (d, J = 8.2 Hz, 2H), 7.86 (s, 1H,
Th H). Microanalysis calculated for C27H21N3O3S2 (%) C, 64.91;
H, 4.24; N, 8.41; S, 12.84. Found: C, 64.72; H, 4.15; N, 8.63; S,
12.61.
7.13 (m, 2H), 7.22 (d, J = 7.9 Hz, 2H), 7.30 (t, J = 7.5 Hz, 1H),
7.63 (d, J = 7.6 Hz, 1H), 7.78 (d, J = 8.2 Hz, 2H), 7.94 (s, 1H,
Th H). Microanalysis calculated for C28H23N3O3S2 (%): C,
65.48; H, 4.51; N, 8.18; S, 12.48. Found (%): C, 65.43; H, 4.24;
N, 8.40;S, 12.25.
5-(4-methoxyphenyl)thiazolyl methyl-3'-(4-methoxyphen-yl)-
spiro[3H-indole-3,2'-thiazolidine]-2,4'(1H)dione Vh. Following
general procedure A was synthesized Vh from IIIb (1.2 g,
0.003mole) and α-bromo-4-methoxyacetophenone IVc (0.69 g,
0.003 moles) by heating in acetic acid/water mixture. The crude
product on crystallization from ethanol afforded 1.2 g (76%
yield) of Vh as colourless crystals, mp = 178-80 °C. Ir (KBr):-
5-(4'-Bromophenyl)thiazolyl methyl-3'-phenyl-spiro[3H-
indole-3,2'-thiazolidine]-2,4'(1H)dione Vd. Following general
procedure A was synthesized Vd from IIIa (1.1 g, 0.003 mole)
and α-bromo-4-bromoacetophenone IVd (0.83 g, 0.003 moles)
by heating in acetic acid/water mixture. The crude product on
crystallization from ethanol afforded 0.90 g (55% yield) of Vd
as colourless crystals, mp = 228-30 °C. Ir (KBr); 3055, 1720,
1696, 1500, 1350, 1271, 1010, 934, 826, 755 cm-1. 1H nmr
(DMSO-d6) δ = 4.11 (center of AB quartet, 2H, SCH2), 5.30
(center of AB quartet, 2H, NCH2), 6.98-7.10 (m, 4H), 7.16-7.19
(m, 3H), 7.29 (t, J = 7.0 Hz, 1H), 7.59-7.64 (m, 3H), 7.84 (d, J =
8.0 Hz, 2H), 8.11 (s, 1H, Th H). Microanalysis calculated for
C26H18BrN3O2S2 (%) C, 56.94; H, 3.31; Br, 14.57; N, 7.66;
S11.69. Found (%) C 57.15; H 3.49; Br, 13.71; N,7.80; S,11.54.
5-(4'-Chlorophenyl)thiazolyl methyl-3'-phenyl-spiro[3H-
indole-3,2'-thiazolidine]-2,4'(1H)dione Ve. Following general
procedure A was synthesized Ve from IIIa (1.1 g, 0.003mole)
and α-bromo-4-chloroacetophenone IVe (0.70 g, 0.003 moles)
by heating in acetic acid/water mixture. The crude product on
crystallization from ethanol afforded 1.0 g (68% yield) of Ve as
colourless crystals,mp = 243-45 °C. Ir (KBr): 3066, 1708, 1610,
1492, 1350, 1271, 1010, 929, 844, 756 cm-1. 1H nmr (DMSO-d6)
δ = 4.14 (center of AB quartet, 2H, SCH2), 5.31 (center of AB
quartet, 2H, NCH2), 6.98-7.11 (m, 4H), 7.14-7.20 (m, 1H), 7.28
(t, J = 6.9 Hz, 1H), 7.48 (d, J = 8.1 Hz, 2H), 7.60 (d, J = 7.8 Hz,
1H), 7.91 (d, J = 8.1 Hz, 2H), 8.10 (s, 1H, Th H). Microanalysis
calculated for C26H18ClN3O2S2 (%): C, 61.96; H, 3.60; Cl, 7.03;
N, 8.34; S, 12.72. Found (%) C, 61.77; H, 3.75; Cl, 7.24; N,
8.62; S, 12.57.
1
3055, 1728, 1691, 1610, 1496, 1250, 1023, 855, 756 cm-1. H
nmr (DMSO-d6) δ = 3.57 (s, 3H), 3.77 (s, 3H), 4.10 (center of
AB quartet, 2H, SCH2), 5.26 (center of AB quartet, 2H, NCH2),
6.69 (d, J = 8.6 Hz, 2H), 6.91 (d, J = 8.6 Hz, 2H), 6.97 (d, J =
8.5 Hz, 2H), 7.01-7.12 (m, 2H), 7.29 (t, J = 7.4 Hz, 1H), 7.63 (d,
J = 7.4 Hz, 1H), 7.81 (d, J = 8.5 Hz, 2H), 7.85 (s, 1H, Th H).
Microanalysis calculated for C28H23N3O4S2 (%): C, 63.50; H,
4.38; N, 7.93; S, 12.11. Found (%): C, 63.29; H, 4.44; N, 7.72;
S, 11.85.
5-(4-bromophenyl)thiazolyl methyl-3'-(4-methoxyphenyl)-
spiro[3H-indole-3,2'-thiazolidine]-2,4'(1H)dione Vi. Following
general procedure A was synthesized Vi from IIIb (1.2 g,
0.003mole) and α-bromo-4-bromoacetophenone IVd (0.83 g,
0.003 moles) by heating in acetic acid/water mixture. The crude
product on crystallization from ethanol afforded 1.1 g (63%
yield) of Vi as colourless crystals, mp = 76-78 °C. Ir (KBr):
3066, 1728, 1690, 1495, 1350, 1271, 1014, 934, 826, 752 cm-1.
