Regioselective synthesis of rac-(1R,4R,6R,6aR)-6′-phenyl-7′, 8′-dihydro-1″H,2′H,6′H-dispiro[cycloalkane-1, 5′-pyrrolo[1,2-c][1,3]thiazole-4′,3″-indole]-2, 2″-diones through 3 + 2 cycloaddition reaction

Article abstract of DOI:10.3184/030823409X430158

Synthesis of a series of novel rac-(1R,4R,6R,6aR)-6′-phenyl-7′, 8′-dihydro-1″H,2′H,6′H-dispiro[cycloalkane-1, 5′-pyrrolo[1,2-c][1,3]thiazole-4′,3″-indole]-2, 2″-diones by cycloaddition reaction is described. The nonstabilised azomethine ylide generated by the reaction of isatin and thiazolidine-2- carboxylic acid has been regioselectively trapped by various substituted benzylidene cycloalkanones.

Full text of DOI:10.3184/030823409X430158

2
40 RESEARCH PAPER
APRILꢂꢀꢉꢇꢊ±ꢉꢇꢋ
JOURNAL OF CHEMICAL RESEARCH 2009
Regioselective synthesis of rac-(1R,4R,6R,6aR)-6'-phenyl-7',8'-dihydro-
1
4
"H,2'H,6'H-dispiro[cycloalkane-1,5'-pyrrolo[1,2-c][1,3]thiazole-
',3"-indole]-2,2"-diones through 3 + 2 cycloaddition reaction
Mahalingam Poornachandran, Mathesan Jayagobi and Raghavachary Raghunathan*
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai – 600 025, India
Synthesis of
a series of novel rac-(1R,4R,6R,6aR)-6'-phenyl-7',8'-dihydro-1"H,2'H,6'H-dispiro[cycloalkane-1,5'-
pyrrolo[1,2-c][1,3]thiazole-4',3"-indole]-2,2"-diones by cycloaddition reaction is described. The nonstabilised
azomethine ylide generated by the reaction of isatin and thiazolidine-2-carboxylic acid has been regioselectively
trapped by various substituted benzylidene cycloalkanones.
Keywords: azomethine ylide, pyrrolidine, cycloaddition, regioselective, spirooxindole
Pyrrolidine based compounds are very useful in preventing
O
1
and treating rheumatoid arthritis, asthma and allergies and
S
N
2
3
DOVRꢀKDYHꢀDQWLꢁLQÀXHQ]DꢀYLUXV and anticonvulsant activities.
S
O
COOH
Natural products having a spiropyrrolidine unit have exhibited
N
H
2
N
H
O
N
H
1
4
important bioactivities. It has also been reported that
synthetic spiropyrrolidine derivatives have activity against
5
3
WKHꢀ DOGRVHꢀ UHGXFWDVHꢀ HQ]\PHꢂꢀ ZKLFKꢀ FRQWUROVꢀ LQÀXHQ]Dꢃ
anti-ylide
The synthesis of spirooxindole ring systems has gained
considerable attention since they are the basic building units
in many natural products like gelsemine, pseudotabersonine
Scheme 1
6,7
and morroniside. In particular, spiroxindolopyrrolidine ring
methods, the ‘decarboxylation route' offers a general and
convenient method in which an aldehyde or a ketone is reacted
V\VWHPVꢀDUHꢀIRXQGꢀLQꢀDꢀQXPEHUꢀRIꢀDONDORLGVꢀOLNHꢀKRUV¿OLQHꢂꢀ
8
spirotrypsostatine A and B and elacomine. Thiazolidine-
2
8-30
with D-amino acids.
The non-stabilised anti-dipole 3, was
based molecular scaffolds have gained much interest since
they showed wide spectrum of bioactivities such as local
anaesthetic, antiseizure, antitubercular, antibacterial, anti-
generated by the decarboxylative condensation reaction of
thiazolidine-2-carboxylic acid, with a 1,2-diketone, isatin in
UHÀX[LQJꢀPHWKDQROꢀꢄ6FKHPHꢀꢅꢆꢃ
9
,10
amoebic and anti-diabetic.
It has also been reported that
Various para substituted benzylidene cycloheptanones and
cyclooctanones were used as dipolarophiles towards 1,3-
dipolar cycloaddition reactions. The required dipolarophiles,
arylidene cycloheptanones and cyclooctanones were
compounds with thiazolidine nucleus have exhibited wide
VSHFWUXPꢀRIꢀELRDFWLYLWLHVꢀVXFKꢀDVꢀDQWLꢁLQÀDPPDWRU\ꢀDQGꢀDQWLꢁ
11,12
hypertensive activities.
Cycloalkanone derivatives also
13
possess substantial antifertility activity in rodents and have
3
1-33
14
prepared as per the literature procedures.
