A facile synthesis and antimycobacterial evaluation of novel spiro-pyrido-pyrrolizines and pyrrolidines

Article abstract of DOI:10.1016/j.ejmech.2009.05.010

An efficient synthesis of 1-methyl-3-[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones was achieved by the reaction of 1-methyl-4-piperidone and aromatic aldehydes in the presence of pyrrolidine under solvent-free microwave irradiation. These dipolarophil

Full text of DOI:10.1016/j.ejmech.2009.05.010

European Journal of Medicinal Chemistry 44 (2009) 3821–3829
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Preliminary communication
A facile synthesis and antimycobacterial evaluation of novel
spiro-pyrido-pyrrolizines and pyrrolidines
,
b
Raju Ranjith Kumar a, Subbu Perumal a , Palaniappan Senthilkumar ,
*
Perumal Yogeeswari b, Dharmarajan Sriram b
a Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Palkalai Nagar, Madurai 625021, Tamil Nadu, 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:
An efficient synthesis of 1-methyl-3-[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones was achieved
by the reaction of 1-methyl-4-piperidone and aromatic aldehydes in the presence of pyrrolidine under
solvent-free microwave irradiation. These dipolarophiles upon cycloaddition with nitrile oxide and
azomethine ylides afford stereoselectively novel spiro-isoxazolines, pyrrolizines and pyrrolidines
respectively in excellent yields. The spiro compounds were screened for their in vitro activity against
Mycobacterium tuberculosis H37Rv (MTB), multi-drug resistant M. tuberculosis (MDR-TB) and Mycobac-
terium smegmatis (MC2) using agar dilution method. Among the synthesized compounds, 1-methyl-4-
(2,4-dichlorophenyl)pyrrolo(spiro[2.300]oxindole)spiro[3.30]-10-methylpiperidin-40-one was found to be
Received 19 March 2009
Received in revised form
5 May 2009
Accepted 13 May 2009
Available online 21 May 2009
Keywords:
Antimycobacterial activity
Spiro-piperidone
Nitrile oxide
the most active with a minimum inhibitory concentration (MIC) of 1.76 and 0.88
MDR-TB respectively.
mM against MTB and
Azomethine ylide
1,3-Dipolar cycloaddition
Ó 2009 Elsevier Masson SAS. All rights reserved.
1. Introduction
Spiro compounds are also known for their antimycobacterial
properties [14]. Our recent studies on the synthesis and screening
of novel spiro-heterocycles disclosed various antimycobacterial
leads [15]. In a previous study, we reported that spiro-pyrido-
pyrrolizines and pyrrolidines 7–9 (Scheme 1) displayed good in
vitro antimycobacterial activity against MTB, MDR-TB and MC2
[15a]. The present work reports the preliminary studies on the
antimycobacterial activity of spiro-pyrido-pyrrolizines and pyrro-
lidines 4–6 which are chemically modified compounds of 7–9.
Compounds 4–6 were synthesized via 1,3-dipolar cycloaddition of
1,3-Dipolar cycloaddition provides an efficient approach for the
synthesis of five-membered ring heterocycles [1]. 1,3-Dipolar
cycloaddition of nitrile oxide to olefins assumes importance since
the resulting isoxazolines are versatile intermediates for the
synthesis of bifunctional [2] and naturally occurring compounds
[3], besides finding medicinal and agricultural applications [4]. The
cycloaddition of nitrile oxide to exocyclic olefins results in
the formation of spiro-isoxazolines [5], which are useful precursors
for many synthetic intermediates [6] and also display important
biological activities [7]. Azomethine ylides are reactive and versa-
tile 1,3-dipoles, which readily react with diverse dipolarophiles
affording pyrrolizines, pyrrolidines and pyrazolidines [8,9]. The
1,3-dipolar cycloaddition of azomethine ylides to dipolarophiles
with exocyclic double bonds affords spiro-heterocycles [10], which
display important biological activities [11]. The spiro-oxindoles are
present in several natural products [12], and act as potent non-
peptide inhibitor of the p53–MDM2 interaction [13].
azomethine ylides from isatin and
a-amino acids (proline and
sarcosine) or isatin and benzylamine to 1-methyl-3-[(E)-arylme-
thylidene]tetrahydro-4(1H)-pyridinones 2. The present work also
discloses the 1,3-dipolar cycloaddition of nitrile oxide generated in
situ from the dehydrohalogenation of 4-chlorobenzohydroximoyl
chloride. It is to be noted that this is the first report on the cyclo-
addition of 2.
2. Chemistry
The dipolarophiles 2 employed in the present work were
synthesized, more efficiently than the literature methods, from the
reaction of 1-methyl-4-piperidone 1 and aromatic aldehydes in the
presence of pyrrolidine in good yields (50–76%) under solvent-free
* 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.2009.05.010

3822
R. Ranjith Kumar et al. / European Journal of Medicinal Chemistry 44 (2009) 3821–3829
microwave irradiation (Scheme 2). Previously, McElvain et al. [16]
reported the synthesis of 2 from the reaction of 1 and benzaldehyde
in 60% alcoholic KOH, but later the product of this reaction was
shown to be a dimer of 2 [17]. The mass spectral data and X-ray
crystallographic studies of these dimers were reported by Lyle et al.
[18]. Gyorgy et al. [19] prepared 2 from 1-methyl-4-morpholino-
1,2,3,6-tetrahydropyridine and benzaldehyde in 40% yield, while
Bell et al. [20] reported 14% yield of 2 from the same reaction. The
above literature methods suffer from longer reaction time and
lower yields.
All the dipolarophiles 2a–e reported in this work are new and
their structural elucidation was done with the help of NMR
spectroscopic data. The HMBC correlations as well as 1H and 13C
NMR chemical shifts for a representative case 2c are shown in Fig. 1.
The structure of 2 deduced from NMR spectroscopic studies is in
good agreement with that determined from single crystal X-ray
studies of 2b [21a] and 2e [21b] (Fig. 2). The structures in Fig. 2
reveal (i) half-chair conformation for the piperidone ring and (ii)
(E)-configuration for the C]C bond of the arylidene functionality.
The 1,3-dipolar cycloaddition of nitrile oxide, generated in situ
from 4-chlorobenzohydroximoyl chloride and triethylamine to 2a–e
(Scheme 3) affords novel 3-(4-chlorophenyl)-7-methyl-4-aryl-1-
oxa-2,7-diazaspiro[4.5]dec-2-en-10-ones (3a–e) in good yields
(55–73%). This reaction is (i) regioselective, as the oxygen of the
Fig. 2. ORTEP diagrams of 2b and 2e.
the intermediate involved in the cycloaddition, viz. the azomethine
ylide generated from the amino acid is achiral.
The structure of 4–6 was elucidated with the help of one and
two-dimensional NMR spectroscopic data as illustrated for 4a. The
HMBC correlations useful in the signal assignments of 4a are shown
in Fig. 5. In the 1H NMR spectrum of 4a, the doublet at 4.08 ppm
(J ¼ 11.7 Hz) is assigned to H-4 on the basis of its multiplicity. From
the H,H-COSY correlation of H-4, the doublet of triplets at 4.48 ppm
(J ¼ 11.7 and 6.6 Hz) is readily assigned to H-4a. Further, from H,H-
COSY correlations, it is evident that 5-CH2 protons appear as
multiplets at 1.51–1.58 ppm and 2.00–2.07 ppm, while 6-CH2
protons occur as a multiplet in the range 1.88–1.99 ppm. The
multiplets at 2.54–2.60 and 2.82–2.90 ppm are due to 7-CH2
protons. The H-20ax and H-20eq appear as a doublet and doublet of
doublets at 1.63 (J ¼ 12.3 Hz) and 3.75 ppm (J ¼ 12.3 and 2.7 Hz)
respectively. The J value of 2.7 Hz is due to the long range coupling
of H-20eq with H-60eq (inferred from H,H-COSY correlation) which
overlaps with 7-CH2 signals at 2.54–2.60 ppm. The H-60ax and one
of the 50-CH2 protons overlap with the 6-CH2 protons, whereas the
other 50-CH2 proton overlaps with that of 5-CH2. The aromatic
protons appear as a multiplet at 6.85–7.27 ppm and the NH and N–
CH3 protons appear as singlets at 8.40 and 2.14 ppm respectively.
