Facile synthesis of active antitubercular, cytotoxic and antibacterial agents: A Michael addition approach

Article abstract of DOI:10.1016/j.ejmech.2005.06.004

Spiro derivatives of oxindole and isoxazole-5-one were synthesized by using Michael addition reaction, highlighting the regioselective approach towards the synthesis of Michael diadduct followed by condensation of Michael diadduct. The spiro compound 4 sh

Full text of DOI:10.1016/j.ejmech.2005.06.004

European Journal of Medicinal Chemistry 40 (2005) 1143–1148
www.elsevier.com/locate/ejmech
Original Article
Facile synthesis of active antitubercular, cytotoxic and antibacterial
agents: a Michael addition approach
Madhukar S. Chande a,*, Ranjit S. Verma a, Pravin A. Barve a, Rahul R. Khanwelkar a,
R.B. Vaidya a, K.B. Ajaikumar b
a Department of Chemistry, The Institute of Science, Madam Cama Road, Mumbai 32, India
b Amla Cancer Research Center, Amlanagar 680555, Trissur, Kerala, India
Received 26 April 2005; received in revised form 13 June 2005; accepted 15 June 2005
Available online 22 July 2005
Abstract
Spiro derivatives of oxindole and isoxazole-5-one were synthesized by using Michael addition reaction, highlighting the regioselective
approach towards the synthesis of Michael diadduct followed by condensation of Michael diadduct. The spiro compound 4 showed antitu-
bercular activity against Mycobacterium tuberculosis H37Rv whereas spiro compound 9 possesses pronounced anticancer and antibacterial
profile.
© 2005 Elsevier SAS. All rights reserved.
Keywords: Antitubercular; Cytotoxic; Antibacterial; Oxindole; Isoxazolone; Michael addition; Dieckmann condensation; Thorpe–Ziegler cyclization
1. Introduction
taining active methylene/methine groups for the synthesis of
spirocompounds [18,19]. Spiro nuclei have drawn consider-
able attention of the chemist because of their antiseptic
[20,21], analgesic [22] and broad-spectrum antimicrobial
activities [23]. Hence, introduction of spiro nucleus to such
vital molecules will enhance their biological activity.Although
it is widely recognized as one of the most important C–C
bond forming reaction in organic chemistry and an important
method of alkylation of active methylene compounds, there
are very few reports on the Michael addition of
1-methyl/ethyl-1,3-dihydro-indol-2-one 1 [24] and 3-phenyl-
4H-isoxazol-5-one 7 [25,26]. We now report the synthesis of
spiro derivatives containing 1-methyl/ethyl-1,3-dihydro-indol-
2-one 1 and 3-phenyl-4H-isoxazol-5-one 7 nuclei.
Tuberculosis (TB), an infection caused by Mycobacte-
rium tuberculosis, still remains the leading cause of world-
wide death among infectious diseases [1]. Indole derivatives
show interesting biological properties [2,3] and some of them
are known for their antitubercular activity [4–6]. Hence, for
the purpose of obtaining new and more potent antitubercular
compounds that can improve the current chemotherapeutic
antituberculosis treatment, we have synthesized and evalu-
ated some spiro oxindole derivatives. Similarly, 3-phenyl-
isoxazole-5-one derivatives are also known for their biologi-
cal activity [7,8]. The recognition of the pharmacological
activity of some isoxazole derivatives such as Gantricin, a
sulfa drug from amino isoxazole [9], cycloserine and oxamy-
cin, simple derivatives of 3-isoxazolidone as antibiotic
[10–12] has aroused a new interest in this field.
2. Chemistry
We have contributed for the synthesis of potential antipara-
sitic [13], antimicrobial [14,15], antiinsecticidal [16] and anti-
cancer [17] agents. Recently, we explored the scope of
Michael addition on various heterocyclic ring systems con-
The aim underlying the synthesis of a spiro compound
starting from 1 was to further enhance its pharmacological
activity. Surprisingly, bases like pyridine, piperidine, triethy-
lamine, metal hydroxides/alkoxides and also fluoride ions in
combination with phase transfer catalyst (PTC) failed to cata-
lyze the addition of 1 with methyl acrylate and the starting
synthon was recovered in quantitative yields.
