Novel three-component domino reactions of ketones, isatin and amino acids: Synthesis and discovery of antimycobacterial activity of highly functionalised novel dispiropyrrolidines

Article abstract of DOI:10.1016/j.ejmech.2009.09.044

One-pot three-component domino reactions of cyclic mono ketones, isatin and sarcosine/phenylglycine furnishing highly functionalised dispiropyrrolidines in moderate yields are described. The reaction when performed with cyclic amino acid, proline resulted

Full text of DOI:10.1016/j.ejmech.2009.09.044

European Journal of Medicinal Chemistry 45 (2010) 411–422
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Preliminary communication
Novel three-component domino reactions of ketones, isatin and amino acids:
Synthesis and discovery of antimycobacterial activity of highly functionalised
novel dispiropyrrolidines
,
b
Raju Suresh Kumar a, Stephen Michael Rajesh a, Subbu Perumal a , Debjani Banerjee ,
*
Perumal Yogeeswari b, Dharmarajan Sriram b
a Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625021, India
b Medicinal Chemistry & Antimycobacterial Research Laboratory, Pharmacy Group, Birla Institute of Technology & Science - Pilani, Hyderabad Campus,
Jawahar Nagar, Hyderabad–500 078, Andhra Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
One-pot three-component domino reactions of cyclic mono ketones, isatin and sarcosine/phenylglycine
furnishing highly functionalised dispiropyrrolidines in moderate yields are described. The reaction
when performed with cyclic amino acid, proline resulted in the dimerization of azomethine ylides.
These compounds have been screened for their in vitro activity against Mycobacterium tuberculosis
H37Rv (MTB) using agar dilution method. Among thirty eight compounds screened, 1-methyl-
pyrrolo(spiro[2.30]-5-bromooxindole)spiro[3.200]-100-nitrosotetrahydro-400(1H)-pyridinone (4t) was found
Received 26 August 2009
Received in revised form
22 September 2009
Accepted 28 September 2009
Available online 2 October 2009
to be the most active with MIC of 1.98
the standard first line TB drugs, ethambutol and pyrazinamide respectively.
Ó 2009 Elsevier Masson SAS. All rights reserved.
mM against MTB and was 3.86 and 25.64 times more potent than
Keywords:
Cascade reactions
Isatin
Sarcosine
Phenylglycine
Spiropyrrolidines
Anti-tubercular activity
1. Introduction
The derivatives of spirooxindole ring systems are useful as
antimicrobial, antitumour agents and as inhibitors of the human
NKI receptor, besides being found in a number of alkaloids like
horsifiline, spirotryprostatin and (þ)-elacomine [16]. Highly func-
tionalised pyrrolidines constitute the main structural element of
many alkaloids and pharmacologically active compounds [17].
Tuberculosis is an infection caused by Mycobacterium tubercu-
losis and is the leading cause of infectious disease mortality in the
world [18]. Around 1.86 billion people, that is, 32% of the world’s
population is infected [19] with M. tuberculosis (MTB). World
health organization estimates about 8 million new active cases of
tuberculosis (TB) per year and nearly 2 million deaths each year
[19,20], that is, 5000 people every day [21]. HIV positive patients
are more susceptible to MTB with a 50-fold risk increase over HIV
negative patients [22,23]. Similarly, the rate of progression of latent
TB to active disease in HIV positive patients is higher than non-HIV
infected individuals. It is pertinent to note that no new drug
against tuberculosis has been developed in the last 30 years.
Increasing incidence of MTB strains resistant to one or more first
line TB drugs such as isoniazid [24], pyrazinamide [25] and
rifampicin [26] has recently intensified the need to develop new
and more efficient drugs for the treatment of mycobacterial
Domino multi-component reactions offer a rapid access to
highly functionalised complex molecules in a single procedural
step [1,2]. The development of new methods for the synthesis of
N-heterocycles with structural diversity is one of the major inter-
ests of modern synthetic organic chemists [3]. Indole fragment
prevails in a variety of pharmacologically and biologically active
compounds [4]. Oxindole derivatives are known to possess a variety
of biological activities [5] such as (i) potent inhibition of mono-
amine oxidase (MAO) in human urine and rat tissues [6], (ii) inhi-
bition of several enzymes such as acetylcholinestrease (AChE) [7]
and atrial natriuretic peptide-stimulated guanylate cyclase and (iii)
potent antagonist of in vitro receptor binding by atrial natriuretic
peptide [8], besides possessing a wide range of central nervous
system activities [9]. Schiff bases and Mannich bases of isatin were
reported to possess antibacterial [10], antifungal [11], antiviral [12],
anti-HIV [13], antiprotozoal [14], and antihelminthic [15] activities.
* Corresponding author. Tel./fax: þ91 452 2459845.
E-mail address: subbu.perum@gmail.com (S. Perumal).
0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2009.09.044

412
R.S. Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 411–422
infections and this is the subject of numerous recent studies
[27,28].
cyclic mono ketones, isatin and sarcosine in a molar ratio of 1:1:2.
In the present work, this reaction has been investigated further
with four more substituted isatins (Scheme 1) and amino acids,
phenylglycine, proline, thiaproline and pipecolic acid. The three-
component reaction of cyclic mono ketones, isatin and phenyl-
gylcine 5 in a 1:1:2 molar ratio in methanol:water (2:1) at reflux for
24 h (Scheme 2) also furnished novel dispiropyrrolidines 6 in
moderate yields (32–45%) as in the case of reaction with sarcosine.
After completion of the reaction (TLC), the dispiropyrrolidines 6 in
pure form was obtained by column chromatographic purification.
The structure of dispiropyrrolidines 4 and 6 are in accord with
their 1D and 2D NMR spectroscopic data (Figs. 1 and 2). The 1H
NMR spectrum of 6e has two doublets at 4.59 and 5.37 ppm
(J ¼ 11.3 Hz) related by a H,H-COSY correlation assignable to H-4
and H-5 respectively. This is also supported by the HMBC correla-
tion (Fig. 2) of the signal at 4.59 ppm with the carbonyl carbon at
207.2 ppm, besides correlating with (i) C-5 at 62.9 ppm, (ii) spiro
carbon C-3 at 68.5 ppm and (iii) C-20 at 58.9 ppm. H-4 and H-5 are
trans to each other. The C,H-COSY correlation of H-4 assigns the
Recently, [29] we have communicated our preliminary results
on the synthesis of dispiropyrrolidines from the novel domino
reactions of isatin, sarcosine and cyclic mono ketones. This manu-
script presents the results of detailed investigations on the
synthetic potential of the domino protocol in the construction of (i)
more dispiroheterocycles of the previously reported series [29] and
(ii) novel spiroheterocycles from the reactions of isatin and cyclic
mono ketones with phenylglycine. The reaction with cyclic amino
acid, proline resulted in the dimerization of azomethine ylides. The
synthesized compounds were subjected to preliminary antituber-
cular screening against M. tuberculosis H37Rv (MTB) and these
results are also presented in this paper.
2. Chemistry
Our previous study [29] reported the synthesis of dis-
piropyrrolidines 4 in moderate yields from the domino reactions of
O
O
O
R
CH3
CH3
O
N
O
3
O
O
O
( )n
N
N
N
R
H
n = 1, 2, 3
3
R'
R" = CH3, N=O
1
NH
R'
NH
( )n
+
N
CH3OH
Reflux
6-7.5 h
CH3OH
Reflux
6-7.5 h
R'
R"
R
CH3NHCH2COOH
R
4
4
2
Comp
Reaction Yield of
n
R
R
R
3 and 4
time (h)
4 (%)
40
45
39
43
38
42
40
38
44
40
39
42
38
52
40
41
43
37
49
38
a
b
c
d
e
f
1
2
3
-
H
H
CH(CH3)2
-
7
6.5
7
CH(CH3)2
-
H
CH(CH3)2
-
H
CH(CH3)2
CH3
6
-
H
CH(CH3)2
N=O
10
7
1
2
3
-
CH3
CH3
CH3
CH3
CH3
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
-
g
h
i
-
6
-
CH3
N=O
-
7.5
6
j
-
10
7
k
l
1
2
3
-
Cl
-
7
m
n
o
p
q
r
s
Cl
-
6.5
6
Cl
CH3
NO
-
-
Cl
10
7.5
6.5
7
1
2
3
-
Br
Br
-
Br
-
Br
CH3
NO
6
t
-
Br
10
Scheme 1. Synthesis of dispiropyrrolidines.

R.S. Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 411–422
413
O
O
O
R
Ph
Ph
N
R"
O
Ph
NH
Ph
O
3
O
( )n
N
O
NH
H
R" = CH3,
O
n = 1, 2, 3
3
R'
( )n
1
CH2C6H5
NH
NH
+
N
R
CH3OH/H2O
CH3OH/H2O
R"
R
COOH
NH2
R'
2:1
Reflux 24 h
2:1
Reflux 24 h
R'
Ph
6
6
H
5
Comp 3
Yield of
6 (%)
35
n
R
R
R
and 6
a
b
c
1
2
3
-
H
H
H
H
H
H
H
H
H
H
H
H
H
H
-
-
38
-
32
d
e
CH3
36
-
CH2C6H5
41
f
1
2
-
CH(CH3)2
-
39
g
h
i
CH(CH3)2
-
CH3
37
CH(CH3)2
40
-
CH(CH3)2
CH2C6H5
-
42
j
2
-
CH3
CH3
CH3
H
H
H
H
H
H
H
H
H
36
k
l
CH3
41
-
CH2C6H5
-
40
m
n
o
p
q
r
2
-
38
Cl
Cl
Cl
Br
Br
Br
CH3
40
-
CH2C6H5
-
41
2
-
36
CH3
39
-
CH2C6H5
40
Scheme 2. Synthesis of dispiropyrrolidines 6.
signal at 54.8 ppm to C-4. The other spiro carbon at 69.8 ppm is
assigned to C-2 as it shows HMBC correlations with (i) the lactum
NH proton at 8.70 ppm, (ii) the aromatic proton of the oxindole ring
and (iii) one of the 20-CH2 protons appearing as a multiplet at 1.66–
1.80 ppm. The other 20-CH2 proton appears as a doublet of doublets
at 3.93 ppm (J ¼ 12.3 and 2.4 Hz). The carbon signal at 50.1 ppm is
assigned to C-60 as it shows HMBC correlations with the 20-CH2
protons and the N–CH2 protons giving doublets at 3.01 and
3.79 ppm (J ¼ 13.2 Hz). The C,H-COSY correlation of C-60 assigns the
multiplets at 1.66–1.80 and 2.51–2.56 ppm to 60-CH2. The multi-
plets centering at 1.44 and 1.99 ppm are due to 50-CH2. The
aromatic protons appear in the region of 6.88–7.50 ppm, the NH
proton of the pyrrolidine ring appears as a singlet at 2.32 ppm and
the oxindole carbonyl appears at 181.9 ppm. The structure of other
spiropyrrolidines was also assigned similarly. X-ray crystallo-
graphic study of a single crystal of 6e (Fig. 3) [30] confirms the
structure deduced from NMR spectroscopic studies.
phenylglycine afford the iminium carboxylic acid
7
which
undergoes (i) decarboxylation to provide the azomethine ylide 13
and (ii) nucleophilic substitution to afford phenylglycolic acid 9.