1H nmr (DMSO-d6) δ = 3.57 (s, 3H), 4.10 (center of AB quartet,
2H, SCH2), 5.27 (center of AB quartet, 2H, NCH2), 6.68 (d, J =
8.6 Hz, 2H), 6.90 (d, J = 8.6 Hz, 2H), 7.04 (d, J = 7.2 Hz, 1H),
7.09(t, J = 7.4 Hz, 1H) 7.29 (t, J = 7.4 Hz, 1H), 7.60-7.68 (m,
3H), 7.83 (d, J = 8.5 Hz, 2H), 8.10 (s, 1H, Th H). Microanalysis
calculated for C27H20BrN3O3S2 (%): C, 56.06; H, 3.48; Br, 13.81;
N, 7.26; S, 11.09. Found (%): C, 56.31; H, 3.40; Br, 14.05; N,
7.52; S, 10.95.
5-(4-Chlorophenyl)thiazolyl methyl-3'-(4-methoxyphenyl)-
spiro[3H-indole-3,2'-thiazolidine]-2,4'(1H)dione Vj. Following
general procedure A was synthesized Vj from IIIb (1.2 g, 0.003
mole) and α-bromo-4-chloroacetophenone IVe (0.70 g, 0.003
moles) by heating in acetic acid/water mixture. The crude
product on crystallization from ethanol afforded 0.72 g (45%
yield) of Vj as colourless crystals, mp = 152-54 °C. Ir (KBr):
3055, 1715, 1695, 1508, 1353, 1274, 1012, 929, 835, 750 cm-1.
1H nmr (DMSO-d6) δ = 3.58 (s, 3H), 4.09 (center of AB quartet,
2H, SCH2), 5.27 (center of AB quartet, 2H, NCH2), 6.68 (d, J =
8.7 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 7.03 (d, J = 7.6 Hz, 1H),
7.09 (t, J = 7.4 Hz, 1H), 7.29 (t, J = 7.4 Hz, 1H), 7.47 (d, J = 8.5
Hz, 2H), 7.63 (d, J = 7.7 Hz, 1H), 7.89 (d, J = 8.5 Hz, 2H), 8.07
(s, 1H, Th H). Microanalysis calculated for C27H20ClN3O3S2 (%):
C, 60.72; H, 3.77; Cl, 6.64; N, 7.87; S, 12.01. Found (%): C,
60.44; H, 3.89; Cl, 6.43; N, 7.56; S, 11.86.
N-Hydroxy-3'-phenyl-spiro[3H-indole-3,2'-thiazolidine]-
2,4'(1H)dione-1-yl-acetamidine Via. A mixture of IIa (16.75 g,
0.05 mole), 15.0 g of Na2CO3 and 21.0 g of hydroxylamine
hydrochloride in 150 mL of 5:1 ethanol/water was refluxed for
45 min. The reaction mixture was cooled in ice-bath at 0-5 °C.
The solid precipitated was collected by filtration, washed with
ethanol/water (1:1) and dried at 50 °C afford 15.64 g (85%
yield) of VIa as colourless amorphous powder, mp 129-31 °C.
The compound obtained by this method was sufficiently pure
5-Phenylthiazolyl methyl-3'-(4-methoxyphenyl)-spiro[3H-
indole-3,2'-thiazolidine]-2,4'(1H)dione Vf. Following general
procedure A was synthesized Vf from IIIb (1.2 g, 0.003 mole)
and α-bromoacetophenone IVa (0.60 g, 0.003 moles) by heating
in acetic acid/water mixture. The crude product on crystal-
lization from ethanol afforded 0.64 g (43% yield) of Vf as
colourless crystals,mp = 88-90 °C. Ir (KBr): 3056, 1728, 1697,
1
1611, 1510, 1490, 1249, 1029, 831, 755 cm-1. H nmr (DMSO-
d6) δ = 3.56 (s, 3H), 4.11 (center of AB quartet, 2H, SCH2), 5.30
(center of AB quartet, 2H, NCH2), 6.68 (d, J = 8.9 Hz, 2H), 6.91
(d, J = 8.9 Hz, 2H), 7.03-7.12 (m, 2H), 7.29-7.34 (m, 2H), 7.42
(t, J = 8.0 Hz, 2H), 7.63 (d, J = 7.4 Hz, 1H), 7.89 (d, J = 7.4 Hz,
2H), 8.03 (s, 1H, Th H). Microanalysis calculated for
C27H21N3O3S2 (%) C, 64.91; H, 4.24; N, 8.41; S, 12.84. Found
(%): C, 65.11; H, 4.01; N, 8.68;S, 12.59.
5-(4-Methylphenyl)thiazolyl methyl-3'-(4-methoxyphenyl)-
spiro[3H-indole-3,2'-thiazolidine]-2,4'(1H)dione Vg. Following
general procedure A was synthesized Vg from IIIb (1.2 g, 0.003
mole) and α-bromo-4-methylacetophenone IVb (0.64 g, 0.003
moles) by heating in acetic acid/water mixture. The crude
product on crystallization from ethanol afforded 1.15 g (75%
yield) of Vg as colourless crystals, mp = 175-77 °C. Ir (KBr):
3050, 1730, 1690, 1602, 1511, 1496, 1250, 1029, 833, 749 cm-1.
