Microwave-Assisted, Solvent-Free Synthesis of 3′-(Aryl/Heteroaryl)-1- morpholinomethyl/piperidinomethylspiro[3H- Indole-3,2′-thiazolidine]-2, 4′(1H)-diones via 3-Isatinimines

Article abstract of DOI:10.1002/jhet.12

The solvent-free, microwave (MW)-assisted synthesis of a new series of 3′-(aryl/heteroaryl)-1-mor-pholinomethyl/piperidinomethylspiro[3H-indole- 3,2′-thiazolidine]-2,4′(1H)-diones has been achieved in an open vessel. Isatins 1 undergo an easy condensation

Full text of DOI:10.1002/jhet.12

January 2009
Microwave-Assisted, Solvent-Free Synthesis of 30-(Aryl/
Heteroaryl)-1-morpholinomethyl/piperidinomethylspiro[3H-
indole-3,20-thiazolidine]-2,40(1H)-diones via 3-Isatinimines
49
Manju Pandey, Dushyant Singh Raghuvanshi, and Krishna Nand Singh*
Department of Chemistry, Banaras Hindu University, Varanasi 221005, India
*E-mail: knsinghbhu@yahoo.co.in
Received February 21, 2007
DOI 10.1002/jhet.12
Published online 5 February 2009 in Wiley InterScience (www.interscience.wiley.com).
The solvent-free, microwave (MW)-assisted synthesis of a new series of 30-(aryl/heteroaryl)-1-mor-
pholinomethyl/piperidinomethylspiro[3H-indole-3,20-thiazolidine]-2,40(1H)-diones has been achieved in
an open vessel. Isatins 1 undergo an easy condensation with various aryl/heteroaryl amines by MW
using montmorillonite K10 clay as a solid support to afford Schiff bases 2, which subsequently undergo
smooth cyclization with TGA under neat MW conditions to afford the spiro thiazolidinones 3. The
spiro-compounds are made to react with morpholine/piperidine and formaldehyde to give the corre-
sponding Mannich bases 4/5 in reasonably good yield.
J. Heterocyclic Chem., 46, 49 (2009).
enhanced reaction rates, higher yields, greater selectiv-
ity, and ease of manipulation [4–7]. Isatin Mannich
bases are found to have cytotoxicity against a panel of
human cancer cells [8]. They also possess antibacterial,
antifungal, antiviral, anti-HIV, anti-protozoal, and ant-
helmintic activities. Indole ring, when joined to the
other aryl/heteroaryl systems through a spiro carbon
atom at C-3, the resulting spiroindoles exhibit an
INTRODUCTION
Microwave-assisted organic synthesis (MAOS) has
been recognized as one of the most fascinating areas of
current research [1–3]. Coupling of microwave (MW)
irradiation with the use of catalysts or mineral supported
reactions, under solvent-free conditions, provides a clean
chemical process with an advantageous merit of
C
V
2009 HeteroCorporation

50
M. Pandey, D. S. Raghuvanshi, and K. N. Singh
Vol 46
Table 1
Physical and analytical data of compounds 2.
Compound
R
R1
Time (min)
Mp (ꢀC)
Yield (%)
Molecular formula
2a
2b
2c
2d
2e
H
H
p-BrC6H4
Ph
3
3
242
183
105
120
190
94
97
90
63
65
C14H9BrN2O
C14H10N2O
Br
Br
Br
CH2C6H5
2-thiazolyl
2-pyridinyl
3
2.5
2
C15H11BrN2O
C11H6BrN3OS
C13H8BrN3O
increased spectrum of biological activities [9–11]. Fur-
ther, spiro[indole-thiazolidine]-diones show a wide range
of pharmacological properties as anticonvulsant, anti-
inflammatory, antibacterial, and anti-fungal [12–14]. N-
Piperidino-(or morpholino-) methylisatin-3-anils possess
potential biological activity and have been prepared by
the condensation of isatin with arylamines followed by
the Mannich reaction with piperidine or morpholine
[15]. Some new spiro[indoline-3,20-thiazolidine]-2,40-
(1H)-diones and bis[spiro[indoline-3,20-thiazolidine]-
2,40(1H)-diones] have been obtained thermally and
under MW irradiation by the condensation of isatin, aro-
matic amines, and mercaptoacetate without isolating the
imine intermediates [16]. 30-Substituted phenylspiro[3H-
indole-3,20-thiazolidine]-2,40-(1H)-diones are reported
to have significant antimicrobial activity [17]. A con-
venient synthesis of spiro[3H-indole-3,20thiazolidine]-
2,40(1H)-diones has also been carried out by the conden-
sation and cyclization of isatin with various aromatic
amines [18]. In view of the above and prompted by the
solvent-free MAOS, we describe herein a MW-assisted
regioselective synthesis of 30-(aryl/heteroaryl)-1-morpho-
linomethyl/piperidinomethylspiro[3H-indole-3,20-thiazo-
lidine]-2,40(1H)-diones under solvent-free conditions.