* Corresponding author. Fax: +91 22 204 7962.
E-mail address: chandems@vsnl.com (M.S. Chande).
0223-5234/$ - see front matter © 2005 Elsevier SAS. All rights reserved.
doi:10.1016/j.ejmech.2005.06.004

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M.S. Chande et al. / European Journal of Medicinal Chemistry 40 (2005) 1143–1148
Scheme 1. Synthesis of spirocyclohexanone derivative of oxindole.
Reagents and conditions: (a) NaNH2, methyl acrylate, DMF, 10–15 °C, 30 min (b) Conc. HCl, reflux, 3 h (c) Na, dry benzene, reflux, 4 h (d) NaNH2,
acrylonitrile, DMF, 10–15 °C, 2 h (e) NaOEt, ethanol, reflux, 4 h (f) aq. HCl, reflux, 4 h.
When 1 was reacted with methyl acrylate in presence of
sodium amide in dry dimethyl formamide (DMF) at 10–15 °C,
Michael diadduct 2 was obtained in quantitative yield. This
compound was oily in nature and found to be unstable at room
temperature. Hence, it was converted into a stable dicarboxy-
lic acid 3 by acid hydrolysis. Here, Michael addition can take
place in two ways, C-Michael addition and O-Michael addi-
reacted with methyl acrylate in the presence of bases like pyri-
dine, piperidine, triethylamine, metal hydroxides/
alkoxides and also fluoride ions in combination with PTC
failed to catalyze the addition, and starting synthon was recov-
ered in quantitative yields. When the reaction was carried out
by using base like sodamide in DMF at 10–15 °C, a light
pink colored solid was obtained in moderate yield. It showed
the presence of an ester linkage. An important feature was
that the reaction exhibited striking regioselectivity yielding 8
as the only product. Presence of triplet of methine proton at d
3.68, multiplets at d 2.20–2.45 of three methylene protons,
singlet of methoxy group of carbmethoxy at d 3.65 in 1H NMR
and peak of cyclohexanone carbon at d 205.2 in 13C NMR
clearly indicated the formation of spiro a-carbmethoxy cyclo-
hexanone derivative of isoxazolone 8 and not Michael diad-
duct or Michael monoadduct. This was further confirmed on
the basis of Mass spectrum displaying M+ peak at 301. It
showed that the reaction went further in situ to give the Dieck-
mann cyclized product. Compound 8 was then converted to
spirocyclohexanone derivative of isoxazolone 9 by its acid
hydrolysis in 75% yield (Scheme 2, route 1).
Compound 9 was alternately prepared by reacting acry-
lonitrile as a Michael acceptor with 7. Acrylonitrile was
reacted with 7 in presence of Tri ethyl amine (TEA) in etha-
nol, Michael diadduct 10 was successfully isolated in quan-
titative yield. Thorpe–Ziegler cyclization of 10 in presence
of sodium metal in benzene afforded desired spirocycloin-
amine derivative of isoxazolone 11. It was then easily hydro-
lyzed in acidic condition to afford 9 in 72% yield (Scheme 2,
route 2), which was confirmed by CO-IR and mixed melting
point with the product prepared by route 1.
1
tion. Presence of multiplet at d 2.06–2.28 in H NMR for
–CH2 protons, and presence of quaternary C at d 94.8 and
carbonyl group at d 163.1 of oxindole moiety in 13C NMR of
3b confirmed the formation of C-Michael adduct, that to diad-
duct and not O-Michael adduct. Hence, regioselectivity of
the reaction is proved on the basis of spectral analysis of the
product 3. Dieckmann condensation of 3 in presence of pul-
verized sodium in dry benzene gave excellent yields of spi-
rocyclohexanone derivatives of oxindole 4 in 80–85% yield
(Scheme 1, route 1).