1H nmr (DMSO-d6) δ = 2.31 (s, 3H), 3.56 (s, 3H), 4.10 (center
of AB quartet, 2H, SCH2), 5.27 (center of AB quartet, 2H,
NCH2), 6.68 (d, J = 9.0 Hz, 2H), 6.91 (d, J = 9.0 Hz, 2H), 7.04-

May-Jun 2008
Synthesis of 1,3-thiazole and 1,2,4-oxadiazole substituted
869
spiro[3H-indole-3,2'-thiazolidine]-2,4'(1H)-diones
and was used as such for the next reaction. Ir (cm-1): 3429, 3354,
1706, 1674, 1593, 1490, 1346, 1207, 1097, 939 and 756 CM-1.
1H nmr (DMSO-d6): δ = 4.09 (center of AB quartet, 2H, SCH2),
4.28 (center of AB quartet, 2H, NCH2), 5.41 (s, 2Η, ΝH2), 6.90-
7.05 (m, 4H), 7.10-7.31 (m, 4H), 7.46 (d, J = 7.5 Hz, 1H),
9.07 (s, 1H, OH). Microanalysis calculated for C18H16N4O3S
(%): 58.68; H, 4.38; N, 15.21; S, 8.70. Found (%): C, 58.49; H,
4.61; N, 15.04; S, 8.48.
N-Hydroxy-3'-(4-methoxyphenyl)-spiro[3H-indole-3,2'-thi-
azolidine]-2,4'(1H)dione-1-yl-acetamidine VIb. Similarly was
synthesized VIb from IIb (17. g, 0.05 moles) in 85% yield, mp.
236-38°C. Ir (KBr): 3473, 3361, 1718, 1658, 1589, 1510, 1363,
1299, 1178, 1103, 945 and 754. 1H nmr (DMSO-d6): δ = 3.66 (s,
3Η), δ = 4.07 (center of AB quartet, 2H, SCH2), 4.26 (center of
AB quartet, NCH2), 5.41 (s, 2Η, ΝH2), 6.82 (d, J = 8.9 Hz, 2H),
6.97 (d, J = 9.5 Hz, 3H), 7.07 (t, J = 7.1 Hz, 1H), 7.30 (t, J = 7.0
Hz, 1H), 7.54 (d, J = 7.9 Hz, 1H), 9.10 (s, 1H, OH).
Microanalysis calculated for C19H18N4O4S (%): C, 57.28; H,
4.55; N, 14.06; S, 8.05. Found: C, 57.53; H, 4.37; N, 13.88; S,
8.21.
acetic acid. The crude product was purified using column
chromatography [Stationary phase Silica gel (120-200 mesh),
Mobile phase hexane:ethyl acetate (70:30)]. The pure product
was obtained as colourless solid, 0.73 g (30% yield), mp. 200-02
°C. Ir (KBr): 2983, 1735, 1710, 1604, 1475, 1213, 1176, 1099,
1
1008, 912, 754. H nmr (DMSO-d6) δ = 4.13 (center of AB
quartet, 2H, SCH2), 5.20 (center of AB quartet, 2H, NCH2),
7.00-7.21 (m, 7H), 7.29 (t, J = 7.8 Hz, 1H), 7.54 (d, J = 7.4 Hz,
1H), 7.62 (t, J = 7.5 Hz, 2H), 7.71 (t, J = 7.8 Hz, 1H), 8.04 (d, J
= 7.4 Hz, 1H). Microanalysis calculated for C25H18N4O3S (%):
C, 66.07; H, 3.99; N, 12.33; S, 7.05. Found (%): C, 65.85; H,
4.19; N, 12.09; S, 7.23.
5-(4-Chlorophenyl)-[1,2,4]oxadiazolyl methyl-3'-phenyl-
spiro[3H-indole-3,2'-thiazolidine]-2,4'(1H)dione VIIId.
Following general procedure B was synthesized VIIId from VIa
(2.0 g, 0.0054 mole) and 4-chlorobenzoyl chloride VIId (1.05 g,
0.006 mole) in acetic acid. The crude product was purified using
column chromatography [Stationary phase Silica gel (120-200
mesh), Mobile phase hexane:ethyl acetate (70:30)]. The pure
product was obtained as colourless solid, 1.3 g (50% yield), mp.
129-31 °C. Yield was 50% (1.3g). mp:- 131°C. Ir (KBr): 2987,
Procedure B: General procedure for the synthesis of
(un)substituted 3-aryl/alkyl[1,2,4]oxadiazolyl methyl-3'-aryl-
spiro[3H-indole-3,2'-thiazolidine]-2,4'(1H)diones VIIIa-j.
1
1730, 1715, 1604, 1562, 1470, 1340, 1210, 1008, 750 cm-1. H
nmr (DMSO-d6) δ = 4.12 (center of AB quartet, 2H, SCH2), 5.20
(center of AB quartet, 2H, NCH2), 6.96-7.09 (m, 4H), 7.11-7.22
(m, 3H), 7.29 (t, J = 7.2 Hz, 1H), 7.55 (d, J = 7.4 Hz, 1H), 7.71
(d, J = 7.5 Hz, 2H), 8.04 (d, J = 7.5 Hz, 2H). Microanalysis
calculated for C25H17ClN4O3S (%): C, 61.41; H, 3.50; Cl, 7.25;
N, 11.46; S, 6.56. Found (%): C, 61.25; H, 3.66; Cl, 7.47; N,
11.63; S, 6.39.