The latter 9 reacts with isatin to afford benzaldehyde, which reacts
with azomethine ylide 13 to afford the iminium alcohol 14. Then, 14
reacts with enol 3 to furnish 15, which cyclises to afford the dis-
piropyrrolidines 6.
It is found that when this domino protocol was applied to the
reaction of ketone, isatin and cyclic amino acid, (L)-proline 17
(Scheme 4) instead of phenylgylcine/sarcosine, no spiroheterocycle
could be obtained, instead a dimer 18 of azomethine ylide (Scheme
5) was isolated in 32–38% yield, besides a non characterisable polar
mixture. The reaction of isatin (1 mmol) and (L)-proline (1 mmol)
in methanol also afforded the dimer 18 only. In case of entries 5–7
involving thiaproline or pipecolic acid (Scheme 4), no reaction
occurred. Presumably, the absence of formation of the spi-
roheterocycles from cyclic amino acids may be ascribed to their
instability arising from enhanced steric interactions. Probably, the
puckered six membered ring of the pipecolic acid could increase
the steric interactions in the dimer rendering its formation difficult.
Presumably, the regio- and stereoselective formation of the
dispiropyrrolidines 6 occurs via domino reactions (Scheme 3) as
postulated for the reaction of sarcosine [29]. Isatin and

414
R.S. Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 411–422
m, 1.51-1.67
m, 3.02-3.10
m, 2.83-2.92
m, 3.22-3.29
30.4
52.5
H
s, 2.08
35.2
H
H
CH3
O
m, 1.51-1.67
m,2.11-2.13
H
H
1
N
H
CH3
H
O
207.7
H
N
5
O
H
4
O
40.9
H
3
65.8
62.7
H
178.4
H
H
74.2
5"
3"
H
2
H
H
NH s, 8.95
H
54.9
H
NH
H
N
1"
N
2"
6"
H
m, 2.03-2.07,
H-2"ax
m, 2.16-2.17, H-6"ax
m, 2.66-2.72, H-6"eq
CH3
Cl
dd, 3.69, J =12.3, 3.0 Hz,
CH3
Cl
H-2"eq)
s, 2.19
44.7
6.81 (d, 1H, J=8.3 Hz
6.94 (d, 1H, J=2.0 Hz
aromatic
7.20 (dd, 1H, J=8.3, 2.0 Hz
Fig. 1. Selected HMBC correlations and 1H and 13C chemical shifts of 4n.
In the case of thiaproline, the sulfur of the azomethine ylide could
conjugate with the anionic centre of the dipole, which could
diminish its reactivity towards further reactions.
3. Biological results and discussion
The compounds were screened for their in vitro anti-
mycobacterial activity against M. tuberculosis H37Rv by agar dilu-
tion method for the determination of MIC in triplicates. The MIC is
defined as the minimum concentration of compound required to
inhibit 99% of bacterial growth, and the MIC values of the synthe-
sized compounds along with the standard drugs for comparison are
presented in Table 1. All the thirty eight compounds screened in the
Structural elucidation of the dimer 18 was accomplished using
1D and 2D NMR spectroscopic data. The 1H NMR spectrum of 18b,
a representative example, shows a singlet at 2.24 ppm due to the
CH3 linked to the aromatic ring, which shows HMBC correlations
(Fig. 4) with C-40 at 127.0 ppm and C-60 at 129.3 ppm. The
C,H-COSY correlation assigns the doublet at 6.86 ppm (J ¼ 7.8 Hz)
to H-60 and the singlet at 7.30 ppm to H-40. The doublet at
6.39 ppm (J ¼ 7.8 Hz) is assigned to H-70 from its H,H-COSY corre-
lation with H-60. Further, H-60 shows HMBC correlation with C-70a
at 138.1 ppm. From the HMBC correlation of H-40, the signal at
68.6 ppm is assigned to the spiro carbon C-5. A triplet of doublets
at 2.62 ppm (J ¼ 8.7 and 2.7 Hz) and a multiplet at 2.12–2.20 ppm
are assigned to 3-CH2 protons. From the C,H-COSY correlation, the
signal at 47.6 ppm is assigned to C-3. The 1-CH2 and 2-CH2 protons
appear as multiplets centering at 1.60 and 1.79 ppm. The multiplet
at 3.61 ppm is due to H-10a and the C,H-COSY assigns C-10a to
59.1 ppm. The NH proton of the indolinone ring occurs as a singlet
at 7.40 ppm and the carbonyl appears at 176.0 ppm. Selected HMBC
correlations and 1H and 13C chemical shifts of 18b are shown in
Fig. 4.
present study against MTB had MICs ranging from 1.98–160.05
and ten compounds inhibited MTB with MIC less than 10 M. In the
first series (4a–t), all the compounds showed moderate to good
activity, except 4a and 4c, with MICs 1.98–41.89 M and were more
potent than the first-line anti-TB drug pyrazinamide (MIC of
50.77 M). Seven compounds (4e, 4j, 4o–r, and 4t) showed good
activity with MICs less than 10 M. Five compounds (4j, 4o, 4q, 4r
and 4t) with MICs ranging from 1.98–4.75 M are more potent than
mM
m
m
m
m
m
the standard drug ethambutol with MIC of 7.64 mM and the com-
pound 1-methylpyrrolo(spiro[2.30]-5-bromooxindole)spiro[3.200]-
100-nitrosotetrahydro-400(1H)-pyridinone (4t) was found to be most
active with MIC of 1.98
inhibited MTB with MICs ranging from 6.24–118.34
compounds are more potent than pyrazinamide. Compounds 6p
and 6q showed good activity with MIC of 6.24 and 6.06
respectively, being more potent than ethambutol. Among dimers
18a–d, the MIC ranged from 5.61–124.85 M and compound 18d
M showing more
mM. In the second series, 6a–b, 6f–r
m
M and twelve
This domino protocol is more advantageous for the synthesis of
spiropyrrolidines which would otherwise require (i) conversion of
mM
the cyclic mono ketones to
a-methylene/arylideneketones and (ii)
m
the dipolar cycloaddition of the
with azomethine ylides.
a
-methylene/arylidene ketones
was found to be the most active with MIC of 5.61
activity than ethambutol and pyrazinamide.
m
4.59, d,
J =11.3 Hz
5.37, d,
J =11.3 Hz
Ph
Ph
Ph
Ph
H
H
O
1.39-1.49, m
1.94-2.04, m
207.2
H
O
H
H
54.8
4
5
62.9
2.32, s
NH
1
H
NH
5'
6'
O
O
68.5
4'
H
H
40.6
3
2.51-2.56, m
1.66-1.80, m
2'CH2 and 6'CH2
181.9
H
2
69.8
2"
1"
H
H
H
H
H
H
58.9
NH
1'
N
NH 8.70
H
2'
50.1
N
3.93, dd,
J =12.3,2.4 Hz
61.4
Ph
3.01, d
3.79, d
J=13.2 Hz
H
H
Ph
H
H
Fig. 2. Selected HMBC correlations and 1H and 13C chemical shifts of 6e.

R.S. Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 411–422
415
domino reactions of cyclic mono ketones, isatin and sarcosine/
phenylglycine. The reaction with cyclic amino acid, proline resulted
in the dimerization of azomethine ylides. Many of the compounds
synthesized in the present work show good to excellent activity
and those with N-nitroso functionality are found to be more
promising against M. tuberculosis.
5. Experimental
Melting points were taken using open capillary tubes and are
uncorrected. 1H, 13C and two-dimensional NMR spectra were
recorded on a Bruker 300 MHz instrument in CDCl3 using TMS
as internal standard. Chemical shifts are given in parts per million
(d-scale) and the coupling constants are given in Hertz. IR spectra
were recorded on a JASCO FT IR instrument (KBr pellet in case of
solids and CHCl3 in case of liquids). Elemental analyses were per-
formed on a Perkin Elmer 2400 Series II Elemental CHNS analyser.
Column chromatography was performed on silica gel (230–400
mesh) using petroleum ether–ethyl acetate as eluent.
Fig. 3. ORTEP diagram of 6e.
5.1. Synthesis of spiropyrrolidines 4
With respect to the structure-MTB activity, introduction of
substituent in the 5-position of isatin enhances the activity
particularly, bromo substitution showed enhanced activity. In
general, the N-nitroso compounds 4e, 4j, 4o and 4t showed better
activity than the N-Me compounds belonging to 4. Among thirty
eight compounds, 1-methylpyrrolo-(spiro[2.30]-5-bromooxindole)
spiro[3.200]-100nitrosotetrahydro-400(1H)-pyridinone 4t is found to
5.1.1. General procedure
A mixture of isatin (0.350 g, 2.38 mmol), sarcosine (0.424 g,
4.76 mmol) and ketone (0.200 g, 2.38 mmol) in methanol (20 mL)
was refluxed on a water bath for 6–7.5 h. After completion of the
reaction (TLC), the excess solvent was removed under vacuum and
the residue was subjected to flash column chromatography using
petroleum ether:ethyl acetate mixture (4:1 v/v) as eluent.
possess the maximum activity with MIC of 1.98 mM against MTB
5.1.1.1. 1-Methylpyrrolo(spiro[2.30]-8-isopropyloxindole)spiro[3.200]
cyclopentanone (4a). Pale yellow solid; (0.295 g, 40%); mp 181–
182 ꢀC; Anal. Calcd. for C19H24N2O2: C, 73.05; H, 7.74; N, 8.97;
displaying higher activity than the standard drugs, ethambutol and
pyrazinamide.
4. Conclusions
Found: C, 73.09; H, 7.81; N, 8.92. IR (KBr): 1692, 1725, 3296 cmꢁ1
;
1H NMR (300 MHz, CDCl3): dH 1.22–1.38 (m, 6H, CH(CH3)2), 1.55–
1.69 (m, 1H, H-4), 1.82–2.08 (m, 4H, cyclopentanone ring protons),
2.16 (s, 3H, CH3), 2.21–2.36 (m, 3H, H-4 and cyclopentanone ring
The present investigation describes a facile access to highly
functionalised dispiropyrrolidines via one-pot three-component
Scheme 3. Mechanism for the formation of dispiropyrrolidines.