Thus, arylidene
important pharmacological properties.
cycloheptanones, 4a–d and arylidene cyclooctanones, 4e–h
were prepared by condensation of cycloheptanone and
cyclooctanone respectively with aromatic aldehydes in the
SUHVHQFHꢀRIꢀEDVHꢀFDWDO\VWꢃꢀ7KHꢀJHRPHWU\ꢀRIꢀWKHꢀROH¿QLFꢀGRXEOHꢀ
bond is found to be E FRQ¿JXUDWLRQꢀLQꢀDOOꢀFDVHVꢀDVꢀHYLGHQFHGꢀ
Cycloaddition of 1,3-dipoles to the dipolarophiles is an
LPSRUWDQWꢀ VWUDWHJ\ꢀ IRUꢀ WKHꢀ HIIHFLHQWꢀ FRQVWUXFWLRQꢀ RIꢀ ¿YHꢁ
15
membered heterocycles. Natural products with very high
degree of regio- and stereoselectivity have been effectively
synthesised by this strategy since it proceeds through a
1
16-20
by +ꢀ105ꢀVSHFWUDꢀZKHUHLQꢀWKHꢀROH¿QLFꢀSURWRQꢀDSSHDUHGꢀ
concerted pathway.
The azomethine ylide represents
around G 7.8 (Scheme 2).
one of the most reactive and versatile classes of 1,3 dipoles
and is readily trapped by a range of dipolarophiles forming
21
rac-(1R,4R,6R,6aR)-6'-phenyl-7',8'-dihydro-1"H,2'H,6'H-
dispiro[cycloalkane-1,5'-pyrrolo[1,2-c][1,3]thiazole-4',3"-
indole]-2,2"-diones
substituted pyrrolidines.
Encouraged by the biological activities shown by the
22,23
spiroheteroycles synthesised by our group
and in
In an one-pot reaction, a solution of 2-arylidene-1-cycloheptan/
octan-ones 6a–h in methanol with thiazolidine-4-carboxylic
acid, 1 isatin 2ꢀDQGꢀZDVꢀUHÀX[HGꢀIRUꢀꢇꢃꢈ±ꢈꢃꢈꢀKRXUVꢀWRꢀDIIRUGꢀ
a series of novel dispiro compounds 7a–h with good yields
continuation of our efforts for the synthesis of pyrrolidine-
24-27
based heterocycles
we aimed to synthesise some
complex spiropyrrolidine systems consisting of oxindole,
cycloalkanone and thiazole moieties. Here, we present a
VWXG\ꢀRQꢀWKHꢀV\QWKHVLVꢀRIꢀQRYHOꢀVSLURS\UUROLGLQHVꢀHI¿FLHQWO\ꢀ
synthesised by a 1,3-dipolar cycloaddition of azomethine
ylide generated from diketone and cyclic secondary amino
acid with the diplarophiles, (E)-arylidenecyloalkanones.
(
Scheme 3, Table 1). The reaction gave single products in all
cases, as evidenced by TLC analysis.
The structure and the regiochemistry of all cycloadducts
ZHUHꢀFRQ¿UPHGꢀE\ꢀWKHLUꢀVSHFWURVFRSLFꢀDQGꢀHOHPHQWDOꢀDQDO\VLVꢀ
O
CHO
Results and discussion
O
In order to achieve the synthesis of spiroheterocycles
incorporated with the aforesaid bioactive scaffolds with
anticipated overall enhanced bioactivity, a non-stabilised
azomethine ylide, 3 was generated in situ and trapped by the
dipolarophiles. Azomethine ylides can be generated by several
methods from easily available starting materials. Among the
NaOH
Ethanol–Water
R
n
a-b
R
5a-d
n = 1, 2
4
6a-h
R = H, Cl, Me, OMe
*
Correspondent. E-mail: ragharaghunathan@yahoo.com
Scheme 2

JOURNAL OF CHEMICAL RESEARCH 2009 241
O
R
1
n
6a-h
3
Methanol
reflux
2
X
O
n
O
n
R
R
N
S
N
S
O
N
H
N
H
O
R
O
O
n
n
Ha
R
Hb
n = 1,2
R = H, Me, OMe, Cl
N
N
N
S
S
N
H
H
O
O
8
a-h
7a-h
Scheme 3
1
data. As a representative compound of the series, 7e in its H
NMR spectrum showed a cluster of multiplets in the range
Gꢀꢊꢃꢌꢍ±ꢉꢃꢎꢍꢀIRUꢀWKHꢀF\FORRFW\OꢀSURWRQVꢃꢀ7KHꢀEHQ]\OLFꢀSURWRQꢀ+
a
was observed as a doublet at G 4.15 (J = 10 Hz). The N-methine
proton, H exhibited a multiplet in the range Gꢀꢇꢃꢎꢍ±ꢇꢃꢌꢅꢃ
b
This high coupling constant value indicated that the benzylic
proton, H and the and the H were trans to each other. The
a
b
WZRꢀPHWK\OHQHꢀSURWRQVꢀÀDQNHGꢀE\ꢀVXOIXUꢀDQGꢀQLWURJHQꢀDWRPVꢀ
appeared as two doublets at G 3.25 (J = 8 Hz) and at G 3.78
(
J = 8 Hz). The NH proton of the oxindole ring resonated at G
1
0.53 as a singlet. If the other regioisomer 8e had formed then
a singlet for the benzylic proton (H ) would be observed. The
a
13
signals appearing at G 211.97 and G 177.89 in the C NMR
spectrum reveal the presence of cyclooctanone carbonyl and
oxindole carbonyl groups. The peaks at G 73.54 and G 70.46
accounted for C4 and C5 spiroquaternary carbons respectively.