resulting compounds 3a–e are then allowed to react with
either morpholine or piperidine and 37% formaldehyde,
under solvent-free MW irradiation conditions, to afford
the corresponding Mannich bases 4a–c and 5a,b (Table 3)
in reasonably good yields (Scheme 1).
To optimize the yield of products, the effect of vari-
ous parameters such as MW power, irradiation time, and
molar proportions of the reactants were investigated in
detail. The preparation of 2a as reference compound
was observed under three different sets of reaction con-
ditions. In the first run, isatin was refluxed with p-bro-
moaniline in absolute ethanol for 2 h, yielding the prod-
uct 2a (83%). In the second run, the reactants were
refluxed in triply distilled water containing a few drops
of glacial acetic acid for 30 min affording 2a (82%).
Finally, the reaction was carried out under MW-assisted
(800 W) solvent free conditions using K10 clay as a
solid support, to afford 2a (94%) in just 3 min. Because
of the unambiguous merits, MW method was adopted
for the preparation of the rest of the compounds (Ta-
ble 1). It is worthwhile to mention that in the case of
compounds 2d and 2e (cf. Table 1); a 500-mL Borosil
beaker containing 200 mL of water was kept as a heat
sink to avoid the burning of the compound. For com-
pound 3a, a higher MW power (420 W and 320 W)
resulted in reasonably poor yield of product probably
due to the loss of low boiling mercaptoacetic acid.
RESULTS AND DISCUSSION
However, 160 W irradiation using equimolar quantities
of 2a and mercaptoacetic acid gave rise to an enhanced
yield (65%) of the product 3a. The yields of 3a–e were
considerably increased (72–86%) when the molar ratio of
the reactants 2a and mercaptoacetic acid were kept to be
1:2. A trace of acidic compound was also observed in this
run. To achieve the optimum yield of Mannich bases 4/5,
The reaction sequence involves MW-induced prepara-
tion of Schiff bases 2a–e (Table 1) from isatins 1a–b
and amines (R2-NH2) using montmorillonite K10 clay
as a solid support, followed by the cyclocondensation of
Schiff bases 2a–e and mercaptoacetic acid under neat
MW irradiation conditions to achieve the synthesis of
spiro[indole-thiazolidine]-diones 3a–e (Table 2). The
Table 2
Physical and analytical data of compounds 3.
Compound
R
R1
Time (min)
Mp (ꢀC)
Yield (%)
Molecular formula
3a
3b
3c
3d
3e
H
H
p-BrC6H4
Ph
6
5
5
4
4
90
230
125
135
120
72
76
75
78
87
C16H11BrN2O2S
C16H12N2O2S
Br
Br
Br
CH2C6H5
2-thiazolyl
2-pyridinyl
C17H13BrN2O2S
C13H8BrN3O2S2
C15H10BrN3O2S
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2009 Microwave-Assisted, Solvent-Free Synthesis of 30-(Aryl/Heteroaryl)-1-morpholinomethyl/
51
piperidinomethylspiro[3H-indole-3,20-thiazolidine]-2,40(1H)-diones via 3-Isatinimines
Table 3
Physical and analytical data of compounds 4/5.
