Regioselective synthesis of dispirocycloalkanooxindolopyrrolidines and dispirocyclalkanoindanopyrrolidines

Article abstract of DOI:10.1080/00397910903004373

Synthesis of a series of novel dispirocycloalkanone-oxindolopyrrolidines and dispirocycloalkanone-indanopyrrolidines is described. The nonstabilized azomethine ylides generated from a secondary amino acid, sarcosine, and carbonyl components (isatin and ninhydrin) have been effectively trapped by the dipolarophiles, arylidene cycloalkanones, to afford dispiropyrrolidines. The one-pot azomethine ylide cycloaddition reactions were highly regioselective. Copyright Taylor & Francis Group, LLC.

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Regioselective Synthesis of
Dispirocycloalkanooxindolopyrrolidines
and Dispirocyclalkanoindanopyrrolidines
Mahalingam Poornachandran a , Mathesan Jayagobi a & Raghavachary
Raghunathan a
a Department of Organic Chemistry , University of Madras, Guindy
Campus , Chennai, India
Published online: 03 Feb 2010.
To cite this article: Mahalingam Poornachandran , Mathesan Jayagobi & Raghavachary
Raghunathan (2010) Regioselective Synthesis of Dispirocycloalkanooxindolopyrrolidines and
Dispirocyclalkanoindanopyrrolidines, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 40:4, 551-563, DOI: 10.1080/00397910903004373
To link to this article: http://dx.doi.org/10.1080/00397910903004373
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Synthetic Communications1, 40: 551–563, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903004373
REGIOSELECTIVE SYNTHESIS OF
DISPIROCYCLOALKANOOXINDOLOPYRROLIDINES
AND DISPIROCYCLALKANOINDANOPYRROLIDINES
Mahalingam Poornachandran, Mathesan Jayagobi, and
Raghavachary Raghunathan
Department of Organic Chemistry, University of Madras, Guindy Campus,
Chennai, India
Synthesis of a series of novel dispirocycloalkanone-oxindolopyrrolidines and dispirocy-
cloalkanone-indanopyrrolidines is described. The nonstabilized azomethine ylides generated
from a secondary amino acid, sarcosine, and carbonyl components (isatin and ninhydrin)
have been effectively trapped by the dipolarophiles, arylidene cycloalkanones, to afford
dispiropyrrolidines. The one-pot azomethine ylide cycloaddition reactions were highly
regioselective.
Keywords: Azomethine ylide; dipolarophile; oxindole; regioselective; spiropyrrolidine
INTRODUCTION
1,3-Dipolar cycloaddition methodology is one effective tool for the construc-
tion of five-membered heterocycles.[1] Many stereochemically important natural
products have been effectively synthesized by this strategy, because the generation
of 1,3-dipoles is often associated with high regio- and stereoselectivities.[2–5] The pyr-
rolidine motif occurs in many families of biologically potent molecules, and because
of the ease of substitution and modifications at several positions, a wide range of
pyrrolidine derivatives have been synthesized with varying properties.[6] Pyrrolidine
based molecules possess anti-influenza[7] and anticonvulsant activities.[8] The azo-
methine ylide represents one of the most reactive and versatile classes of 1,3-dipoles
and is readily trapped by a range of dipolarophiles, forming substituted pyrroli-
dines.[9] The spiro ring system is frequently encountered in many pharmacologically
important alkaloids. Synthetic spiropyrrolidine derivatives have activity against the
aldose reductase enzyme, which controls influenza.[10] The synthesis of spirooxindole
ring systems has gained considerable attention because they are the basic building
units in many natural products such as gelsemine, pseudotabersonine, and morroni-
side.[11] In particular, spiroxindolopyrrolidine ring systems are found in a number of
alkaloids such as horsfiline, spirotrypsostatine A and B, and elacomine.[12]
Received February 22, 2009.
Address correspondence to Raghavachary Raghunathan, Department of Organic Chemistry,
University of Madras, Guindy Campus, Chennai 600 025, India. E-mail: ragharaghunathan@yahoo.com
551

552
M. POORNACHANDRAN, M. JAYAGOBI, AND R. RAGHUNATHAN
It has been well established that cycloalkanone derivatives possess substantial
antifertility activity in rodents[13] and have important pharmacological properties.[14]
In continuation of our efforts in the synthesis of pyrrolidine-based heterocycles, and
encouraged by the recent findings,[15] we present an efficient synthesis of some new
spiropyrrolidines.
RESULTS AND DISCUSSION
We envisaged complex spiroheterocycles incorporating the aforesaid bioactive
scaffolds with enhanced bioactivity. Two types of nonstabilized azomethine ylides
were generated in situ and were trapped by the dipolarophiles. Among the methods
for the generation of azomethine ylides, the decarboxylation route offers a general
method in which an aldehyde or a ketone is reacted with a-amino acids.[16] In the
first effort of our synthetic studies, we generated in situ a nonstabilized anti-dipole
3 by the decarboxylative condensation reaction of sarcosine with an 1,2-diketone,
isatin (Scheme 1). Second, a triketone, indane-1,2,3-trione, was reacted with
sarcosine to form the anti-ylide 8 (Scheme 2).