+
Apeak at m/z 432.81 (M ) in the mass spectrum of 7eꢀFRQ¿UPHGꢀ
the formation of cycloadduct. Moreover, the regiochemistry
RIꢀWKHꢀF\FORDGGXFWꢀZDVꢀFRQ¿UPHGꢀE\ꢀVLQJOHꢀFU\VWDOꢀ;ꢁUD\ꢀ
diffraction analysis3 of 7a and 7e (Figs 1 and 2).
Fig. 1 ORTEP diagram of 7a.
4,35
dipolar cycloaddition reaction. It was observed that the non-
stabilised azomethine ylide generated by the reaction between
a diketone and secondary cyclic D-amino acid, cycloadded
regioselectively across the exocyclic double bonds of the
dipolarophiles to give novel spiroheterocycles.
Conclusion
In conclusion, a novel synthesis of some dispirothiapyrrol-
izidines containing cycloalkanone, and oxindole moieties
has been accomplished in a one-pot, three component 1,3-
Table 1 Cycloaddition of ylide generated from isatin and thiaproline towards arylidenecycloheptanones 6a–d and arylidene-
cyclooctanones 6e–h
Entry
Product
R
Yield/%
n
M.p./°C
Reaction time/h
1
2
3
4
5
6
7
8
7a
7b
7c
7d
7e
7f
H
Me
OMe
Cl
71
73
68
67
68
67
66
69
1
1
1
1
2
2
2
2
199–201
209–211
201–203
160–162
206–208
190–192
201–203
195–197
5
5
5.5
4.5
5.5
5
6
4
H
Me
OMe
Cl
7g
7h

2
42 JOURNAL OF CHEMICAL RESEARCH 2009
rac-(1R,4R,6R,6aR)-6'-(p-methoxyphenyl)-7',8'-dihydro-
"H,2'H,6'H-dispiro[cycloheptane-1,5'-pyrrolo[1,2-c][1,3]thiazole-
',3"-indole]-2,2"-dione (7c): Colourless solid, 65% (0.291 g); m.p.
1
4
-1 1
ꢉꢊꢅ±ꢉꢊꢋ°C; IR (KBr): 1714, 1694, 1474 and 3398 cm ; H NMR
(
CDCl , 400 MHz): Gꢀꢊꢃꢑꢇ±ꢉꢃꢎꢌꢀꢄPꢂꢀꢅꢊ+ꢂꢀF\FORKHSW\Oꢆꢂꢀꢉꢃꢍꢅ±ꢉꢃꢍꢇꢀ
3
ꢄPꢂꢀꢅ+ꢆꢂꢀꢉꢃꢑꢑ±ꢋꢃꢊꢅꢀꢄPꢂꢀꢅ+ꢆꢂꢀꢋꢃꢇꢑꢀꢄGꢂꢀꢅ+ꢂꢀJ = 8 Hz), 3.79 (s, 3H,
U±2&+ ), 3.85 (d, 1H, J = 8 Hz), 4.28 (d, 1H, Jꢀ ꢀꢅꢊꢀ+]ꢆꢂꢀꢇꢃꢎꢑ±ꢇꢃꢌꢉꢀ
$
3
1
3
ꢄPꢂꢀꢅ+ꢆꢂꢀꢎꢃꢑꢈ±ꢌꢃꢈꢉꢀꢄPꢂꢀꢍ+ꢆꢂꢀꢅꢊꢃꢉꢍꢀꢄVꢂꢀꢅ+ꢂꢀ1+ꢆꢒꢀ C NMR (CDCl ,
3
1
5
1
00 MHz): G 24.66, 27.60, 29.04, 30.35, 34.40, 35.01, 41.39, 50.77,
1.25, 71.00, 72.50, 110.09, 122.55, 124.74, 128.71, 128.88, 129.87,
30.56, 133.78, 136.35, 140.63, 179.32 and 209.73; mass spectrum
EI, 70 eV): m/z 448.18 (M ); Anal. Calcd for C H N O S: C,
+
(
2
6
28
2
3
6
9.62, H, 6.29, N, 6.24. Found: C, 69.51, H, 6.20, N, 6.31%.
rac-(1R,4R,6R,6aR)-6'-(p-chlorophenyl)-7',8'-dihydro-
"H,2'H,6'H-dispiro[cycloheptane-1,5'-pyrrolo[1,2-c][1,3]thiazole-
',3"-indole]-2,2"-dione (7d): Colourless solid, 64% (0.290 g); m.p.