Compound
R
R1
X
Time (min)
Mp (ꢀC)
Yield (%)
Molecular formula
4a
4b
4c
5a
5b
H
H
p-BrC6H4
Ph
O
O
O
C
C
2
114
101
70
85
120
71
77
74
70
72
C21H20N3O3S
C21H21N3O3S
1.5
2.5
2
Br
Br
Br
2-pyridinyl
CH2C6H5
2-thiazolyl
C20H19BrN4O3S
C23H24BrN3O2S
CI9H19BrN4O2S2
3
FTNMR spectrometer. The chemical shifts are given in d ppm
with respect to TMS as internal standard. The TLC spots were
detected using iodine chamber. All commercially available
chemicals were purchased from Aldrich and Merck.
General procedure for the synthesis of isatin Schiff bases
(2). Equimolar quantities (1 mmole) of either isatin or 5-bro-
moisatin and corresponding amino reagent were blended with
Montmorillonite K10 clay (20 mg) and heated for 2–3 min in
a MW oven set (LG, Model MS-194W) for 900 W. Upon
completion of the reaction, as checked by TLC, the product
was extracted with CH2Cl2 (3 ꢁ 10 mL). After evaporation of
the reaction mixture was irradiated intermittently (30 s/
cycle) to avoid the loss of low boiling reactants.
All the reactions were monitored by TLC and then
worked up to afford the products, which exhibited phys-
ical and spectral data consistent with their structures.
EXPERIMENTAL
IR spectra were recorded on a JASCO FT/IR-5300 spectro-
photometer, whereas NMR was run on a JEOL AL300
Scheme 1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

52
M. Pandey, D. S. Raghuvanshi, and K. N. Singh
Vol 46
30-(Phenyl)spiro[3H-indole-3,20-thiazolidine]-2,40(1H)-dione
(3b). From 2b, dark brown solid (76%), mp 230ꢀC; ir (potas-
sium bromide): NH 3258, C¼¼O 1730, 1695, C¼¼N 1608
ArAH), 3.5 ppm (SACH2AC); 13C NMR (DMSO-d6): 77
(spiro C), 170,168 (2 C¼¼O), 35 (SACH2AC), 120–141 ppm
(Aromatic-C); Anal. Calcd. For C16H12N2O2S: C, 64.85; H,
4.08; N, 9.45; O, 10.80; S, 10.82. Found: C, 64.91; H, 3.95;
N, 9.52; O, 10.87; S, 10.90.
5-Bromo-30-(benzyl)spiro[3H-indole-3,20-thiazolidine]-2,40
(1H)-dione (3c). From 2c, brown solid (75%), mp 125ꢀC; ir
the solvent under reduced pressure, the product was recrystal-
lized from ethanol.
3-(p-Bromophenylimino)-isatin (2a). From p-bromoaniline,
yellow crystals (94%), mp 242ꢀC; ir (potassium bromide): NH
1
cmꢂ1; H NMR (CDCl3): d 8.1 (s, 1H, NH), 6.8–7.5 (m, 9H,
1
3236, C¼¼O 1700, C¼¼N 1619 cmꢂ1; H NMR (DMSO-d6): d
9.2 (s, 1H, NH), 7.0–7.8 ppm (m, 8H, ArAH); 13C NMR
(DMSO-d6): 168 (C¼¼O), 160 (C¼¼N), 152 (CAN¼¼C), 120–
139 ppm (ArAC’s). Anal. Calcd. For C14H9BrN2O: C, 55.84;
H, 3.01; Br, 26.53; N, 9.30; O, 5.31. Found: C, 55.89; H, 3.06;
Br, 26.48; N, 9.33; O, 5.28.
3-(Phenylimino)-isatin (2b). From aniline, yellow solid
(97%), mp 183ꢀC; ir (potassium bromide): NH 3260, C¼¼O
(potassium bromide): NH 3345, C¼¼O 1732, 1687 cmꢂ1
;
1H
1695, C¼¼N 1612 cmꢂ1
;
1H NMR (DMSO-d6): d 9.3 (s, 1H,
NMR (CDCl3): d 8.3 (s, 1H, NH), 7.1–7.4 (m, 8H, ArAH), 3.4
(SACH2AC), 4.5 ppm (NACH2AC); 13C NMR (DMSO-d6):
74 (spiro C), 170,171 (2 C¼¼O), 35 (SACH2AC), 47
(NACH2AC) 119–137 ppm (Aromatic-C), Anal. Calcd. For
C17H13BrN2O2S: C, 52.45; H, 3.37; N, 7.20; O, 8.22; S, 8.24.