The structure of 4a determined from NMR spectroscopic studies
was further confirmed from a single crystal X-ray crystallographic
study (Fig. 6) [23]. The ORTEP diagram of 4a shows that (i) the
piperidin-4-one ring adopts a chair conformation, (ii) H-4 and H-4a
are trans and (iii) the two carbonyls linked to C-2 and C-3 of 4a are
in trans, which is explicable by the fact that the corresponding
transition state (A) would require less free energy of activation than
the transition state (B) leading to 40 as the latter would result in
electrostatic repulsion between the cis carbonyls increasing the free
energy of activation (Scheme 5). Further, the chemical shifts of
H-20eq (3.75 ppm) and H-20ax (1.63 ppm) of 4a differ significantly
(2.12 ppm) suggesting that presumably, H-20eq is proximate to the
carbonyl of spiro-oxindole ring shifting it downfield, while H-20ax
lies in the shielding zone of the spiro-oxindole ring placing it
upfield.
nitrile oxide adds to the a-carbon of 2 furnishing exclusively the
spiro-isoxazolines 3, (ii) chemoselective, as the nitrile oxide prefers
to react with C]C and not with C]O bond of 2 and (iii) stereo-
selective as only one diastereomer of 3 is formed. The structure of
the spiro-isoxazolines 3 was determined by 1H, 13C and two-
dimensional NMR spectroscopic techniques. The HMBC correla-
tions and the NMR chemical shifts for 3a are shown in Fig. 3. The
structure of 3 determined from NMR spectroscopic studies and
single crystal X-ray crystallographic study (Fig. 4) is in good
agreement with each other. The ORTEP diagrams of 3a [22] (Fig. 4)
show that the piperidin-4-one and the isoxazoline ring adopt
a chair and an envelope conformation respectively with one carbon
atom lying out of plane in the latter. It is also seen that the addition
of nitrile oxide has occurred from the bottom side of 2 accounting
for the facial selectivity.
The 1,3-dipolarcycloaddition of azomethineylides generated in situ
from the reaction of isatin with (i) proline, (ii) sarcosine and (iii) ben-
zylamine to 2a–e afforded respectively spiro[2.300]oxindolespiro[3.30]-
10-methyltetrahydro-40(1H)-pyridinone-4-arylhexahydro-1H-pyrroli-
zines 4a–e,1-methyl-4-arylpyrrolo(spiro[2.300]oxindole)spiro[3.30]-10-
methylpiperidin-40-ones 5a–e and 4-aryl-5-phenylpyrrolo(spiro
[2.300]oxindole)spiro[3.30]-10-methylpiperidin-40-ones 6a–e in excel-
lent yields in a regio- and stereoselective manner (Scheme 4). All these
reactions were effected by refluxing an equimolar ratio of the reactants
in methanol on a water bath. After completion of the reactions (TLC),
the reaction mixtures were poured into water to get pure 4–6 as solids.
The compounds 4a–e are obtained in racemic form, although the
amino acid precursor proline is chiral. This is ascribable to the fact that
Similarly, by straightforward considerations, the 1H and 13C
chemical shifts of 5 and 6 were also assigned, the HMBC correlations
of representative examples 5e and 6e are furnished in Figs. 7 and 9
respectively. The structure deduced from NMR spectroscopic data
and X-ray crystallographic study for 5e [23] (Fig. 8) agrees well.
7.67, br s
O
H
Cl
O
H
H
Cl
H
H
4
197.7
H
132.6
2.69, t, 6.3 Hz
39.3
H
H
5
3
1
N
H
H6
2 H
H
H
2.82, t, 6.3 Hz
53.1
3. Biological results and discussion
N
H
CH3
3.48, d, 1.8 Hz
57.2
CH3
2.40, s
46.1
The spiro compounds 4–6 were screened for their in vitro
antimycobacterial activity against MTB, MDR-TB and MC2 by agar
dilution method for the determination of MIC in triplicates. The
MDR-TB clinical isolate was resistant to isoniazid (INH), rifampicin,
Fig. 1. HMBC correlations and 1H and 13C NMR chemical shifts of 2c.

R. Ranjith Kumar et al. / European Journal of Medicinal Chemistry 44 (2009) 3821–3829
3823
3.31, ddd, 13.8,11.5, 6.0 Hz
2
N
O
1
O
N
158.5
2.64, dd, 12.9, 2.4 Hz
3
Ar'
H
H
Ar'
H
90.1
53.0
N
H
Ar
N
2.23, s H3C
45.5
5
61.2
7
38.0
H3C
Ar
4
6
H
H
5.25, s
H
8
203.5
H
9
55.3
H
H
O
3.06-3.12, m
H
O
H
H
H
2.47, dt, 13.8, 3.3 Hz
2.39, td, 11.4, 3.3 Hz
2.03, d, 12.6 Hz
Fig. 3. HMBC correlations and 1H and 13C NMR chemical shifts of 3a.
ethambutol and ciprofloxacin. The MICs of 4–6 along with the
standard drugs for comparison are reported in Table 1. In the first
phase of screening against MTB, the newer compounds showed
ylide cycloadditions are obtained in a pure form without employing
column chromatography. Three of the spiro compounds synthe-
sized show better activity against MDR-TB than the standard drugs
and some compounds display either enhanced or comparable
activity with reference to the standard anti-TB drugs.
good activity with MICs ranging from 1.76 to 30.83
compounds 4c, 4e, and 5e showed excellent activity with MIC of
less than 4.0 M. When compared to ethambutol (MIC of 7.64 M),
six compounds viz., 4a, 4c, 4d, 4e, 5e and 6d were more potent with
MICs of 7.53, 3.58, 7.46, 3.32, 1.76 and 6.87 M respectively and
compound 5c was equally active. All the compounds were more
potent than first-line anti-TB drug pyrazinamide (MIC of 50.77 M).
mM. Three
m
m
5. Experimental
m
The melting points were measured in open capillary tubes and
are uncorrected. The 1H, 13C and the 2D NMR spectra were recorded
on a Bruker (Avance) 300 MHz NMR instrument using TMS as
internal standard and CDCl3 as solvent. Standard Bruker software
was used throughout. Chemical shifts are given in parts per million
m
The synthesized compounds were less active than isoniazid.
Among the fifteen compounds screened, 5e was found to be the
most potent anti-tubercular agent.
Subsequently, those compounds which showed good activity
with MTB were screened against MDR-TB. All the three compounds
4c, 4e and 5e inhibited MDR-TB with MIC ranging from 0.88 to
(d-scale) and the coupling constants are given in hertz. An IFB
Microwave oven (Model: Electron) operating at 230 V and 50 Hz
with consumption of 1000 W with microwave power maximum
level of 600 W and microwave frequency of 2450 MHz was
employed for the irradiation done in this work. Silica gel-G plates
(Merck) were used for TLC analysis with a mixture of petroleum
ether (60–80 ꢀC) and ethyl acetate as eluent. Elemental analyses
were performed on a Perkin Elmer 2400 Series II Elemental CHNS
analyzer.