5-(4-Nitrophenyl)-[1,2,4]oxadiazolyl methyl-3'-phenyl-spiro-
[3H-indole-3,2'-thiazolidine]-2,4'(1H)dione VIIIe. Following
general procedure B was synthesized VIIIe from VIa (2.0 g,
0.0054 mole) and 4-nitrobenzoyl chloride VIIe (1.11 g, 0.006
mole) in acetic acid. The crude product was purified using
column chromatography [Stationary phase Silica gel (120-200
mesh), Mobile phase hexane:ethyl acetate (70:30)]. The pure
product was obtained as colourless solid, 1.4 g (53% yield), mp.
177-79 °C. Ir (KBr): 2980, 1725, 1710, 1608, 1470, 1345, 1215,
1002, 933, 743 cm-1. 1H nmr (DMSO-d6) δ = 4.11 (center of AB
quartet, 2H, SCH2), 5.24 (center of AB quartet, 2H, NCH2),
6.98-7.20 (m, 7H), 7.30 (t, J = 7.2 Hz, 1H), 7.57 (d, J = 7.5 Hz,
1H), 8.29 (d, J = 7.8 Hz, 2H), 8.44 (d, J = 7.8 Hz, 2H).
Microanalysis calculated for C25H17N5O5S (%): C, 60.11; H,
3.43; N, 14.02; S, 6.42. Found (%): C, 59.93; H, 3.35; N, 14.20;
S, 6.27.
5-Chloromethyl-[1,2,4]oxadiazolyl methyl-3'-(4-methoxy-
phenyl)-spiro[3H-indole-3,2'-thiazolidine]-2,4'(1H)dione VIIIf.
Following general procedure B was synthesized VIIIf from VIb
(2.15 g, 0.0054mole) and chloroacetylchloride VIIa (0.68 g,
0.006 mole) in acetic acid. The crude product was purified using
column chromatography [Stationary phase Silica gel (120-200
mesh), Mobile phase hexane:ethyl acetate (70:30)]. The pure
product was obtained as colourless solid, 0.8 g (35% yield), mp
151-53 °C. Ir (KBr): 2975, 1720, 1715, 1610, 1465, 1340, 1223,
1002, 944, 750 cm-1. 1H nmr (DMSO-d6) δ = 3.66 (s, 3H,
OCH3), 4.08 (center of AB quartet, 2H, SCH2), 5.07 (s, 2H),
5.13 (center of AB quartet, 2H, NCH2), 6.78 (d, J = 8.4 Hz, 2H),
6.92 (d, J = 8.4Hz, 2H), 7.00 (d, J = 7.5 Hz, 1H), 7.09 (t, J = 7.2
Hz, 1H), 7.30 (t, J = 7.2 Hz, 1H), 7.58 (d, J = 7.5 Hz, 1H).
Microanalysis calculated for C21H17ClN4O4S (%): C, 55.20; H,
3.75; Cl, 7.76; N, 12.26; S, 7.02. Found (%): C, 55.03, H, 3.67;
Cl, 7.52; N, 12.02; S, 6.87.
5-Chloromethyl-[1,2,4]oxadiazolyl methyl-3'-phenyl-spiro-
[3H-indole-3,2'-thiazolidine]-2,4'(1H)dione VIIIa. The
synthesis of VIIIa is representative. VIa (2.0 g, 0.0054 mole)
and chloroacetyl chloride VIIa (0.68 g, 0.006 mole) were taken
in 6 mL of acetic acid and heated at reflux temperature. After 30
min, reaction mixture was cooled down to room temperature and
poured into ice water. The resulting solid was filtered, washed
with aqueous solution of NaHCO3, washed with water and dried.
The crude product was purified using column chromatography
[Stationary phase Silica gel (120-200 mesh), Mobile phase
hexane:ethyl acetate (70:30)]. The pure product was obtained as
colourless solid, 0.8 g (38% yield), mp 165-67 °C. Ir (KBr):
2991, 2964, 1730, 1693, 1610, 1508, 1357, 1251, 1178, 1031,
1
900 and 831 cm-1. H nmr (DMSO-d6): δ = 4.11 (center of AB
quartet, 2H, SCH2), 5.08 (s, 2H), 5.16 (center of AB quartet, 2H,
NCH2), 6.95-7.08 (m, 4H), 7.15-7.32 (m, 4H), 7.52 (d, J = 7.4
Hz, 1H), ms: m/z 427(M+1). Microanalysis calculated for
C20H15ClN4O3S (%) C, 56.27; H, 3.54; Cl, 8.31; N, 13.12; S,
7.51. Found (%): C, 56.08; H, 3.30; Cl, 8.10; N, 13.33; S, 7.29.
5-Dichloromethyl-[1,2,4]oxadiazolyl methyl-3'-phenyl-spiro-
[3H-indole-3,2'-thiazolidine]-2,4'(1H)dione VIIIb. Following
general procedure B was synthesized VIIIb from VIa (2.0 g,
0.0054mole) and dichloroacetyl chloride VIIb (0.88 g, 0.006
mole) in acetic acid. The crude product was purified using column
chromatography [Stationary phase Silica gel (120-200 mesh),
Mobile phase hexane:ethyl acetate (70:30)]. The pure product was
obtained as colourless solid, 1.29 g (52% yield), mp. 135-37 °C. Ir
(KBr): 2991, 1724, 1687, 1606, 1490, 1423, 1350, 1209, 1174,
1
1035, 906, 767 cm-1. H nmr (DMSO-d6) δ = 4.10 (center of AB
quartet, 2H, SCH2), 5.22 (center of AB quartet, 2H, NCH2), 6.95-
7.10 (m, 4H), 7.15-32 (m, 4H), 7.53 (d, J = 7.5 Hz, 1H), 7.93 (s,
1H, CHCl2). Microanalysis calculated for C20H14Cl2N4O3S for C,
52.07, H, 3.06; Cl, 15.37; N, 12.14; S, 6.95. Found (%): C, 52.20;
H, 3.21; Cl, 15.18; N, 12.40; S, 7.12.