1
4
-1 1
ꢅꢎꢊ±ꢅꢎꢉ°C; IR (KBr): 1715, 1694, 1474 and 3398 cm ; H NMR
(
CDCl , 400 MHz): Gꢀꢊꢃꢑꢈ±ꢉꢃꢈꢇꢀꢄPꢂꢀꢅꢊ+ꢂꢀF\FORKHSW\Oꢆꢂꢀꢉꢃꢌꢑ±ꢉꢃꢍꢈꢀ
3
ꢄPꢂꢀꢅ+ꢆꢂꢀꢉꢃꢑꢈ±ꢋꢃꢊꢊꢀꢄPꢂꢀꢅ+ꢆꢂꢀꢋꢃꢇꢍꢀꢄGꢂꢀꢅ+ꢂꢀJ = 8 Hz), 3.85 (d, 1H,
J = 8 Hz), 4.28 (d, 1H, Jꢀ ꢀꢅꢊꢀ+]ꢆꢂꢀꢇꢃꢎꢌ±ꢇꢃꢌꢊꢀꢄPꢂꢀꢅ+ꢆꢂꢀꢎꢃꢑꢊ±ꢌꢃꢈꢇꢀ
13
(
m, 8H), 10.36 (s, 1H, NH); C NMR (CDCl , 100 MHz): G 24.60,
3
2
7.45, 29.56, 30.56, 35.91, 41.32, 50.54, 51.23, 71.64, 72.77, 110.46,
Fig. 2 ORTEP diagram of 7e.
122.20, 124.68, 128.14, 128.87, 129.84, 130.17, 133.81, 136.63,
1
40.77, 179.32 and 209.45; mass spectrum (EI, 70 eV): m/z 454.54
+
(
M ); Anal. Calcd for C H ClN O S: C, 66.28, H, 5.56, N, 6.18.
25
25
2
2
Experimental
Found: C, 66.35, H, 5.48, N, 6.10%.
General considerations
rac-(1R,4R,6R,6aR)-6'-phenyl-7',8'-dihydro-1"H,2'H,6'H-
dispiro[cyclooctane-1,5'-pyrrolo[1,2-c][1,3]thiazole-4',3"-indole]-
2,2"-dione (7eꢆꢏꢀ&RORXUOHVVꢀVROLGꢂꢀꢌꢊꢐꢀꢄꢊꢃꢋꢊꢉꢀJꢆꢒꢀPꢃSꢃꢀꢉꢊꢎ±ꢉꢊꢍ°C; IR
Infrared spectra were recorded on a Shimadzu IR-8300 series FT-IR
1
13
spectrophotometer. H NMR and C NMR spectra were recorded on
-
1 1
a Jeol 400 MHz instrument in CDCl solvent with TMS as a standard.
(KBr): 1715, 1695, 1473 and 3398 cm ; H NMR (CDCl , 400 MHz):
3
3
Mass spectra were recorded by JEOL-DX303 HF mass spectrometer.
Elemental analyses were carried out by Perkin-Elmer CHNS 2400
instrument. Single crystal X-ray diffraction analysis was performed
using Endraf-Nonius CHD4 diffractometer and Bruker Smart Apex
CCD area detector diffractometer. Column chromatography was
SHUIRUPHGꢀRQꢀVLOLFDꢀJHOꢀꢄ$&0(ꢂꢀꢅꢊꢊ±ꢉꢊꢊꢀPHVKꢆꢃꢀ5RXWLQHꢀPRQLWRULQJꢀ
of the reaction was made using thin-layer chromatography developed
on glass plates coated with silica gel-G (ACME) of 25 mm thickness
and visualised with iodine.
Gꢀꢊꢃꢌꢍ±ꢉꢃꢎꢍꢀꢄPꢂꢀꢅꢉ+ꢂꢀF\FORRFW\Oꢆꢂꢀꢉꢃꢌꢅ±ꢉꢃꢌꢇꢀꢄPꢂꢀꢅ+ꢆꢂꢀꢉꢃꢑꢍ±ꢋꢃꢊꢊꢀꢄPꢂꢀ
1H), 3.25 (d, 1H, J = 8 Hz), 3.78 (d, 1H, J = 8 Hz), 4.15 (d, 1H,
Jꢀ ꢀꢍꢀ+]ꢆꢂꢀꢇꢃꢎꢎ±ꢇꢃꢎꢍꢀꢄPꢂꢀꢅ+ꢆꢂꢀꢎꢃꢍꢅ±ꢌꢃꢎꢇꢀꢄPꢂꢀꢑ+ꢆꢂꢀꢅꢊꢃꢈꢋꢀꢄVꢂꢀꢅ+ꢂꢀ1+ꢆꢒꢀ
1
3
C NMR (CDCl3, 100 MHz): G 23.83, 25.21, 25.89, 26.10, 26.38,
35.67, 38.70, 51.03, 52.06, 70.46, 73.54, 109.80, 121.08, 124.84,
1
2
26.85, 127.99, 128.20, 129.62, 130.20, 137.93, 142.22, 177.89 and
+
11.97; mass spectrum (EI, 70 eV): m/z 432.81 (M ); Anal. Calcd for
C H N O S: C, 72.19, H, 6.52, N, 6.48. Found: C, 72.28, H, 6.61,
26 28
2
2
N, 6.39%.