3.58 mM. These compounds were more potent than standard anti-TB
drugs like isoniazid, ethambutol and pyrazinamide. Compound 5e
was found to be the most potent being 13.0, 69.5, 461.5 times more
potent than isoniazid, ethambutol and pyrazinamide respectively.
All the compounds 4–6 inhibited non-tubercular mycobacteria MC2
with MICs ranging from 15.04 to 110.72 mM and five compounds
(4a, 4c, 4d, 5a, 5c) were found to be more active than isoniazid.
5.1. General procedure for the synthesis of 1-methyl-3-[(E)-
arylmethylidene]tetrahydro-4(1H)-pyridinones (2a–e)
4. Conclusions
A mixture of 1-methyl-4-piperidone 1 (1 mmol) and pyrrolidine
(1.2 mmol) was taken in a glass tube, mixed well and kept aside for
5 min at ambient temperature. To this mixture, aromatic aldehyde
(1 mmol) was added, mixed thoroughly and the tube containing the
mixture was partially immersed in a silica bath placed in a micro-
wave oven and irradiated at 4 power level (480 W) for the appro-
priate time interval (Scheme 1). The progress of the reaction was
monitored after every 1 min of irradiation by TLC with petroleum
ether:ethyl acetate (1:2 v/v mixture) as eluent. After each
In conclusion, an efficient synthesis of 1-methyl-3-[(E)-aryl-
methylidene]tetrahydro-4(1H)-pyridinones (2) in higher yields
than the literature methods is described. The 1,3-dipolar
cycloaddition of azomethine ylides to 2 proceeds regio- and
stereoselectively affording novel spiro-cycloadducts comprising
piperidone, oxindole and pyrrolidine or pyrrolizine rings in excel-
lent yields under mild conditions. The products in the azomethine
H
H
H
H
H
HN
H
N
H
H
H
O
H
N
H3C
H
H
H
O
H
CH3
Fig. 4. ORTEP diagram of 3a.
Fig. 5. HMBC correlations of 4a.

3824
R. Ranjith Kumar et al. / European Journal of Medicinal Chemistry 44 (2009) 3821–3829
Fig. 6. ORTEP diagram of 4a.
Fig. 8. ORTEP diagram of 5e.
irradiation, the reaction mixture was cooled to room temperature
and mixed well. The maximum temperature of the silica bath,
measured immediately after each irradiation was over by stirring
the silica bath with the thermometer, was found to be 65 ꢀC. The
product 2 was purified by column chromatography using petro-
leum ether:ethyl acetate (7:2 v/v) mixture.
(KBr) 1670 cmꢁ1
;
dH (300 MHz, CDCl3) 7.67 (1H, br s, C]CH), 7.17–
7.45 (4H, m, Ar–H), 3.48 (2H, d, J ¼ 1.8 Hz, 2-CH2), 2.82 (2H, t,
J ¼ 6.0 Hz, 6-CH2), 2.69 (2H, t, J ¼ 6.3 Hz, 5-CH2), 2.40 (3H, s, N–
CH3); dC (75 MHz, CDCl3) 197.7, 135.0, 134.6, 133.3, 132.6, 130.3,
130.0, 129.8, 126.3, 57.2, 53.1, 46.1, 39.3.
5.1.1. 1-Methyl-3-[(E)-(4-methylphenyl)methylidene]tetrahydro-
4(1H)-pyridinone (2a)
5.1.4. 3-[(E)-(3-Fluorophenyl)methylidene]-1-methyltetrahydro-
4(1H)-pyridinone (2d)
Yellow viscous paste; Yield: 1.45 g, 76% (Found: C, 78.17; H, 7.90;
N, 6.47. C14H17NO requires C, 78.10; H, 7.96; N, 6.51); ymax (CHCl3)
Yellow viscous paste; Yield: 1.22 g, 63% (Found: C, 71.29; H, 6.51;
N, 6.32. C13H14FNO requires C, 71.21; H, 6.44; N, 6.39); ymax (CHCl3)
1670 cmꢁ1
; dH (300 MHz, CDCl3) 7.57 (1H, br s, C]CH), 7.26 (2H,
1675 cmꢁ1
; dH (300 MHz, CDCl3) 7.48 (1H, br s, C]CH), 6.97–7.39
d, J ¼ 8.4 Hz, Ar–H), 7.21 (2H, d, J ¼ 8.1 Hz, Ar–H), 3.66 (2H, d,
J ¼ 1.8 Hz, 2-CH2), 2.81 (2H, t, J ¼ 6.0 Hz, 6-CH2), 2.67 (2H, t,
J ¼ 6.0 Hz, 5-CH2), 2.45 (3H, s, N–CH3), 2.38 (3H, s, Ar–CH3); dC
(75 MHz, CDCl3) 197.7, 139.4, 136.1, 132.0, 131.9, 130.5, 129.2, 57.8,
52.7, 46.2, 39.0, 21.4.
(4H, m, Ar–H), 3.60 (2H, d, J ¼ 2.1 Hz, 2-CH2), 2.80 (2H, t, J ¼ 6.0 Hz,
6-CH2), 2.66 (2H, t, J ¼ 6.0 Hz, 5-CH2), 2.43 (3H, s, N–CH3); dC
(75 MHz, CDCl3) 197.5, 162.4, 136.80, 134.3, 133.8, 130.0, 126.15,
116.6, 115.9, 57.4, 52.6, 46.1, 39.0.
5.1.5. 3-[(E)-(2,4-Dichlorophenyl)methylidene]-1-
5.1.2. 3-[(E)-(4-Methoxyphenyl)methylidene]-1-methyltetrahydro-
4(1H)-pyridinone (2b)
methyltetrahydro-4(1H)-pyridinone (2e)
Yellow solid; Yield: 1.19 g, 50%; m.p. 79–80 ꢀC (Found: C, 66.33;
H, 6.05; N, 6.01. C13H13Cl2NO requires C, 57.80; H, 4.85; N, 5.18);
Yellow solid; Yield: 1.04 g, 51%; m.p. 64–65 ꢀC (Found: C, 72.63;
H, 7.49; N, 6.14. C14H17NO2 requires C, 72.70; H, 7.41; N, 6.06); ymax
ymax (KBr) 1670 cmꢁ1
; dH (300 MHz, CDCl3) 7.58 (1H, br s, C]CH),
(KBr) 1673 cmꢁ1
; dH (300 MHz, CDCl3) 7.54 (1H, s, C]CH), 7.32 (2H,
7.10–7.45 (4H, m, Ar–H), 3.45 (2H, d, J ¼ 1.8 Hz, 2-CH2), 2.81 (2H, t,
J ¼ 6.3 Hz, 6-CH2), 2.68 (2H, t, J ¼ 6.0 Hz, 5-CH2), 2.40 (3H, s, N–
CH3); dC (75 MHz, CDCl3) 197.4,135.8,135.1,134.9,131.7,131.3,130.9,
129.7, 126.7, 57.1, 52.9, 46.0, 39.2.
d, J ¼ 8.7 Hz, Ar–H), 6.92 (2H, d, J ¼ 8.7 Hz, Ar–H), 3.82 (3H, s, Ar–
OCH3), 3.65 (2H, s, 2-CH2), 2.79 (2H, t, J ¼ 6.0 Hz, 6-CH2), 2.64 (2H, t,
J ¼ 6.3 Hz, 5-CH2), 2.45 (3H, s, N–CH3); dC (75 MHz, CDCl3) 198.0,
160.7, 136.4, 132.9, 131.2, 127.9, 114.5, 58.3, 55.7, 53.1, 46.7, 39.4.