5-Phenyl-[1,2,4]oxadiazolyl
indole-3,2'-thiazolidine]-2,4'(1H)dione
methyl-3'-phenyl-spiro[3H-
VIIIc. Following
general procedure B was synthesized VIIIc from VIa (2.0 g,
0.0054 mole) and benzoyl chloride VIIc (0.84 g, 0.006 mole) in

870
U. C. Mashelkar, D. M. Rane and R. S. Kenny
Vol 45
3.56 (s, 3H, OCH3), 4.10 (center of AB quartet, 2H, SCH2), 5.21
(center of AB quartet, 2H, NCH2), 6.69 (d, J = 8.2 Hz, 2H), 6.93
(d, J = 8.2 Hz, 2H), 7.04 (d, J = 7.2 Hz, 1H), 7.10 (t, J = 7.1 Hz,
1H), 7.31 (t, J = 7.2 Hz, 1H), 7.62 (d, J = 7.4 Hz, 1H), 8.28 (d, J
= 8.2 Hz, 2H), 8.42 (d, J = 8.2 Hz, 2H). Microanalysis
calculated for C26H19N5O6S (%): C, 58.97; H, 3.62; N, 13.23; S,
6.06. Found (%): C, 60.13; H, 3.47; N, 13.03; S, 6.19.
5-Dichloromethyl-[1,2,4]oxadiazolyl
methyl-3'-(4-meth-
oxyphenyl)-spiro[3H-indole-3,2'-thiazolidine]-2,4'(1H)dione
VIIIg. Following general procedure B was synthesized VIIIg
from VIb (2.15 g, 0.0054mole) and dichloroacetylchloride VIIb
(0.88 g, 0.006 mole) in acetic acid. The crude product was
purified using column chromatography [Stationary phase Silica
gel (120-200 mesh), Mobile phase hexane:ethyl acetate (70:30)].
The pure product was obtained as colourless solid, 1.1 g (45%
yield), mp 157-59 °C. Ir (KBr): 2989, 1730, 1695, 1608, 1508,
1031, 933, 752 cm-1. 1H nmr (DMSO-d6) δ = 3.65 (s, 3H,
OCH3), 4.08 (center of AB quartet, 2H, SCH2), 5.20 (center of
AB quartet, 2H, NCH2), 6.78 (d, J = 8.5 Hz, 2H), 6.92 (d, J =
8.5 Hz, 2H), 7.02 (d, J = 7.4 Hz, 1H), 7.09 (t, J = 7.2 Hz, 1H),
7.31 (t, J = 7.2 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.93 (s, 1H).
Microanalysis calculated for C21H16Cl2N4O4S (%): C, 51.33; H,
3.28; Cl, 14.43; N, 11.40; S, 6.53. Found (%): C, 51.21, H, 3.19;
Cl, 14.64; N, 11.51; S, 6.40.
3'-Phenyl-spiro[3H-indole-3,2'-thiazolidine]-2,4'(1H)-
dione-1-yl-acetic acid (Xa). A suspension of IXa (15.3 g,
0.04 mole) in a 50mL of 2% aqueous solution of sodium
hydroxide, was heated with vigorous stirring on water-bath for
1 h. After cooling the reaction mixture at room temperature, it
was slowly poured into ice cold 10% dilute HCl with vigorous
stirring. The resulted solid was collected by filtration, washed
with water and dried. Crude product on crystallization from
methanol afforded colourless crystals of Xa, 11.3 g (80%
yield) mp 125-27 °C. Ir (KBr): 2976, 1712, 1691, 1612, 1510,
1411, 1247, 1022, 831 cm-1. 1H nmr (DMSO-d6) δ = 4.09
(center of AB quartet, 2H, SCH2), 4.48 (center of AB quartet,
2H, NCH2), 6.9-7.06 (m, 4H), 7.12-7.30 (m, 4H), 7.45 (d, J =
7.8 Hz, 1H), 13.23 (s, 1H, OH). Microanalysis calculated for
C18H14N2O4S (%) C, 61.01; H, 3.98; N, 7.90; S, 9.05. Found:
C, 60.87; H, 3.91; N, 7.66; S, 8.95.
5-Phenyl-[1,2,4]oxadiazolyl
methyl-3'-(4-methoxyphenyl)-
spiro[3H-indole-3,2'-thiazolidine]-2,4'(1H)dione VIIIh.
Following general procedure B was synthesized VIIIh from VIb
(2.15 g, 0.0054 mole) and benzoylchloride VIIc (0.84 g, 0.006
mole) in acetic acid. The crude product was purified using
column chromatography [Stationary phase Silica gel (120-200
mesh), Mobile phase hexane:ethyl acetate (70:30)]. The pure
product was obtained as colourless solid, 0.96 g (40% yield), mp
176-78 °C. Ir (KBr): 2997, 1732, 1701, 1610, 1562, 1417, 1180,
1039, 933, 823 cm-1. 1H nmr (DMSO-d6) δ = 3.50 (s, 3H,
OCH3), 4.09 (center of AB quartet, 2H, SCH2), 5.17 (center of
AB quartet, 2H, NCH2), 6.67 (d, J = 8.0 Hz, 2H), 6.94 (d, J =
8.0 Hz, 2H), 7.02 (d, J = 7.4 Hz, 1H), 7.08 (t, J = 7.2 Hz, 1H),
7.31 (t, J = 7.2 Hz, 1H), 7.58-7.65 (m, 3H), 7.72 (t, J = 7.2 Hz,
1H), 8.03 (d, J = 7.9 Hz, 2H). Microanalysis calculated for
C26H20N4O4S (%): C, 64.45; H, 4.16; N, 11.56; S, 6.62. Found
(%): C, 64.62, H, 4.01; N, 11.29; S, 6.47.