416
R.S. Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 411–422
H
N
R'
O
O
O
R
X
X
CH3OH
Reflux
O
R
+
+
N
COOH
N
N
N
R
N
H
H
R'
X
CH3
O
N
X = CH2, (CH2)2, S
R'
H
3
1
17
18
Comp 1
Yield of 18
Entry
R
R
X
and 18
(%)
36
1
2
3
4
5
6
7
a
b
c
d
e
f
H
CH3
Cl
H
H
H
H
CH2
38
CH2
CH2
CH2
36
Br
32
a
H
H
H
CH(CH3)2
-
CH2
a
H
H
(CH2)2
-
a
g
S
-
aProduct not obtained
Scheme 4. Synthesis of azomethine ylide dimers.
protons), 2.98–3.07 (m, 1H, CH), 3.30–3.38 (m, 1H, H-5), 3.44–3.51
(m, 1H, H-5), 6.95–7.03 (m, 2H, aromatic), 7.16–7.19 (m, 1H,
aromatic), 9.69 (s, 1H, NH). 13C NMR (75 MHz, CDCl3): dC 19.1, 22.4,
22.7, 28.4, 31.6, 33.7, 35.7, 39.0, 51.5, 60.3, 77.2, 123.0, 123.4, 125.4,
126.1, 129.9, 139.5, 179.9.
Found: C, 74.13; H, 8.35; N, 8.17. IR (KBr): 1623, 1720, 3215 cmꢁ1. 1H
NMR (300 MHz, CDCl3): 0.98–1.17 (m, 2H, cycloheptanone ring
d
protons), dH 1.29 (d, 3H, J ¼ 6.9 Hz, (CH3)2), 1.33 (d, 3H, J ¼ 6.9 Hz,
(CH3)2), 1.50–2.06 (m, 7H, H-4 and cycloheptanone ring protons),
2.11 (s, 1H, CH3), 2.13–2.19 (m, 2H, cycloheptanone ring protons),
2.57–2.66 (m, 1H, H-4), 2.97–3.06 (m, 1H, CH), 3.26–3.34 (m, 1H, H-
5), 3.42–3.49 (m, 1H, H-5), 6.81 (d, 1H, J ¼ 7.5 Hz, aromatic), 6.94–
6.99 (m, 1H, aromatic), 7.18 (d, 1H, J ¼ 7.8 Hz, aromatic), 9.43 (s, 1H,
5.1.1.2. 1-Methylpyrrolo(spiro[2.30]-8-isopropyloxindole)spiro[3.200]
cyclohexanone (4b). White solid; (0.300 g, 45%); mp 147–148 ꢀC;
Anal. Calcd. for C20H26N2O2: C, 73.59; H, 8.03; N, 8.58; Found: C,
NH). 13C NMR (75 MHz, CDCl3):
d 22.6, 22.7, 25.2, 27.5, 28.4, 29.8,
73.65; H, 8.10; N, 8.54. IR (KBr): 1689, 1721, 3287 cmꢁ1
.
1H NMR
32.2, 32.8, 35.6, 43.8, 52.1, 64.1, 78.7, 122.5, 123.4, 124.8, 126.0, 130.1,
139.4, 180.0, 216.0.
(300 MHz, CDCl3): dH 1.29 (d, 3H, J ¼ 4.5 Hz, (CH3)2), 1.31 (d, 3H,
J ¼ 4.5 Hz, (CH3)2), 1.42–2.01 (m, 7H, H-4 and cyclohexanone ring
protons), 2.09 (s, 3H, CH3), 2.17–2.18 (m, 1H, cyclohexanone ring
proton), 2.41–2.52 (m, 1H, cyclohexanone ring proton), 2.63–2.71
(m, 1H, H-4), 2.99–3.01 (m, 1H, CH), 3.21–3.34 (m, 2H, H-5), 6.87 (d,
1H, J ¼ 7.2 Hz, aromatic), 6.96–7.01 (m, 1H, aromatic), 7.17 (d, 1H,
J ¼ 7.5 Hz, aromatic), 9.55 (s, 1H, NH). 13C NMR (75 MHz, CDCl3): dC
21.3, 22.2, 22.9, 25.2, 28.4, 33.9, 35.5, 35.6, 41.2, 51.8, 62.4, 77.1,
122.7, 124.0, 125.9, 126.8, 130.2, 139.1, 180.0, 212.5.
5.1.1.4. 1-Methylpyrrolo(spiro[2.30]-8-isopropyloxindole)spiro[3.200]-10-
methylpiperidin-4-one (4d). Yellow solid; (0.260 g, 43%); mp 128–
129 ꢀC; Anal. Calcd. for C20H27N3O2: C, 70.35; H, 7.97; N, 12.31;
Found: C, 70.41; H, 7.94; N, 12.37. IR (KBr): 1706, 1733, 3210 cmꢁ1
.
1H NMR (300 MHz, CDCl3): dH 1.27–1.32 (m, 6H, CH(CH3)2), 1.51–
1.62 (m, 2H, H-4 and H-500), 1.97–2.01 (m, 1H, H-500), 2.05 (d, 1H,
J ¼ 12.3 Hz, H-200ax), 2.09 (s, 3H, 1-N–CH3), 2.12-2.18 (m, 1H, H-
600ax), 2.19 (s, 3H, 100-N–CH3), 2.60–2.66 (m, 1H, H-600eq), 2.84–2.93
(m, 1H, H-4), 3.01–3.14 (m, 2H, CH and H-5), 3.25–3.32 (m, 1H, H-5),
3.70 (dd, 1H, 12.3, 2.4 Hz, H-200eq), 6.28 (d, 1H, J ¼ 7.2 Hz, aromatic),
6.90–6.95 (m, 1H, aromatic), 7.14 (d, 1H, J ¼ 7.5 Hz, aromatic), 9.33
5.1.1.3. 1-Methylpyrrolo(spiro[2.30]-8-isopropyloxindole)spiro[3.200]
cycloheptanone (4c). Pale yellow solid; (0.235 g, 39%); mp 185–
186 ꢀC; Anal. Calcd. for C21H28N2O2: C, 74.08; H, 8.29; N, 8.23;
O
R
O
N
R
H
N
O
N
N
H
N
R'
R
R'
18
+
O
N
O
N
R'
H
H
R'
COOH
N
H
R
Scheme 5. Formation of dimer 18.

R.S. Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 411–422
417
1.60, m
1.79, m
1.60, m
1.79, m
2.16, m
2.62, td
20.8
27.4
3.61, m
59.1
J =8.7, 2.7 Hz
47.6
O
H
H
H
H
H
H
H
O
N
H
H
N
H
H
7.30, s
127.0
1
H
H
H
H
2
3
10
H
10a
5
N
4
H3C
126.3
2.24, s
21.1
N
N
H
9
68.6
N
4'
CH3
CH3
8
3'
3'a
H3C
5a
5'
6.86, d
J =7.8 Hz
129.3
O
7
H
2'
131.6
7'a
O
6
N
6'
176.0
N
H
1'
H
H
7'
H
138.1
H
6.39, d
7.40, s
J =7.8 Hz
108.6
Fig. 4. Selected HMBC correlations and 1H and 13C chemical shifts of 18b.
(s, 1H, NH). 13C NMR (75 MHz, CDCl3): dC 22.1, 22.8, 28.4, 30.3, 35.2,
40.6, 44.8, 52.2, 55.0, 62.9, 65.1, 74.6, 122.1, 123.9, 125.3, 127.2, 129.6,
139.1, 179.0, 208.4.
Anal. Calcd. for C17H20N2O2: C, 71.81; H, 7.09; N, 9.85; Found: C,
71.87; H, 7.16; N, 9.81. IR (KBr): 1692, 1728, 3292 cmꢁ1 1H NMR
.
(300 MHz, CDCl3): dH 1.26–1.41 (m, 1H, cyclopentanone ring
proton), 1.59–1.68 (m, 1H, H-4), 1.83–2.06 (m, 3H, cyclopentanone
ring protons), 2.15 (s, 3H, CH3), 2.19–2.24 (m, 1H, cyclopentanone
ring proton), 2.27 (s, 3H, CH3), 2.31–2.41 (m, 2H, H-4 and cyclo-
pentanone ring proton), 3.28–3.56 (m, 1H, H-5), 3.43–3.49 (m, 1H,
H-5), 6.74 (d, 1H, J ¼ 7.8 Hz, aromatic), 6.99 (s,1H, aromatic), 7.04 (d,
1H, J ¼ 7.8 Hz, aromatic), 9.19 (s, 1H, NH). 13C NMR (75 MHz, CDCl3):
dC 19.1, 21.0, 31.6, 33.6, 35.7, 39.0, 51.5, 60.3, 76.9, 109.5, 125.8, 126.8,
129.7, 132.4, 139.6, 178.9.
5.1.1.5. 1-Methylpyrrolo(spiro[2.30]-8-isopropyloxindole)spiro[3.200]-10-
nitrosopiperidin-4-one (4e). White solid; (0.210 g, 38%); mp 112–
113 ꢀC; Anal. Calcd. for C19H24N4O3: C, 64.03; H, 6.79; N, 15.72;
Found: C, 64.10; H, 6.84; N, 15.66. IR (KBr): 1618, 1709, 3294 cmꢁ1
.
1H NMR (300 MHz, CDCl3): dH 1.22 (d, 3H, J ¼ 6.9 Hz, (CH3)2), 1.28
(d, 3H, J ¼ 7.2 Hz, (CH3)2), 2.13 (s, 1H, CH3), 2.16–2.23 (m, 2H, H-4
and H-600), 2.43–2.54 (m, 2H, H-4 and H-500), 2.58–2.71 (m, 1H,
H-500), 2.79–2.88 (m, 1H, CH), 3.38–3.50 (m, 3H, H-5 and H-600), 4.24
(d, 1H, J ¼ 14.7 Hz, H-200), 5.21 (d, 1H, J ¼ 14.7 Hz, H-200), 6.80 (d, 1H,
J ¼ 7.5 Hz, aromatic), 6.94–6.99 (m, 1H, aromatic), 7.16 (d, 1H,
J ¼ 7.2 Hz, aromatic), 9.12 (s, 1H, NH). 13C NMR (75 MHz, CDCl3): dC
22.6, 22.7, 28.3, 30.2, 34.9, 36.3, 39.5, 51.2, 51.9, 61.0, 76.3, 122.5,
123.0, 123.7, 126.9, 130.3, 139.0, 177.1, 207.7.
5.1.1.7. 1-Methylpyrrolo(spiro[2.30]-5-methyloxindole)spiro[3.200]
cyclohexanone (4g). Yellow solid; (0.240 g, 40%); mp 150–151 ꢀC;
Anal. Calcd. for C18H22N2O2: C, 72.46; H, 7.43; N, 9.39%; Found: C,
72.51; H, 7.50; N, 9.34. IR (KBr): 1689, 1721, 3286 cmꢁ1 1H NMR
.