5.1.3. 3-[(E)-(2-Chlorophenyl)methylidene]-1-methyltetrahydro-
4(1H)-pyridinone (2c)
Yellow solid; Yield: 1.12 g, 54%; m.p. 70–71 ꢀC (Found: C, 66.33;
H, 6.05; N, 6.01. C13H14ClNO requires C, 66.24; H, 5.99; N, 5.94); ymax
5.2. General procedure for the synthesis of 3-(4-chlorophenyl)-7-
methyl-4-aryl-1-oxa-2,7-diazaspiro[4.5]dec-2-en-10-ones (3a–e)
To a well-stirred mixture of 1-methyl-3-[(E)-arylmethylidene]-
tetrahydro-4(1H)-pyridinones (2, 1 mmol) and benzohydroximinoyl
CH3
HN
H
H
N
H
HN
H
N
H
H
H
H
O
N
O
H
H
H
H3C
N
H3C
H
Ar
Ar
H
H
O
H
H
O
H
H
Fig. 7. HMBC correlations of 5e.
Fig. 9. HMBC correlations of 6e.

R. Ranjith Kumar et al. / European Journal of Medicinal Chemistry 44 (2009) 3821–3829
3825
Table 1
130.6, 129.2, 129.1, 127.3, 124.7, 114.9, 90.5, 61.7, 55.7, 55.6, 53.2,
46.0, 38.5.
Minimum inhibitory concentrations of 4–6 against mycobacterial species.
Comp.
MIC (mM)
5.2.3. 4-(2-Chlorophenyl)-3-(4-chlorophenyl)-7-methyl-1-oxa-2,7-
diazaspiro[4.5]dec-2-en-10-one (3c)
MTB
7.53
MDR-TB
MC2
15.04
4a
NT
White solid; Yield: 0.23 g, 70%; m.p. 105–106 ꢀC (Found: C,
61.79; H, 4.73; N, 7.27. C20H18Cl2N2O2 requires C, 61.71; H, 4.66; N,
7.20); dH (300 MHz, CDCl3); 6.97–7.49 (8H, m, Ar–H), 5.92 (1H, s,
4-CH), 3.29 (1H, ddd, J ¼ 14.1, 11.7, 6.3 Hz, H-9ax), 3.05–3.12 (1H,
m, H-8eq), 2.52–2.63 (2H, m, H-6eq and H-9eq), 2.41 (1H, td,
J ¼ 11.4, 3.3 Hz, H-8ax), 2.22 (3H, s, N–CH3), 2.16 (1H, d,
J ¼ 12.9 Hz, H-6ax); dC (75 MHz, CDCl3) 202.1, 158.4, 136.3, 133.8,
130.7, 130.5, 130.1, 129.6, 128.9, 128.6, 127.5, 126.2, 89.8, 60.4, 55.0,
49.6, 45.4, 37.8.
4b
4c
4d
4e
5a
5b
5c
5d
5e
6a
6b
6c
6d
6e
14.48
3.58
7.46
NT
3.58
NT
1.66
NT
NT
NT
NT
0.88
NT
NT
NT
NT
NT
11.38
61.18
406.13
57.94
28.68
29.79
53.15
32.09
61.65
30.49
63.53
56.26
110.72
53.46
52.97
54.88
98.74
45.57
122.36
406.13
3.32
16.05
30.83
7.64
7.95
1.76
27.68
26.73
13.24
6.87
12.34
0.39
5.2.4. 3-(4-Chlorophenyl)-4-(3-fluorophenyl)-7-methyl-1-oxa-2,7-
diazaspiro[4.5]dec-2-en-10-one (3d)
Isoniazid
Ethambutol
Pyrazinamide
Viscous paste; Yield: 0.19 g, 55% (Found: C, 64.49; H, 4.81; N,
7.59. C20H18ClFN2O2 requires C, 64.43; H, 4.87; N, 7.51); dH
(300 MHz, CDCl3); 6.92–8.00 (8H, m, Ar–H), 4.45 (1H, s, 4-CH), 3.59
(1H, d, J ¼ 13.2, Hz, H-9ax), 3.54 (1H, d, J ¼ 13.2, Hz, H-9eq), 3.04–
3.07 (2H, t, 5.7 Hz, 8-CH2), 2.47 (3H, s, N–CH3), 2.33–2.40 (2H, m, 6-
CH2); dC (75 MHz, CDCl3) 203.3, 157.4, 137.9, 131.2, 129.9, 129.1,
128.5, 128.0, 124.6, 112.8, 90.2, 51.9, 44.2, 34.2.
7.64
50.77
MTB: M. tuberculosis; MDR-TB: Multi-drug resistant M. tuberculosis; MC2: M. smeg-
matis; NT: Not tested.
chloride (3 mmol) in benzene (15 mL), triethylamine (3 mmol) was
added drop-wise over a period of 10 min and stirring continued for 5 h
at ambient temperature. The triethylamine hydrochloride was filtered
off, solvent evaporated in vacuo and the product 3 was purified by
column chromatography using petroleum ether:ethyl acetate (4:1 v/v)
mixture.
5.2.5. 3-(4-Chlorophenyl)-4-(2,4-dichlorophenyl)-7-methyl-1-oxa-
2,7-diazaspiro[4.5]-dec-2-en-10-one (3e)
White solid; Yield 0.21 g, 67%; m.p. 146–147 ꢀC (Found: C, 56.62;
H, 4.12; N, 6.69. C20H17Cl3N2O2 requires C, 56.69; H, 4.04; N, 6.61);
dH (300 MHz, CDCl3); 6.90–7.50 (7H, m, Ar–H), 5.86 (1H, s, 4-CH),
3.28 (1H, ddd, J ¼ 13.8, 11.4, 6.0 Hz, H-9ax), 3.05–3.13 (1H, m, H-
8eq), 2.60 (1H, dd, J ¼ 12.9, 2.4 Hz, H-6eq), 2.55 (1H, dt, J ¼ 13.8,
3.0 Hz, H-9eq), 2.49 (1H, td, J ¼ 11.4, 3.3 Hz, H-8ax), 2.15 (3H, s, N–
CH3), 2.18 (1H, d, J ¼ 12.6 Hz, H-6ax); dC (75 MHz, CDCl3) 202.0,
158.2, 136.5, 135.0, 134.5, 131.4, 130.0, 129.5, 129.1, 128.5, 128.0,
126.0, 89.8, 60.4, 55.1, 49.2, 45.5, 37.8.
5.2.1. 3-(4-Chlorophenyl)-7-methyl-4-(4-methylphenyl)-1-oxa-
2,7-diazaspiro[4.5]-dec-2-en-10-one (3a)
White solid; Yield: 0.25 g, 73%; m.p. 135–136 ꢀC (Found: C,
68.31; H, 5.79; N, 7.67. C21H21ClN2O2 requires C, 68.38; H, 5.74; N,
7.59); dH (300 MHz, CDCl3); 7.03–7.52 (8H, m, Ar–H), 5.25 (1H, s, 4-
CH), 3.31 (1H, ddd, J ¼ 13.8, 11.5, 6.0 Hz, H-9ax), 3.06–3.12 (1H, m,
H-8eq), 2.64 (1H, dd, J ¼ 12.9, 2.4 Hz, H-6eq), 2.47 (1H, dt, J ¼ 13.8,
3.3 Hz, H-9eq), 2.39 (1H, td, J ¼ 11.4, 3.3 Hz, H-8ax), 2.31 (3H, s, Ar–
CH3), 2.23 (3H, s, N–CH3), 2.03 (1H, d, J ¼ 12.6 Hz, H-6ax); dC
(75 MHz, CDCl3) 203.5, 158.5, 138.1, 136.0, 129.8, 129.3, 128.8, 128.7,
126.8, 90.1, 61.2, 55.3, 53.0, 45.5, 38.0, 21.1.