3'-(4-Methoxyphenyl)-spiro[3H-indole-3,2'-thiazolidine]-
2,4'(1H)dione-1-yl-acetic acid Xb. Similarly was synthesized
Xb from IXb (16.0 g, 0.04 moles) using 2% aqueous sodium
hydroxide solution. The product on crystallization from
methanol afforded Xb, 12 g (78% yield); mp 223-25 °C. Ir
(KBr) 2985, 17202, 1695, 1604, 1510, 1411, 1250, 1022, 825
cm-1. 1H nmr (DMSO-d6) δ = 3.72 (s, 3H, OCH3), 4.11 (center of
AB quartet, 2H, SCH2), 4.46 (center of AB quartet, 2H, NCH2),
6.84 (d, J = 8.2 Hz, 2H), 6.93-7.00 (m, 3H), 7.09 (t, J = 6.5 Hz,
1H), 7.30 (t, J = 6.4 Hz, 1H), 7.68 (d, J = 7.9 Hz, 1H), 13.25 (s,
1H, OH). Microanalysis calculated for C19H16N2O5S (%) C,
59.37; H, 4.20; N, 7.29; S, 8.34. Found (%): C, 59.51; H, 4.11;
N, 7.35; S, 8.18.
5-(4-Chlorophenyl)-[1,2,4]oxadiazolyl methyl-3'-(4-meth-
oxyphenyl)-spiro[3H-indole-3,2'-thiazolidine]-2,4'(1H)dione
VIIIi. Following general procedure B was synthesized VIIIi
from VIb (2.15 g, 0.0054 mole) and 4-chlorobenzoylchloride
VIId (1.05 g, 0.006 mole) in acetic acid. The crude product was
purified using column chromatography [Stationary phase Silica
gel (120-200 mesh), Mobile phase hexane:ethyl acetate (70:30)].
The pure product was obtained as colourless solid, 0.77 g (30%
yield), mp 206-08 °C. Ir (KBr): 2983, 1725, 1701, 1610, 1570,
Procedure C: General procedure for the synthesis of
(un)substituted 3-phenyl-1,2,4-oxadiazolyl methyl-3'-aryl-
spiro[3H-indole-3,2'-thiazolidine]-2,4'(1H)diones XIIa-g.
3-Phenyl-1,2,4-oxadiazolyl methyl-3'-phenyl-spiro[3H-
indole-3,2'-thiazolidine]-2,4'(1H)dione XIIa. Xa (1.5 g,
0.0042 mole) and 3mL thionyl chloride were refluxed together
for 1 h. Excess of thionyl chloride was distilled off completely
under reduced pressure and reaction mixture was cooled at room
temperature. The resulting acid chloride was diluted with 3 mL
glacial acetic acid and preformed N-hydroxybenzene-
carboximidamide XIa (0.63 g, 0.0046 moles) was added to same
flask. The reaction mixture was heated on oil-bath at 160°C for
30 min. On completion, the reaction mixture was cooled to room
temperature, poured into ice-water and extracted with ethyl
acetate (2 X 25 mL). Organic phase was thoroughly washed with
2% aqueous NaOH, and with water, followed by drying over
anhydrous Na2SO4. After evaporation of the organic phase, the
resulting crude product was further purified by column
chromatography [Stationary phase Silica gel (120-200 mesh),
Mobile phase hexane:ethyl acetate (70:30)]. The pure product
was obtained as colourless solid, 0.63 g (33% yield), mp 170-72
°C. Ir (KBr) 2927, 1739, 1691, 1612, 1587, 1514, 1209, 1170,
1014, 941, 893, 765 cm-1. 1H nmr (DMSO-d6) δ = 4.13 (center of
AB quartet, 2H, SCH2), 5.44 (center of AB quartet, 2H, NCH2),
7.00-7.15 (m, 4H), 7.18-7.25 (m, 3H), 7.31 (t, J = 7.2 Hz, 1H),
1
1420, 1180, 1039, 940, 824 cm-1. H nmr (DMSO-d6) δ = 3.56
(s, 3H, OCH3), 4.10 (center of AB quartet, 2H, SCH2), 5.17
(center of AB quartet, 2H, NCH2), 6.67 (d, J = 8.2 Hz, 2H), 6.92
(d, J = 8.2 Hz, 2H), 7.02 (d, J = 7.4 Hz, 1H), 7.09 (t, J = 7.1 Hz,
1H), 7.30 (t, J = 7.2 Hz, 1H), 7.60 (d, J = 7.4 Hz, 1H), 7.69 (d, J
= 7.9 Hz, 2H), 8.03 (d, J = 7.9 Hz, 2H). Microanalysis
calculated for C26H19ClN4O4S (%): C, 60.17; H, 3.69; Cl, 6.83;
N, 10.80; S, 6.18. Found (%): C, 60.32, H, 3.84; Cl, 6.67; N,
10.57; S, 6.35.
5-(4-Nitrophenyl)-[1,2,4]oxadiazolyl methyl-3'-(4-meth-
oxyphenyl)-spiro[3H-indole-3,2'-thiazolidine]-2,4'(1H)dione
VIIIj. Following general procedure B was synthesized VIIIj
from VIb (2.15 g, 0.0054 mole) and 4-nitrobenzoylchloride
VIIe (1.11 g, 0.006 mole) in acetic acid. The crude product was
purified using column chromatography [Stationary phase Silica
gel (120-200 mesh), Mobile phase hexane:ethyl acetate (70:30)].