(300 MHz, CDCl3): dH 1.26–1.88 (m, 6H, cyclohexanone ring
protons), 1.90–2.01 (m, 1H, H-4), 2.07 (s, 3H, CH3), 2.27 (s, 3H,
N–CH3), 2.30–2.51 (m, 2H, cyclohexanone ring protons), 2.62–2.76
(m, 1H, H-4), 3.19–3.34 (m, 2H, H-5), 6.80 (d, 1H, J ¼ 7.6 Hz,
aromatic), 6.86 (s, 1H, aromatic), 7.04 (d, 1H, J ¼ 7.6 Hz, aromatic),
8.94 (s, 1H, NH). 13C NMR (75 MHz, CDCl3): dC 21.0, 21.5, 25.3, 33.9,
35.5, 35.6, 41.2, 51.9, 62.6, 76.6, 109.7, 127.1, 127.4, 129.6, 132.0, 139.1,
179.2, 212.1.
5.1.1.6. 1-Methylpyrrolo(spiro[2.30]-5-methyloxindole)spiro[3.200]
cyclopentanone (4f). White solid; (0.282 g, 42%); mp 176–177 ꢀC;
Table 1
MIC values of the dispiropyrrolidines, 4 and 6 and dimers, 18
Comp
(MTB)a
Comp.
(MTB)a
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
160.05
38.29
73.43
36.60
8.78
6a
6b
6c–6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
61.20
5.1.1.8. 1-Methylpyrrolo(spiro[2.30]-5-methyloxindole)spiro[3.200]
cycloheptanone (4h). Pale yellow solid; (0.210 g, 38%); mp 198–
199 ꢀC; Anal. Calcd. for C19H24N2O2: C, 73.05; H, 7.74; N, 8.97;
Found: C, 73.12; H, 7.80; N, 8.91. IR (KBr): 1617, 1720, 3215 cmꢁ1. 1H
118.34
b
–
27.74
13.45
26.06
22.49
114.54
55.36
23.69
13.68
26.48
22.81
6.24
b
–
NMR (300 MHz, CDCl3):
d 0.97–1.60 (m, 4H, cycloheptanone ring
41.89
40.01
19.94
4.75
41.01
39.20
18.78
37.45
4.47
8.96
4.29
4.13
33.05
1.98
protons), 1.70–2.06 (m, 5H, H-4 and cycloheptanone ring protons),
2.11 (s, 3H, CH3), 2.14–2.17 (m, 2H, cycloheptanone ring protons),
2.26 (s, 3H, CH3), 2.58–2.66 (m, 1H, H-4), 3.26–3.34 (m, 1H, H-5),
3.42 (td, 1H, J ¼ 8.7, 4.8 Hz, H-5), 6.79–7.82 (m, 2H, aromatic), 7.05
(d, 1H, J ¼ 7.8 Hz, aromatic), 8.70 (s, 1H, NH). 13C NMR (75 MHz,
CDCl3): d 20.9, 25.2, 27.5, 29.8, 32.2, 32.8, 35.6, 43.8, 52.2, 64.2, 78.3,
6q
6r
6.06
109.6, 125.2, 126.8, 129.6, 131.8, 139.4, 179.0, 216.5.
10.55
124.85
29.17
26.63
5.61
4q
4r
4s
4t
18a
18b
18c
18d
0.36
4.71
7.64
50.77
5.1.1.9. 1-Methylpyrrolo(spiro[2.30]-5-methyloxindole)spiro[3.200]-10-
methylpiperidin-4-one (4i). Pale yellow solid; (0.240 g, 44%); mp
166–167 ꢀC; Anal. Calcd. for C18H23N3O2: C, 68.98; H, 7.40; N, 13.41;
Isoniazid
Ciprofloxacin
Ethambutol
Pyrazinamide
Found: C, 68.92; H, 7.46; N, 13.35. IR (KBr): 1708, 1739, 3205 cmꢁ1
.
1H NMR (300 MHz, CDCl3): dH 1.51–1.68 (m, 2H, H-4 and H-500),
1.98–2.01 (m, 1H, H-500), 2.03 (d, 1H, J ¼ 12.0 Hz, H-200ax), 2.08 (s,
3H, CH3), 2.13–2.18 (m, 1H, H-600ax), 2.19 (s, 3H, 1-N–CH3), 2.26 (s,
3H, 100-N–CH3), 2.62–2.73 (m, 1H, H-600eq), 2.86–2.94 (m, 1H, H-4),
3.04–3.12 (m, 1H, H-5), 3.23–3.30 (m, 1H, H-5), 3.77 (dd, 1H, 12.0,
a
Minimum inhibitory concentrations (mM) against M. tuberculosis H37Rv and the
MICs of the compounds with higher activity are given in bold.
b
Not tested.

418
R.S. Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 411–422
2.4 Hz, H-200eq), 6.76 (s, 1H, aromatic), 6.79 (d, 1H, J ¼ 7.8 Hz,
aromatic), 7.01 (d, 1H, J ¼ 7.8 Hz, aromatic), 9.60 (s, 1H, NH). 13C
NMR (75 MHz, CDCl3): dC 21.0, 30.4, 35.2, 40.9, 44.6, 52.6, 54.9, 62.9,
65.5, 74.0, 109.5, 127.2, 127.5, 129.3, 131.3, 139.1, 179.1, 208.2.
aromatic), 7.20 (dd, 1H, J ¼ 8.3, 2.0 Hz, aromatic), 8.95 (s, 1H, NH).
13C NMR (75 MHz, CDCl3): dC 30.4, 35.2, 40.9, 44.7, 52.5, 54.9, 62.7,
65.8, 74.2, 110.5, 127.1, 127.5, 129.1, 129.3, 139.9, 178.4, 207.7 (Fig. 1).
5.1.1.15. 1-Methylpyrrolo(spiro[2.30]-5-chlorooxindole)spiro[3.200]-100
nitrosotetrahydro-400(1H)-pyridinone (4o). White solid; (0.325 g,
40%); mp 172–173 ꢀC; Anal. Calcd. for C16H17ClN4O3: C, 55.10; H,
4.91; N, 16.06; Found: C, 55.16; H, 4.85; N, 16.12. IR (KBr): 1618,
5.1.1.10. 1-Methylpyrrolo(spiro[2.30]-5-methyloxindole)spiro[3.200]-10-
nitrosopiperidin-4-one (4j). White solid, (0.204 g, 40%), mp 117–
118 ꢀC; Anal. Calcd. for C17H20N4O3: C, 62.18; H, 6.14; N, 17.06;
Found: C, 62.24; H, 6.09; N, 17.13. IR (KBr): 1622, 1703, 3206 cmꢁ1
.
1702, 3209 cmꢁ1 1H NMR (300 MHz, CDCl3): dH 2.12 (s, 1H, CH3),
.
1H NMR (300 MHz, CDCl3): dH 0.86–1.00 (m, 1H, H-4), 2.02–2.08 (m,
1H, H-500), 2.17 (s, 3H, CH3), 2.31 (s, 3H, N–CH3), 2.35–2.54 (m, 2H,
H-4 and H-600), 2.63–2.76 (m, 1H, H-500), 3.38–3.52 (m, 3H, H-5 and
H-600), 4.26 (d, 1H, J ¼ 14.7 Hz, H-200), 5.20 (d, 1H, J ¼ 14.7 Hz, H-200),
6.71 (d, 1H, J ¼ 7.5 Hz, aromatic), 6.78 (s, 1H, aromatic), 7.03 (d, 1H,
J ¼ 7.5 Hz, aromatic), 8.82 (s, 1H, NH). 13C NMR (75 MHz, CDCl3): dC
21.0, 30.1, 34.9, 36.2, 39.8, 51.2, 52.0, 61.0, 76.1, 110.7, 123.9, 125.6,
130.5, 132.4, 139.3, 176.3, 207.6.
2.14–2.20 (m, 1H, H-4), 2.28–2.47 (m, 2H, H-4 and H-600), 2.55–2.78
(m, 2H, H-500), 3.36–3.50 (m, 3H, H-5 and H-600), 4.24 (d, 1H,
J ¼ 14.7 Hz, H-200), 5.21 (d, 1H, J ¼ 14.7 Hz, H-200), 6.73 (d, 1H,
J ¼ 8.4 Hz, aromatic), 6.95 (d, 1H, J ¼ 2.0 Hz, aromatic), 7.21 (dd, 1H,
J ¼ 8.4, 2.0 Hz, aromatic), 8.34 (s, 1H, NH). 13C NMR (75 MHz,
CDCl3): dC 30.2, 34.9, 36.2, 39.5, 51.2, 51.9, 61.5, 76.0, 110.7, 125.6,
126.1, 128.2, 130.2, 140.1, 176.1, 207.0.
5.1.1.16. 1-Methylpyrrolo(spiro[2.30]-5-bromooxindole)spiro[3.200]
cyclopentanone (4p). White solid; (0.510 g, 41%); mp 177–178 ꢀC;
Anal. Calcd. for C16H17BrN2O2: C, 55.03; H, 4.91; N, 8.02; Found: C,
5.1.1.11. 1-Methylpyrrolo(spiro[2.30]-5-chlorooxindole)spiro[3.200]
cyclopentanone (4k). White solid; (0.420 g, 39%); mp 169–170 ꢀC;
Anal. Calcd. for C16H17ClN2O2: C, 63.05; H, 5.62; N, 9.19; Found: C,
55.10; H, 4.85; N, 8.07. IR (KBr): 1686, 1725, 3298 cmꢁ1 1H NMR
.
63.10; H, 5.56; N, 9.12. IR (KBr): 1692, 1726, 3291 cmꢁ1 1H NMR
.
(300 MHz, CDCl3): dH 1.32–1.47 (m, 1H, H-4), 1.60–1.79 (m, 2H,
H-500), 1.88–1.99 (m, 3H, H-400and H-300), 2.16 (s, 3H, CH3), 2.18–2.36
(m, 2H, H-400and H-4), 3.28 (td, 1H, J ¼ 9.5, 5.0 Hz, H-5), 3.45 (td, 1H,
J ¼ 9.0, 5.0 Hz, H-5), 6.75 (d, 1H, J ¼ 8.3 Hz, aromatic), 7.33 (d, 1H,
J ¼ 2.1 Hz, aromatic), 7.38 (dd, 1H, J ¼ 8.3, 2.1 Hz, aromatic), 8.35 (s,
1H, NH). 13C NMR (75 MHz, CDCl3): dC 19.2, 31.7, 33.5, 35.8, 39.0,
51.5, 60.5, 76.8, 111.2, 115.8, 128.1, 129.6, 132.4, 141.0, 178.2, 212.3.