Scope of the work was also extended to acrylonitrile as a
Michael acceptor with 1. Michael diadduct 5 was synthe-
sized by reacting acrylonitrile with 1 in presence of soda-
mide in dry DMF at 10–15 °C, which was stable at room
temperature. Thorpe–Ziegler cyclization of 5 in presence of
sodium ethoxide in ethanol afforded desired spirocycloin-
amine derivative of oxindole 6. It was then easily hydrolyzed
to 4 by refluxing it in aqueous HCl in 75–80% yield (Scheme
1, route 2). Formation of 4 was confirmed by CO-IR and
mixed melting point with the compound synthesized by route
1. This is an alternate route for the synthesis of 4.
We followed this strategy for the synthesis of novel spiro-
cyclohexanone derivative of isoxazolone 9. When 7 was

M.S. Chande et al. / European Journal of Medicinal Chemistry 40 (2005) 1143–1148
1145
Scheme 2
. Synthesis of spirocyclohexanone derivative of 3-phenyl-isoxazole-5-one. Reagents and conditions: (a) methyl acrylate, NaNH2, DMF, 10–15 °C,
7 h, 77%; (b) acrylonitrile, TEA, EtOH, reflux, 10 h, 88%; (c) Na, benzene, reflux, 8 h, 72%; (d) HBr, AcOH, reflux, 4 h, 70–75%.
We have explored the scope and generality of this syn-
thetic strategy successfully to other heterocyclic systems,
which will be communicated in due course.
0.05 µg ml–1. The compounds 3 and 6 showed the MIC at
0.1 µg ml–1. This is comparable with current TB drugs like
Isoniazid (MIC = 0.025–0.2 µg ml–1) and Refampin
(MIC = 0.06–0.5 µg ml–1) (Table 1).
3.2. Cytotoxicity and antibacterial activity
3. Biological activity
Most of the isoxazolone derivatives synthesized were stud-
ied for their cytotoxic activity on cancer cells and antibacte-
rial activity using short-term toxicity assay (in vitro) (Trypan
blue exclusion method). The cells [Dalton’s lymphoma ascites
(DLA) and Ehrlisch’s ascites carcinoma (EAC)] were main-
tained in the intraperitoneal cavity of Swiss albino mice. The
cells were removed by aspiration and washed three times in
phosphate buffered saline (PBS). Cells (1 × 106) were then
incubated in 1 ml of PBS with varying concentration of drug
dissolved in DMSO at 37 °C for 3 h. The cell viability was
determined by Trypan blue exclusion method [27]. Viable
cells exclude the dye while nonviable cells take up the dye
and appear as blue color. The stained and unstained cells were
counted using a hemocytometer and the percentage of cell
death was calculated.All the experiments were done in dupli-
cate and mean cytotoxicity was recorded (Table 2). Com-
pound 8 was found to be the most active anticancer agent.
Compound 10 also gave considerable anticancer activity.
The antibacterial activity of the compounds 8–10 was stud-
ied using drug diffusion method. Compound 8 was found to
be the most active antibacterial agent. Compound 10 gave
3.1. Antitubercular activity
Compounds 3, 4 and 6 were screened for their activity
against M. tuberculosis H37Rv. The medium used was pre-
pared in 10 ml slopes in glass universal bottles. The incuba-
tion time was 28 days at 37 °C. The MIC was taken when
there were fewer than 20 colonies. The control slope yielded
confluent growth. The compound 4 exhibited the best activ-
ity and the MIC was observed for the concentration of
Table 1
Antitubercular activity studies of compounds 3, 4 and 6 against M. tubercu-
losis H37Rv
Compounds
MIC (µg ml–1
)
3a
3b
4a
4b
6a
6b
Isoniazid
Refampin
0.1
0.1
0.05
0.05
0.1
0.1
0.025–0.2
0.06–0.5
Table 2
Anticancer activity studies of compounds 8 and 10; short-term toxicity assay (in vitro): trypan blue exclusion method
Compounds
EAC
DLA
% Cell death
Concentration (µg ml–1
)
% Cell death
Concentration (µg ml–1
)
8
8
8
8
5
10
14
21
33
56
06
10
17
23
36
5
13
18
27
45
67
06
09
19
37
50
10
20
50
100
5
10
20
50
100
5
8
10
10
10
10
10
10
20
50
100
10
20
50
100

1146
M.S. Chande et al. / European Journal of Medicinal Chemistry 40 (2005) 1143–1148
Table 3
was found to decompose as soon as it was isolated and hence
was used immediately for further reaction or was converted
to a more stable carboxylic acid derivative 3b. Yield 3.1 g
(92%).