rac-(1R,4R,6R,6aR)-6'-(p-methylphenyl)-7',8'-dihydro-
"H,2'H,6'H-dispiro[cycloctane-1,5'-pyrrolo[1,2-c][1,3]thiazole-
',3"-indole]-2,2"-dione (13f): Colourless solid, 67% (0.298 g); m.p.
1
4
General procedure for the synthesis of cycloadducts (7a–h)
A mixture of isatin (0.147 g, 1 mmol), thiazolidine-4-carboxylic acid,
-1 1
ꢅꢑꢊ±ꢅꢑꢉ°C; IR (KBr): 1717, 1695, 1474 and 3396 cm ; H NMR
2
3,24
(
0.135 g, 1 mmol) and arylidene-cycloheptan/octan-ones 6a–h,
(
CDCl , 400 MHz): Gꢀꢊꢃꢑꢇ±ꢉꢃꢎꢌꢀꢄPꢂꢀꢅꢉ+ꢂꢀF\FORRFW\OꢆꢂꢀꢉꢃꢋꢋꢀꢄVꢂꢀꢋ+ꢂꢀ
3
3
ꢄꢅꢀPPROꢆꢀLQꢀPHWKDQROꢀꢄꢉꢊꢀP/ꢆꢀZDVꢀUHÀX[HGꢀXQWLOꢀWKHꢀGLVDSSHDUDQFHꢀ
of starting materials. The reaction mixture was then concentrated
in vacuo and extracted with water (50 mL) and dichloromethane
Ar-CH ꢆꢂꢀꢉꢃꢍꢊ±ꢉꢃꢍꢈꢀꢄPꢂꢀꢅ+ꢆꢂꢀꢉꢃꢑꢌ±ꢋꢃꢊꢉꢀꢄPꢂꢀꢅ+ꢆꢂꢀꢋꢃꢇꢍꢀꢄGꢂꢀꢅ+ꢂꢀJ =
8
Hz), 3.85 (d, 1H, J = 8 Hz), 4.28 (d, 1H, Jꢀ ꢀꢅꢊꢀ+]ꢆꢂꢀꢇꢃꢎꢍ±ꢇꢃꢌꢊꢀ
13
ꢄPꢂꢀꢅ+ꢆꢂꢀꢎꢃꢑꢅ±ꢌꢃꢋꢑꢀꢄPꢂꢀꢍ+ꢆꢂꢀꢅꢊꢃꢇꢋꢀꢄVꢂꢀꢅ+ꢂꢀ1+ꢆꢒꢀ C NMR (CDCl ,
3
(
50 mL). The organic layer was washed with brine solution, dried with
1
5
1
00 MHz): G 21.76, 24.87, 27.64, 29.89, 30.12, 35.87, 41.38, 50.77,
1.25, 71.43, 72.57, 110.39, 122.55, 124.75, 128.70, 128.98, 129.86,
30.15, 133.70, 136.68, 140.67, 179.33 and 209.78; mass spectrum
anhydrous sodium sulfate and concentrated in vacuo. The residue was
SXUL¿HGꢀE\ꢀFROXPQꢀFKURPDWRJUDSK\ꢀZLWKꢀKH[DQHꢁHWK\ODFHWDWHꢀꢄꢍꢏꢉꢆꢀ
mixture to get compounds 7a–h in good yield.
(EI, 70 eV): m/z 446.20 (M+); Anal. Calcd for C H N O S: C,
27
30
2
2
rac-(1R,4R,6R,6aR)-6'-phenyl-7',8'-dihydro-1"H,2'H,6'H-
dispiro[cycloheptane-1,5'-pyrrolo[1,2-c][1,3]thiazole-4',3"-indole]-
72.61, H, 6.77, N, 6.27. Found: C, 72.69, H, 6.70, N, 6.20%.
rac-(1R,4R,6R,6aR)-6'-(p-methoxyphenyl)-7',8'-dihydro-
1"H,2'H,6'H-dispiro[cyclooctane-1,5'-pyrrolo[1,2-c][1,3]thiazole-
4',3"-indole]-2,2"-dione (7g): Colourless solid, 66% (0.305 g); m.p.