(300 MHz, CDCl3): dH 1.31–1.48 (m, 1H, H-4), 1.60–1.74 (m, 1H, H-
500), 1.84–1.88 (m, 1H, H-500), 1.91–1.99 (m, 3H, H-400and H-300), 2.16
(s, 3H, CH3), 2.20–2.25 (m, 1H, H-400), 2.27–2.36 (m, 1H, H-4), 3.29
(td, 1H, J ¼ 9.2, 4.8 Hz, H-5), 3.46 (td, 1H, J ¼ 9.2, 4.8 Hz, H-5), 6.81
(d, 1H, J ¼ 8.1, aromatic), 7.19–7.28 (m, 2H, aromatic), 8.47 (s, 1H,
NH). 13C NMR (75 MHz, CDCl3): dC 19.2, 31.7, 33.5, 35.8, 39.0, 51.5,
60.5, 76.8, 110.7, 126.8, 127.8, 128.5, 129.5, 140.5, 178.4, 212.4.
5.1.1.17. 1-Methylpyrrolo(spiro[2.30]-5-bromooxindole)spiro[3.200]
cyclohexanone (4q). Solid; (0.475 g, 43%), mp 164–166 ꢀC; Anal.
Calcd. for C17H19BrN2O2: C, 56.21; H, 5.27; N, 7.71; Found: C, 56.25;
H, 5.34; N, 7.76. IR (KBr): 1685, 1721, 3286 cmꢁ1. 1H NMR (300 MHz,
CDCl3): dH 1.32–1.58 (m, 3H, cyclohexanone ring protons), 1.62–
2.06 (m, 5H, H-300, H-4 and cyclohexanone ring protons), 2.09 (s, 1H,
N–CH3), 2.29–2.40 (m, 1H, H-300), 2.58–2.68 (m, 1H, H-4), 3.22–3.25
(m, 2H, H-5), 6.79 (d,1H, J ¼ 8.3 Hz, aromatic), 7.23 (s,1H, aromatic),
7.39 (d, 1H, J ¼ 8.3 Hz, aromatic), 8.86 (s, 1H, NH). 13C NMR (75 MHz,
CDCl3): dC 21.5, 25.2, 33.8, 35.1, 35.7, 41.0, 51.8, 62.8, 76.6, 111.4,
115.4, 129.4, 130.0, 132.2, 140.6, 178.7, 211.4.
5.1.1.12. 1-Methylpyrrolo(spiro[2.30]-5-chlorooxindole)spiro[3.200]
cyclohexanone (4l). Pale yellow solid; (0.410 g, 42%); mp 197–
198 ꢀC; Anal. Calcd. for C17H19ClN2O2: C, 64.05; H, 6.01; N, 8.79;
Found: C, 64.12; H, 6.08; N, 8.85. IR (KBr): 1685, 1723, 3287 cmꢁ1
.
1H NMR (300 MHz, CDCl3): dH 1.32–1.92 (m, 6H, cyclohexanone ring
protons), 1.95–2.05 (m, 1H, H-4), 2.08 (s, 1H, N–CH3), 2.31–2.36
(m, 2H, cyclohexanone ring protons), 2.59–2.67 (m, 1H, H-4), 3.22–
3.29 (m, 2H, H-5), 6.86 (d, 1H, J ¼ 8.1, aromatic), 7.09 (s, 1H,
aromatic), 7.22–7.28 (m, 1H, aromatic), 8.96 (s, 1H, NH). 13C NMR
(75 MHz, CDCl3): dC 21.5, 25.2, 33.8, 35.1, 35.6, 41.0, 51.8, 62.8, 76.6,
111.0, 127.2, 128.1, 129.0, 129.4, 140.1, 178.8, 211.4.
5.1.1.18. 1-Methylpyrrolo(spiro[2.30]-5-bromooxindole)spiro[3.200]
cycloheptanone (4r). Solid, (0.375 g, 37%), mp 179–180 ꢀC; Anal.
Calcd. for C18H21BrN2O2: C, 57.30; H, 5.61; N, 7.43; Found: C, 57.38;
H, 5.56; N, 7.48. IR (KBr): 1620, 1722, 3315 cmꢁ1. 1H NMR (300 MHz,
5.1.1.13. 1-Methylpyrrolo(spiro[2.30]-5-chlorooxindole)spiro[3.200]
cycloheptanone (4m). Solid; (0.336 g, 38%); mp 167–168 ꢀC; Anal.
Calcd. for C18H21ClN2O2: C, 64.96; H, 6.36; N, 8.42; Found: C, 64.90;
H, 6.42; N, 8.49. IR (KBr): 1617, 1722, 3312 cmꢁ1. 1H NMR (300 MHz,
CDCl3): dH 0.98–1.59 (m, 5H, cycloheptanone ring protons), 1.72–
2.05 (m, 4H, H-4 and cycloheptanone ring protons), 2.11 (s, 1H,
CH3), 2.16–2.22 (m, 2H, cycloheptanone ring protons), 2.57–2.66
(m,1H, H-4), 3.21–3.31 (m,1H, H-5), 3.40–3.47 (m,1H, H-5), 6.80 (d,
1H, J ¼ 8.3 Hz, aromatic), 6.97 (d, 1H, J ¼ 1.8 Hz, aromatic), 7.24 (dd,
1H, J ¼ 8.3, 1.8 Hz, aromatic), 8.80 (s, 1H, NH). 13C NMR (75 MHz,
CDCl3): dC 25.2, 27.5, 29.8, 32.3, 32.8, 35.6, 43.8, 52.2, 64.5, 78.3,
111.0, 126.4, 127.2, 128.1, 129.4, 140.3, 178.8, 214.5.
CDCl3): d 0.98–1.58 (m, 5H, cycloheptanone ring protons),1.73–2.07
(m, 4H, H-4 and cycloheptanone ring protons), 2.11 (s, 1H, CH3),
2.14–2.22 (m, 2H, cycloheptanone ring protons), 2.56–2.66 (m, 1H,
H-4), 3.23–3.31 (m, 1H, H-5), 3.40–3.47 (m, 1H, H-5), 6.79 (d, 1H,
J ¼ 8.1 Hz, aromatic), 7.11 (s, 1H, aromatic), 7.36–7.40 (m, 1H,
aromatic), 8.76 (s, 1H, NH). 13C NMR (75 MHz, CDCl3):
d 25.2, 27.5,
29.8, 32.3, 32.8, 35.6, 43.8, 52.2, 64.5, 78.2, 111.4, 115.3, 127.6, 129.2,
132.3, 140.8, 178.7, 214.5.
5.1.1.14. 1-Methylpyrrolo(spiro[2.30]-5-chlorooxindole)spiro[3.200]-
100-methyltetrahydro-400(1H)-pyridinone (4n). Colorless crystals;
(0.460 g, 52%); mp 201–202 ꢀC; Anal. Calcd. for C17H20ClN3O2: C,
61.17; H, 6.04; N, 12.59; Found: C, 61.12; H, 6.10; N, 12.53. IR (KBr):
1702, 1734, 3205 cmꢁ1. 1H NMR (300 MHz, CDCl3): dH 1.51–1.67 (m,
2H, H-4 and H-500), 2.03–2.07 (m,1H, H-200ax), 2.08 (s, 3H,1-N–CH3),
2.11–2.13 (m, 1H, H-500), 2.16–2.17 (m, 1H, H-600ax), 2.19 (s, 3H, 100-N–
CH3), 2.66–2.72 (m, 1H, H-600eq), 2.83–2.92 (m, 1H, H-4), 3.02–3.10
(m, 1H, H-5), 3.22–3.29 (m, 1H, H-5), 3.69 (dd, 1H, 12.3, 3.0 Hz,
H-200eq), 6.81 (d, 1H, J ¼ 8.3 Hz, aromatic), 6.94 (d, 1H, J ¼ 2.0 Hz,
5.1.1.19. 1-Methylpyrrolo(spiro[2.30]-5-bromooxindole)spiro[3.200]-100-
methyltetrahydro-400(1H)-pyridinone (4s). White solid; (0.490 g,
49%); mp 164–165 ꢀC; Anal. Calcd. for C17H20BrN3O2: C, 53.98; H,
5.33; N, 11.11; Found: C, 53.92; H, 5.26; N, 11.18. IR (KBr): 1698, 1734,
3204 cmꢁ1 1H NMR (300 MHz, CDCl3): dH 1.50–1.66 (m, 2H, H-4
.
and H-500), 2.02–2.04 (m, 1H, H-200ax), 2.07 (s, 3H, 1-N–CH3), 2.10–
2.14 (m, 1H, H-500), 2.18 (s, 3H, 100-N–CH3), 2.22–2.26 (m, 1H,
H-600ax), 2.65–2.71 (m, 1H, H-600eq), 2.82–2.91 (m, 1H, H-4), 3.01–
3.09 (m, 1H, H-5), 3.21–3.28 (m, 1H, H-5), 3.68 (dd, 1H, 12.3, 2.7 Hz,
H-200eq), 6.76 (d, 1H, J ¼ 8.4 Hz, aromatic), 7.07 (d, 1H, J ¼ 1.7 Hz,

R.S. Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 411–422
419
aromatic), 7.35 (dd, 1H, J ¼ 8.4, 1.7 Hz, aromatic), 8.91 (s, 1H, NH).
13C NMR (75 MHz, CDCl3): dC 30.4, 35.2, 40.9, 44.7, 52.5, 54.9, 62.7,
65.8, 74.2, 111.1, 114.7, 129.7, 129.8, 132.0, 140.4, 178.3, 207.6.
5.2.1.4. 4,5-Diphenylpyrrolo(spiro[2.300]oxindole)spiro[3.30]-10-methyl-
piperidin-4-one (6d). Yellow solid; (0.275 g, 36%), mp 168–169 ꢀC;
Anal. Calcd for C28H27N3O2: C, 76.86; H, 6.22; N, 9.60; Found: C,
76.91; H, 6.16; N, 9.55. IR (KBr): 1620, 1699, 3335 cmꢁ1 1H NMR
;
5.1.1.20. 1-Methylpyrrolo(spiro[2.30]-5-bromooxindole)spiro[3.200]-100
nitrosotetrahydro-400(1H)-pyridinone (4t). Solid; (0.350 g, 38%); mp
195–196 ꢀC; Anal. Calcd. for C16H17BrN4O3: C, 48.87; H, 4.36; N,
14.25; Found: C, 48.81; H, 4.29; N, 14.30. IR (KBr): 1617, 1703,
(300 MHz, CDCl3): dH 1.42–1.47 (m, 1H, 50CH2), 1.51 (d, 1H,
J ¼ 12.3 Hz, 20CH2), 1.92–2.05 (m, 2H, 50CH2 and 60CH2), 2.15 (s, 1H,
CH3), 2.35 (s, 1H, NH), 2.55–2.61 (m, 1H, 60CH2), 3.72 (dd, 1H,
J ¼ 12.3, 2.4 Hz, 20CH2), 4.54 (d, 1H, J ¼ 11.6 Hz, H-4), 5.28 (d, 1H,
J ¼ 11.6 Hz, H-5), 6.82 (d, 1H, J ¼ 7.8 Hz, aromatic), 6.99–7.24 (m, 9H,
aromatic), 7.32 (d, 2H, J ¼ 7.5 Hz, aromatic), 7.46 (d, 2H, J ¼ 7.2 Hz,
aromatic), 7.65 (s, 1H, NH). 13C NMR (75 MHz, CDCl3): dC 40.5, 44.7,
54.0, 54.5, 58.8, 62.9, 68.5, 69.7, 109.6, 122.4, 125.9, 126.6, 127.5,
127.6, 128.0, 128.2, 129.2, 129.8, 130.9, 136.6, 140.2, 140.9, 182.2,
206.8.