Antibacterial activity studies of compounds 8–10; drug diffusion method
Compounds
Concentration Diameter of zone of inhibitory
(µg ml–1
)
(mm)
S.
E. coli
S.
typhosa
10
aureus
5.2. Synthesis of 3-[3-(2-methoxycarbonyl-ethyl)-1-ethyl-
2-oxo-2,3-dihydro-1H-indol-3-yl]-propionic acid (3b)
8
8
8
9
9
9
10
10
50
9
11
13
14
6
100
150
50
10
13
9
11
13
9
Compound 2b (3.33 g, 10 mmol) was refluxed in concen-
trated hydrochloric acid (30 ml) for 3 h The reaction mixture
was cooled when solid began to separate as crystalline com-
pound. It was filtered, washed with water, dried and crystal-
lized from aqueous ethanol. It went into aq. sodium bicarbon-
ate and was regenerated by acidifying with hydrochloric acid
under cold conditions in pure form.Yield 2.75 g (90%), m.p.
100
150
50
10
12
12
14
17
14
10
7
13
8
11
7
100
150
12
8
10
14
10
Silver sulfa-
diazine
Gentamicin
1
136 °C. IR (KBr) 1705, 1644 cm−1; H NMR (DMSO-d6):
12
ppm 1.03 (t, 3H, J = 7 Hz, –CH3), 2.06-2.28 (m, 8H, 4X
–CH2), 3.6 (q, 2H, = 7 Hz, N–CH2), 7.23–7.49 (m, 4H, aro-
antibacterial activity. Compound 9 was moderately active
against the bacteria used in the experiment. The results are
comparable with current drugs like Silver sulfadiazine and
Gentamicin. (Table 3)
mat.) and 12.32 (s, 2H, 2 X–COOH; D2O exchangeable), 13
C
NMR (DMSO-d6): d 12.0 (–CH3), 28.2, 28.3 (4 X–CH2), 47.4
(N–CH2), 94.8 (quaternary C), 129.0–138.6 (4X aromat. C),
163.1, 172.7 (2X C = O). Anal. (C16H19NO5) C, H, N.
5.3. Synthesis of 2-aza-3, 4-benz-1, 8-dioxo-2-ethyl-spiro
4. Conclusion
[5.4] decane (4b) from (2b)
It can be concluded that the spirocyclohexanones contain-
ing oxindole moiety have potent antitubercular activity and
spirocyclohexanone containing isoxazolone moiety have con-
siderable cytotoxicity on cancer cells and antimicrobial activi-
ties.
Compound 2b (3.33 g, 10 mmol) was added slowly to a
mixture of finely pulverized sodium (0.03 g, 11 mmol) in
25 ml dry benzene. The reaction mixture was cooled exter-
nally till the exotherm ceased. The contents were refluxed on
water bath for 4 h Benzene was removed by distillation, and
then the residue treated with methanol to destroy any unre-
acted sodium. The reaction mixture was then poured onto
crushed ice containing hydrochloric acid. A white colored
compound separated out which was filtered, washed with
water, dried and crystallized from chloroform, Yield 2.1 g
5. Experimental
1H NMR
and 13C NMR spectra were recorded on Bruker
AMX 500 spectrometer at 300 K, using TMS as an internal
standard. Melting points were taken in open capillaries and
are uncorrected.