5.3. General procedure for the synthesis of
spiro[2.300]oxindolespiro[3.30]-10-methyltetrahydro-40(1H)-
pyridinone-4-arylhexahydro-1H-pyrrolizine (4a–e)
A
mixture of 1-methyl-3-[(E)-arylmethylidene]tetrahydro-
5.2.2. 3-(4-Chlorophenyl)-4-(4-methoxyphenyl)-7-methyl-1-oxa-
2,7-diazaspiro[4.5]-dec-2-en-10-one (3b)
4(1H)-pyridinone (2, 1 mmol), isatin (1 mmol) and proline
(1 mmol) in methanol (15 mL) was refluxed for 10–15 min. After
completion of the reaction (TLC), the mixture was poured into
water (30 mL) and the precipitated 4 was filtered off and washed
with water.
White solid; Yield: 0.21 g, 63%; m.p. 127–128 ꢀC (Found: C,
65.50; H, 5.56; N, 7.21. C21H21ClN2O3 requires C, 65.54; H, 5.50;
N, 7.28); dH (300 MHz, CDCl3); 6.98–7.67 (8H, m, Ar–H), 5.38 (1H,
s, 4-CH), 3.93 (3H, s, Ar–OCH3), 3.44 (1H, ddd, J ¼ 13.8, 11.4,
6.3 Hz, H-9ax), 3.19–3.26 (1H, m, H-8eq), 2.78 (1H, dd, J ¼ 12.9,
2.4 Hz, H-6eq), 2.64 (1H, dt, J ¼ 13.8, 3.3 Hz, H-9eq), 2.54 (1H, td,
J ¼ 11.4, 3.3 Hz, H-8ax), 2.38 (3H, s, N–CH3), 2.18 (1H, d,
J ¼ 12.9 Hz, H-6ax); dC (75 MHz, CDCl3) 204.0, 159.9, 159.0, 136.4,
5.3.1. Spiro[2.300]oxindolespiro[3.30]-10-methyltetrahydro-40(1H)-
pyridinone-4-(4-methylphenyl)hexahydro-1H-pyrrolizine (4a)
White solid; Yield: 0.18 g, 93%; m.p. 178–179 ꢀC (Found: C, 75.10;
H, 7.09; N, 10.17. C26H29N3O2 requires C, 75.15; H, 7.03; N, 10.11); dH
7
1''
HN
1''
HN
1''
HN
6
1
CH3
N1
H
2''
N
2''
2''
2'
N1
2
3
5
2
3
2
3
Ph
4a
O
O
O
5
5
1'N
1'N
1'
N
2'
H
Ar
2'
H
Ar
H3C
H3C
H3C
Ar
4
4
4
4'
4'
4'
6'
H
6'
H
6'
H
5'
5'
5'
O
O
O
Ar
Ar
Ar
7
8
9
Scheme 1. Structure of compounds investigated for antimycobacterial activities previously.

3826
R. Ranjith Kumar et al. / European Journal of Medicinal Chemistry 44 (2009) 3821–3829
50-CH2 and 5-CH2); dC (75 MHz, CDCl3) 207.6, 181.4, 158.7, 141.9,
131.2, 129.7, 129.5, 128.2, 127.0, 122.0, 113.9, 110.3, 74.1, 72.8, 66.4,
58.3, 55.6, 54.5, 51.7, 48.2, 45.1, 41.4, 29.8, 26.8.
O
O
4
3
ArCHO
5
6
Ar
1
Pyrrolidine
MW
2
N
N
5.3.3. Spiro[2.300]oxindolespiro[3.30]-10-methyltetrahydro-40(1H)-
pyridinone-4-(2-chlorophenyl)hexahydro-1H-pyrrolizine (4c)
White solid; Yield: 0.16 g, 86%; m.p. 120–122 ꢀC (Found: C,
68.82; H, 6.09; N, 9.57. C25H26ClN3O2 requires C, 68.88; H, 6.01; N,
9.64); dH (300 MHz, CDCl3) 8.93 (1H, s, NH), 7.02–7.90 (8H, m, Ar),
4.85 (1H, d, J ¼ 10.2 Hz, 4-CH), 4.65–4.73 (1H, m, 4a-CH), 3.73 (1H,
d, J ¼ 12.1 Hz, H-20eq), 3.23–3.28 (1H, m, 7-CH2), 2.55–2.74 (2H, m,
H-60eq and 7-CH2), 2.18 (3H, s, N–CH3), 1.91–2.23 (7H, m, 5-CH2, 6,
CH2, 50-CH2, and H-60ax) 1.85 (1H, d, 12.1 Hz, H-20ax),1.64–1.73 (2H,
m, 50-CH2 and 5-CH2); dC (75 MHz, CDCl3) 207.5, 179.4, 141.7, 136.0,
135.7, 130.9, 129.9, 129.2, 127.8, 126.7, 126.2, 121.8, 109.9, 74.6, 70.4,
68.2, 59.7, 53.8, 49.3, 47.8, 45.2, 40.1, 28.6, 25.4.
CH3
CH3
1
2
Irradiation
Yield
Comp 2
Ar
time (min)
a
b
c
p-MeC6H4
p-MeOC6H4
o-ClC6H4
4
8
6
5
7
76
51
54
63
50
d
e
m-FC6H4
o,p-Cl2C6H3
5.3.4. Spiro[2.300]oxindolespiro[3.30]-10-methyltetrahydro-40(1H)-
pyridinone-4-(3-fluorophenyl)hexahydro-1H-pyrrolizine (4d)
White solid; Yield: 0.18 g, 94%; m.p.169–170 ꢀC (Found: C, 71.67;
H, 6.17; N, 9.95. C25H26FN3O2 requires C, 71.58; H, 6.25; N, 10.02); dH
(300 MHz, CDCl3) 8.82 (1H, s, NH), 6.88–7.27 (8H, m, Ar), 4.48 (1H, dt,
J ¼ 11.4, 6.6 Hz, 4a-CH), 4.11 (1H, d, J ¼ 11.4 Hz, 4-CH), 3.75 (1H, d,
J ¼ 12.3 Hz, H-20eq), 2.82–2.90 (1H, m, 7-CH2), 2.54–2.60 (2H, m, H-
60eq and 7-CH2), 2.14 (3H, s, N–CH3), 2.03–2.09 (1H, m, 5-CH2),1.91–
1.99 (4H, m, 6-CH2, 50-CH2 and H-60ax), 1.57 (1H, d, 12.3 Hz, H-20ax),
1.47–1.52 (2H, m, 50-CH2 and 5-CH2); dC (75 MHz, CDCl3) 206.1,179.5,
140.4,139.0,128.5,128.4,126.7,125.5,124.5,120.7,115.7,112.7,108.9,
72.3, 71.4, 64.7, 57.0, 53.1, 50.4, 46.6, 43.6, 39.8, 28.0, 25.3.
Scheme 2. Synthesis of tetrahydro-4(1H)-pyridinones 2.