Arylidene cycloheptanones and arylidene cyclooctanones were used as dipolar-
ophiles toward 1,3-dipolar cycloaddition reactions. Thus, arylidene cycloheptanones
4a–d and arylidene cyclooctanones 4e–h were prepared by condensation of cyclohep-
tanone and cyclooctanone, respectively, with aromatic aldehydes in the presence of
a base catalyst.[17,18] The geometry of the olefinic double bond was found to be
1
E configuration in all cases, as evidenced by H NMR spectra.
Synthesis of Dispirooxindolo Cycloalkanone Pyrrolidines
In a one-pot reaction, a solution of 2-arylidene-1-cycloheptan=octan-ones 4a–h
in methanol with isatin 1 and sarcosine 2 was refluxed for 3–4.5 h to afford a series of
1-N-methyl-spiro[2.30]oxindole-spiro[3.200]100-cycloheptan=octan-one-4-aryl-pyrrolidines
5a–h (Scheme 3; Table 1, entries 1–8). The reaction gave single products in all cases, as
evidenced by thin-layer chromatography (TLC).
The cycloadducts have been formed through regioselective cycloaddition of
azomethine ylide 3 to the exocyclic double bond of the 2-arylidene-1-cycloheptan=
octanones, 4a–h, in all cases (Scheme 4). No traces of other regioisomers (6a–h) were
detected.
The regio- and stereochemical outcomes of the cycloaddition were determined
by spectroscopic data. For instance, the infrared (IR) spectrum of the product 5e
exhibited a peak at 1693 cmꢀ1 for cyclooctanone carbonyl, at 1716 cmꢀ1 for the
oxindole carbonyl, and at 3180 cmꢀ1 for the NH absorption of the oxindole ring.
Scheme 1. Generation of azomethine ylide from isatin and sarcosine.

INDOLOPYRROLIDINES AND INDANOPYRROLIDINES
553
Scheme 2. Generation of azomethine ylide from ninhydrin and sarcosine.
Scheme 3. Reaction of azomethine ylide generated from isatin and cycloalkanones.
Table 1. Cycloaddition of azomethine ylide generated from isatin=sarcosine and ninhydrin=
sarcosine toward arylidene cycloheptanones 4a–d and arylidene cyclooctanones 4e–h
Yield
(%)
Mp
(ꢁC)
Reaction
time (h)
Entry
Product
R
n
1
2
5a
5b
5c
5d
5e
5f
H
Cl
69
71
68
67
70
71
65
64
71
73
68
67
68
67
66
69
1
1
1
1
2
2
2
2
1
1
1
1
2
2
2
2
210–212
224–226
192–194
207–209
188–190
160–162
199–201
188–190
128–130
169–171
139–141
151–153
120–122
162–164
142–144
159–161
4
4.5
4
3
Me
OMe
H
4
3.5
3
5
6
Cl
5
7
5g
5h
9a
9b
9c
9d
9e
9f
Me
OMe
H
4.5
3
8
9
5
10
11
12
13
14
15
16
Cl
4.5
5
Me
OMe
H
6
5.5
5
Cl
Me
OMe
9g
9h
6.5
5.5

554
M. POORNACHANDRAN, M. JAYAGOBI, AND R. RAGHUNATHAN
Scheme 4. Mode of attack of dipole 3 on the dipolarophile 4.
1
In the H NMR spectrum of 5e, the cyclooctyl protons exhibited a cluster of
multiplets in the range d 0.63–2.47. The N-methyl protons appeared as a singlet at
d 2.12. The two NCH2 protons appeared as two distorted triplets at (3.39 and
3.75. The benzylic proton appeared as a triplet at d 4.83. The unusual triplet splitting
patterns rather than doublet of doublets for these protons may be due to the geo-
metrical disposition of the atoms and is analogous with our previous report.[19]
The NH proton of the oxindole ring was observed as a singlet at d 9.16. The 13C
NMR spectrum of 5e exhibited a peak at 214.04 ppm for cyclooctanone carbonyl
and at 179.26 ppm for oxindole carbonyl carbon. A peak at 59.85 ppm was due to
C3-spiroquarternary carbon, and a peak at 70.85 ppm was due to C2 spirocarbon.
Identical results were obtained for other derivatives of 5a–h.
Furthermore, the structure of cycloadduct 5e was unambiguously corroborated
by single-crystal x-ray diffraction analysis (Fig. 1). The pyrrolidine ring in the
˚
oxindole system is not strictly planar with a slight deviation of C6 by 0.091 A from
the plane of the remaining atoms. The dihedral angle between the six- and
˚
five-membered rings in the oxindole system is 6.5 A. Atom O1 deviates by 0.175 A
˚
Figure 1. ORTEP diagram of 5e.