2
,2"-dione (7aꢆꢏꢀ&RORXUOHVVꢀVROLGꢂꢀꢌꢊꢐꢀꢄꢊꢃꢉꢑꢉꢀJꢆꢒꢀPꢃSꢃꢀꢅꢑꢑ±ꢉꢊꢅ°C;
-1 1
IR (KBr): 1715, 1695, 1473 and 3398 cm ; H NMR (CDCl , 400
3
-1 1
MHz): Gꢀꢊꢃꢑꢌ±ꢉꢃꢈꢈꢀꢄPꢂꢀꢅꢊ+ꢂꢀF\FORKHSW\Oꢆꢂꢀꢉꢃꢌꢑ±ꢉꢃꢍꢈꢀꢄPꢂꢀꢅ+ꢆꢂꢀꢉꢃꢑꢈ±
ꢉꢊꢅ±ꢉꢊꢋꢀƒ&ꢒꢀ,5ꢀꢄ.%UꢆꢏꢀꢅꢌꢅꢌꢂꢀꢅꢎꢑꢈꢂꢀꢅꢇꢌꢇꢀDQGꢀꢋꢋꢑꢎꢀFP ; H NMR
(CDCl3, 400 MHz): Gꢀꢊꢃꢑꢊ±ꢉꢃꢎꢎꢀꢄPꢂꢀꢅꢉ+ꢂꢀF\FORRFW\Oꢆꢂꢀꢉꢃꢍꢉ±ꢉꢃꢍꢈꢀ
ꢄPꢂꢀꢅ+ꢆꢂꢀꢉꢃꢑꢌ±ꢋꢃꢊꢅꢀꢄPꢂꢀꢅ+ꢆꢂꢀꢋꢃꢇꢑꢀꢄGꢂꢀꢅ+ꢂꢀJ = 8 Hz), 3.77 (s, 3H,
3
(
1
3
1
2
.00 (m, 1H), 3.49 (d, 1H, J = 8 Hz), 3.85 (d, 1H, J = 8.4 Hz), 4.28
d, 1H, J ꢀꢅꢊꢀ+]ꢆꢂꢀꢇꢃꢎꢌ±ꢇꢃꢌꢊꢀꢄPꢂꢀꢅ+ꢆꢂꢀꢎꢃꢑꢊ±ꢌꢃꢈꢇꢀꢄPꢂꢀꢑ+ꢆꢂꢀꢅꢊꢃꢅꢊꢀꢄVꢂꢀ
1
3
$U±2&+ ), 3.84 (d, 1H, J = 8 Hz), 4.27 (d, 1H, Jꢀ ꢀꢅꢊꢀ+]ꢆꢂꢀꢇꢃꢎꢍ±ꢇꢃꢌꢅꢀ
3
13
H, NH); C NMR (CDCl , 100 MHz): G 24.60, 27.45, 29.56, 30.56,
3
ꢄPꢂꢀꢅ+ꢆꢂꢀꢎꢃꢑꢉ±ꢌꢃꢈꢊꢀꢄPꢂꢀꢍ+ꢆꢂꢀꢅꢊꢃꢋꢌꢀꢄVꢂꢀꢅ+ꢂꢀ1+ꢆꢒꢀ C NMR (CDCl ,
5.91, 41.32, 50.09, 51.23, 71.60, 72.78, 110.47, 122.25, 124.78,
3
1
00 MHz): G 24.45, 27.66, 29.23, 30.33, 34.67, 35.08, 41.87, 50.71,
28.15, 128.97, 129.88, 130.16, 133.71, 136.69, 140.77, 179.30 and
+
51.26, 71.33, 72.55, 110.03, 122.54, 124.76, 128.67, 128.89, 129.86,
09.38; mass spectrum (EI, 70 eV): m/z 418.17 (M ); Anal. Calcd for
1
30.98, 133.73, 136.37, 140.56, 179.02 and 209.43; mass spectrum
C H N O S: C, 71.74, H, 6.26, N, 6.69. Found: C, 71.68, H, 6.20,
25
26
2
2
+
(
EI, 70 eV): m/z 462.20 (M ); Anal. Calcd for C H N O S: C,
27
30
2
3
N, 6.75%.
7
0.10, H, 6.54, N, 6.06. Found: C, 70.17, H, 6.60, N, 6.13%.
rac-(1R,4R,6R,6aR)-6'-(p-methylphenyl)-7',8'-dihydro-
"H,2'H,6'H-dispiro[cycloheptane-1,5'-pyrrolo[1,2-c][1,3]thiazole-
',3"-indole]-2,2"-dione (7b): Colourless solid, 68% (0.293 g); m.p.
rac-(1R,4R,6R,6aR)-6'-(p-chlorophenyl)-7',8'-dihydro-
"H,2'H,6'H-dispiro[cycloctane-1,5'-pyrrolo[1,2-c][1,3]thiazole-
',3"-indole]-2,2"-dione (7h): Colourless solid, 69% (0.322 g); m.p.