3210 cmꢁ1 1H NMR (300 MHz, CDCl3): dH 2.11 (s, 1H, CH3), 2.16–
.
2.32 (m, 2H, H-4 and H-600), 2.35–2.47 (m, 1H, H-4), 2.54–2.79 (m,
2H, H-500), 3.35–3.50 (m, 3H, H-5 and H-600), 4.24 (d, 1H, J ¼ 14.7 Hz,
H-200), 5.20 (d, 1H, J ¼ 14.7 Hz, H-200), 6.69 (d, 1H, J ¼ 8.3 Hz,
aromatic), 7.07 (d, 1H, J ¼ 1.8 Hz, aromatic), 7.35 (dd, 1H, J ¼ 8.3,
1.8 Hz, aromatic), 8.81 (s, 1H, NH). 13C NMR (75 MHz, CDCl3): dC
30.1, 34.9, 36.1, 39.8, 51.2, 51.9, 61.4, 76.0, 112.4, 115.9, 126.3, 128.3,
133.1, 140.7, 175.8, 207.0.
5.2.1.5. 4,5-Diphenylpyrrolo(spiro[2.300]oxindole)spiro[3.30]-10-benzyl-
piperidin-4-one (6e). White solid; (0.220 g, 41%), mp 173–174 ꢀC;
Anal. Calcd for C34H31N3O2: C, 79.51; H, 6.08; N, 8.18; Found: C,
5.2. Synthesis of spiropyrrolidines 6
79.45; H, 6.12; N, 8.12. IR (KBr): 1618, 1699, 3334 cmꢁ1 1H NMR
;
5.2.1. General procedure
(300 MHz, CDCl3): dH 1.39–1.49 (m, 1H, 50CH2), 1.66–1.80 (m, 2H,
20CH2 and 60CH2), 1.94–2.04 (m, 1H, 50CH2), 2.32 (s, 1H, NH), 2.51–
2.56 (m, 1H, 60CH2), 3.01 (d, 1H, J ¼ 13.2 Hz, CH2Ph), 3.79 (d, 1H,
J ¼ 13.2 Hz, CH2Ph), 3.93 (dd, 1H, J ¼ 12.3,2.4 Hz, 20CH2), 4.59 (d, 1H,
J ¼ 11.3 Hz, H-4), 5.37 (d, 1H, J ¼ 11.3 Hz, H-5), 6.90 (d, 1H, J ¼ 7.5 Hz,
aromatic), 6.97–7.10 (m, 3H, aromatic), 7.17–7.26 (m, 12H,
aromatic), 7.37 (d, 2H, J ¼ 7.2 Hz, aromatic), 7.49 (d, 1H, J ¼ 6.9 Hz,
aromatic), 8.70 (s, 1H, NH). 13C NMR (75 MHz, CDCl3): dC 40.6, 50.1,
54.8, 58.9, 61.4, 62.9, 68.5, 69.8, 109.5, 122.7, 126.0, 126.7, 126.9,
127.5, 127.6, 128.1, 128.2, 128.8, 129.2, 129.9, 130.8, 136.7, 138.0,
140.5, 140.7, 181.9, 207.2.
A mixture of ketone (0.200 g, 1.78 mmol), isatin (0.262 g,
1.78 mmol) and phenylglycine (0.540 g, 3.56 mmol) in methanol:-
water (2:1 v/v; 30 mL) was refluxed in a water bath for 24 h. After
completion of the reaction as monitored by tlc, the excess solvent
was removed under vacuum and the residue subjected to flash
column chromatography using petroleum ether:ethyl acetate
mixture (8:2 v/v) as eluent.
5.2.1.1. 4,5-Diphenylpyrrolo(spiro[2.300]oxindole)spiro[3.20]cyclopenta-
none (6a). White solid; (0.340 g, 3), mp 140–141 ꢀC; Anal. Calcd for
C27H24N2O2: C, 79.39; H, 5.92; N, 6.86; Found: C, 79.45; H, 5.87; N,
6.81. IR (KBr): 1620,1703, 3324 cmꢁ1; 1H NMR (300 MHz, CDCl3): dH
1.21–1.45 (m, 3H, 30CH2, 40CH2 and 50CH2), 1.64–1.74 (m, 1H, 50CH2),
1.84–1.96 (m, 1H, 40CH2), 2.14–2.17 (m, 1H, 30CH2), 2.53 (s, 1H, NH),
4.03 (d, 1H, J ¼ 9.6 Hz, H-4), 5.49 (d, 1H, J ¼ 9.6 Hz, H-5), 6.87 (d, 1H,
J ¼ 7.8 Hz, aromatic), 7.02–7.06 (m, 1H, aromatic), 7.18–7.31 (m, 8H,
aromatic), 7.42 (d, 2H, J ¼ 6.9 Hz, aromatic), 7.48 (d, 1H, J ¼ 7.2 Hz,
aromatic), 8.43 (s, 1H, NH). 13C NMR (75 MHz, CDCl3): dC 18.7, 33.0,
37.5, 60.5, 66.4, 67.2, 73.0, 109.7, 123.0, 126.6, 126.8, 127.4, 127.5,
127.8, 128.2, 128.3, 129.6, 130.4, 138.6, 141.1, 141.5, 180.4, 219.0.
5.2.1.6. 4,5-Diphenylpyrrolo(spiro[2.300]-8-isopropyloxindole)spiro[3.20]
cyclopeantanone (6f). White solid; (0.415 g, 39%), mp 191–192 ꢀC;
Anal. Calcd for C30H30N2O2: C, 79.97; H, 6.71; N, 6.22; Found: C,
79.92; H, 6.78; N, 6.26. IR (KBr): 1619, 1698, 3280 cmꢁ1 1H NMR
;
(300 MHz, CDCl3): dH 1.16–1.35 (m, 3H, 30CH2, 40CH2 and 50CH2),
1.38–1.42 (m, 6H, CH(CH3)2), 1.63–1.80 (m, 1H, 50CH2), 1.84–1.98 (m,
1H, 40CH2), 2.21–2.32 (m, 1H, 30CH2), 2.55 (s, 1H, NH), 3.20–3.29 (m,
1H, CH), 4.09 (d, 1H, J ¼ 9.5 Hz, H-4), 5.51 (d, 1H, J ¼ 9.5 Hz, H-5),
6.96–7.48 (m, 13H, aromatic), 10.22 (s, 1H, NH). 13C NMR (75 MHz,
CDCl3): dC 18.7, 22.6, 22.7, 28.8, 33.3, 37.5, 60.3, 66.4, 67.4, 73.5,
123.3, 123.7, 126.3, 126.8, 127.3, 127.4, 127.5, 128.3, 130.2, 130.3,
138.8, 138.9, 141.3, 181.8.
5.2.1.2. 4,5-Diphenylpyrrolo(spiro[2.300]oxindole)spiro[3.20]cyclohexa-
none (6b). White solid; (0.325 g, 38%), mp 144–145 ꢀC; Anal. Calcd
for C28H26N2O2: C, 79.59; H, 6.20; N, 6.63; Found: C, 79.54; H, 6.15;
N, 6.67. IR (KBr): 1618, 1700, 3325 cmꢁ1; 1H NMR (300 MHz, CDCl3):
dH 1.05–1.70 (m, 6H, 30CH2, 40CH2, 50CH2 and 60CH2), 2.14(d, 1H,
J ¼ 13.8 Hz, 60CH2), 2.46 (s, 1H, NH), 2.66 (d, 1H, J ¼ 14.1 Hz, 30CH2),
4.69 (d, 1H, J ¼ 11.0 Hz, H-4), 5.30 (d, 1H, J ¼ 11.0 Hz, H-5), 6.89 (d,
1H, J ¼ 7.8 Hz, aromatic), 7.04–7.09 (m, 1H, aromatic), 7.16–7.26 (m,
8H, aromatic), 7.36 (d, 2H, J ¼ 7.2 Hz, aromatic), 7.48 (d, 1H,
J ¼ 7.2 Hz, aromatic), 8.32 (s, 1H, NH). 13C NMR (75 MHz, CDCl3): dC
21.9, 25.2, 32.0, 41.8, 57.3, 63.7, 67.1, 71.0, 109.9, 123.2, 126.2, 126.6,
127.5,127.6,128.0,128.2,129.4,130.2,130.5,137.5,140.2,140.7,181.1,
210.2.
5.2.1.7. 4,5-Diphenylpyrrolo(spiro[2.300]-8-isopropyloxindole)spiro[3.20]
cyclohexanone (6g). White solid; (0.350 g, 37%), mp 95–96 ꢀC; Anal.
Calcd for C31H32N2O2: C, 80.14; H, 6.94; N, 6.03; Found: C, 80.20; H,
6.89; N, 6.08. IR (KBr): 1621, 1702, 3327 cmꢁ1 1H NMR (300 MHz,
;
CDCl3): dH 0.83–1.17 (m, 6H, 30CH2, 40CH2, 50CH2 and 60CH2), 1.34–
1.45 (m, 6H, CH(CH3)2), 2.14 (d, 1H, J ¼ 12.6 Hz, 60CH2), 2.35 (s, 1H,
NH), 2.65 (d, 1H, J ¼ 14.1 Hz, 30CH2), 3.12–3.24 (m, 1H, CH), 4.73 (d,
1H, J ¼ 10.8 Hz, H-4), 5.37 (d, 1H, J ¼ 10.8 Hz, H-5), 7.01–7.49 (m,
13H, aromatic), 10.11 (s, 1H, NH). 13C NMR (75 MHz, CDCl3): dC 22.5,
22.7, 25.1, 26.8, 28.7, 32.4, 41.7, 57.7, 64.1, 66.7, 72.0, 123.2, 123.3,
126.1, 126.6, 127.5, 128.0, 128.2, 129.5, 130.4, 130.5, 130.6, 137.9,
138.2, 140.8, 182.1, 210.7.