INDOLOPYRROLIDINES AND INDANOPYRROLIDINES
555
from the plane of atoms C1, C6, N2, C7, and C12. The pyrrolidine ring adopts a
twisted conformation with a pseudo-twofold axis passing through atom C2 and
the midpoint of the C4-N1 bond. It was further observed that the molecule is
stabilized by weak intramolecular C-H . . . O and C-H. . .p interactions.[20]
Synthesis of Dispiroindano Cycloalkanone Pyrrolidines
We performed a similar three-component reaction in which the azomethine
ylide, 8, generated from sarcosine, 2, and ninhydrin, 7, was reacted with dipolarophiles
4a–h to yield a series of novel dispiroindano cycloheptan=octan-one pyrrolidines 9a–h
in good yields. The products were formed by the regioselective cycloaddition of the
ylide, 8, across the exocyclic double bond of the dipolarophiles 4a–h (Schemes 5
and 6; Table 1, entries 9–16).
The structure and regiochemistry of the products 9a–h were established by IR,
1H and 13C NMR spectroscopic, and mass spectrometric studies. For instance, the
1H NMR spectrum of compound 9e showed a sharp singlet at d 2.20 due to
N-methyl protons and multiplets in the range d 0.72–2.51 due to cyclooctyl protons.
One of the N-CH2 protons exhibited a doublet of doublet at d 3.48 (J ¼ 9 and 6 Hz),
whereas the other proton appeared as a triplet at d 3.66 (J ¼ 9 Hz). The benzylic pro-
ton appeared as a doublet of doublet at d 4.48 (J ¼ 9 and 6 Hz). If the other regiomer
10e had formed, a singlet would be observed for the benzylic proton.
In the 13C NMR spectrum of cycloadduct 9e, the spiroquaternary carbons
showed peaks at 74.68 ppm and 78.43 ppm. The two unsymmetrical ninhydrin car-
bonyl carbons resonated at 201.60ppm and 203.29ppm, whereas the ketone carbonyl
of cyclooctanone ring exhibited a peak at 214.20ppm. The mass spectrum of 9e exhib-
ited the molecular ion peak at m=z 401.98, and the compound gave satisfactory
elemental analysis. The regiochemistry of the cycloaddition reaction was further con-
firmed by the single-crystal x-ray diffraction analysis of 9b and 9e (Figs. 2 and 3).[21,22]
In the molecular structure of 9e, the indanedione group is planar, with
˚
a maximum deviation of 0.069 A for atom C1. The keto atoms O1 and O2
˚
deviate from the mean plane through the fused-ring system by 0.241 and 0.236 A,
Scheme 5. Reaction of azomethine ylide generated ninhydrin with cycloalkanones.

556
M. POORNACHANDRAN, M. JAYAGOBI, AND R. RAGHUNATHAN
Scheme 6. Mode of attack of dipole 8 on the dipolarophile 4.
Figure 2. ORTEP diagram of 9b.
Figure 3. ORTEP diagram of 9e.

INDOLOPYRROLIDINES AND INDANOPYRROLIDINES
557
respectively. The dihedral angle between the fused six-membered and five-membered
˚
rings is 1.2 A. The cyclooctanone ring adopts a boat–chair conformation. The mol-
ecular structure is stabilized by weak C-H- - -O interactions and further influenced by
˚
a C-H- - -p interaction, such that atom H15b is 2.66 A from the centoid of the C21–
C26 benzene ring, with a C15-H15B- - -centroid angle of 154 and a C15 . . . . centroid
˚
distance of 3.557 A.
CONCLUSION
In conclusion, a novel synthesis of some dispiropyrrolidines containing
cycloalkanone, oxindole, and indanedione moieties has been accomplished in a
one-pot, three-component 1,3-dipolar cycloaddition reaction. It was observed that
the nonstabilized azomethine ylide generated by the reaction between diketone=
triketone and secondary a-amino acids added regioselectively across the exocyclic
double bonds of the dipolarophiles to give novel spiroheterocycles.
EXPERIMENTAL
General Considerations
IR spectra were recorded on a Shimadzu IR-8300 series Fourier transform
(FT)–IR spectrophotometer. 1H NMR and 13C NMR spectra were recorded on a Jeol
400-MHz instrument in CDCl3 solvent with tetramethylsilane (TMS) as a standard.
Mass spectra were recorded on a Jeol-DX303 HF mass spectrometer. Elemental
analyses were carried out on a Perkin-Elmer CHNS 2400 instrument. Single-crystal
x-ray diffraction analysis was performed using a Endraf-Nonius CHD4 diffract-
ometer and Bruker Smart Apex CCD area detector diffractometer. Column chroma-
tography was performed on silica gel (Acme, 100–200 mesh). Routine monitoring of
the reaction was made using thin-layer chromatography (TLC) developed on glass
plates coated with silica gel G (Acme) 25 mm thick and visualized with iodine.