The pure product was obtained as colourless solid, 0.92 g (35%
yield),mp 178-80 °C. Ir (KBr): 2990, 1730, 1712, 1698, 1608,
1570, 1420, 1180, 1030, 936, 855 cm .-1 1H nmr (DMSO-d6) δ =

May-Jun 2008
Synthesis of 1,3-thiazole and 1,2,4-oxadiazole substituted
871
spiro[3H-indole-3,2'-thiazolidine]-2,4'(1H)-diones
7.52-7.63 (m, 4H), 7.91 (d, J = 8.2 Hz, 2H), ms: m/z 455(M+1).
Microanalysis calculated for C25H18N4O3S (%) C, 66.07; H,
3.99; N, 12.33; S, 7.05. Found (%): C, 66.29; H, 4.12; N, 12.17;
S, 7.28.
(70:30)]. The pure product was obtained as colourless solid, 0.64
g (33% yield), mp 163-65 °C. Ir (KBr): 2930, 1721, 1697, 1612,
1513, 1350, 1249, 1170, 1011, 901, 841, 760 cm-1 .1H nmr
(DMSO-d6) δ = 2.45 (s, 3H, CH3), 3.58 (s, 3H, OCH3), 4.11
(center of AB quartet, 2H, SCH2), 5.43 (center of AB quartet, 2H,
NCH2), 6.69 (d, J = 9.0 Hz, 2H), 6.92 (d, J = 9.0 Hz, 2H), 7.02-
7.18 (m, 2H), 7.26-7.42 (m, 3H), 7.46 (t, J = 7.0 Hz, 1H), 7.64 (d,
J = 7.5 Hz, 1H), 7.77 (d, J = 7.5 Hz, 1H). Microanalysis
calculated for C27H22N4O4S (%) C, 65.05; H, 4.45; N, 11.24; S,
6.43. Found (%): C, 65.19; H, 4.30; N, 11.07; S, 6.29.
3-(3-Methylphenyl)-1,2,4-oxadiazolyl methyl-3'-phenyl-
spiro[3H-indole-3,2'-thiazolidine]-2,4'(1H)dione XIIb.
Following general procedure C was synthesized XIIb from Xa
(1.5 g, 0.0042 mole) and N-hydroxy-3-methylbenzenecarbox-
imidamide XIb (0.69 g, 0.0046 moles). The crude product was
purified using column chromatography [Stationary phase Silica
gel (120-200 mesh), Mobile phase hexane:ethyl acetate (70:30)].
The pure product was obtained as colourless solid, 0.7 g (36%
yield), mp 102-04 °C. Ir (KBr): 2934, 1730, 1692, 1605, 1590,
3-(4-Chlorophenyl)-1,2,4-oxadiazolyl methyl-3'-(4-meth-
oxyphenyl)-spiro[3H-indole-3,2'-thiazolidine]-2,4'(1H)dione
XIIf. Following general procedure C was synthesized XIIf from
Xb (1.6 g, 0.0042mole) and N-hydroxy-4-chlorobenzenecar-
boximidamide XIc (0.78 g, 0.0046 moles). The crude product
was purified using column chromatography [Stationary phase
Silica gel (120-200 mesh), Mobile phase hexane:ethyl acetate
(70:30)]. The pure product was obtained as colourless solid, 0.82
g (41% yield), mp 183-85 °C. Ir (KBr): 2927, 1728, 1697, 1610,
1514, 1469, 1353, 1257, 1176, 1014, 900, 833, 766 cm-1. 1H nmr
(DMSO-d6) δ = 3.58 (s, 3H, OCH3), 4.09 (center of AB quartet,
2H, SCH2), 5.40 (center of AB quartet, 2H, NCH2), 7.06 (d, J =
7.9 Hz, 1H), 7.13 (t, J = 7.1 Hz, 1H), 7.32 (t, J = 7.1 Hz, 1H),
7.61 (d, J = 8.8 Hz, 2H), 7.66 (d, J = 7.9 Hz, 1H), 7.90 (d, J =
8.8 Hz, 2H). Microanalysis calculated for C26H19ClN4O4S (%) C,
60.17; H, 3.69; Cl, 6.83; N, 10.80; S, 6.18. Found (%): C, 60.33;
H, 3.88; Cl, 6.59; N, 11.01; S, 6.02.
1
1515, 1470, 1257, 1355, 1023, 935, 810, 760 cm-1. H nmr
(CDCl3) δ = 2.54 (s, 3H, CH3), 3.88 (AX splitting, 1H, SCH2),
4.40 (AX splitting, 1H, SCH2), 5.03 (AX splitting, 1H, NCH2),
5.28 (AX splitting, 1H, NCH2), 6.74 (d, J = 7.8 Hz, 1H), 7.00-
7.30 (m, 9H), 7.38 (t, J = 7.2 Hz, 1H), 7.48 (d, J = 7.5 Hz, 1H),
7.86 (d, J = 7.5 Hz, 1H). Microanalysis calculated for
C26H20N4O3S (%) C, 66.65; H, 4.30; N, 11.96; S, 6.84. Found
(%): C, 66.43; H, 4.57; N, 12.13; S, 6.61.
3-(4-Chlorophenyl)-1,2,4-oxadiazolyl methyl-3'-phenyl-
spiro[3H-indole-3,2'-thiazolidine]-2,4'(1H)dione XIIc.