Found: C, 52.39; H, 3.31; N, 7.14; O, 8.30; S, 8.38.
NAH,); 6.8–7.6 ppm (m, 9H, ArAH); 13C NMR (DMSO-d6):
166 (C¼¼O), 162 (C¼¼N), 155 (CAN¼¼C), 120–138 ppm
(ArAC’s); Anal. Calcd. For C14H10N2O: C, 75.66; H, 4.54; N,
12.60; O, 7.20. Found: C, 75.63; H, 4.55; N, 12.63; O, 7.18.
5-Bromo-3-(benzylimino)-isatin (2c). From benzyl amine,
shiny light brown solid (90%), mp 105ꢀC, ir (potassium bro-
5-Bromo-30-(2-thiazolyl)spiro[3H-indole-3,20-thiazolidine]-
2,40(1H)-dione (3d). From 2d, shiny blackish solid (78%), mp
135ꢀC; ir (potassium bromide): NH 3360, C¼¼O 1730, 1698
mide): NH 3350, C¼¼O 1690, C¼¼N 1610 cmꢂ1
;
1H NMR
(CDCl3): d 9.1 (s, 1H, NH); 7.1–7.7 (m, 8H, ArAH); 4.8 ppm
(m, 2H, NACH2AC); 13C NMR (DMSO-d6): 168 (C¼¼O), 161
(C¼¼N), 152 (CAN¼¼C), 118–137 (ArAC’s), 57 ppm
(NACH2AC); Anal. Calcd. For C15H11BrN2O: C, 57.16; H,
3.52; Br, 25.35; N, 8.89; O, 5.08. Found: C, 57.21; H, 3.57;
Br, 25.27; N, 8.91; O, 4.91.
1
cmꢂ1; H NMR (CDCl3): d 8.5 (s, 1H, NH), 7.2–7.4 (m, 3H,
ArAH), 3.5 (SACH2AC), 6.6–7.5 ppm (2H, thiazolyl), 13C
NMR (DMSO-d6): 76 (spiro C), 170,168 (2 C¼¼O), 35
(SACH2AC), 119–141 ppm (Aromatic-C), 108, 138, 172 (thia-
zolyl C), Anal. Calcd. For C13H8BrN3O2S2: C, 40.85; H, 2.11;
Br, 20.90; N, 10.99; O, 8.37; S, 16.78. Found: C, 40.91; H,
2.04; Br, 20.83; N, 11.03; O, 8.31; S, 16.84.
5-Bromo-3-(2-thiazolylimino)-isatin (2d). From 2-thiazolyl
amine, dark brown solid (63%), mp 120ꢀC; ir (potassium bro-
mide): NH 3370, C¼¼O 1692, C¼¼N 1615 cmꢂ1
;
1H NMR
5-Bromo-30-(2-piperidinyl)spiro[3H-indole-3,20-thiazolidine]-
2,40(1H)-dione (3e). From 2e, brown solid (87%), mp 120ꢀC;
(CDCl3): d 9.2 (s, 1H, NH); 7.4–7.8 (m, 3H, ArAH); 7.3, 8.0
ppm (m, 2H, heteroArAH); 13C NMR (DMSO-d6): 166
(C¼¼O), 163 (C¼¼N), 154 (CAN¼¼C), 118–153 ppm (Ar and
heteroAr C’s); Anal. Calcd. For C11H6BrN3OS: C, 42.87; H,
1.96; Br, 25.93; N, 13.64; O, 5.19; S, 10.41. Found: C, 42.79;
H, 1.91; Br, 25.97; N, 13.60; O, 5.24; S, 10.50.
1
ir (potassium bromide): NH 3450, C¼¼O 1732, 1690 cmꢂ1; H
NMR (CDCl3): d 8.7 (s, 1H, NH), 7.2–7.4 (m, 3H, ArAH),
7.1–8.5 (4H, pyridine), 3.5 ppm (SACH2AC), 13C NMR
(DMSO-d6): 76 (spiro C), 170,168 (2 C¼¼O), 35 (SACH2AC),
119–152 ppm (Aromatic-C and heteroAr-C), Anal. Calcd. for
C15H10BrN3O2S: C, 47.89; H, 2.68; Br, 21.25; N, 11.17; O,
8.51; S, 8.52. Found: C, 47.95; H, 2.73; Br, 21.19; N, 11.11;
O, 8.57; S, 8.46.