General Procedure for the Synthesis of Cycloadducts 5a–h
A mixture of isatin (0.147 g, 1 mmol), sarcosine (0.089 g, 1 mmol), and aryli-
dene cycloheptan=octan-ones 4a–h (1 mmol) in methanol (20 mL) was refluxed until
the disappearance of the starting materials. The reaction mixture was then concen-
trated in vacuo, diluted with water (50 mL), and extracted with dichloromethane
(50 mL). The organic layer was then washed with brine solution, dried over
anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified
by column chromatography with a hexane–ethyl acetate mixture (8:2) to get pure
products 5a–h in good yields.
Selected Data
1-N-Methyl-spiro[2.30]oxindole-spiro[3.200]100-cycloheptanone-4-phenyl-
pyrrolidine, 5a. Colorless solid, 69% (0.258 g); mp: 210–212ꢁC; IR (KBr): 1714,
1
1696, 1476, 2913 and 3397 cmꢀ1; H NMR (CDCl3, 400 MHz): d 0.88–2.10 (m,

558
M. POORNACHANDRAN, M. JAYAGOBI, AND R. RAGHUNATHAN
10H, cycloheptyl), 2.15 (s, 3H, N-Me), 3.36 (t, 1H, NCH2), 3.83 (t, 1H, NCH2), 4.82
(t, 1H, benzyl), 6.72–7.47 (m, 9H, Ar-H), 8.34 (s, 1H, NH); 13C NMR (CDCl3,
100 MHz): 24.89, 27.55, 29.90, 30.67, 43.11, 45.00, 55.32, 59.65, 68.66, 109.29,
113.97, 122.03, 126.69, 126.23, 129.10, 131.10, 131.21, 141.55, 158.11, 178.60 and
212.65 ppm; mass spectrum (EI, 70 eV): m=z 374.20 (Mþ). Anal. calcd. for
C24H26N2O2: C, 76.98; H, 7.00; N, 7.48%. Found: C, 75.87; H, 7.12; N, 7.39%.
1-N-Methyl-spiro[2.30]oxindole-spiro[3.200]100-cycloheptanone-4-(p-chloro)
phenyl-pyrrolidine, 5b. Colorless solid; 71% (0.289 g); mp: 224–226ꢁC; IR
;
(KBr): 1714, 1693, 1477, 2911 and 3396 cmꢀ1 1H NMR (CDCl3, 400 MHz): d
0.88–2.09 (m, 10H, cycloheptyl), 2.14 (s, 3H, N-Me), 3.37 (t, 1H, NCH2), 3.84 (t,
1H, NCH2), 4.81 (t, 1H, benzyl), 6.67–7.47 (m, 8H, Ar-H), 8.24 (s, 1H, NH); 13C
NMR (CDCl3, 100 MHz): 24.87, 27.11, 29.90, 30.66, 43.31, 45.17, 55.66, 59.69,
68.11, 109.93, 113.77, 122.33, 126.66, 126.09, 129.18, 131.13, 131.29, 141.37,
158.30, 178.66 and 212.06 ppm; mass spectrum (EI, 70 eV): m=z 408.16 (Mþ). Anal.
calcd. for C24H25ClN2O2: C, 70.49; H, 6.16; N, 6.85%. Found: C, 70.38; H, 6.23; N,
6.73%.
1-N-Methyl-spiro[2.30]oxindole-spiro[3.200]100-cycloheptanone-4-(p-methyl)-
phenylpyrrolidine, 5c. Colorless solid, 68% (0.263 g); mp: 192–194ꢁC; IR (KBr):
1
1717, 1690, 1474, 2913 and 3396 cmꢀ1; H NMR (CDCl3, 400 MHz): d 0.87–2.09
(m, 10H, cycloheptyl), 2.12 (s, 3H, Ar-Me), 2.14 (s, 3H, N-Me), 3.37 (t, 1H,
NCH2), 3.84 (t, 1H, NCH2), 4.82 (t, 1H, benzyl), 6.77–7.40 (m, 8H, Ar-H), 8.34
(s, 1H, NH); 13C NMR (CDCl3, 100 MHz): 21.01, 24.23, 27.56, 29.67, 30.67,
35.44, 43.55, 45.34, 55.11, 59.34, 68.00, 109.12, 113.78, 122.46, 126.00, 126.16,
129.73, 131.34, 131.67, 141.30, 158.47, 178.13 and 212.49 ppm; mass spectrum (EI,
70 eV): m=z 388.22 (Mþ). Anal. calcd. for C25H28N2O2: C, 77.29; H, 7.26; N,
7.21%. Found: C, 77.20; H, 7.38; N, 7.30%.