1
4
1
4
-1 1
ꢉꢊꢑ±ꢉꢅꢅ°C; IR (KBr): 1715, 1694, 1474 and 3396 cm ; H NMR
-1 1
ꢅꢑꢈ±ꢅꢑꢌꢀƒ&ꢒꢀ,5ꢀꢄ.%UꢆꢏꢀꢅꢌꢅꢈꢂꢀꢅꢎꢑꢇꢂꢀꢅꢇꢌꢋꢀDQGꢀꢋꢋꢑꢍꢀFP ; H NMR
(
CDCl , 400 MHz): Gꢀꢊꢃꢑꢈ±ꢉꢃꢎꢍꢀꢄPꢂꢀꢅꢊ+ꢂꢀF\FORKHSW\OꢆꢂꢀꢉꢃꢋꢅꢀꢄVꢂꢀꢋ+ꢂꢀ
3
(CDCl , 400 MHz): Gꢀꢊꢃꢑꢋ±ꢉꢃꢈꢈꢀꢄPꢂꢀꢅꢉ+ꢂꢀF\FORRFW\Oꢆꢂꢀꢉꢃꢌꢌ±ꢉꢃꢍꢇꢀ
3
Ar-CH ꢆꢂꢀꢉꢃꢍꢅ±ꢉꢃꢍꢈꢀꢄPꢂꢀꢅ+ꢆꢂꢀꢉꢃꢑꢑ±ꢋꢃꢊꢋꢀꢄPꢂꢀꢅ+ꢆꢂꢀꢋꢃꢇꢑꢀꢄGꢂꢀꢅ+ꢂꢀJ = 8 Hz),
3
ꢄPꢂꢀꢅ+ꢆꢂꢀꢉꢃꢑꢈ±ꢋꢃꢊꢉꢀꢄPꢂꢀꢅ+ꢆꢂꢀꢋꢃꢇꢑꢀꢄGꢂꢀꢅ+ꢂꢀJ = 8 Hz), 3.86 (d, 1H,
3
.84 (d, 1H, J = 8 Hz), 4.29 (d, 1H, Jꢀ ꢀꢅꢊꢀ+]ꢆꢂꢀꢇꢃꢎꢍ±ꢇꢃꢌꢅꢀꢄPꢂꢀꢅ+ꢆꢂꢀ
J = 8 Hz), 4.27 (d, 1H, Jꢀ ꢀꢅꢊꢀ+]ꢆꢂꢀꢇꢃꢎꢌ±ꢇꢃꢌꢉꢀꢄPꢂꢀꢅ+ꢆꢂꢀꢎꢃꢑꢌ±ꢌꢃꢈꢇꢀ
13
ꢎꢃꢑꢅ±ꢌꢃꢇꢇꢀꢄPꢂꢀꢍ+ꢆꢂꢀꢅꢊꢃꢋꢋꢀꢄVꢂꢀꢅ+ꢂꢀ1+ꢆꢒꢀ C NMR (CDCl , 100 MHz):
13
3
(m, 8H), 10.26 (s, 1H, NH); C NMR (CDCl , 100 MHz): G 24.65,
3
G 21.00, 24.66, 27.60, 29.04, 30.35, 35.01, 41.39, 50.77, 51.25, 71.00,
27.56, 29.77, 30.59, 35.23, 41.22, 50.09, 51.33, 71.30, 72.44, 110.40,
122.21, 124.78, 128.16, 128.89, 129.88, 130.18, 133.84, 136.73,
140.70, 179.12 and 209.48; mass spectrum (EI, 70 eV): m/z 467.02
7
1
2.50, 110.09, 122.55, 124.75, 128.70, 128.98, 129.86, 130.15, 133.70,
36.68, 140.67, 179.33 and 209.78; mass spectrum (EI, 70 eV):
+
+
m/z 432.19 (M ); Anal. Calcd for C H N O S: C, 72.19, H, 6.52, N,
(M ); Anal. Calcd for C H ClN O S: C, 66.87, H, 5.83, N, 6.00.
26
28
2
2
26 27
2
2
6
.48. Found: C, 72.10, H, 7.00, N, 6.57%.
Found: C, 66.80, H, 5.89, N, 5.51%.

JOURNAL OF CHEMICAL RESEARCH 2009 243
3
&ꢀ WKDQNVꢀ &RXQFLOꢀ RIꢀ 6FLHQWL¿Fꢀ DQGꢀ ,QGXVWULDOꢀ 5HVHDUFKꢀ
CSIR), New Delhi, India for the award of Senior Research
Fellowship (SRF). M. J. thanks University Grants Commission
1974, 17, 1253.
1
4
6
M.I. Ali, M.A.-F. El-kaschef, A.G. Hammam and S. Khallaf, A. J. Chem.
Eng. Data, 1979, 24, 377.
(
15
A. Padwa, 1,3-Dipolar cycloaddition chemistry, Vols 1 and 2. Wiley,
New York, 1984.
(
UGC), for the fellowship. Financial support from DST
1
P. Garner, W.B. Ho, S.K. Grandhee, W.J. Youngs and V.O. Kennedy,
J. Org. Chem., 1991, 56, 5893.
and DST-FIST, Department of Science and Technology,
New Delhi, India is also gratefully acknowledged.