(300 MHz, CDCl3) 8.40 (1H, s, NH), 6.85–7.27 (8H, m, Ar), 4.48 (1H,
dt, J ¼ 11.7, 6.6 Hz, 4a-CH), 4.08 (1H, d, J ¼ 11.7 Hz, 4-CH), 3.75 (1H,
dd, J ¼ 12.3, 2.7 Hz, H-20eq), 2.82–2.90 (1H, m, 7-CH2), 2.54–2.60
(2H, m, H-60eq and 7-CH2), 2.33 (3H, s, Ar–CH3), 2.14 (3H, s, N–CH3),
2.00–2.07 (1H, m, 5-CH2), 1.88–1.99 (4H, m, 6-CH2, 50-CH2 and H-
60ax), 1.63 (1H, d, 12.3 Hz, H-20ax), 1.51–1.58 (2H, m, 50-CH2 and 5-
CH2); dC (75 MHz, CDCl3) 207.2, 180.4, 141.3, 136.3, 134.1, 129.7,
129.2, 128.9, 127.8, 127.0, 121.6, 109.7, 73.5, 72.4, 65.9, 58.0, 54.0,
51.5, 47.6, 44.7, 40.9, 29.1, 26.3, 21.0.
5.3.5. Spiro[2.300]oxindolespiro[3.30]-10-methyltetrahydro-40(1H)-
pyridinone-4-(2,4-dichlorophenyl)hexahydro-1H-pyrrolizine (4e)
White solid; Yield: 0.16 g, 92%; m.p. 110–112 ꢀC (Found: C, 63.74;
H, 5.27; N, 8.97. C25H26FN3O2 requires C, 63.83; H, 5.36; N, 8.93); dH
(300 MHz, CDCl3); 8.42 (1H, s, NH), 7.00–7.74 (7H, m, Ar), 4.79 (1H, d,
J ¼ 11.2 Hz, 4-CH), 4.62–4.69 (1H, m, 4a-CH), 3.66 (1H, dd, J ¼ 12.3,
2.4 Hz, H-20eq), 2.61–2.76 (2H, m, H-60eq and 7-CH2), 2.22–2.30 (1H,
m, 7-CH2), 2.19 (3H, s, N–CH3), 2.06–2.15 (1H, m, 5-CH2), 1.83–2.03
(4H, m, 6-CH2, 50-CH2 and H-60ax),1.80 (1H, d,12.3 Hz, H-20ax),1.70–
1.75 (2H, m, 50-CH2 and 5-CH2); dC (75 MHz, CDCl3) 207.4, 178.8,
141.6,136.6,134.5,132.9,131.7,129.5,129.3,127.7,126.2,121.9,109.8,
74.4, 70.2, 68.2, 59.8, 53.8, 48.9, 47.7, 45.2, 40.0, 28.5, 25.4.
5.3.2. Spiro[2.300]oxindolespiro-[3.30]-10-methyltetrahydro-40(1H)-
pyridinone-4-(4-methoxyphenyl)hexahydro-1H-pyrrolizine (4b)
White solid; Yield: 0.17 g, 91%; m.p. 163–164 ꢀC (Found: C,
72.31; H, 6.72; N, 9.79. C26H29N3O3 requires C, 72.37; H, 6.77; N,
9.74); dH (300 MHz, CDCl3) 9.10 (1H, s, NH), 6.97–7.42 (8H, m, Ar),
4.61 (1H, dt, J ¼ 11.7, 6.6 Hz, 4a-CH), 4.21 (1H, d, J ¼ 11.4 Hz, 4-CH),
3.95 (3H, s, Ar–OCH3), 3.90 (1H, dd, J ¼ 12.3, 2.4 Hz, H-20eq), 2.96–
3.04 (1H, m, 7-CH2), 2.68–2.76 (2H, m, H-60eq and 7-CH2), 2.28 (3H,
s, N–CH3), 2.14–2.24 (1H, m, 5-CH2), 2.05–2.11 (4H, m, 6-CH2, 50-
CH2 and H-60ax), 1.79 (1H, d, 12.3 Hz, H-20ax), 1.64–1.73 (2H, m,
5.4. General procedure for the synthesis of 1-methyl-4-
arylpyrrolo(spiro[2.300]oxindole)-spiro[3.30]-10-methylpiperidin-40-
ones (5a–e)
Cl
OH
N
2
N
O
1O
4
3
H
Ar'
3
7N
H
Ar'
5
6
H
4
Ar
5
Ar
H3C
6
A
mixture of 1-methyl-3-[(E)-arylmethylidene]tetrahydro-
1
9
H
2
Et3N rt, 5 h
C6H6
8
N
4(1H)-pyridinone (2, 1 mmol), isatin (1 mmol) and sarcosine
(1 mmol) was refluxed in methanol (15 mL) for 4 h. After comple-
tion of the reaction (TLC), the mixture was poured into water
(30 mL) and the precipitated 5 was filtered off and washed with
water.
H
O
H
CH3
H
3
2
Comp 3a
Ar
Yield
73
5.4.1. 1-Methyl-4-(4-methylphenyl)pyrrolo(spiro[2.300]oxindole)-
spiro[3.30]-10-methylpiperidin-40-one (5a)
a
p-MeC6H4
White solid; Yield: 0.29 g, 80%; m.p. 132–133 ꢀC (Found: C,
74.12; H, 6.90; N, 10.72. C24H27N3O2 requires C, 74.01; H, 6.99; N,
10.79); dH (300 MHz, CDCl3) 8.31 (1H, s, NH), 6.81–7.27 (8H, m, Ar),
4.63 (1H, dd, J ¼ 10.8, 6.3 Hz, 4-CH), 3.79 (1H, t, J ¼ 10.8 Hz, 5-CH2),
3.48 (1H, dd, J ¼ 12.6, 2.4 Hz, H-20eq), 3.20 (1H, t, J ¼ 8.4 Hz, 5-CH2),
2.49 (1H, t, J ¼ 6.0 Hz, H-60eq), 2.31 (3H, s, 1-N–CH3), 2.17 (3H, s, Ar–
CH3), 2.05 (3H, s, 10-N–CH3), 1.90–1.98 (1H, m, H-60ax), 1.85 (1H, br
s, 50-CH2),1.40–1.46 (1H, m, 50-CH2) 1.36 (1H, d, J ¼ 12.6 Hz, H-20ax);
dC (75 MHz, CDCl3) 207.4, 177.7, 141.4, 136.2, 135.1, 130.1, 129.2,
b
c
p-MeOC6H4
o-ClC6H4
63
70
55
67
d
e
m-FC6H4
o,p-Cl2C6H3
a
Ar'=p-ClC6H4 in all cases
Scheme 3. Synthesis of spiro-isoxazolines 3.

R. Ranjith Kumar et al. / European Journal of Medicinal Chemistry 44 (2009) 3821–3829
3827
6''
7''
5''
4''
3a''
7a''
7
6
5
1''
HN
1
N
3 H
H
H
N
2''
COOH
2
H
1'
4a
H
O
N
4
H3C
2'
4'
H
Ar
MeOH
reflux, 10 min
5'
6'
O
H
H
H
4
6''
5''
4''
7''
7a''
3a''
CH3
1''
HN
O
N1
H
2''
H
5
H
2
N
COOH
H
3 H
O
1'
H3C
H
O
Ar
N
4
H3C
+
2'
4'
H
Ar
MeOH
reflux, 4 h
5'
N
6'
O
O
N
H
H
CH3
H
H
5
2
6''
5''
4''
7''
7a''
3a''
1''
HN
NH2
1 H
N
H
H
5
2''
2
3
H
1'
H
O
N
4
H3C
MeOH
2'
4'
H
Ar
5'
reflux, 3 h
6'
O
H
H
H
6
Yield
5
Comp
Ar
4
6
a
b
c
p-MeC6H4
p-MeOC6H4
o-ClC6H4
93
91
86
94
92
80
85
81
80
86
80
85
92
d
e
m-FC6H4
94
o,p-Cl2C6H3
85
Scheme 4. Synthesis of spiro-cycloadducts 4–6.
129.0,128.8, 126.4, 122.4, 109.2, 74.2, 67.8, 59.4, 56.1, 54.3, 44.8, 44.1,
40.5, 34.9, 21.0.