5.2.1.3. 4,5-Diphenylpyrrolo(spiro[2.300]oxindole)spiro[3.20]cyclohepta-
none (6c). White solid; (0.248 g, 32%), mp 137–138 ꢀC; Anal. Calcd
for C29H28N2O2: C, 79.79; H, 6.46; N, 6.42; Found: C, 79.85; H, 6.40;
5.2.1.8. 4,5-Diphenylpyrrolo(spiro[2.300]-8-isopropyloxindole)spiro[3.30]-
10methylpiperidin-4-one (6h). Yellow solid; (0.336 g, 40%), mp
104–105 ꢀC; Anal. Calcd for C31H33N3O2: C, 77.63; H, 6.94; N, 8.76;
Found: C, 77.58; H, 6.99; N, 8.70. IR (KBr): 1619,1697, 3328 cmꢁ1; 1H
NMR (300 MHz, CDCl3): dH 1.06 (d, 3H, J ¼ 6.6 Hz, CH(CH3)2),1.22 (d,
3H, J ¼ 6.6 Hz, CH(CH3)2), 1.32–1.42 (m, 1H, 50CH2), 1.81 (d, 1H,
J ¼ 12.3 Hz, 20CH2), 2.12 (s, 1H, CH3), 2.35–2.40 (m, 1H, 50CH2), 2.46
(s, 1H, CH3), 2.88–2.98 (m, 2H, CH and 60CH2), 3.38 (d, 1H,
N, 6.48. IR (KBr): 1623, 1706, 3329 cmꢁ1 1H NMR (300 MHz,
;
CDCl3): dH 0.94–2.68 (m, 11H, 30CH2, 40CH2, 50CH2, 60CH2, 70CH2 and
NH), 4.63 (d, 1H, J ¼ 10.0 Hz, H-4), 5.39 (d, 1H, J ¼ 10.0 Hz, H-5), 6.86
(d, 1H, J ¼ 7.5 Hz, aromatic), 6.99–7.48 (m, 13H, aromatic), 8.14 (s,
1H, NH). 13C NMR (75 MHz, CDCl3): dC 24.5, 27.5, 30.0, 31.0, 43.1,
56.5, 66.1, 68.8, 73.6, 109.8, 122.8, 126.3, 126.6, 127.4, 127.5, 127.8,
128.1, 128.2, 128.4, 129.4, 137.9, 140.8, 141.4, 181.4, 212.8.

420
R.S. Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 411–422
J ¼ 14.7 Hz, 60CH2), 3.48 (d, 1H, J ¼ 12.3 Hz, 20CH2), 4.73 (d, 1H,
J ¼ 10.8 Hz, H-4), 5.44 (d, 1H, J ¼ 10.8 Hz, H-5), 6.99–7.54 (m, 13H,
aromatic), 8.94 (s, 1H, NH). 13C NMR (75 MHz, CDCl3): dC 22.0, 22.5,
28.7, 44.7, 55.5, 56.6, 56.9, 63.7, 67.4, 71.8, 122.0, 124.1, 125.5, 126.7,
127.7,128.1,128.2,128.3,129.0,129.6,129.7,133.5,135.0,137.2,137.3,
138.9, 140.6, 181.6, 198.8.
5.2.1.13. 4,5-Diphenylpyrrolo(spiro[2.300]-5-chlorooxindole)spiro[3.20]
cyclohexanone (6m). Solid; (0.280 g, 38%), mp 189–190 ꢀC; Anal.
Calcd for C28H25ClN2O2: C, 73.59; H, 5.51; N, 6.13; Found: C, 73.65;
H, 5.58; N, 6.07. IR (KBr): 1621, 1697, 3323 cmꢁ1; 1H NMR (300 MHz,
CDCl3): dH 1.09–1.73 (m, 6H, 30CH2, 40CH2, 50CH2 and 60CH2), 2.24(d,
1H, J ¼ 14.4 Hz, 60CH2), 2.47 (s, 1H, NH), 2.63 (d, 1H, J ¼ 13.8 Hz,
30CH2), 4.65 (d, 1H, J ¼ 11.0 Hz, H-4), 5.29 (d, 1H, J ¼ 11.0 Hz, H-5),
6.84 (d, 1H, J ¼ 8.1 Hz, aromatic), 7.11–7.85 (m, 12H, aromatic), 8.29
(s, 1H, NH). 13C NMR (75 MHz, CDCl3): dC 21.8, 25.0, 31.8, 41.8, 57.5,
63.5, 67.0, 71.2, 111.5, 115.2, 126.2, 126.7, 127.6, 127.8, 128.1, 128.3,
128.6, 130.6, 130.8, 137.7, 140.2, 140.8, 181.3, 210.4.
5.2.1.9. 4,5-Diphenylpyrrolo(spiro[2.300]-8-isopropyloxindole)spiro[3.30]-
10-benzylpiperidin-4-one (6i). White solid; (0.245 g, 42%), mp 182–
183 ꢀC; Anal. Calcd for C37H37N3O2: C, 79.97; H, 6.71; N, 7.56;
Found: C, 79.91; H, 6.78; N, 7.52. IR (KBr): 1620, 1696, 3331 cmꢁ1
;
1H NMR (300 MHz, CDCl3): dH 1.36 (d, 3H, J ¼ 6.9 Hz, CH(CH3)2),1.39
(d, 3H, J ¼ 6.9 Hz, CH(CH3)2), 1.43–1.48 (m, 1H, 50CH2), 1.64–1.72 (m,
2H, 20CH2 and 60CH2), 1.99 (dd, 1H, J ¼ 15.6, 2.4 Hz, 50CH2), 2.44–
2.53 (m, 2H, NH and 60CH2), 2.91 (d, 1H, J ¼ 12.9 Hz, CH2Ph), 3.08–
3.17 (m, 1H, CH), 3.75 (d, 1H, J ¼ 12.9 Hz, CH2Ph), 3.96 (dd, 1H,
J ¼ 12.6, 2.4 Hz, 20CH2), 4.63 (d, 1H, J ¼ 11.4 Hz, H-4), 5.40 (d, 1H, J ¼
11.4 Hz, H-5), 6.98–7.38 (m, 11H, aromatic), 7.47 (d, 2H, J ¼ 6.9 Hz,
aromatic), 9.23 (s, 1H, NH). 13C NMR (75 MHz, CDCl3): dC 21.1, 22.6,
40.5, 50.3, 54.5, 59.5, 61.5, 62.8, 68.2, 70.2, 122.9, 123.2, 125.9, 126.7,
126.9, 127.5, 127.6, 128.0, 128.1, 128.2, 128.7, 129.7, 129.8, 130.4,
137.0, 138.2, 138.3, 140.4, 182.0, 207.4.
5.2.1.14. 4,5-Diphenylpyrrolo(spiro[2.300]-5-chlorooxindole)spiro[3.30]-
10-methyltetrahydro-40(1H)-pyridinone (6n). Pale yellow solid;
(0.498 g, 40%); mp 206–207 ꢀC; Anal. Calcd for C28H26ClN3O2: C,
71.25; H, 5.55; N, 8.90; Found: C, 71.30; H, 5.48; N, 8.96. IR (KBr):
1621, 1696, 3331 cmꢁ1; 1H NMR (300 MHz, CDCl3): dH 1.42–1.47 (m,
1H, 50CH2), 1.52 (d, 1H, J ¼ 12.6 Hz, 20CH2), 1.90–2.09 (m, 2H, 50CH2
and 60CH2), 2.11 (s, 1H, CH3), 2.34 (s, 1H, NH), 2.53–2.61 (m, 1H,
60CH2), 3.70 (d, 1H, J ¼ 12.6 Hz, 20CH2), 4.72 (d, 1H, J ¼ 11.3 Hz, H-4),
5.25 (d, 1H, J ¼ 11.3 Hz, H-5), 6.79 (d, 1H, J ¼ 8.4 Hz, aromatic), 7.12–
7.46 (m, 12H, aromatic), 8.63 (s, 1H, NH). 13C NMR (75 MHz, CDCl3):
dC 40.6, 44.7, 53.9, 54.5, 58.7, 62.8, 68.5, 69.6, 110.6, 126.7, 127.2,
127.6,127.7,128.1,128.3,129.0,129.2,129.9,132.7,136.3,139.4,140.1,
181.8, 206.3.
5.2.1.10. 4,5-Diphenylpyrrolo(spiro[2.300]-5-methyloxindole)spiro[3.20]
cyclohexanone (6j). White solid; (0.320 g, 36%), mp 154–155 ꢀC;
Anal. Calcd for C29H28N2O2: C, 79.79; H, 6.46; N, 6.42; Found: C,
79.85; H, 6.39; N, 6.46. IR (KBr): 1615, 1703, 3326 cmꢁ1
;
1H NMR
5.2.1.15. 4,5-Diphenylpyrrolo(spiro[2.300]-5-chlorooxindole)spiro[3.30]-
10-benzyltetrahydro-40(1H)-pyridinone (6o). White solid; (0.356 g,
41%), mp 170–172 ꢀC; Anal. Calcd for C34H30ClN3O2: C, 74.51; H,
5.52; N, 7.67; Found: C, 74.56; H, 5.48; N, 7.73. IR (KBr): 1620, 1701,
3332 cmꢁ1; 1H NMR (300 MHz, CDCl3): dH 1.44–1.52 (m, 1H, 50CH2),
1.68–1.76 (m, 2H, 20CH2 and 60CH2), 1.96–2.10 (m, 1H, 50CH2), 2.27
(s, 1H, NH), 2.53–2.59 (m, 1H, 60CH2), 3.02 (d, 1H, J ¼ 13.2 Hz,
CH2Ph), 3.77 (d, 1H, J ¼ 13.2 Hz, CH2Ph), 3.92 (dd, 1H,
J ¼ 12.3,2.4 Hz, 20CH2), 4.54 (d, 1H, J ¼ 11.3 Hz, H-4), 5.34 (d, 1H, J ¼
11.3 Hz, H-5), 6.84 (d, 1H, J ¼ 8.4 Hz, aromatic), 7.04–7.54 (m, 17H,
aromatic), 8.96 (s, 1H, NH). 13C NMR (75 MHz, CDCl3): dC 40.6, 50.0,
54.6, 58.7, 61.4, 62.9, 68.6, 69.7,110.5,126.5, 126.9,127.0,127.6,127.7,
128.0, 128.1, 128.3, 128.4, 128.7, 129.3, 130.0, 132.7, 136.4, 137.8,
139.3, 140.2, 182.0, 206.6.