1
1
7
8
P. Garner, W.B. Ho and C. Shin, J. Am. Chem. Soc., 1993, 115, 10742.
J.A. Monn and M.J. Valli, J. Org. Chem., 1994, 59, 2773.
Received 5 December 2008; accepted 2 February 2009
Paper 08/0323 doi: 10.3184/030823409X430158
Published online: 21 April 2009
19 V.C. Pham and J.L. Charlton, J. Org. Chem., 1995, 60, 8051.
20 C.W.G. Fiswick, R.J. Foster and R.E. Carr, Tetrahedron Lett., 1996, 37,
3915.
2
1
A. Padwa, Comprehensive organic synthesis Vol. 4, B.M. Trost and
I. Fleming, eds, Pergamon: Oxford, 1991, p.1085.
References
1
22 A.A. Raj, R. Raghunathan, M.R. Sridevikumari and N. Raman, Bioorg.
Med. Chem., 2003, 11, 407.
O. Mitsuaki, K. Toshiyuki, W. Fumihiko and S. Koaru, PCT Int. Appl.
1997) 129, Chem. Abstr., 1997, 126, 225294u,
R. Galeazzi, S. Geremia, G. Mobbili and M. Orena, Tetrahedron Asymm.,
999, 10, 587.
2
3
G. Periyasami, R. Raghunathan, G. Surendiran and N. Mathivanan,
Bioorg. Med. Chem. Lett., 2008, 18, 2342.
(
2
24
25
26
A.A. Raj and R. Raghunathan, Tetrahedron, 2001, 57, 10293.
M. Poornachandran and R. Raghunathan, Tetrahedron, 2006, 62, 11274.
M. Poornachandran, R. Muruganantham and R. Raghunathan, Synth.
Commun., 2006, 36, 141.
1
3
4
J. Obniska, A. Zeic and A. Zagorska, Acta Pol. Pharm., 2002, 59, 209.
J.W. Daly, T.W.F. Spande, N. Whittaker, R.J. Highet, D. Feigl,
T. Nishimori, T. Tokuyama and C.W. Myers, J. Nat. Prod., 1986, 49, 265.
I. Stylianakis, A. Kolocouris, N. Kolocouris, G. Fytas, G.B. Foscolos,
E. Padalko, J. Neyts and E. De Clercq, Bioorg. Med. Chem. Lett., 2003,
2
7
8
M. Poornachandran and R. Raghunathan, Synth. Commun., 2007, 37, 2507.
R. Grigg, S. Surendrakumar, S. Thianpatanagul and D. Vipond, J. Chem.
Soc., Perkin Trans. 1, 1988, 2693.
5
2
1
3, 1699.
2
9
R. Grigg, J. Idle, P. McMeekin and D. Vipond, J. Chem. Soc., Perkin
Trans. 1, 1988, 2703.
6
7
8
W.A. Carroll and P.A. Grieco, J. Am. Chem. Soc., 1993, 115, 1164.
W.G. Earley, T. Oh and L.E. Overman, Tetrahedron Lett., 1988, 29, 3785.
S.T. Hilton, T.C. Ho, G. Pljevaljcic and K. Jones, Org. Lett., 2000, 2,
3
0
O. Tsuge and S. Kanemasa, Adv. Heterocycl. Chem., 1989, 45, 231.
2
639.
31 R. Baltzly, E. Lorz, R.B. Russel and F.M. Smith, J. Am. Chem. Soc., 1955,
77, 624.
9
0
M.R. Chaurasia, Indian. J. Pharm., 1971, 33, 17.
1
B. Zimenkovsky, R. Lesyk, O. Vladzimirska, I. Nektegayev, S. Golota
and I. Chorniy, J. Pharm. Pharmacol., 1999, 51, 264.
32 E.A. Braude, W.F. Forbes, B.F. Goften, R.B. Houghton and E.S. Waight,
J. Chem. Soc., 1957, 4711.
11
T. Moulard, J.F. Lagorce, J.C. Thomes and C. Raby, J. Pharm. Pharmacol.,
33 P.G. Farrel and E.A. Read, Can. J. Chem., 1968, 46, 3685.
34 S. Sundaramoorthy, D. Gayathri, D. Velmurugan, M. Poornachandran and
K. Ravikumar, Acta Crystallogr., 2008, E64, o488.
1
993, 45, 731.
1
2
3
I.F. Faermark, G. Shvarts, S.I. Grizik and V.G. Gravik, Khim.-Farm. Zh.,
990, 24, 35.
H.I. Hall, G.L. Carlson, G.S. Abernethy and C. Piantadosi, J. Med. Chem.,
1
35 D. Gayathri, S. Kalyani, D. Velmurugan, K. Ravikumar and
M. Poornachandran, Acta Crystallogr., 2007, E63, o852.
1