1
(85%), m.p. 167 °C. IR (KBr) 1703, 1644 cm−1. H NMR
(DMSO-d6): ppm 1.03 (t, 3H, J = 7 Hz, –CH3), 2.1–2.24 (m,
8H, 4X –CH2), 3.6 (q, 2H, J = 7 Hz, N–CH2), 7.27–7.43 (m,
4H, aromat.), 13C NMR (DMSO-d6): d 12.0 (–CH3), 28.5,
29.3 (4X –CH2), 47.6 (N–CH2), 92.7 (quaternary carbon)
128.5–129.6 (4X aromat. C), 163.7, 172.7 (2X C = O). Anal.
(C15H17NO2) C, H, N.
5.1. Synthesis of 3-[1-ethyl-3-(2-methoxycarbonyl-ethyl)-2-
oxo-2,3-dihydro-1H-indol-3-yl]-propionic acid methyl
ester (2b)
To a well-stirred solution of sodamide (0.8 g, 20 mmol)
in DMF (25 ml) was added 1b (1.61 g, 10 mmol) at ambi-
ent temperature. The reaction was then cooled to about
10–15 °C. The cooling was followed by the dropwise addi-
tion of methyl acrylate (1.72 g, 20 mmol). The reaction mix-
ture was then stirred at ambient temperature till TLC showed
complete consumption of 1-ethyl-1,3-dihydro-indol-2-one
(30 min). The contents were then poured onto crushed ice
containing a little hydrochloric acid. A semisolid separated
which attained an oily nature as the temperature rose to room
temperature. The oil was extracted with diethyl ether, washed
with water and dried over anhydrous sodium sulfate. Excess
of solvent was removed to yield oil, in its pure state. The oil
5.4. Synthesis of 3-[3-(2-cyano-ethyl)-1-ethyl-2-oxo-2,3-
dihydro-1H-indol-3-yl]-propionitrile (5b)
To a well-stirred solution of sodium amide (0.8 g, 20 mmol)
and 1b (1.61 g, 10 mmol) in DMF (25 ml) was added acry-
lonitrile (1.06 g, 20 mmol) dropwise maintaining tempera-
ture between 10 and 15 °C. The reaction mixture was then
stirred at room temperature for 2 h and then poured onto
crushed ice containing a little HCl. A brown colored com-
pound separated which slowly became gummy. This when
chilled yielded a fine brown colored compound. It was fil-
tered, washed with water, dried and crystallized from

M.S. Chande et al. / European Journal of Medicinal Chemistry 40 (2005) 1143–1148
1147
DMF/water as amorphous light brown compound 5b. Yield
5.8. Synthesis of 3-aza-2-oxa-4-phenyl-spiro [4.5]
dec-3-ene-1, 8-dione (9) from (8)
2.5 g (95%). m.p. > 270 °C. IR (KBr) 2247, 1650 cm−1. 1H
NMR (DMSO-d6) ppm 1.13 (t, 3H, J = 7 Hz, –CH3), 2.16–
2.41 (m, 8H, 4X –CH2), 3.6 (q, 2H, J = 7 Hz, N–CH2), 7.02–
7.18 (m, 4H, aromat.), 13C NMR (DMSO-d6) d 12.8 (–CH3),
12.5, 30.9 (4X –CH2), 43.0 (N–CH2), 95.5 (quaternary C),
117.8 (–CN), 120.5–140.6 (4X aromat. C), 174.0 (C=O).Anal.
(C16H17N3O) C, H, N.
Compound 8 (3.01 g, 10 mmol) was taken in 25 ml glacial
acetic acid and 10 ml of hydrobromic acid in acetic acid was
added. The reaction mixture was refluxed for 4 h. On workup
a blackish brown colored solid was obtained which was crys-
tallized from aqueous methanol. Yield 1.8 g (75%),
m.p. = 172 °C. IR (KBr) 1720, 1598 cm−1. 1H NMR (CDCl3):
d 2.09–2.86 (m, 8H, 4X –CH2), 7.43–8.0 (m, 5H, aromat.),
13C NMR (CDCl3): d 31.0, 31.5, 32.7, 33.7 (4X –CH2), 96.2
(quaternary C), 128.5–134.6 (6X aromat. C), 168.8 (–C=N),
182.5, 205.2 (–C=O). MS: m/z = 243 [M+].Anal. C14H13NO3
(C, H, N).