5-Bromo-3-(2-pyridinylimino)-isatin(2e). From 2-pyridinyl
amine, yellow–orange solid (65%), mp 190ꢀC; ir (potassium
bromide): NH 3452, C¼¼O 1685, C¼¼N 1618 cmꢂ1
;
1H NMR
(CDCl3): d 9.0 (s, 1H, NH ); 7.4–7.8 (m, 3H, ArAH); 7.2, 8.6
ppm (m, 2H, heteroArAH); 13C NMR (DMSO-d6): 168
(C¼¼O), 162 (C¼¼N), 152 (CAN¼¼C), 118–175 ppm (Ar and
heteroAr C’s); Anal. Calcd. For C13H8BrN3O: C, 51.68; H,
2.67; Br, 26.45; N, 13.91; O, 5.30. Found: C, 51.61; H, 2.72;
Br, 26.50; N, 13.85; O, 5.38.
General procedure for the synthesis of 30-aryl-1-morpho-
lino/piperidinomethylspiro[3H-indole-thiazolidine]-2,40(1H)-
dione (4/5). An equimolar quantity of 3 (5 mmol) and
morpholine/piperidine (5 mmol) was blended with 37 % form-
aldehyde (0.5 mL) and then irradiated in a MW oven at
640 W with 30 s/cycle for 2–3 min, as checked by TLC. After
cooling, the product mixture was recrystallized from aqueous
ethanol to afford product.
General procedure for the synthesis of 30-arylspiro[3H–
indole-3,20-thiazolidine]-2,40(1H)-2,4-dione (3). A mixture of
2 (1 mmol) and mercaptoacetic acid (2 mmol) was heated for
4–6 min in a MW oven set for 160 W. The completion of the
reaction was checked by TLC. The reaction content was then
treated with 15 mL, 10% NaHCO3 solution and stirred well.
The resulting compound was filtered, washed with water, dried
and recrystallized from ethanol to give the pure product.
3-(p-Bromophenyl)spiro[3H-indole-3,20-thiazolidine]-2,40
(1H)-dione (3a). From 2a, yellow solid (72%), mp 90ꢀC; ir
(potassium bromide): NH 3260, C¼¼O 1720, 1690, C¼¼N 1608
30-(p-Bromophenyl)-1-morpholinomethylspiro[3H-indole-
thiazolidine]-2,40(1H)-dione (4a). From 3a, yellow solid
(71%), mp 114ꢀC; ir (potassium bromide): C¼¼O 1720, 1690
cmꢂ1 1H NMR (CDCl3): d 6.9–7.5 (m, 8H, ArAH), 2.4–3.7
;
(m, 10H, 5 ꢁ CH2), 4.6 ppm (s, NACH2AN); 13C NMR
(DMSO-d6): 74 (spiro C), 170,168 (2 C¼¼O), 35 (ACH2A), 70
(NACH2AN), 54–71 (4 ꢁ CH2), 118–142 ppm (Aromatic-C);
Anal. Calcd. for C21H20BrN3O3S: C, 53.17; H, 4.25; Br,
16.84; N, 8.86; O, 10.12; S, 6.76. Found: C, 53.26; H, 4.18;
Br, 16.76; N, 8.80; O, 10.21; S, 6.82
1
cmꢂ1; H NMR (CDCl3): d 8.5 (s, 1H, NH), 6.8–7.5 ppm (m,
8H, ArAH); 13C NMR (DMSO-d6): 77 (spiro C), 170,168 (2
C¼¼O), 35 (SACH2AC), 118–141 ppm (Aromatic-C); Anal.
Calcd. For C16H11BrN2O2S: C, 51.21; H, 2.95; Br, 21.29; N,
7.49; O, 8.53; S, 8.55. Found: C, 51.17; H, 3.09; Br, 21.37; N,
7.53; O, 8.44; S, 8.61.