1.63 (1H, m, 50-CH2), 1.49 (1H, d, J ¼ 12.6 Hz, H-20ax); dC (75 MHz,
CDCl3) 207.9, 178.0, 158.7, 141.8, 130.7, 129.4, 126.8, 122.9, 113.9,
109.6, 74.6, 68.3, 59.9, 56.6, 55.6, 54.9, 45.3, 44.2, 41.0, 35.3.
5.4.2. 1-Methyl-4-(4-methoxyphenyl)pyrrolo(spiro[2.300]oxindole)-
spiro[3.30]-10-methylpiperidin-40-one (5b)
5.4.3. 1-Methyl-4-(2-chlorophenyl)pyrrolo(spiro[2.300]oxindole)-
spiro[3.30]-10-methylpiperidin-40-one (5c)
White solid; Yield: 0.30 g, 85%; m.p.139–141 ꢀC (Found: C, 71.19;
H, 6.80; N,10.30. C24H27N3O3 requires C, 71.09; H, 6.71; N,10.36); dH
(300 MHz, CDCl3) 8.35 (1H, s, NH), 6.96–7.42 (8H, m, Ar), 4.77 (1H,
dd, J ¼ 11.1, 6.6 Hz, 4-CH), 3.87–3.95 (4H, m, Ar–OCH3 and 5-CH2),
3.61 (1H, dd, J ¼ 12.6, 2.4 Hz, H-20eq), 3.35 (1H, dd, J ¼ 11.1, 6.9 Hz,
5-CH2), 2.64–2.70 (1H, m, H-60eq), 2.32 (3H, s, 1-N–CH3), 2.20 (3H,
s, 10-N–CH3), 2.05–2.18 (1H, m, H-60ax), 1.90 (1H, br s, 50-CH2), 1.55–
White solid; Yield: 0.32 g, 92%; m.p. 90–91 ꢀC (Found: C, 67.33;
H, 5.99; N, 10.20. C23H24ClN3O2 requires C, 67.39; H, 5.90; N, 10.25);
dH (300 MHz, CDCl3) 8.63 (1H, s, NH), 6.83–8.05 (8H, m, Ar), 5.04
(1H, dd, J ¼ 7.5, 5.7 Hz, 4-CH), 3.54–3.59 (1H, m, 5-CH2), 3.42–3.48
(1H, m, 5-CH2), 3.10 (1H, dd, J ¼ 12.6, 2.4 Hz, H-20eq), 2.47–2.52
(1H, m, H-60eq), 2.08 (3H, s,1-N–CH3), 2.00–2.05 (2H, m, 50-CH2 and

3828
R. Ranjith Kumar et al. / European Journal of Medicinal Chemistry 44 (2009) 3821–3829
(30 mL) and the precipitated 6 was filtered off and washed with
water.
δ+
N
O
H
O
N
δ+
δ -
N
H
2
HN
H
H
5.5.1. 4-(4-Methylphenyl)-5-
H
2'
H
N
phenylpyrrolo(spiro[2.300]oxindole)spiro[3.30]-10-methylpiperidin-
40-one (6a)
H3C
3
Ar
Ar
H
N
H3C
H
O
H
H
White solid; Yield: 0.36 g, 85%; m.p.105–107 ꢀC (Found: C, 77.17;
H, 6.42; N, 9.36. C29H29N3O2 requires C, 77.13; H, 6.47; N, 9.31); dH
(300 MHz, CDCl3) 8.33 (1H, s, NH), 6.99–7.48 (13H, m, Ar), 5.25 (1H,
d, J ¼ 11.7 Hz, 4-CH), 4.51 (1H, d, J ¼ 11.7 Hz, 5-CH), 3.73 (1H, dd,
J ¼ 12.3, 2.7 Hz, H-20eq), 2.55–2.60 (1H, m, H-60eq), 2.26 (3H, s, Ar–
CH3), 2.15 (3H, s, N–CH3), 1.93–2.06 (2H, m, H-60ax and 50-CH2), 1.55
(1H, d, J ¼ 12.3 Hz, H-20ax), 1.38–1.50 (1H, m, 50-CH2); dC (75 MHz,
CDCl3) 206.9, 181.6, 140.7, 140.3, 136.1, 133.4, 130.9, 129.6, 129.1,
128.7, 128.2, 127.7, 125.9, 122.5, 109.4, 69.6, 68.5, 62.9, 58.8, 54.1,
54.0, 44.8, 40.6, 21.0.
H
O
4
(formed)
Transition state A
δ+
N
δ -
δ+
HN
H
N
H
2
H
O
H
H
HN
N
O
H3C
3
2'
Ar
Ar
H
N
H3C
O
H
H
H
H
O
5.5.2. 4-(4-Methoxyphenyl)-5-
phenylpyrrolo(spiro[2.300]oxindole)spiro[3.30]-10-methylpiperidin-
40-one (6b)
4'
(not formed)
Transition state B
White solid; Yield: 0.33 g, 81%; m.p. 96–98 ꢀC (Found: C, 74.61; H,
6.13; N, 9.09. C29H29N3O3 requires C, 74.50; H, 6.25; N, 8.99); dH
(300 MHz, CDCl3) 8.17 (1H, s, NH), 6.73–7.46 (13H, m, Ar), 5.20 (1H, d,
J ¼ 11.7 Hz, 4-CH), 4.48 (1H, d, J ¼ 11.7 Hz, 5-CH), 3.69–3.75 (4H, m,
Ar–OCH3 and H-20eq), 2.54–2.59 (1H, m, H-60eq), 2.14 (3H, s, N–
CH3),1.92 2.02 (2H, m, H-60ax and 50-CH2),1.53 (1H, d, J ¼ 12.3 Hz, H-
20ax), 1.38–1.49 (1H, m, 50-CH2); dC (75 MHz, CDCl3) 207.0, 181.7,
158.2,140.4,130.9,130.8,129.8,129.0,128.4,128.2,127.7,127.6,125.9,
122.5, 113.4, 109.4, 69.5, 68.4, 63.0, 58.9, 55.0, 53.8, 44.8, 40.6.
Scheme 5. Stereochemistry of cycloadducts differing in their relative configurations at
C-2 and C-3.
H-60ax), 1.94 (3H, s, 10-N–CH3), 1.46–1.66 (1H, m, 50-CH2), 1.44
(1H, d, J ¼ 12.6 Hz, H-20ax); dC (75 MHz, CDCl3) 206.7, 178.0, 141.5,
138.3, 135.2,130.8,129.7,129.0, 127.8,127.1,126.9,126.8,122.1,109.7,
75.4, 66.8, 60.0, 59.5, 53.9, 45.2, 40.9, 40.3, 35.2.
5.4.4. 1-Methyl-4-(3-
fluorophenyl)pyrrolo(spiro[2.300]oxindole)spiro[3.30]-10-methyl-
piperidin-40-one (5d)
5.5.3. 4-(2-Chlorophenyl)-5-
phenylpyrrolo(spiro[2.300]oxindole)spiro[3.30]-10-methylpiperidin-
40-one (6c)
White solid; Yield: 0.34 g, 94%; m.p. 101–103 ꢀC (Found:
C, 70.30; H, 6.08; N,10.62. C23H24FN3O2 requires C, 70.21; H, 6.15; N,
10.68); dH (300 MHz, CDCl3) 8.25 (1H, s, NH), 6.82–7.28 (8H, m, Ar),
4.61 (1H, dd, J ¼ 10.8, 6.6 Hz, 4-CH), 3.76 (1H, dd, J ¼ 10.8, 9.0 Hz, 5-
CH2), 3.47 (1H, dd, J ¼ 12.3, 2.7 Hz, H-20eq), 3.22 (1H, dd, J ¼ 8.7,
6.6 Hz, 5-CH2), 2.49–2.59 (1H, m, H-60eq), 2.17 (3H, s, 1-N–CH3),
2.05 (3H, s, 10-N–CH3), 1.92–1.99 (1H, m, H-60ax), 1.77 (1H, br s, 50-
CH2), 1.41–1.49 (1H, m, 50-CH2), 1.32 (1H, d, J ¼ 12.6 Hz, H-20ax); dC
(75 MHz, CDCl3) 207.2, 177.8, 141.2, 129.6, 129.4, 129.1, 128.7, 126.4,
125.0, 122.5, 116.1, 113.7, 109.3, 74.0, 67.8, 59.3, 55.8, 54.3, 44.8, 44.2,
40.4, 34.8.