(300 MHz, CDCl3): dH 0.85–1.62 (m, 6H, 30CH2, 40CH2, 50CH2 and
60CH2), 2.14 (d, 1H, J ¼ 17.4 Hz, 60CH2), 2.32 (s, 3H, CH3), 2.40 (s, 1H,
NH), 2.67 (d, 1H, J ¼ 16.8 Hz, 30CH2), 4.68 (d, 1H, J ¼ 10.8 Hz, H-4),
5.30 (d, 1H, J ¼ 10.8 Hz, H-5), 6.79 (d, 1H, J ¼ 7.5 Hz, aromatic), 7.02-
7.25 (m, 8H, aromatic), 7.36 (d, 2H, J ¼ 6.9 Hz, aromatic), 7.48 (d, 2H,
J ¼ 6.9 Hz, aromatic), 8.78 (s, 1H, NH). 13C NMR (75 MHz, CDCl3): dC
21.1, 21.9, 25.3, 32.1, 41.8, 57.4, 63.7, 67.0, 71.1, 109.7, 126.6, 126.7,
127.5, 127.6, 128.0, 128.2, 129.8, 130.2, 130.5, 132.7, 137.6, 137.8,
140.7, 181.3, 210.3.
5.2.1.11. 4,5-Diphenylpyrrolo(spiro[2.300]-5-methyloxindole)spiro[3.30]-
10-methylpiperidin-4-one (6k). White solid; (0.325 g, 41%), mp
125–126 ꢀC; Anal. Calcd for C29H29N3O2: C, 77.13; H, 6.47; N, 9.31;
Found: C, 77.19; H, 6.42; N, 9.38. IR (KBr): 1621, 1702, 3324 cmꢁ1; 1H
NMR (300 MHz, CDCl3): dH 1.41–1.52 (m, 2H, 20CH2 and 50CH2),
1.92–2.08 (m, 2H, 50CH2 and 60CH2), 2.13 (s, 3H, CH3), 2.32 (s, 3H,
N–CH3), 2.37 (s, 1H, NH), 2.50–2.60 (m, 1H, 60CH2), 3.74 (dd, 1H,
J ¼ 12.3, 2.4 Hz, 20CH2), 4.54 (d, 1H, J ¼ 11.5 Hz, H-4), 5.27 (d, 1H,
J ¼ 11.5 Hz, H-5), 6.74 (d, 1H, J ¼ 7.8 Hz, aromatic), 6.97–7.48 (m,
12H, aromatic), 8.27 (s, 1H, NH). 13C NMR (75 MHz, CDCl3): dC 21.1,
40.6, 44.8, 54.1, 54.4, 58.9, 62.9, 68.4, 69.6, 109.2, 126.5, 126.6, 127.6,
127.7, 128.0, 128.2, 129.6, 129.8, 130.9, 132.0, 136.6, 138.3, 140.2,
181.8, 206.9.
5.2.1.16. 4,5-Diphenylpyrrolo(spiro[2.300]-5-bromooxindole)spiro[3.20]
cyclohexanone (6p). White solid; (0.290 g, 36%), mp 203–204 ꢀC;
Anal. Calcd for C28H25BrN2O2: C, 67.07; H, 5.03; N, 5.59; Found: C,
67.15; H, 5.10; N, 5.53. IR (KBr): 1618, 1702, 3324 cmꢁ1 1H NMR
;
(300 MHz, CDCl3): dH 0.88–1.75 (m, 6H, 30CH2, 40CH2, 50CH2 and
60CH2), 2.24 (d, 1H, J ¼ 14.1 Hz, 60CH2), 2.38 (s, 1H, NH), 2.62 (d, 1H,
J ¼ 13.8 Hz, 30CH2), 4.65 (d, 1H, J ¼ 10.8 Hz, H-4), 5.29 (d, 1H,
J ¼ 10.8 Hz, H-5), 6.83–7.90 (m, 13H, aromatic), 8.99 (s, 1H, NH). 13C
NMR (75 MHz, CDCl3): dC 21.8, 25.0, 31.7, 41.8, 57.5, 63.7, 67.0, 71.0,
111.5, 115.7, 126.7, 127.1, 127.6, 128.0, 128.3, 128.6, 129.5, 130.5, 130.8,
132.4, 137.2, 140.4, 181.0, 209.9.
5.2.1.12. 4,5-Diphenylpyrrolo(spiro[2.300]-5-methyloxindole)spiro[3.30]-
10-benzylpiperidin-4-one (6l). Pale yellow solid; (0.220 g, 40%), mp
156–157 ꢀC; Anal. Calcd for C35H33N3O2: C, 79.67; H, 6.30; N, 7.96;
5.2.1.17. 4,5-Diphenylpyrrolo(spiro[2.300]-5-bromooxindole)spiro[3.30]
-10-methyltetrahydro-40(1H)-pyridinone (6q). Pale yellow solid;
(0.532 g, 39%); mp 193–194 ꢀC; Anal. Calcd for C28H26BrN3O2: C,
65.12; H, 5.07; N, 8.14; Found: C, 65.19; H, 5.13; N, 8.08. IR (KBr):
1622, 1697, 3336 cmꢁ1; 1H NMR (300 MHz, CDCl3): dH 1.42–1.48 (m,
1H, 50CH2), 1.53 (d, 1H, J ¼ 12.0 Hz, 20CH2), 1.87–2.06 (m, 2H, 50CH2
and 60CH2), 2.11 (s, 1H, CH3), 2.34 (s, 1H, NH), 2.51–2.65 (m, 1H,
60CH2), 3.70 (d, 1H, J ¼ 12.0 Hz, 20CH2), 4.50 (d, 1H, J ¼ 11.9 Hz, H-4),
5.26 (d, 1H, J ¼ 11.9 Hz, H-5), 6.76 (d, 1H, J ¼ 8.1 Hz, aromatic), 7.13–
7.73 (m, 12H, aromatic), 8.77 (s, 1H, NH). 13C NMR (75 MHz, CDCl3):
dC 40.6, 44.7, 53.9, 54.3, 58.7, 62.8, 68.6, 69.5, 111.1, 115.0, 126.8,
127.6, 128.1, 128.3, 129.2, 129.8, 130.5, 132.1, 133.1, 136.2, 139.8,
140.0, 181.8, 206.3.
Found: C, 79.62; H, 6.26; N, 7.99. IR (KBr): 1619, 1698, 3330 cmꢁ1
;
1H NMR (300 MHz, CDCl3): dH 1.42–1.53 (m, 1H, 50CH2), 1.65–1.79
(m, 2H, 20CH2 and 60CH2), 1.95–2.01 (m, 1H, 50CH2), 2.27 (s, 1H, NH),
2.31 (s, 3H, CH3), 2.49–2.60 (m, 1H, 60CH2), 3.01 (d, 1H, J ¼ 13.0 Hz,
CH2Ph), 3.80 (d, 1H, J ¼ 13.0 Hz, CH2Ph), 3.96 (dd, 1H, J ¼
12.3,2.4 Hz, 20CH2), 4.59 (d, 1H, J ¼ 11.4 Hz, H-4), 5.36 (d, 1H,
J ¼ 11.4 Hz, H-5), 6.78 (d, 1H, J ¼ 8.1 Hz, aromatic), 6.98–7.38 (m,
15H, aromatic), 7.45 (d, 2H, J ¼ 6.9 Hz, aromatic), 8.39 (s, 1H, NH).
13C NMR (75 MHz, CDCl3): dC 21.1, 40.6, 50.1, 54.7, 58.9, 61.4, 62.9,
68.5, 69.9, 109.2, 126.6, 126.7, 126.9, 127.6, 127.7, 128.0, 128.2, 128.8,
129.0, 129.6, 130.0, 130.9, 132.2, 136.8, 138.0, 138.3, 140.5, 181.8,
207.3.

R.S. Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 411–422
421
5.2.1.18. 4,5-Diphenylpyrrolo(spiro[2.300]-5-bromooxindole)spiro[3.30]-
10-benzyltetrahydro-40(1H)-pyridinone (6r). White solid; (0.375 g,
40%); mp 178–179 ꢀC; Anal. Calcd for C34H30BrN3O2: C, 68.92; H,
5.10; N, 7.09; Found: C, 68.98; H, 5.15; N, 7.03. IR (KBr): 1618, 1698,
3332 cmꢁ1; 1H NMR (300 MHz, CDCl3): dH 1.40–1.52 (m, 1H, 50CH2),
1.74 (d, 1H, J ¼ 12.3 Hz, 20CH2), 1.98–2.12 (m, 2H, 50CH2), 2.35–2.62
(m, 2H, 60CH2 and NH), 3.03 (d, 1H, J ¼ 13.1 Hz, CH2Ph), 3.77 (d, 1H,
J ¼ 13.1 Hz, CH2Ph), 3.92 (d, 1H, J ¼ 12.3 Hz, 20CH2), 4.54 (d, 1H,
J ¼ 11.3 Hz, H-4), 5.33 (d, 1H, J ¼ 11.3 Hz, H-5), 6.80 (d, 1H, J ¼ 8.1 Hz,
aromatic), 6.90–7.67 (m, 17H, aromatic) 8.85 (s, 1H, NH). 13C NMR
(75 MHz, CDCl3): dC 40.6, 50.0, 54.6, 58.7, 61.4, 62.9, 68.6, 69.7, 111.0,
115.2,126.8, 127.0, 127.6,127.7,128.1,128.3,128.7,129.3,130.0,132.2,
133.1, 136.3, 137.8, 139.7, 140.2, 181.8, 206.6.
7.44 (s, 1H, aromatic), 7.59 (s, 1H, NH). 13C NMR (75 MHz, CDCl3): dC
20.9, 27.3, 47.7, 59.1, 68.0, 110.6, 115.1, 128.1, 129.4, 131.2, 139.6, 175.1.
Acknowledgements
S.P. thanks the Department of Science and Technology, New
Delhi, for funding for a major research project (No. SR/S1/OC-70/
2006) and for funds under (i) IRHPA program for funds for the
purchase of a high resolution NMR spectrometer and (ii) FIST
program and the University Grants Commission, New Delhi, for (i)
funds under the DRS and ASIST programs and (ii) for funding for
a major research project [F. No. 36-155/2008(SR)]. RSK thanks CSIR,
New Delhi for Senior Research Fellowship and SMR thanks UGC,
New Delhi for Junior Research Fellowship.
5.3. Synthesis of spiroheterocycles 18
Appendix. Supplementary information
5.3.1. General procedure
A mixture of isatin (0.100 g, 0.68 mmol) and (L)-proline (0.078 g,
0.68 mmol) in methanol (15 mL) was refluxed on a water bath for
1 h. After completion of the reaction as monitored by TLC, the
excess solvent was removed under vacuum and the residue sub-
jected to flash column chromatography using petroleum ether:-
ethyl acetate mixture (8:4) as eluent to afford the product.
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.ejmech.2009.09.044.
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