5.5. Synthesis of 2 aza-3, 4-benz-7-cyano-2-ethyl-8-imino-
1-oxo-spiro [5.4] decane (6b)
Compound 5b (2.67 g, 10 mmol) was added to a solution
of freshly prepared sodium ethoxide (0.25 g of sodium,
10 mmol) in ethanol (50 ml) at ambient temperature. The reac-
tion mixture was then refluxed for 4 h cooled to room tem-
perature. It was poured onto crushed ice. The solution made
to neutral pH to yield dark colored compound 6b.Yield 2.1 g
(79%). m.p. 250–252 °C. IR (KBr) 2245, 1647 cm−1. 1H NMR
(DMSO-d6): ppm 1.03 (t, 3H, J = 7 Hz, –CH3), 1.80–2.40
(m, 4H, 2XCH2), 2.65 (d, 2H, –CH2), 2.90 (t, 1H, –CH), 3.6
(q, 2H, J = 7 Hz, N–CH2), 7.30–7.60 (m, 4H, aromat.), 7.96
(s, 1H, =NH), 13C NMR (DMSO-d6): d 12.7 (–CH3), 25.3
(–CH), 29.4, 31.8, 32.2 (3X CH2), 42.7 (N–CH2), 93.8 (qua-
ternary C), 117.7 (–CN), 121.0–141.2 (4X aromat. C), 174.3
(C=O). Anal. (C16H17N3O) C, H, N.
5.9. Synthesis of 3-[4-(2-cyno-ethyl)-5-oxo-3-phenyl-4,5-
dihydro-isoxazol-4yl]-propionitrile (10)
Compound 1 (1.61 g, 10 mmol) was dissolved in 40 ml
ethanol and triethylamine (3.45 ml, 25 mmol) was added and
heated for 10 min. Acrylonitrile (1.02 ml, 20 mmol) was then
added and the contents refluxed for 10 h. On working up the
reaction, a sticky mass was isolated. On trituration with metha-
nol, a white solid was obtained in pure form. Yield 2.3 g
(88%), m.p. = 115 °C. IR (KBr): 2245, 1797 cm−1. 1H NMR
(CDCl3): ppm 2.27 (t, 4H, J = 7.5 Hz, 2X –CH2), 2.48 (t, 4H,
J = 7.5 Hz, 2X –CH2), 7.57–7.78 (m, 5H, aromat.). 13C NMR
(CDCl3): d 13.8, 15.6, 19.0, 25.2 (4X –CH2), 98.9 (quater-
nary C), 119.0 (–CN), 126.5–131.8 (6X aromat. C), 163.6
(–C=N), 172.6 (–C=O). MS: m/z = 267 [M+]. Anal. C15H16
N3O2 (C, H, N).
5.6. Synthesis of 2-aza-3, 4-benz-1, 8-dioxo-2-ethyl-spiro
[5.4] decane (4b) from (6b)
Compound 6b (2.67 g, 10 mmol) and aq. hydrochloric acid
(25 ml, 50%) were refluxed for 4–6 h. The solvent was
removed by distillation and the contents poured onto crushed
ice to yield the cream colored crystalline compound 4b. It
was filtered, washed with water, dried and crystallized from
chloroform, Yield 1.8 g (75%), m.p. 167 °C, Anal.
(C16H17NO2) C, H, N.