1-N-Methyl-spiro[2.30]oxindole-spiro[3.200]100-cycloheptanone-4-(p-meth-
oxy)phenylpyrrolidine, 5d. Colorless solid, 67% (0.268 g); mp: 207–209ꢁC; IR
1
(KBr): 1715, 1693, 1474, 2912.3 and 3398 cmꢀ1; H NMR (CDCl3, 400 MHz): d
0.90–2.09 (m, 10H, cycloheptyl), 2.15 (s, 3H, N-Me), 3.38 (t, 1H, NCH2), 3.84
(t, 1H, NCH2), 3.79 (s, 3H, OMe), 4.80 (t, 1H, benzyl), 6.83–7.47 (m, 8H, Ar-H),
8.11 (s, 1H, NH); 13C NMR (CDCl3, 100 MHz): 24.45, 27.82, 29.91, 30.25, 35.01,
43.30, 45.17, 55.19, 59.66, 68.13, 109.63, 113.47, 122.89, 126.59, 126.76, 129.38,
131.14, 131.89, 141.30, 158.33, 178.26 and 212.76 ppm; mass spectrum (EI, 70 eV):
m=z 401.48 (Mþ). Anal. calcd. for C25H28N2O3: C, 74.23; H, 6.98; N, 6.93%. Found:
C, 74.38; H, 6.87; N, 6.99%.
1-N-Methyl-spiro[2.30]oxindole-spiro[3.200]100-cyclooctanone-4-phenyl
pyrrolidine, 5e. Colorless solid, 70% (0.271 g); mp: 188–190ꢁC; IR (KBr): 1716,
1
1693, 1473, 2912 and 3398 cmꢀ1; H NMR (CDCl3, 400 MHz): d 0.64–2.48 (m,
12H, cyclooctyl), 2.12 (s, 3H, N-Me), 3.39 (t, 1H, NCH2), 3.75 (t, 1H, NCH2),
4.83 (t, 1H, benzyl), 6.92–7.67 (m, 9H, Ar-H), 9.16 (s, 1H, NH); 13C NMR (CDCl3,
100 MHz): 23.67, 25.06, 26.88, 27.12, 28.00, 35.21, 40.43, 45.06, 59.85, 70.85, 110.00,
122.70, 126.65, 127.27, 128.18, 128.41, 129.38, 130.05, 133.28, 140.89, 141.24, 179.26
and 214.04 ppm; mass spectrum (EI, 70 eV): m=z 388.37 (Mþ). Anal. calcd. for
C25H28N2O2: C, 77.29; H, 7.26; N, 7.21%. Found: C, 77.21; H, 7.35; N, 7.10%.

INDOLOPYRROLIDINES AND INDANOPYRROLIDINES
559
1-N-Methyl-spiro[2.30]oxindole-spiro[3.200]100-cyclooctanone-4-(p-chloro)-
phenylpyrrolidine, 5f. Colorless solid, 71% (0.299 g); mp: 160–162ꢁC; IR (KBr):
1
1715, 1695, 1473, 2912 and 3397 cmꢀ1; H NMR (CDCl3, 400 MHz): d 0.64–2.38
(m, 12H, cyclooctyl), 2.14 (s, 3H, N-Me), 3.41 (t, 1H, NCH2), 3.74 (t, 1H, NCH2),
4.81 (t, 1H, benzyl), 6.89–7.66 (m, 8H, Ar-H), 8.67 (s, 1H, NH); 13C NMR (CDCl3,
100 MHz): d 23.70, 25.12, 26.43, 28.43, 35.99, 40.54, 45.24, 59.46, 70.90, 109.98,
122.70, 126.70, 127.31, 128.29, 130.30, 140.11, 141.29, 178.61 and 214.23; mass spec-
trum (EI, 70 eV): m=z 422.18 (Mþ). Anal. calcd. for C25H27ClN2O2: C, 70.99; H,
6.43; N, 6.62%. Found: C, 70.84; H, 6.52; N, 6.50%.
1-N-Methyl-spiro[2.30]oxindole-spiro[3.200]100-cyclooctanone-4-(p-methyl)-
phenylpyrrolidine, 5g. Colorless solid, 65% (0.261 g); mp: 199–201ꢁC; IR (KBr):
1
1715, 1696, 1473, 2912 and 3398cmꢀ1; H NMR (CDCl3, 400 MHz): d 0.69–2.42 (m,
12H, cyclooctyl), 2.12 (s, 3H, Ar-CH3), 2.15 (s, 3H, N-Me), 3.43 (t, 1H, NCH2), 3.75
(t, 1H, NCH2), 4.81 (t, 1H, benzyl), 6.77–7.56 (m, 8H, Ar-H), 8.37 (s, 1H, NH); 13C
NMR (CDCl3, 100 MHz): 221.34, 23.34, 25.56, 26.77, 28.88, 35.34, 40.87, 45.89,
59.44, 70.80, 109.34, 122.86, 126.29, 127.83, 128.74, 130.55, 140.58, 141.09, 178.99
and 214.99 ppm; mass spectrum (EI, 70eV): m=z 402.23 (Mþ). Anal. calcd. for
C26H30N2O2: C, 77.58; H, 7.51; N, 6.96%. Found: C, 77.47; H, 7.62; N, 6.82%.