White solid; Yield: 0.32 g, 80%; m.p. 95–97 ꢀC (Found: C, 71.33;
H, 5.46; N, 8.99. C28H26ClN3O2 requires C, 71.25; H, 5.55; N, 8.90); dH
(300 MHz, CDCl3) 8.01 (1H, s, NH), 6.81–7.53 (13H, m, Ar), 5.46 (1H,
d, J ¼ 9.9 Hz, 5-CH), 5.10 (1H, d, J ¼ 9.9 Hz, 4-CH), 3.23 (1H, d,
J ¼ 12.6 Hz, H-20eq), 2.46–2.52 (1H, m, H-60eq), 2.26 (1H, dd, J ¼ 17.1,
4.8 Hz, 50-CH2), 2.09 (1H, td, J ¼ 10.8, 5.1 Hz, H-60ax), 1.99 (3H, s, N–
CH3), 1.77–1.89 (1H, m, 50-CH2), 1.65 (1H, d, J ¼ 12.6 Hz, H-20ax); dC
(75 MHz, CDCl3) 207.7, 179.5, 141.3, 140.6, 136.0, 135.7, 130.8, 129.5,
129.2, 129.1, 128.4, 127.9, 127.7, 127.6, 126.5, 125.5, 122.6, 109.6, 72.8,
65.8, 65.3, 60.2, 53.8, 52.1, 45.8, 39.6.
5.4.5. 1-Methyl-4-(2,4-
dichlorophenyl)pyrrolo(spiro[2.300]oxindole)spiro[3.30]-10-methyl-
piperidin-40-one (5e)
5.5.4. 4-(3-Fluorophenyl)-5-
phenylpyrrolo(spiro[2.300]oxindole)spiro[3.30]-10-methylpiperidin-
40-one (6d)
White solid; Yield: 0.28 g, 85%; m.p. 190–191 ꢀC (Found: C,
62.10; H, 5.15; N, 9.56. C23H23Cl2N3O2 requires C, 62.17; H, 5.22;
N, 9.46); dH (300 MHz, CDCl3) 8.78 (1H, s, NH), 6.85–8.08 (8H, m,
Ar), 4.99 (1H, t, J ¼ 6.3 Hz, 4-CH), 3.41–3.50 (2H, m, 5-CH2), 3.10
(1H, dd, J ¼ 12.3, 2.4 Hz, H-20eq), 2.49–2.56 (1H, m, H-60eq), 2.07
(3H, s, 1-N–CH3), 2.02–2.14 (2H, m, 50-CH2 and H-60ax), 1.98 (3H, s,
10-N–CH3), 1.56–1.64 (1H, m, 50-CH2), 1.43 (1H, d, J ¼ 12.3 Hz, H-
20ax); dC (75 MHz, CDCl3) 206.9, 178.5, 141.8, 137.7, 136.2, 133.2,
132.2, 129.6, 129.1, 127.6, 127.5, 127.1, 122.6, 110.3, 75.6, 67.4, 60.5,
60.2, 54.4, 45.6, 40.9, 40.8, 35.6.
White solid; Yield: 0.36 g, 86%; m.p. 90–92 ꢀC (Found: C, 73.91;
H, 5.86; N, 9.29. C28H26FN3O2 requires C, 73.83; H, 5.75; N, 9.22); dH
(300 MHz, CDCl3) 8.12 (1H, s, NH), 6.82–7.48 (13H, m, Ar), 5.23 (1H,
d, J ¼ 11.6 Hz, 4-CH), 4.54 (1H, d, J ¼ 11.6 Hz, 5-CH), 3.72 (1H, dd,
J ¼ 12.3, 2.7 Hz, H-20eq), 2.56–2.62 (1H, m, H-60eq), 2.15 (3H, s, N–
CH3), 1.92–2.06 (2H, m, H-60ax and 50-CH2), 1.49 (1H, d, J ¼ 12.3 Hz,
H-20ax), 1.39–1.46 (1H, m, 50-CH2); dC (75 MHz, CDCl3) 206.7, 181.4,
140.6, 139.9, 139.2, 130.6, 129.5, 129.4, 129.3, 128.3, 127.8, 127.6,
125.9, 125.5, 122.6, 116.7, 113.7, 109.5, 69.4, 68.3, 62.8, 58.8, 54.1,
44.8, 40.5.
5.5.5. 4-(2,4-Dichlorophenyl)-5-
5.5. General procedure for the synthesis of 4-aryl-5-
phenylpyrrolo(spiro[2.300]oxindole)spiro [3.30]-10-methylpiperidin-
40-ones (6a–e)
phenylpyrrolo(spiro[2.300]oxindole)spiro[3.30]-10-methylpiperidin-
40-one (6e)
A
mixture of 1-methyl-3-[(E)-arylmethylidene]tetrahydro-
White solid; Yield: 0.30 g, 80%; m.p. 124–125 ꢀC (Found:
C, 66.49; H, 4.89; N, 8.20. C28H25Cl2N3O2 requires C, 66.41; H,
4.98; N, 8.30); dH (300 MHz, CDCl3) 8.01 (1H, s, NH), 6.82–7.91
(12H, m, Ar), 5.39 (1H, d, J ¼ 9.9 Hz, 5-CH), 5.06 (1H, d, J ¼ 9.9 Hz,
4(1H)-pyridinones (2, 1 mmol), isatin (1 mmol) and benzylamine
(1 mmol) was refluxed in methanol (15 mL) for 3 h. After comple-
tion of the reaction (TLC), the mixture was poured into water

R. Ranjith Kumar et al. / European Journal of Medicinal Chemistry 44 (2009) 3821–3829
3829
4-CH), 3.21 (1H, dd, J ¼ 12.6, 2.4 Hz, H-20eq), 2.48–2.54 (1H, m, H-
60eq), 2.27 (1H, dd, J ¼ 16.8, 4.5 Hz, 50-CH2), 2.11 (1H, td, J ¼ 10.8,
4.8 Hz, H-60ax), 2.00 (3H, s, N–CH3), 1.79–1.91 (1H, m, 50-CH2),
1.64 (1H, d, J ¼ 12.6 Hz, H-20ax); dC (75 MHz, CDCl3) 208.0, 179.8,
141.7, 140.8, 137.1, 134.9, 133.4, 132.1, 129.7, 129.3, 128.9, 128.3,
128.0, 127.2, 125.9, 123.1, 110.1, 73.2, 66.0, 65.8, 60.7, 54.2, 52.2,
46.2, 40.0.
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S.P. thanks the Council of Scientific and Industrial Research, New
Delhi for a major research project [No. 01(1926/04/EMR II)] and the
Department of Science and Technology, New Delhi for funds under
(i) IRHPA programme for the purchase of a high resolution NMR
spectrometer and (ii) FIST programme and the University Grants
Commission, New Delhi for funds under the DRS and ASIST
programmes.
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