5.10. Synthesis of 3-aza-8-imino-2-oxa-1-oxo-4-phenyl-
spiro [4.5] dec-3-ene (11)
Compound 10 (2.67 g, 10 mmol) was dissolved in 25 ml
benzene. Pulverized sodium (0.23 g, 10 mmol) was then
added. The reaction mixture was refluxed for 8 h. The solid
obtained was filtered, dissolved in water and regenerated with
dilute hydrochloric acid. Methanol was added to the filtrate
to react with the unreacted sodium metal. Product was recrys-
tallized from aqueous methanol. Yield 1.9 g (72%),
m.p. = 90 °C. IR (KBr): 1787, 1555 cm−1.
5.7. Synthesis of 3-aza-1,8-dioxo-7-methoxycarbonyl-2-
oxa-4-phenyl-spiro [4.5] dec-3-ene (8)
Compound 7 (1.61 g, 10 mmol) was dissolved in 15 ml
DMF and was cooled to 10 °C. To the cold solution, a cata-
lytic amount of sodium amide was added and stirred for
10 min. Methyl acrylate (1.8 ml, 20 mmol) was added drop-
wise and stirring was continued for 7 h. The contents were
poured on to ice and acidified. The sticky mass thus obtained
was triturated with 50 ml petroleum ether to get light pink
colored solid. The product was crystallized from aqueous
methanol. Yield 2.3 g (77%), m.p. = 135 °C. IR (KBr) 1760,
1720, 1598 cm−1. 1H NMR (CDCl3): ppm 2.20–2.47 (m, 6H,
3X –CH2), 3.65 (s, 3H, –CH3), 3.68 (t, 1H, –CH), 7.56–7.83
(m, 5H, aromat.), 13C NMR (CDCl3): d 29.1, 31.1, 40.4 (3X
–CH2), 51.9 (CH), 53.9 (OCH3), 98.2 (quaternary C), 126.4–
132.3 (6X aromat. C), 166.1 (–C=N), 171.6, 179.7, 212.0 (3X
–C=O). MS: m/z = 301 [M+]. Anal. C16H15NO5 (C, H, N).
1H NMR (CDCl3): ppm 2.15 (s, 8H, –NH), 2.25–2.40 (m,
8H, 4X –CH2), 7.50–7.80 (m, 5H, aromat.), 13CMR (CDCl3):
d 29.0, 31.1, 52.0, 53.9 (4X –CH2), 83.9 (quaternary C),
126.4–132.3 (6X aromat. C), 166.1 (–C=N), 171.6 (–C=NH),
179.7 (–C=O). MS: m/z = 242 [M+]. Anal. C14H14N2O2 (C,
H, N).
5.11. Synthesis of 4-phenyl-2-oxa-3-aza-spiro [4.5]
dec-3-ene-1, 8-dione (9) from (11)
Compound 11 (10 mmol, 2.67 g) was taken in 25 ml gla-
cial acetic acid and 10 ml of hydrobromic acid in acetic acid
was added. The reaction mixture was refluxed for 4 h. On

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M.S. Chande et al. / European Journal of Medicinal Chemistry 40 (2005) 1143–1148
[11] A.F. Kuehl, J.F. Wolf, R.N. Trenner, L.R. Peck, P.R. Buhs, E. Howe,
I. Putter, D.B. Hunnewell, R. Ormond, G. Downing, E.J. Lyons,
E. Newstead, L. Chaiet, K. Folkers, J. Am. Chem. Soc. 77 (1955)
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workup a blackish brown colored solid was obtained which
was crystallized from aqueous methanol.Yield 1.75 g (72%).
[12] H.C. Stammer, N.A. Wilson, W.F. Holly, K. Folkers, J. Am. Chem.
Soc. 77 (1955) 2346–2347.
Acknowledgements
[13] M.S. Chande, B.M. Karnik, J. Indian Chem. Soc. 70 (1993) 268–269.
[14] M.S. Chande, B.M. Karnik, N. Ganguly, J. Indian Chem. Soc. 67
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The help rendered by RSIC, IIT and TIFR; Department of
Chemistry, University of Pune, is gratefully acknowledged.
[15] M.S. Chande, A.V. Karnik, A.N. Dravid, D.S. Damle, Indian J. Chem.
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