1-N-Methyl-spiro[2.30]oxindole-spiro[3.200]100-cyclooctanone-4-(p-meth-
oxy)phenylpyrrolidine, 5h. Colorless solid, 64% (0.274 g); mp: 188–190ꢁC; IR
;
(KBr): 1716, 1695, 1474, 2912 and 3397 cmꢀ1 1H NMR (CDCl3, 400 MHz): d
0.66–2.46 (m, 12H, cyclooctyl), 2.15 (s, 3H, N-Me), 3.43 (t, 1H, NCH2), 3.75 (t,
1H, NCH2), 3.78 (s, 3H, OMe), 4.82 (t, 1H, benzyl), 6.70–7.56 (m, 8H, Ar-H), 8.47
(s, 1H, NH); 13C NMR (CDCl3, 100 MHz): d 23.34, 25.16, 26.72, 28.23, 35.33,
40.56, 45.55, 59.41, 70.80, 109.67, 122.88, 126.11, 127.77, 128.22, 130.88, 140.13,
141.07, 178.23 and 214.67; mass spectrum (EI, 70 eV): m=z 428.23 (Mþ). Anal. calcd.
for C26H30N2O3: C, 74.61; H, 7.22; N, 6.69%. Found: C, 74.50; H, 7.34; N, 6.81%.
General Procedure for the Synthesis of Cycloadducts, 9a–h
A mixture of ninhydrin (0.178 g, 1 mmol), sarcosine (0.089 g, 1 mmol), and ary-
lidenecycloheptanones 4a–d=arylidenecyclooctanones 4e–h (1 mmol) in methanol
(20 mL) was refluxed until the disappearance of starting materials as shown by the
TLC analysis. The reaction mixture was then concentrated in vacuo, diluted with
water (50 mL), and extracted with dichloromethane (50 mL). The organic layer
was washed with brine solution, dried over anhydrous sodium sulfate, and concen-
trated in vacuo. The residue was purified by column chromatography with hexane–
ethyl acetate mixture (8:2) to get compounds 9a–h in good yields. The cycloadducts
9a and 9e were recrystallized from methanol by slow evaporation method for x-ray
crystallographic analysis.
Selected Data
1-N-Methyl-spiro[2.10]-indane,10,30-dione-spiro[3.200]100-cycloheptanone-
4-phenylpyrrolidine, 9a. Orange=red solid, 71% (0.274 g); mp: 128–130ꢁC; IR
1
(KBr): 1742, 1716 and 1705 cmꢀ1; H NMR (CDCl3, 400 MHz): d 0.73–2.51 (m,

560
M. POORNACHANDRAN, M. JAYAGOBI, AND R. RAGHUNATHAN
10H, cycloheptyl), 2.22 (s, 3H, N-Me), 3.48 (dd, 1H, N-CH2, J ¼ 6, 9 Hz), 3.69 (t, 1H,
NCH2, J ¼ 9 Hz), 4.47 (dd, 1H, benzyl, J ¼ 6, 9 Hz), 7.28–7.99 (m, 9H, Ar-H); 13C
NMR (CDCl3, 100 MHz): 24.53, 26.66, 26.08, 29.07, 35.98, 39.64, 48.54, 61.75,
74.34, 78.43, 122.11, 122.54, 127.98, 128.03, 128.41, 129.27, 130.73, 135.45, 136.25,
139.38, 141.53, 142.10, 201.77, 203.09 and 214.83 ppm; mass spectrum (EI, 70 eV):
m=z 387.18 (Mþ). Anal. calcd. for C25H25NO3: C, 77.49; H, 6.50; N, 3.61%. Found:
C, 77.61; H, 6.41; N, 3.74%.
1-N-Methyl-spiro[2.10]-indane,10,30-dione-spiro[3.200]100-cycloheptanone-
4-(p-chloro)phenylpyrrolidine, 9b. Orange=red solid, 73% (0.307 g); mp:
1
169–171ꢁC; IR (KBr): 1743, 1718 and 1704 cmꢀ1; H NMR (CDCl3, 400 MHz): d
0.76–2.32 (m, 10H, cycloheptyl), 2.20 (s, 3H, N-Me), 3.39 (dd, 1H, N-CH2, J ¼ 6,
9 Hz), 3.66 (t, 1H, NCH2, J ¼ 9 Hz), 4.44 (dd, 1H, benzyl, J ¼ 6, 9 Hz), 7.29–7.99
(m, 8H, Ar-H); 13C NMR (CDCl3, 100 MHz): d 24.79, 26.98, 28.90, 35.43, 40.33,
46.90, 61.12, 122.65, 122.76, 128.35, 128.96, 130.68, 131.52, 135.67, 136.04, 138.10,
141.25, 142.72, 201.87, 202.53 and 213.53; mass spectrum (EI, 70 eV): m=z 421.14
(Mþ). Anal. calcd. for C25H24ClNO3: C, 71.17; H, 5.73; N, 3.32%. Found: C,
71.28; H, 5.81; N, 3.20%.
1-N-Methyl-spiro[2.10]-indane,10,30-dione-spiro[3.200]100-cycloheptanone-
4-(p-methyl)phenylpyrrolidine, 9c. Orange=red solid, 68% (0.272 g); mp:
1
139–141ꢁC; IR (KBr): 1742, 1714 and 1704 cmꢀ1; H NMR (CDCl3, 400 MHz): d
0.73–2.51 (m, 10H, cycloheptyl), 2.19 (s, 3H, Ar-Me), 2.24 (s, 3H, N-Me), 3.49
(dd, 1H, N-CH2, J ¼ 6, 9 Hz), 3.67 (t, 1H, NCH2, J ¼ 9 Hz), 4.48 (dd, 1H, benzyl,
J ¼ 6, 9 Hz), 7.09–7.96 (m, 8H, Ar-H); 13C NMR (CDCl3, 100 MHz): 21.89, 24.53,
26.67, 26.88, 29.43, 35.56, 39.46, 48.85, 61.42, 74.12, 78.43, 122.86, 122.65, 127.23,
128.86, 128.98, 129.29, 130.79, 135.45, 136.54, 139.08, 141.99, 142.34, 201.09,
203.64 and 214.98 ppm; mass spectrum (EI, 70 eV): m=z 401.20 (Mþ). Anal. calcd.
for C26H27NO3: C, 77.78; H, 6.78; N, 3.49%. Found: C, 77.89; H, 6.87; N, 3.40%.
1-N-Methyl-spiro[2.10]-indane,10,30-dione-spiro[3.200]100-cycloheptanone-
4-(p-methoxy)phenylpyrrolidine, 9d. Orange=red solid, 67% (0.279 g); mp:
1
151–153ꢁC; IR (KBr): 1742, 1714 and 1704 cmꢀ1. H NMR (CDCl3, 400 MHz): d
0.73–2.51 (m, 10H, cycloheptyl), 2.24 (s, 3H, N-Me), 3.49 (dd, 1H, N-CH2, J ¼ 6,
9 Hz), 3.67 (t, 1H, NCH2, J ¼ 9 Hz), 3.79 (s, 3H, Ar-OMe), 4.48 (dd, 1H, benzyl,
J ¼ 6, 9 Hz), 7.09–7.96 (m, 8H, Ar-H); 13C NMR (CDCl3, 100 MHz): 24.53, 26.67,
26.88, 29.43, 34.56, 35.56, 39.46, 48.85, 61.42, 74.12, 78.43, 122.86, 122.65, 127.23,
128.86, 128.98, 129.29, 130.79, 135.45, 136.54, 139.08, 141.99, 142.34, 201.09,
203.64 and 214.98; mass spectrum (EI, 70 eV): m=z 417.19 (Mþ). Anal. calcd. for
C26H27NO4: C, 74.80; H, 6.52; N, 3.35%. Found: C, 74.90; H, 6.61; N, 3.23%.
1-N-Methyl-spiro[2.10]-indane,10,30-dione-spiro[3.200]100-cyclooctanone-
4-phenylpyrrolidine, 9e. Orange=red solid, 68% (0.273 g); mp: 120–122ꢁC; IR
1
(KBr): 1743, 1716 and 1704 cmꢀ1; H NMR (CDCl3, 400 MHz): d 0.72–2.51 (m,
12H, cyclooctyl), 2.20 (s, 3H, N-Me), 3.48 (dd, 1H, N-CH2, J ¼ 6, 9 Hz), 3.66 (t,
1H, NCH2, J ¼ 9 Hz), 4.48 (dd, 1H, benzyl, J ¼ 6, 9 Hz), 7.28–7.99 (m, 9H, Ar-H);
13C NMR (CDCl3, 100 MHz): d 24.72, 25.75, 26.24, 26.79, 29.03, 35.61, 39.92,
48.04, 61.52, 74.68, 78.43, 122.14, 122.90, 127.18, 128.23, 128.44, 129.65, 130.72,
135.45, 136.35, 139.78, 141.21, 142.22, 201.60, 203.29 and 214.20; mass spectrum

INDOLOPYRROLIDINES AND INDANOPYRROLIDINES
561
(EI, 70 eV): m=z 401.98 (Mþ). Anal. calcd. for C26H27NO3: C, 77.78; H, 6.78; N,
3.49%. Found: C, 77.85; H, 6.85; N, 3.40%.
1-N-Methyl-spiro[2.10]-indane,10,30-dione-spiro[3.200]100-cyclooctanone-
4-(p-chloro)phenylpyrrolidine, 9f. Orange=red solid, 67% (0.291 g); mp: 162–
1
164ꢁC; IR (KBr): 1742, 1713 and 1705 cmꢀ1; H NMR (CDCl3, 400MHz): d 0.76–
2.35 (m, 12H, cyclooctyl), 2.17 (s, 3H, N-Me), 3.37 (dd, 1H, N-CH2, J ¼ 6, 9 Hz), 3.66
(t, 1H, NCH2, J ¼ 9 Hz), 4.49 (dd, 1H, benzyl, J ¼ 6, 9 Hz), 7.28–7.99 (m, 8H, Ar-H);
13C NMR (CDCl3, 100MHz): d 24.58, 25.81, 26.43, 28.93, 35.54, 40.02, 46.96, 61.41,
122.26, 122.96, 128.35, 128.66, 130.87, 131.85, 135.69, 136.44, 138.70, 141.22, 142.02,
201.33, 202.94 and 213.50; mass spectrum (EI, 70eV): m=z 435.16 (Mþ). Anal. calcd.
for C26H26ClNO3: C, 71.63; H, 6.01; N, 3.21%. Found: C, 71.54; H, 6.10; N, 3.30%.
1-N-Methyl-spiro[2.10]-indane,10,30-dione-spiro[3.200]100-cyclooctanone-
4-(p-methyl)phenylpyrrolidine, 9g. Orange solid, 66% (0.274 g); mp: 142–144ꢁC;
1
IR (KBr): 1742, 1712 and 1704 cmꢀ1; H NMR (CDCl3, 400 MHz): d 0.71–2.50 (m,
12H, cyclooctyl), 2.20 (s, 3H, Ar-Me), 2.23 (s, 3H, N-Me), 3.50 (dd, 1H, N-CH2,
J ¼ 6, 9 Hz), 3.67 (t, 1H, NCH2, J ¼ 9 Hz), 4.49 (dd, 1H, benzyl, J ¼ 6, 9 Hz),
7.00–7.90 (m, 8H, Ar-H); 13C NMR (CDCl3, 100 MHz): d 21.08, 24.09, 26.97,
26.88, 29.43, 35.77, 39.47, 48.37, 61.13, 74.67, 78.89, 122.86, 122.67, 127.20,
128.82, 128.88, 129.20, 130.75, 135.44, 136.56, 139.02, 141.93, 142.39, 201.05,
203.66 and 214.48; mass spectrum (EI, 70 eV): m=z 415.21 (Mþ). Anal. calcd. for
C27H29NO3: C, 78.04; H, 7.03; N, 3.37%. Found: C, 78.17; H, 6.92; N, 3.30%.
1-N-Methyl-spiro[2.10]-indane,10,30-dione-spiro[3.200]100-cyclooctanone-
4-(p-methoxy)phenylpyrrolidine, 9h. Orange=red solid, 69% (0.297 g); mp:
1
159–161ꢁC; IR (KBr): 1743, 1713 and 1704 cmꢀ1; H NMR (CDCl3, 400 MHz): d
0.73–2.51 (m, 10H, cyclooctyl), 2.24 (s, 3H, N-Me), 3.47 (dd, 1H, N-CH2, J ¼ 6,
9 Hz), 3.67 (t, 1H, NCH2, J ¼ 9 Hz), 3.77 (s, 3H, Ar-OMe), 4.49 (dd, 1H, benzyl,
J ¼ 6, 9 Hz), 7.00–7.96 (m, 8H, Ar-H); 13C NMR (CDCl3, 100 MHz): d 24.58,
26.07, 26.82, 29.87, 34.54, 35.76, 39.09, 48.34, 61.42, 74.10, 78.47, 122.85, 122.65,
127.33, 128.87, 128.90, 129.20, 130.77, 135.40, 136.64, 139.18, 141.98, 142.34,
201.49, 203.66 and 214.92; mass spectrum (EI, 70 eV): m=z 431.21 (Mþ). Anal. calcd.
for C27H29NO4: C, 75.15; H, 6.77; N, 3.25%. Found: C, 75.25; H, 6.66; N, 3.37%.
ACKNOWLEDGMENTS
Poornachandran thanks the Council of Scientific and Industrial Research
(CSIR), New Delhi, India, for the award of senior research fellowship (SRF).
M. J. thanks the University Grants Commission (UGC) for the fellowship. Financial
support from DST and DST-FIST (Department of Science and Technology),
New Delhi, India, is also gratefully acknowledged.
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