Following general procedure C was synthesized XIIc from Xa
(1.5 g, 0.0042 mole) and N-hydroxy-4-chlorobenzenecar-
boximidamide XIc (0.78 g, 0.0046 moles). The crude product
was purified using column chromatography [Stationary phase
Silica gel (120-200 mesh), Mobile phase hexane:ethyl acetate
(70:30)]. The pure product was obtained as colourless solid, 0.63
g (31% yield), mp 194-96 °C. Ir (KBr): 2930, 1721, 1700, 1611,
1592, 1504, 1475, 1360, 1255, 1033, 950, 895, 756 cm-1. 1H nmr
(CDCl3) δ = 3.89 (AX splitting, 1H, SCH2), 4.40 (AX splitting,
1H, SCH2), 5.01 (AX splitting, 1H, NCH2), 5.26 (AX splitting,
1H, NCH2), 6.71 (d, J = 7.8 Hz, 1H), 7.02-7.29 (m, 7H), 7.44 (d,
J = 8.3 Hz, 2H), 7.49 (d, J = 7.8 Hz, 1H), 7.92 (d, J = 8.4 Hz,
2H). Microanalysis calculated for C25H17ClN4O3S (%) C, 61.41;
H, 3.50; Cl, 7.25; N, 11.46; S, 6.56. Found (%): C, 61.59; H,
3.24; Cl, 7.48; N, 11.31; S, 6.76.
3-(4-Biphenyl)-1,2,4-oxadiazolyl methyl-3'-(4-methoxy-
phenyl)-spiro[3H-indole-3,2'-thiazolidine]-2,4'(1H)dione XIIg.
Following general procedure C was synthesized XIIg from Xb
(1.6 g, 0.0042 mole) and N-hydroxy-4-biphenylcarbox-
imidamide XId (0.975 g, 0.0046 moles). The crude product was
purified using column chromatography [Stationary phase Silica
gel (120-200 mesh), Mobile phase hexane:ethyl acetate (70:30)].
The pure product was obtained as colourless solid, 0.82 g (41%
yield), mp 183-85 °C. Ir (KBr): 2927, 1728, 1697, 1610, 1514,
1
1469, 1353, 1257, 1176, 1014, 900, 833, 766 cm-1. H nmr
(DMSO-d6) δ = 3.58 (s, 3H, OCH3), 4.10 (center of AB quartet,
2H, SCH2), 5.43 (center of AB quartet, 2H, NCH2), 6.74 (d, J =
8.6 Hz, 2H), 6.94 (d, J = 8.6 Hz, 2H), 7.08 (d, J = 7.9 Hz, 1H),
7.13 (t, J = 7.1 Hz, 1H), 7.33 (t, J = 7.3 Hz, 1H), 7.41 (t, J = 7.3
Hz, 1H), 7.50 (t, J = 7.5 Hz, 2H), 7.66 (d, J = 7.8 Hz, 1H), 7.72
(d, J = 7.9 Hz, 2H), 7.85 (d, J = 7.3 Hz, 2H), 7.98 (d, J = 7.8 Hz,
2H). Microanalysis calculated for C32H24N4O4S (%) C, 68.56; H,
4.31; N, 9.99; S, 5.72. Found (%): C, 68.33; H, 4.10; N, 9.76; S,
5.50.
3-Phenyl-1,2,4-oxadiazolyl methyl-3'-(4-methoxyphenyl)-
spiro[3H-indole-3,2'-thiazolidine]-2,4'(1H)dione XIId. Following
general procedure C was synthesized XIId from Xb (1.6 g,
0.0042 mole) and N-hydroxybenzenecarboximidamide XIa
(0.63 g, 0.0046 moles). The crude product was purified using
column chromatography [Stationary phase Silica gel (120-200
mesh), Mobile phase hexane:ethyl acetate (70:30)]. The pure
product was obtained as colourless solid, 0.71 g (38% yield), mp
160-62 °C. Ir (KBr): 2932, 1730, 1695, 1610, 1510, 1245, 1004,
1
910, 843 cm-1. H nmr (DMSO-d6) δ = 3.61 (s, 3H, OCH3), 4.12
REFERENCES
(center of AB quartet, 2H, SCH2), 5.43(center of AB quartet,
2H, NCH2), 6.75 (d, J = 9.0 Hz, 2H), 6.96 (d, J = 9.0 Hz, 2H),
7.09 (d, J = 7.8 Hz, 1H), 7.15 (t, J = 7.2 Hz, 1H), 7.35 (t, J = 7.2
Hz, 1H), 7.52-7.65 (m, 3H), 7.68 (d, J = 7.8 Hz, 1H), 7.93 (d, J
= 9.0 Hz, 2H). Microanalysis calculated for C26H20N4O4S (%) C,
64.45; H, 4.16; N, 11.56; S, 6.62. Found (%): C, 64.21; H, 3.98;
N, 11.73; S, 6.49.
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3-(3-Methylphenyl)-1,2,4-oxadiazolyl methyl-3'-(4-meth-
oxyphenyl)-spiro[3H-indole-3,2'-thiazolidine]-2,4'(1H)dione
XIIe. Following general procedure C was synthesized XIIe from
Xb (1.6 g, 0.0042 mole) and N-hydroxy-3-methylbenzene-
carboximidamide XIb (0.69 g, 0.0046 moles). The crude product
was purified using column chromatography [Stationary phase
Silica gel (120-200 mesh), Mobile phase hexane:ethyl acetate

872
U. C. Mashelkar, D. M. Rane and R. S. Kenny
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