30-(Phenyl)-1-morpholinomethylspiro[3H-indole-thiazoli-
dine]-2,40(1H)-dione (4b). From 3b, yellow solid (77%), mp
101ꢀC; ir. (potassium bromide): C¼¼O 1730, 1695 cmꢂ1
ꢁ CH2), 4.6 (s, NACH2AN), 3.4 ppm (SACH2AC), 13C NMR
;
1H
NMR (CDCl3): d 6.9–7.3 (m, 9H, ArAH), 2.4–3.4 (m, 10H, 5
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2009 Microwave-Assisted, Solvent-Free Synthesis of 30-(Aryl/Heteroaryl)-1-morpholinomethyl/
53
piperidinomethylspiro[3H-indole-3,20-thiazolidine]-2,40(1H)-diones via 3-Isatinimines
(DMSO-d6): 74 (spiro C), 169,168 (2 C¼¼O), 33 (ACH2A), 71
(NACH2AN), 54–71 (4 ꢁ CH2), 120–140 ppm (Aromatic-C),
Anal. Calcd. for C21H21N3O3S: C, 63.78; H, 5.35; N, 10.63;
O, 12.14; S, 8.11. Found: C, 63.85; H, 5.28 N, 10.60; O,
12.08; S, 8.28.
6.67; S, 13.38. Found: C, 47.51; H, 3.56; Br, 16.71; N, 11.75;
O, 6.59; S, 13.47
Acknowledgment. The authors are thankful to the Department
of Biotechnology, New Delhi for financial assistance.
5-Bromo-30-(2-piperidinyl)-1-morpholinomethylspiro [3H-
indole-thiazolidine]-2,40(1H)-dione (4c). From 3e, brown solid
(74%), mp 70ꢀC; ir (potassium bromide): C¼¼O 1740, 1700
REFERENCES AND NOTES
cmꢂ1 1H NMR (CDCl3): d 6.9–7.3 (m, 3H, ArAH), 2.3–3.7
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170,168 (2 C¼¼O), 33 (SACH2AC), 70 (NACH2AN), 54–71
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(m, 12H, 6 ꢁ CH2), 4.6 (s, NACH2AN), 4.5 ( NACH2AC),
3.3 ppm (SACH2AC), 13C NMR (DMSO-d6): 68 (spiro C),
171,168 (2 C¼¼O), 35 (SACH2AC), 70 (NACH2AN), 54–71
(4 ꢁ CH2), 125–141 ppm (Aromatic-C), Anal. Calcd. for
C23H24BrN3O3S: C, 56.79; H, 4.97; Br, 16.43; N, 8.64; O,
6.58; S, 6.59. Found: C, 56.67; H, 5.08; Br, 16.49; N, 8.70; O,
6.49; S, 6.50.
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5-Bromo-30-(2-thiazolyl)-1-piperidinomethylspiro[3H-indole-
thiazolidine]-2,40(1H)-dione (5b). From 3d, coffee colored
shiny powder (72%), mp 120ꢀC; ir (potassium bromide): C¼¼O
[14] Rajopadhye, M.; Popp, F. D. J Heterocycl Chem 1984, 21,
28.
1735, 1692 cmꢂ1 1H NMR (CDCl3): d 6.8–7.3 (m, 3H,
;
[15] Varma, R. S. Pol. J Pharmacol Pharm 1975, 27, 641.
[16] Azizian, J.; Morady, A. V.; Jadidi, K.; Mehrdad, M.; Sar-
rafi, Y. Synth Commun 2000, 30, 537.
ArAH), 1.5–2.4 (m, 10H, 5 ꢁ CH2), 4.5 (s, NACH2AN),
6.5,7.5 (2H, thiazole), 3.3 ppm (SACH2AC), 13C NMR
(DMSO-d6): 74 (spiro C), 173,172 (2 C¼¼O), 35 (SACH2AC),
70 (NACH2AN), 54–71 (5 ꢁ CH2), 119–141 (Aromatic-
C), 138,168,171 ppm (thiazole), Anal. Calcd. for
C19H19BrN4O2S2: C, 47.60; H, 3.49; Br, 16.67; N, 11.69; O,
[17] Diurno, M. V.; Mazzoni, O.; Piscopo, E.; Bolognese, A.
Farmaco 1993, 48, 435.
[18] Joshi, K. C.; Patni, R.; Chand, P. Heterocycles 1981, 16,
1555.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet