Microwave mediated synthesis of spiro-(indoline-isoxazolidines): Mechanistic study and biological activity evaluation

Article abstract of DOI:10.1016/j.tet.2005.03.027

Regioisomeric spiro-(indoline-isoxazolidines) have been synthesized in moderate yields by the cycloaddition reaction between ethyl (3-indolylidene) acetate and various substituted α,N-diphenylnitrones, using environmentally benign microwave technology. A

Full text of DOI:10.1016/j.tet.2005.03.027

Tetrahedron 61 (2005) 5687–5697
Microwave mediated synthesis of spiro-(indoline-isoxazolidines):
mechanistic study and biological activity evaluation*
Raunak,a Vineet Kumar,a Shubhasish Mukherjee,a Poonam,a Ashok K. Prasad,a Carl E. Olsen,b
c
a,d
Susan J. C. Schaffer, Sunil K. Sharma, Arthur C. Watterson,d William Erringtone
¨
and Virinder S. Parmara,d,
*
aBioorganic Laboratory, Department of Chemistry, University of Delhi, Delhi 110 007, India
bChemistry Department, Royal Veterinary and Agricultural University, Frederiksberg C, DK-1871 Copenhagen, Denmark
cDepartment of Chemistry, Building 207, Technical University of Denmark, DK-2800 Lyngby, Denmark
dDepartment of Chemistry, Institute for Nano Science and Engineering Technology, University of Massachusetts, Lowell, MA 01854, USA
eDepartment of Chemistry, University of Warwick, Coventry CV4 7AL, UK
Received 16 March 2004; revised 15 February 2005; accepted 3 March 2005
Available online 3 May 2005
Abstract—Regioisomeric spiro-(indoline-isoxazolidines) have been synthesized in moderate yields by the cycloaddition reaction between
ethyl (3-indolylidene)acetate and various substituted a,N-diphenylnitrones, using environmentally benign microwave technology. A novel
concerted reaction mechanism is described that explains the preferential formation of the regioisomeric spiro-(indoline-isoxazolidine)
analogs 6 over 5. These compounds were screened for anti-mycobacterial and anti-invasive activities against tumor cells.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
synthesis.11–13 Microwave radiation generally results in
enhanced reaction rates and higher product yields as
compared to those by conventional heating.14,15
The 1,3-dipolar cycloaddition reactions belong to the most
important and versatile methods for building five membered
heterocycles; they have been applied to the synthesis of
natural products such as sugar derivatives,1 b-lactams,2
amino acids3 and alkaloids.4 Among dipoles, nitrile oxides
and nitrile imines have been used extensively. The 1,3-
dipolar cycloaddition of nitrones with alkenes in particular
has received considerable attention over the past few years
in the synthesis of isoxazolidines.5–9 One of the reasons for
the success of the synthetic applications of nitrones is that,
contrary to the majority of other 1,3-dipoles, most nitrones
are stable compounds which readily undergo cycloadditions
to a wide variety of alkenes, affording isoxazolidines and
isoxazolines, extremely useful classes of heterocycles.10
In view of above, we have investigated the reaction of
indolylidene acetate with a series of nitrones yielding a large
number of isomeric spiro-(indoline-isoxazolidines) in a one-
pot reaction sequence using microwave radiation. Several of
these compounds exhibited interesting anti-tubercular and
anti-invasive activities against MCF 7/6 cancer cells.
2. Results and discussion
Spiro-(indoline-isoxazolidines) were synthesized by the
cycloaddition reaction between ethyl (3-indolylidene)-
acetate (3)16 and various substituted a,N-diphenylnitrones
4a–4j (Scheme 1). The ethoxycarbonylmethylenetriphenyl
phosphorane (2) was synthesized by the Wittig reaction of
triphenylphosphine and ethyl bromoacetate in benzene,17
which on condensation with the commercially available
indoline-2,3 dione (1) in acetic acid (glacial) at 80 8C
afforded the ethyl (3-indolylidene)acetate (3). The nitrones
4a–4j18–22 were prepared by the condensation of appro-
priately substituted aromatic aldehydes with phenyl-
hydroxylamine in ethanol at room temperature. Though,
all the nitrones 4a–4j are known compounds, the spectral
Recently, a number of publications and reviews have
advocated the use of microwave technology in organic
* Presented at the ‘First International Microwaves in Chemistry Con-
ference’ held at Gainesville (Florida, USA) in March 2003.
Keywords: Nitrone; Cycloaddition reaction; Microwave; Spiro-(indoline-
isoxazolidines); Anti-mycobacterial; Anti-invasive.
*
Corresponding author. Address: Bioorganic Laboratory, Department of
Chemistry, University of Delhi, Delhi 110 007, India. Tel.: C91 11 2766
6555; fax: C91 11 2766 7206; e-mail: virparmar@yahoo.co.in
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.03.027

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Raunak et al. / Tetrahedron 61 (2005) 5687–5697
Scheme 1.
data and melting point for a-(3-fluorophenyl)-N-phenyl-
nitrone (4i) have not been reported earlier. The cyclo-
addition reaction between the nitrones 4a–4j and ethyl
(3-indolylidene)acetate (3) in benzene at 60 8C afforded a
mixture of two regioisomeric spiro-(indoline-isoxazo-
lidines), that is 5a–5j and 6a–6j in just 10–15% combined
yields even after 150–180 h of stirring.
to reach between 55 and 60 8C. However, by irradiating the
reaction mixture in a single attempt for 4–5 min led to a
charred mass with the temperature reaching 132–140 8C.
The reaction did not proceed when the two reactants were
heated (without solvent) in an oil bath at 55 8C for 20 h.
Thus, the use of microwave irradiation in dry media resulted
in drastic reduction of reaction time and enhancement in
yields in comparison to classical heating conditions. In
addition, the microwave methodology developed here
possesses the currently much demanded ‘Green Appeal’
and avoids the use of hazardous and toxic solvent(s).
To increase the yield of the spiro-(indoline-isoxazolidines),
different reaction conditions and methodologies were
attempted, of which a solvent-free reaction coupled with
microwave activation provided the desired spiro-(indoline-
isoxazolidines) in better yields. Thus, under microwave
conditions, spiro compounds 5a–5j and 6a–6j have been
prepared just by irradiating the mixture of ethyl (3-indolyl-
idene)acetate (3) and the a,N-diphenylnitrones 4a–4j in the
absence of any solvent for 4–5 min (1 min at a time with
10 s interval) in 35–56% combined yields. The temperature
of the reaction mixture under these conditions was observed
The nitrone addition to the olefinic bond of ethyl (3-indolyl-
idene)acetate (3) seems to follow a concerted cyclization
mechanism (Scheme 2). The preferential formation of
isomers 6 (23–44% yields) over 5 (9–22% yields) indicates
that path II is more favorable over path I (Scheme 2). The
isomer 6 was found to be the major product in all the cases.
1
This was ascertained by recording the H NMR spectra of

Raunak et al. / Tetrahedron 61 (2005) 5687–5697
5689
Scheme 2.
the reaction products containing both the regioisomers 5 and
6. This mixture was then subjected to isomeric separation by
column chromatography, compounds of both the series were
obtained in pure forms along with their inseparable
mixtures. The relative ratios of the two isomers in the
in the ranges d 5.24–5.28 and d 5.30–5.45 (Table 1),
indicating them to be on non-adjacent positions. On the
other hand, in the case of the regioisomers 6a–6j, the two
isoxazolidine ring protons coupled with each other and
appeared as two distinct doublets with J values in the range
of 9.0–9.7 Hz (Table 1), suggesting them to be on adjacent
ring carbon atoms. Furthermore, the C-30H appeared quite
downfield in 6a–6j (d 5.20–5.41, Table 1) as compared to
the C-40H (d 4.16–4.24, Table 1). The structures of the two
regioisomeric spiro derivatives were also compatible with
their respective 13C NMR spectra. In the case of
regioisomers 6a–6j, the spiro carbon, that is the C-5
appeared downfield (d 82.96–83.67) in comparison to the
spiro carbon, that is C-4 in compounds 5a–5j (d 66.34–
68.87, Table 1) because in the former, C-5 is directly
attached to the ring oxygen in the isomers 6a–6j. The
structures of two regioisomeric spiro-(indoline-isoxazoli-
dines) were finally confirmed by X-ray crystallographic
studies of two compounds, one representative example from
each series of two regioisomers, that is of the compounds 5a
and 6c (Diagrams 1 and 2).24 Interestingly, the X-ray
structures clearly indicate the preference for the C-50 side
chain in 5a and the C-40 side chain in 6c to be cis to the
larger group at the adjacent spiro carbon (Diagrams 1 and
2).24 Since both these groups are present in the common
starting compound 3, that is 3-(indolylidene)acetate for both
the isomers, the formation of cis-products of both the series
1
mixtures were determined from H NMR spectral analysis
and this information was used to calculate the yields of the
two isomers, 5 and 6. The formation of two regioisomeric
spiro-(indoline-isoxazolidines) 5a–5j and 6a–6j can be
explained on the basis of the intermolecular cycloaddition
involving exocyclic double bond shifting in 3 in two
different modes as depicted mechanistically in Scheme 3.
The partial negative charge calculated using the Cache Pro
5.04 (PM3) programme23 was found to be higher on C-10
(K0.091) as compared to that on C-3 (K0.028). This may
be due to the consequence of having an (equivalent of)
o-aminophenyl substituent on C-3 in 3 conjugated to the
ester carbonyl group on C-10, thus the shifting
(or polarizability) of the p-electrons towards C-10 is
favored over that towards C-3 (Scheme 3). This explains
higher yields of the spiro-(indoline-isoxazolidine) isomers 6
over those of 5 (cf. Section 5 and Table 1). Additionally 6 is
also calculated to be thermodynamically preferred over 5.
The two regioisomeric spiro-(indoline-isoxazolidines) were
1
well characterized on the basis of their H and 13C NMR
spectra. In case of the regioisomers 5a–5j, the two
isoxazolidine ring protons appeared as two distinct singlets
Scheme 3.

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Raunak et al. / Tetrahedron 61 (2005) 5687–5697
Diagram 1. X-ray crystallography of 5a.
can only be explained if the two groups also have cis
relationship in the precursor 3. To establish the geometry,
we carried out the NOE experiments on compound 3 but
were not able to ascertain the stereo-chemical features in the
compound. However, the X-ray crystallographic study on
compound 3 (Diagram 3)24 fully established that ethoxy-
carbonyl group and phenyl group are in cis configuration,
this further supports the proposed concerted mechanism.
The 1H and 13C NMR spectra of the spiro-(indoline-
isoxazolidines) 5a–5j and 6a–6j exhibited only one set of
peaks, thereby confirming the formation of single dia-
stereoisomers during the cycloaddition reactions. All 20
spiro-(indoline-isoxazolidines) are new compounds in the
literature and have been fully characterized from their
spectral data (cf. Section 5).
3. Anti-mycobacterial and anti-invasive activity
evaluation of 5a–5j and 6a–6j
All the spiro compounds, viz. 5a–5j and 6a–6j were
submitted to the NIH Center at SRI (Birmingham, Alabama)
for ascertaining their anti-tubercular activity against Myco-
bacterium tuberculosis H37Rv (ATCC 27294);25 the spiro-
(indoline-isoxazolidines) having structures belonging to
series 6 showed better anti-tubercular activities (15–29%
inhibition of Mycobacterium tuberculosis) than those of the

Raunak et al. / Tetrahedron 61 (2005) 5687–5697
5691
Diagram 2. X-ray crystallography of 6c.
spiro compounds belonging to the series 5 (2–8% inhibition,
Table 2).
5. Experimental
5.1. General
Furthermore, we tested the spiro compounds 5a–5j and 6a–
6j in an organotypic assay for invasion. The assay of anti-
invasive activity was based on confrontation of invasive
human MCF-7/6 mammary carcinoma cells with embryonic
chick heart fragments.26–29 The spiro compounds 5b, 5c, 5d,
5e, 5g, 5j, 6c and 6e (Table 3) showed significant inhibition
of invasion at 100 mM concentration. The compounds 5c, 5e
and 6e showed activity at 10 mM concentration also; none of
the compounds exhibited any activity at further dilutions. It
is interesting to note that unlike the anti-tubercular activity,
the compounds of the series 5 exhibited better anti-invasive
activities against tumor cells than the spiro-(indoline-
isoxazolidines) 6.
Materials were obtained from commercial suppliers and
were used without further purification unless otherwise
noted. Petroleum ether (60–80 8C) and ethyl acetate were
distilled over P2O5 and K2CO3, respectively prior to use. IR
spectra were recorded on a Perkin–Elmer 2000 FT-IR
spectrometer. The 1H NMR and 13C NMR spectra (in
CDCl3) were recorded on a Bruker Avance 300 spec-
trometer at 300 MHz and at 75.5 MHz, respectively using
TMS as internal standard. The chemical shifts values are on
d scale and the coupling constants (J) are in Hz. The HRMS
determinations were made in FAB positive mode on a JEOL
JMS-AX505W high-resolution mass spectrometer using
bis-hydroxyethyldisulfide (HEDS) doped with sodium
acetate as matrix. All flash chromatographic separations
were performed on 100–120 mesh silica gel. Analytical
TLCs were performed on Merck silica gel 60 F254 plates.
Microwave reactions were performed in a domestic
microwave oven of 850 W 1.2 Cft (33 L, Infodisplay,
Sharp Carosel). Melting points were recorded in a sulphuric
acid bath and are uncorrected.
4. Conclusions
We have synthesized 20 novel spiro compounds taking
advantage of the complementarity of the eco-friendly
microwave technology under solvent-free conditions. The
use of microwave technique resulted in drastic reduction of
reaction time and enhancement in yields in comparison to
the classical heating method. Furthermore, these com-
pounds showed moderate anti-mycobacterial and anti-
invasive activities.
5.2. Preparation of ethyl 2-oxo-3(2H)-indolylidene
acetate (3)
A mixture of indolin-2,3-dione (1, 7.3 g, 50.0 mmol),

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Raunak et al. / Tetrahedron 61 (2005) 5687–5697
Diagram 3. X-ray crystallography of 3.
ethoxycarbonylmethylene-triphenylphosphorane (2, 17.3 g,
50.0 mmol) and glacial acetic acid (60 mL) was heated for
4 h at 80 8C.16 Acetic acid was removed under vacuum, and
the residue was washed onto a filter funnel with a small
quantity of methanol. Recrystallization from ethanol gave
compound 3 (17.6 g, 69%) as an orange solid, mp 168–
170 8C (lit.30 mp 169–170 8C).
ethyl alcohol were obtained as crystalline solids in 69–85%
yields.
5.3.1. a-(3-Fluorophenyl)-N-phenylnitrone (4i). Obtained
as a white solid (3.63 g, 74%), mp 100–102 8C (from
ethanol); Rf: 0.45 (petroleum ether–ethyl acetate 4:1); H
1
NMR (300 MHz; CDCl3): d 7.46–7.51 (3H, m, C-2H, C-4H
and C-6H), 7.58–7.62 (2H, m, C-3H and C-5H), 7.74–7.78
(2H, m, C-20H and C-50H), 7.89 (1H, s, a-H) and 8.28 (2H,
5.3. General method for preparation of a,N-diphenyl-
nitrones 4a–4j
Table 3. Effect of Spiroisoxazolidines on invasion of MCF-7/6 Cells in
vitro
Phenylhydroxylamine (1 mmol)31 and appropriately sub-
stituted benzaldehydes (1 mmol) were dissolved in ethyl
alcohol (20 mL). The reaction mixture was stirred overnight
at room temperature when a solid precipitated out; the
desired compounds 4a–4j18–22 after recrystallization from
Compound no.
100 mM
10 mM
1 mM
5a
5b
5c
5d
5e
5f
5g
5h
5i
K
C
C
C
C
0
C
K
K
C
K
K
C
K
C
K
Toxic
0
0
0
0
0
C
K
C
K
0
0
0
K
0
0
0
0
C
0
0
K
K
K
K
0
0
0
K
0
0
0
0
0
0
0
0
0
Table 2. Anti-tuberculosis activity data of spiroisoxazolidines in Alamar
assay at 6.25 mg/mL MIC level
Compound
% Inhibition
5c
5d
5e
5f
5
4
5
8
5j
6a
6b
6c
6d
6e
6f
6g
6h
6i
5i
5
5j
2
6a
6b
6c
6d
6e
6f
16
26
15
27
20
29
0
0
0
6j
0
0
0
C, anti-invasive; K, not anti-invasive; 0, not tested.

Raunak et al. / Tetrahedron 61 (2005) 5687–5697
5693
d, JZ8.6 Hz, C-40H and C-60H); 13C NMR (75.5 MHz;
CDCl3): d 115.5 (d, JZ24.7 Hz, C-20), 118.1 (d, JZ
21.7 Hz, C-40), 122.0 (C-4), 125.4 (d, JZ2.4 Hz, C-60),
129.6 (C-3 and C-5), 130.3 (d, JZ6.09 Hz, C-50), 130.5 (C-2
and C-6), 132.9 (d, JZ7.2 Hz, C-1 ), 133.75 (C-a), 149.3
(C-1) and 162.9 (d, JZ245.47 Hz, C-30). HRMS Calcd for
C13H10FNO: 215.0746. Found: 215.0735.
petroleum ether–ethyl acetate), Rf: 0.37 (petroleum ether–
ethyl acetate, 3:2); IR (KBr): 3205 (NH), 1729 (COOC2H5),
1
1621 (CONH), 1491, 1339, 1192, 1031 and 903 cmK1; H
NMR (300 MHz; CDCl3): d 0.69 (3H, t, JZ7.1 Hz,
COOCH2CH3), 3.65–3.82 (2H, m, COOCH2CH3), 4.16
(1H, d, JZ9.5 Hz, C-40H), 5.22 (1H, d, JZ9.5 Hz, C-300H0 ),
6.87 (1H, d, JZ7.8 Hz, C-7H), 6.92–6.99 (4H, m, C-2 H,
C-300H, C-500H and C-600H), 7.09–7.19 (3H, m, C-5H, C0-006H
and C-400H), 7.35 (2H, d, JZ8.4 Hz, C-2000H and C-6 H)
and 7.63–7.66 (3H, m, C-4H, C-3000H and C-5000H); 13C NMR
5.4. General method of preparation of spiro-(indoline-
3,40/3,50-isoxazolidines)
(75.5 MHz; CDCl3):
d
13.7 (COOCH2CH3), 610.7
(COOCH2CH3), 64.8 (C-40), 71.2 (C-30), 83.5 (C-5 ),
110.9 (C-400), 117.5 (C-200 and C-600), 123.4 00(C-7), 123.9
(C-5), 126.0000(C-9), 126.6 (C-6), 129.0 (C-3 and C-500),
(a) By conventional heating. To a solution of ethyl
(3-indolylidene)acetate (3, 9.21 mmol) in benzene
(50 mL), various substituted a,N-diphenylnitrones 4a–4j
(9.21 mmol) were added, and the reaction mixture was
heated at 60 8C. Progress of the reaction was monitored by
TLC; after 150–180 h, the reaction mixture was concen-
trated under reduced pressure. Crude products were
chromatographed over silica gel using ethyl acetate–
petroleum ether as eluent to afford 5a–5j and 6a–6j as
light yellow solids, which were recrystallized from ethyl
acetate–petroleum ether to afford the white to light yellow
crystals of regioisomeric spiro derivatives in combined
yields of 10–15%.
129.6 (C-2 and C-6 ), 129.7 (C-3000 and C-5 ),
000
000
000
00
131.1 (C-4), 134.6 (C-1 ), 137.2 (C-8), 141.8 (C-1 ),
149.8 (C-4000), 167.8 (CONH) and 176.0 (COOC2H5);
HRMS Calcd for C25H21N2 35ClO4: 448.1190. Found:
448.1187.
5.4.3. 30-(4-Bromophenyl)-50-ethoxycarbonyl-20-phenyl-
spiro[indoline-3,40-isoxazolidine]-2-one (5b). Obtained as
a light yellow solid (111 mg, 12%), mp 170–171 8C (from
petroleum ether–ethyl acetate), Rf: 0.41 (petroleum ether–
ethyl acetate, 3:2); IR (KBr): 3274 (NH), 1737 (COOC2H5),
(b) By microwave method. A mixture of ethyl (3-indolyl-
idene)acetate (3, 1.84 mmol) and variously substituted a,N-
diphenylnitrones 4a–4j (1.84 mmol) were irradiated in a
microwave (850 W 1.2 Cft). The progress of the reaction
was monitored by TLC; after irradiating the reaction
mixture for 4–5 min (1 min at a time with 10 s interval),
the mixture was chromatographed over silica gel using ethyl
acetate–petroleum ether as eluent to afford the spiro
compounds 5a–5j and 6a–6j as light yellow solids, which
were recrystallized from ethyl acetate–petroleum ether to
afford the white to light yellow crystals of regioisomeric
spiro derivatives in combined yields of 35–56%.
1
1618 (CONH), 1476, 1399, 1230, 1075 and 750 cmK1; H
NMR (300 MHz; CDCl3): d 0.80 (3H, t, JZ7.0 Hz,
COOCH2CH3), 3.80–3.98 (2H, m, COOCH2CH3), 5.25
(1H, s, C-30H), 5.30 (1H, s, C-50H), 060 .69 (1H, d, JZ7.7 Hz,
C-7H), 6.93 00(1H, t, JZ7.5 Hz, C-4 H), 7.03–7.10 (4H, m,
00
C-2 H, C-3 H, C-500H and C-600H), 7.15–7.17 (2H, m,
000
C-2 H and C-6000H), 7.23–7.29 (4H, m, C-5H, C-6H, C-3000H
and C-5000H) and 7.53 (1H, d, JZ7.4 Hz, C-40H); 13C NMR
(75.5 MHz; CDCl3):
d
13.9 (COOCH2CH3), 610.8
(COOCH2CH3), 66.7 (C-40), 78.0 (C-30), 82.5 (C-5 ),
102.9 (C-400), 109.9 (C-200 and C-600), 122.5 (C-9), 123.1
(C-7), 123.6 (C-5), 125.0100 (C-1000), 102007.4 (C-6), 128.7 (C-300
and C-500), 120900.4 (C-2 and C-6 ), 129.7 (C-4), 131.9
(C-3000 and C-5 ), 134.8 (C-8), 140.5 (C-100), 151.2 (C-4000),
166.0 (CONH) and 174. 2 (COOC2H5); HRMS Calcd for
C25H21N2 79BrO4: 492.0685. Found: 492.0670.
5.4.1. 30-(4-Chlorophenyl)-50-ethoxycarbonyl-20-phenyl-
spiro[indoline-3,40-isoxazolidine]-2-one (5a). Obtained as
a white solid (188 mg, 22%), mp 158–159 8C (from
petroleum ether–ethyl acetate), Rf: 0.34 (petroleum ether–
ethyl acetate, 3:2); IR (KBr): 3272 (NH), 1737 (COOC2H5),
1
1616 (CONH), 1486, 1230, 1078, 1011 and 751 cmK1; H
5.4.4. 30-(4-Bromophenyl)-40-ethoxycarbonyl-20-phenyl-
spiro[indoline-3,50-isoxazolidine]-2-one (6b). Obtained as
a light yellow solid (351 mg, 39%), mp 161–162 8C (from
petroleum ether–ethyl acetate), Rf: 0.43 (petroleum ether–
ethyl acetate, 3:2); IR (KBr): 3426 (NH), 1729 (COOC2H5),
NMR (300 MHz; CDCl3): d 0.80 (3H, t, JZ7.1 Hz,
COOCH2CH3), 3.80–3.98 (2H, m, COOCH2CH3), 5.25
(1H, s, C-30H), 5.32 (1H, s, C-50H), 060 .68 (1H, d, JZ7.7 Hz,
C-7H), 6.93 (1H, t, 0J0 Z7.1 Hz, C-4 00H0 ), 7.00–7.13 (6H, m,
C-200H, C-300H, C-5 H, C-600H, C-2 H an0d00 C-6000H), 7.21–
7.29 (4H, m, C-5H, C-6H, C-3000H and C-5 H), 7.53 (1H, d,
JZ7.4 Hz, C-4H) and 7.78 (1H, br s, NH); 13C NMR
1
1619 (CONH), 1474, 1190, 1023 and 755 cmK1; H NMR
(300 MHz; CDCl3): d 0.70 (3H, t, JZ7.1 Hz, COOCH2-
CH3), 3.69–3.78 (2H, m, COOCH2CH3), 4.16 (1H, d, JZ
9.4 Hz, C-40H), 5.21 (1H, d, JZ9.4 Hz, C-30H), 6.85 (1H, d,
JZ7.5 Hz, C-7H), 6.93–6.97 (4H, m, C-200H, C-300H, C-500H
and C-600H), 7.09–7.19 (3H, m, C-5H, C-0600H and C-400H)
and 7.49–7.60 (5H, m, C-4H, C-2000H, C-3 H, C-5000H and
C-6000H); 13C NMR (75.5 MHz; CDCl3): d 13.7 (COOCH2-
CH3), 61.6 (COOCH2CH3), 64.8 (C-40), 71.2 (C-30), 83.2
(C-50), 110.5 (C-400), 117.6 (C-200 and C-600), 122.8 (C-1000),
123.4 (C-7), 123.9 (C-5), 126.0 (C-9), 126.7 (C-6), 128.9
(75.5 MHz; CDCl3):
d
13.4 (COOCH2CH3), 610.3
(COOCH2CH3), 66.3 (C-40), 77.5 (C-30), 81.9 (C-5 ),
109.3 (C-400), 115.7 (C-200 and C-600), 122.6 00(C-7), 123.1
(C-5), 124.6 (C-9), 126.9 (C-6), 127.9 (C-3 and C-500),
128.4 (C-2000 and C-6000), 128.9 (C-3000 a0n0 d C-5000), 129.2
(C-4), 133.8 (C-8 and C-1000), 140.0 (C-1 ), 150.8 (C-4000),
165.5 (CONH) and 173.7 (COOC2H5); HRMS Calcd for
C25H21N2 35ClO4: 448.1190. Found: 448.1205.
00
(C-3 and C-500), 130.0 (C-2000 and C-6000), 131.1 (C-4), 132.5
5.4.2. 30-(4-Chlorophenyl)-40-ethoxycarbonyl-20-phenyl-
spiro[indoline-3,50-isoxazolidine]-2-one (6a). Obtained as
a white solid (280 mg, 33%), mp 159–160 8C (from
(C-3 and C-5000), 137.8 (C-8), 141.5 (C-100), 149.7 (C-4000),
000
167.8 (CONH) and 175.2 (COOC2H5); HRMS Calcd for
C25H21N729BrO4: 492.0685. Found: 492.0682.

5694
Raunak et al. / Tetrahedron 61 (2005) 5687–5697
5.4.5. 50-Ethoxycarbonyl-30-(4-nitrophenyl)-20-phenyl-
spiro[indoline-3,40-isoxazolidine]-2-one (5c). Obtained as
a light yellow solid (109 mg, 12%), mp 169–170 8C (from
petroleum ether–ethyl acetate), Rf: 0.34 (petroleum ether–
ethyl acetate, 3:2); IR (KBr): 3280 (NH), 1724 (COOC2H5),
128.4 (d, JZ21.8 Hz, C-3000), 128.9 (C-300 and C-500), 129.2
(C-4), 131.1 (d, JZ2.9 Hz, C-1000), 140.1 (C-8), 150.9
(C-100), 162.3 (d, JZ247.0 Hz, C-4000), 165.7 (CONH), 173.9
(COOC2H5); HRMS Calcd for C25H21FN2O4: 432.1485.
Found: 432.1505.
1
1619 (CONH), 1474, 1344, 1230, 1075 and 834 cmK1; H
5.4.8. 40-Ethoxycarbonyl-30-(4-florophenyl)-20-phenyl-
spiro[indoline-3,50-isoxazolidine]-2-one (6d). Obtained
as a light yellow solid (348 mg, 43%), mp 149–150 8C
(from petroleum ether–ethyl acetate), Rf: 0.45 (petroleum
ether–ethyl acetate, 3:2); IR (KBr): 3449 (NH), 1729
NMR (300 MHz; CDCl3): d 0.81 (3H, t, JZ7.1 Hz,
COOCH2CH3), 3.81–3.99 (2H, m, COOCH2CH3), 5.26
(1H, s, C-30H), 5.44 (1H, s, C-50H), 6.68 (1H, d, JZ7.7 Hz,
00
C-7H), 6.91–6.94 (1H, m, C-4 H), 7.00–7.10 (4H, m,
00
00
C-2 H, C-300H, C-500H and C-6 H), 7.27–7.31 (2H, m,
000
C-2 H and C-6000H), 7.47–7.50 (4H, m, C-5H, C-6H, C-3000H
(COOC2H5), 1621 (CONH), 1473, 1193 and 754 cmK1
;
and C-5000H) and 7.98–8.01 (2H, m, C-40H and NH); 13C
NMR (75.5 MHz; CDCl3): d 15.9 (COOCH2CH3), 63.9
(COOCH2CH3), 68.8 (C-40), 79.9 (C-30), 84.7 (C-50), 111.9
(C-400), 117.9 (C-200 and C-600), 125.3 (C-7), 125.9 (C-5),
126.0 (C-300 an0d00 C-500), 126.6000(C-9), 129.2 (C-6), 129.8
(C-2000 and 00C0 -6 ), 131.5 (C-3 and C-5000), 132.0 (C-0400),
142.4 (C-1 ), 145.4 (C-8), 150.0 (C-100), 152.9 (C-4 ),
167.6 (CONH) and 175.8 (COOC2H5); HRMS Calcd for
C25H21N3O6: 459.1430. Found: 459.1435.
1H NMR (300 MHz; CDCl3): d 0.69 (3H, t, JZ7.0 Hz,
COOCH2CH3), 3.69–3.80 (2H, m, COOCH2CH3), 4.18
(1H, d, JZ9.5 Hz, C-40H), 5.23 (1H, d, JZ9.5 Hz, C-300H0 ),
6.88 (1H, d0,0 JZ7.8 Hz, C-7H), 6.92–6.99 (4H, m, C-2 H,
C-300H, C-5 H and C-600H), 7.04–7.19 (5H, m, C-4H, C-5H,
C-6H, C-2000H and C-6000H), 7.23–7.29 (1H, m, C-400H),
7.66–7.70 (2H, m, C-3000H and C-5000H) and 7.83 (1H, br s,
NH); 13C NMR (75.5 MHz; CDCl3): d 13.7 (COOCH2CH3),
61.6 (COOCH2CH3), 64.8 (C-40), 71.2 (C-30), 83.2 (C-50),
110.6 (C-4),000116.1 (d, JZ6.8 Hz, C-6000), 116.4 (d, JZ
21.8 Hz, C-5 ), 117.6 (C-200 and C-600), 123.4 (C-7), 123.8
(C-5), 126.0 (C-9), 126.6 (d, JZ7.1 Hz, C-2000), 128.9 (C-300
and C-500), 129.9 (C-6), 130.0 (d, JZ22.6 Hz, C-3000), 131.0
(C-4), 134.3 (d, JZ3.1 Hz, C-1000), 141.5 (C-8), 149.7
(C-100), 163.2 (d, JZ247.0 Hz, C-4000), 167.8 (CONH) and
175.5 (COOC2H5); HRMS Calcd for C25H21FN2O4:
432.1485. Found: 432.1494.
5.4.6. 40-Ethoxycarbonyl-30-(4-nitrophenyl)-20-phenyl-
spiro[indoline-3,50-isoxazolidine]-2-one (6c). Obtained as
a light yellow solid (229 mg, 27%), mp 171–172 8C (from
petroleum ether–ethyl acetate), Rf: 0.38 (petroleum ether–
ethyl acetate, 3:2); IR (KBr): 3203 (NH), 1729 (COOC2H5),
1
1621 (CONH), 1599, 1472, 1243, 1029 and 855 cmK1; H
NMR (300 MHz; CDCl3): d 0.70 (3H, t, JZ7.1 Hz,
COOCH2CH3), 3.68–3.85 (2H, m, COOCH2CH3), 4.18
(1H, d, JZ9.2 Hz, C-40H), 5.41 (1H, d, JZ9.1 Hz, 0C0 -30H),
6.90–7.01 (5H, m, C-7H, C-200H, C-300H, C-5 H and
C-600H), 7.08 (1H, d, JZ7.3 Hz, C-400H), 7.15–7.20 (2H,
m, C-5H and C-6H), 7.25–7.31 (1H, m, C-4H), 7.91 (2H, d,
JZ8.7 Hz, C-2000H and C-6000H), 8.12 (1H, br s, NH) and
8.26 (2H, d, JZ8.7 Hz, C-3000H and C-5000H); 13C NMR
5.4.9. 50-Ethoxycarbonyl-30-(4-methylphenyl)-20-phenyl-
spiro[indoline-3,40-isoxazolidine]-2-one (5e). Obtained as
a light yellow solid (123 mg, 15%), mp 155–156 8C (from
petroleum ether–ethyl acetate), Rf: 0.46 (petroleum ether–
ethyl acetate, 3:2); IR (KBr): 2924 (NH), 1739 (COOC2H5),
1
1593 (CONH), 1475, 1401, 1233, 1074 and 742 cmK1; H
(75.5 MHz; CDCl3):
d
13.2 (COOCH2CH3), 610.4
NMR (300 MHz; CDCl3): d 0.80 (3H, t, JZ7.0 Hz,
COOCH2CH3), 2.17 (3H, s, C6H4–CH3), 3.79–3.97 (2H,
m, COOCH2CH3), 5.25 (1H, s, C-30H), 5.32 (1H, s, C-500H0 ),
6.64 (1H, d, JZ7.7 Hz, C-7H), 6.89–6.93 (3H, m, C-400H,
C-2000H and C-6000H), 7.00–7.08 (4H, m, C-300H, 00C0 -5 H,
(COOCH2CH3), 64.3 (C-40), 70.2 (C-30), 83.0 (C-5 ),
110.2 (C-400), 116.9 (C-200 and C-600), 123.0 (C-7), 123.6
(C-5), 124.1 (C-300 and C-500), 125.2000(C-9), 126.1 (C-6),
128.6 (C-2000 and C-6000), 128.7 (C-3 and C-5 ), 130.8
000
00
(C-4), 141.1 (C-1000), 145.8 (C-8), 147.9 (C-1 ), 148.7
00
C-6 H and C-200H), 7.15 (2H, d, JZ8.0 Hz, C-3 H and
(C-4000), 167.1 (CONH) and 174.4 (COOC2H5); HRMS
Calcd for C25H21N3O6: 459.1430. Found: 459.1451.
000
C-5 H), 7.21–7.24 (2H, m, C-5H and C-6H), 7.39 (1H, br s,
NH) and 7.58 (1H, d, JZ7.2 Hz, C-4H); 13C NMR
(75.5 MHz; CDCl3):
d
13.9 (COOCH2CH3), 210.4
(C6H4CH3), 61.7 (COOCH2CH3), 66.9 (C-40), 78.5 (C-3 ),
82.3 (C-50), 109.6 (C-400), 116.2 (C-200 and C-600), 122.9
(C-7), 123.3 (C-5), 125.5 (C-9), 126.9 (C-300 and C-500),
5.4.7. 50-Ethoxycarbonyl-30-(4-florophenyl)-20-phenyl-
spiro[indoline-3,40-isoxazolidine]-2-one (5d). Obtained
as a white solid (80 mg, 10%), mp 154–155 8C (from
petroleum ether–ethyl acetate), Rf: 0.42 (petroleum ether–
ethyl acetate, 3:2); IR (KBr): 3277 (NH), 1738 (COOC2H5),
127.5 (C-6), 129.2 (C-4) 129.3 (C-3000, C-5000, C-2000, C-6 ),
000
000
132.5 (C-1000), 138.1 (C-8), 140.5 (C-100), 151.6 (C-4 ),
166.2 (CONH) and 174. 5 (COOC2H5); HRMS Calcd for
C26H24N2O4: 428.1736. Found: 428.1725.
1
1617 (CONH), 1473, 1226, 1153, 908 and 754 cmK1; H
NMR (300 MHz; CDCl3): d 0.80 (3H, t, JZ7.0 Hz,
COOCH2CH3), 3.80–3.98 (2H, m, COOCH2CH3), 5.25
(1H, s, C-30H), 5.33 (1H, s, C-50H), 6.66 (1H, d, JZ7.6 Hz,
C-7H), 6.77–6.95 (3H, m, C-400H, C-2000H and C-6000H),
7.00–7.12 (5H, m, C-200H, C-300H, C-500H, C-600H and
C-3000H), 7.23–7.29 (3H, m, C-5H, C-6H and C-5000H), 7.48
(1H, br s, NH) and 7.54 (1H, d, JZ7.3 Hz, C-4H); 13C NMR
5.4.10.
40-Ethoxycarbonyl-30-(4-methylphenyl)-20-
phenylspiro[indoline-3,50-isoxazolidine]-2-one (6e).
Obtained as a light yellow solid (309 mg, 39%), mp 160–
162 8C (from petroleum ether–ethyl acetate), Rf: 0.48
(petroleum ether–ethyl acetate, 3:2); IR (KBr): 2924
(NH), 1728 (COOC2H5), 1619 (CONH), 1471, 1376,
(300 MHz; CDCl3):
d
13.5 (COOCH2CH3), 610.3
1
(COOCH2CH3), 66.5 (C-40), 77.7 (C-30), 82.0 (C-5 ),
109.3 (C-400)0,00 115.1 (d, JZ7.2 Hz, C-6000), 115.4 (d, JZ
22.4 Hz, C-5 ), 115.9 (C-200 and C-600), 122.6 (C-7), 123.2
(C-5), 124.9 (C-9), 127.1 (d, JZ6.9 Hz, C-2000), 128.2 (C-6),
1243, 1027 and 828 cmK1; H NMR (300 MHz; CDCl3):
d 0.69 (3H, t, JZ7.0 Hz, COOCH2CH3), 2.34 (3H, s,
C6H4CH3), 3.63–3.80 (2H, m, COOCH2CH3), 4.21 (1H, d,
JZ9.7 Hz, C-40H), 5.20 (1H, d, JZ9.7 Hz, C-30H), 6.84

Raunak et al. / Tetrahedron 61 (2005) 5687–5697
5695
(1H, d, JZ7.7 Hz, C-7H), 6.92–6.98 (4H, m, C-200H,
C-300H, C-500H a0n0 d C-600H), 7.12–7.23 (6H, m, C-4H,
C-5H, C-6H, C-4 H, C-2000H and C-6000H), 7.44 (1H, br s,
NH) and 7.58 (2H, d, JZ8.0 Hz, C-3000H and C-5000H); 13C
NMR (75.5 MHz; CDCl3): d 13.7 (COOCH2CH3), 21.5
(C6H4CH3), 61.4 (COOCH2CH3), 64.9 (C-40), 71.7 (C-30),
83.1 (C-50), 110.4 (C-400), 117.6 (C-200 and C-600), 123.3
(C-7), 1020 3.6 (C-5), 126.2 (C-9)0,00 126.7 (C-6),0010 28.2 (C-300
and C-5 ), 128.8 (C-2000 and C-6 ), 130.0 (C-3 an0d0 C-5000),
130.9 (C-4), 135.5 (C-1000), 138.5 (C-8), 141.5 (C-1 ), 150.1
(C-4000), 167.9 (CONH) and 175.5 (COOC2H5); HRMS
Calcd for C26H24N2O4: 428.1736. Found: 428.1721.
(NH), 1739 (COOC2H5), 1618 (CONH), 1469, 1231,
1
1073, 753 and 694 cmK1; H NMR (300 MHz; CDCl3): d
0.80 (3H, t, JZ7.0 Hz, COOCH2CH3), 3.80–3.98 (2H, m,
COOCH2CH3), 5.24 (1H, s, C-30H), 5.32 (1H, s, C-50H),
6.69 (1H, d0,0 JZ7.7 Hz, C-0700H), 6.91–7.12 (6H, m, C-200H,
C-300H, C-5 H, C-600H, C-2 H and C-6000H), 7.19–7.23 (2H,
m, C-400H and C-5000H), 7.25–7.30 (0200H, m, C-5H and C-6H)
7.47–7.51 (2H, m, C-4H and C-4 H) and 7.89(1H, br s,
NH); 13C NMR (75.5 MHz; CDCl3): d 13.5 (COOCH2CH3),
61.4 (COOCH2CH3), 66.5 (C-40), 77.6 (C-30), 82.2 (C-50),
109.4 (C-400), 115.5 (C-200 and C-600), 122.5 (C-7), 123.1
(C-5), 1020 4.7 (C-9), 125.1 (C-6), 127.0 (C-4), 129.0 (C-300
and C-5 ), 129.3 (C-6000), 129.6 (C-5000), 129.8 (C-4000), 131.2
(C-2000), 137.9 (C-8 and C-1000), 140.1 (C-100), 150.9 (C-3000),
165.5 (CONH) and 173.8 (COOC2H5); HRMS Calcd for
C25H21N2 79BrO4: 492.0685. Found: 492.0696.
5.4.11.
30-(3-Chlorophenyl)-50-ethoxycarbonyl-20-
phenylspiro[indoline-3,40-isoxazolidine]-2-one (5f).
Obtained as a light yellow solid (177 mg, 21%), mp 158–
159 8C, (from petroleum ether–ethyl acetate), Rf: 0.35
(petroleum ether–ethyl acetate, 3:2); IR (KBr): 3317
(NH), 1741 (COOC2H5), 1619 (CONH), 1595, 1399,
5.4.14.
30-(3-Bromophenyl)-40-ethoxycarbonyl-20-
phenylspiro[indoline-3,50-isoxazolidine]-2-one (6g).
Obtained as a light yellow solid (402 mg, 44%) mp 145–
146 8C (from petroleum ether–ethyl acetate), Rf: 0.38
(petroleum ether–ethyl acetate, 3:2); IR (KBr): 3206
(NH), 1730 (COOC2H5), 1620 (CONH), 1474, 1338,
1
1230, 1075 and 750 cmK1; H NMR (300 MHz; CDCl3):
d 0.81 (3H, t, JZ7.0 Hz, COOCH2CH3), 3.80–3.98 (2H, m,
COOCH2CH3), 5.24 (1H, s, C-30H), 5.32 (1H, s, C-50H),
6.68 (1H, d, JZ7.7 Hz,00C-7H), 060 .91–6.96 (1H, m, C-5000H),
7.01–7.17 (7H, m, C-2 H, C-3 H, C-400H, C-500H, C-600H,
1
1192, 1027 and 834 cmK1; H NMR (300 MHz; CDCl3):
000
C-2 H and C-6000H), 7.25–7.31 (3H, m, C-5H, C-6H and
d 0.70 (3H, t, JZ7.0 Hz, COOCH2CH3), 3.67–3.84 (2H, m,
COOCH2CH3), 4.20 (1H, d, JZ9.5 Hz, C-40H), 5.25 (1H, d,
JZ9.5 Hz, C-30H), 6.90–7.00 (5H, m, C-7H, C-200H,
000
C-4 H), 7.51 (1H, d, JZ7.4 Hz, C-4H) and 7.62 (1H, br s,
NH); 13C NMR (75.5 MHz; CDCl3): d 15.94 (COOCH2-
CH3), 63.8 (COOCH2CH3), 68.8 (C-40), 80.0 (C-30), 84.5
(C-50), 111.75 (C-400), 117.9 (C-200 and C-600), 125.0 (C-7),
125.5 (C-5), 127.0 (C-6), 127.2 0(0C-9), 129.0 (C-5000), 129.4
(C-6000), 130.7 (C-4), 131.400(0C-3 and C-500), 131.7 (C-4000),
131.9 (C-2000), 136.7 (C-1 ), 140.0 (C-8), 142.4 (C-100),
153.3 (C-3000), 167.9 (CONH) and 176.0 (COOC2H5); HRMS
Calcd for C25H21N2 35ClO4: 448.1190. Found: 448.1182.
00
C-3 H, C-500H and C-600H), 7.04 (1H, d, JZ7.2 Hz,
000
C-6 H), 7.15–7.20 (2H, m, C-400H and C-5000H), 7.23–7.29
(2H, m, C-5H and C-6H), 7.44–7.47 (1H, m, C-4000H), 7.65
(1H, d, JZ7.7 Hz, C-4H), 7.89–7.90 (1H, m, C-2000H) and
8.47 (1H, br s, NH); 13C NMR (300 MHz; CDCl3): d 13.7
(COOCH2CH3), 61.7 (COOCH2CH3), 64.8 (C-40), 71.1
(C-30), 83.6 (C-50), 110.9 (C-400), 117.2 (C-200 and C-600),
123.4 (C-7), 123.7 (C-5), 125.9 (C-9), 126.6 (C-6), 126.9
(C-4), 129.0 (C-300 and C-500), 130.9 (C-6000), 131.1 (C-5000),
131.1 (C-4000), 132.0 (C-2000), 141.2 (C-8 and C-1000), 141.7
(C-100), 149.9 (C-3000), 167.6 (CONH) and 175.6
(COOC2H5); HRMS Calcd for C25H21N2 79BrO4:
492.0685. Found: 492.0704.
5.4.12.
30-(3-Chlorophenyl)-40-ethoxycarbonyl-20-
phenylspiro[indoline-3,50-isoxazolidine]-2-one (6f).
Obtained as a light yellow solid (272 mg, 33%), mp 159–
160 8C (from petroleum ether–ethyl acetate), Rf: 0.38
(petroleum ether–ethyl acetate, 3:2); IR (KBr): 3205
(NH), 1729 (COOC2H5), 1620 (CONH), 1472, 1339,
1292, 1033, 1097 and 841 cmK1 1H NMR (300 MHz;
;
5.4.15. 50-Ethoxycarbonyl-30-(3-nitrophenyl)-20-phenyl-
spiro[indoline-3,40-isoxazolidine]-2-one (5h). Obtained
as a light yellow solid (123 mg, 12%), mp 165–166 8C
(from petroleum ether–ethyl acetate), Rf: 0.28 (petroleum
ether–ethyl acetate, 3:2); IR (KBr): 3310 (NH), 1741
(COOC2H5), 1619 (CONH), 1474, 1348, 1231, 1076 and
830 cmK1; 1H NMR (300 MHz; CDCl3): d 0.81 (3H, t, JZ
7.0 Hz, COOCH2CH3), 3.81–3.99 (2H, m, COOCH2CH3),
5.28 (1H, s, C-30H), 5.45 (1H, s, C-50H), 6.68 (1H, d, JZ
7.7 Hz,00C-7H), 6.87–6.93 (1H, m, C-5000H), 7.03–7.10 (4H,
m, C-2 H, C-300H, C-500H and C-600H),7.29–7.35 (3H, m,
C-5H, C-6H and C-400H), 7.49 (1H, d, JZ7.3 Hz, C-4H),
7.63–7.67 (2H, m, C-2000H and C-6000H), 7.95–7.98 (1H, m,
C-4000H) and 8.16 (1H, br s, NH); 13C NMR (75.5 MHz;
CDCl3): d 13.9 (COOCH2CH3), 61.9 (COOCH2CH3), 66.9
(C-40), 77.9 (C-30), 82.7 (C-50), 109.9 (C-400), 116.0 (C-200
and C-600), 121.9 (C-7), 123.2 (C-5), 123.5 (C-6), 123.9
(C-6000), 124.7 (C-9), 127.200(0 C-5000), 129.5 (C-300 and C-500),
129.8 (C-4000), 129.9 (C-2 ), 132.9 00(0 C-4), 138.5 (C-1000),
140.4 (C-8), 148.5 (C-100), 150.9 (C-3 ), 165.7 (CONH) and
173.8 (COOC2H5); HRMS Calcd for C25H21N3O6:
459.1430. Found: 459.1438.
CDCl3): d 0.70 (3H, t, JZ7.1 Hz, COOCH2CH3), 3.69–3.82
(2H, m, COOCH2CH3), 4.17 (1H, d, JZ9.5 Hz, C-40H),
5.23 (1H, d0,0 JZ9.5 Hz, C-30H), 6.89–6.99 (5H, m, C-7H,
00
C-2 H, C-3 H, C-500H and C-600H), 7.05 (1H, d, JZ7.4 Hz,
000
C-6 H) 7.15–7.20 (2H, m, C-400H and C-5000H), 7.23–7.33
(3H, m, C-5H, C-6H and C-4000H), 7.60–7.62 (1H, m, C-4H),
7.73 (1H, br s, C-2000H) and 8.13 (1H, br s, NH); 13C NMR
(75.5 MHz; CDCl3):
d
13.3 (COOCH2CH3), 610.3
(COOCH2CH3), 64.4 (C-40), 70.6 (C-30), 82.9 (C-5 ),
110.1 (C-400), 116.8 (C-200 and C-600), 120300.0 (C-7), 123.3
000
(C-5), 125.4 (C-9), 125.9 (C-6), 126.3 (C-5 ), 127.8 (C-6 ),
128.6 (C-4, C-300 and C-500), 130.2 (C-4 ), 130.6 (C-2 ),
000
000
000
134.8 (C-1000), 140.5 (C-8), 141.0 (C-1 ), 149.4 (C-3 ),
167.2 (CONH) and 174.6 (COOC2H5); HRMS Calcd for
C25H21N2 35ClO4: 448.1190. Found: 448.1183.
00
5.4.13.
30-(3-Bromophenyl)-50-ethoxycarbonyl-20-
phenylspiro[indoline-3,40-isoxazolidine]-2-one (5g).
Obtained as a light yellow solid (83 mg, 9%), mp 160–
161 8C (from petroleum ether–ethyl acetate), Rf: 0.36
(petroleum ether–ethyl acetate, 3:2); IR (KBr): 3284

5696
Raunak et al. / Tetrahedron 61 (2005) 5687–5697
5.4.16. 40-Ethoxycarbonyl-30-(3-nitrophenyl)-20-phenyl-
spiro[indoline-3,50-isoxazolidine]-2-one (6h). Obtained
as a light yellow solid (356 mg, 42%), mp 159–160 8C
(from petroleum ether–ethyl acetate), Rf: 0.32 (petroleum
ether–ethyl acetate, 3:2); IR (KBr): 3093 (NH), 1730
(COOC2H5), 1619 (CONH), 1472, 1351, 1198, 1024 and
906 cmK1; 1H NMR (300 MHz; CDCl3): d 0.68 (3H, t, JZ
7.0 Hz, COOCH2CH3), 3.66–3.83 (2H, m, COOCH2CH3),
4.17 (1H, d, JZ9.0 Hz, C-40H), 5.40 (1H,00d, JZ9.1 Hz,
C-3000H), 6.86–6.97 (5H, m, C-7H, C-200H, C-3 H, C-500H and
C-6 H), 7.05 (1H, d, JZ7.3 Hz, C-400H), 7.12–7.27 (3H, m,
C-5H, C-6H and C-6000H), 7.55 (1H, t, JZ7.9 Hz, C-5000H),
7.87 (1H, br s, NH), 8.07–8.17 (2H, m, C-4H and C-4000H)
and 8.53 (1H, br s, C-2000H); 13C NMR (75.5 MHz; CDCl3):
d 13.2 (COOCH2CH3), 61.4 (COOCH2CH3), 64.2 (C-40),
70.3 (C-30), 83.1 (C-50), 110.3 (C-400), 116.9 (C-200 and
C-600), 122.9 (C-7), 123.0 (C-5), 123.3 (C-6), 123.6 (C-6000),
125.3 (C-9), 126.1 (C-5000), 128.6000(C-300 and C-500), 129.9
(C-4), 130.8 (C-4000), 133.8 (C-2 ), 140.8 (C-1000), 141.1
(C-8), 148.6 (C-100), 148.8 (C-3000), 167.1 (CONH) and 174.6
(COOC2H5); HRMS Calcd for C25H21N3O6: 459.1430.
Found: 459.1425.
8.0 Hz, C-5000), 116.9 (C-200 and C-600), 123.0 (C-7), 123.3
(C-5), 123.4 (d, JZ22.6 Hz, C-4000), 125.5 (C-9), 126.3
(C-6), 128.6 (C-300 and C-500), 130.5 (d, JZ21.2 Hz,
C-2000),130.7 (C-4), 141.1 (d, JZ6.4 Hz, C-1000), 141.2
(C-8), 149.4 (C-100), 162.9 (d, JZ246.7 Hz, C-3000), 167.4
(CONH) and 175.0 (COOC2H5); HRMS Calcd for
C25H21FN2O4: 432.1485. Found: 432.1464.
5.4.19.
50-Ethoxycarbonyl-30-(3-methylphenyl)-20-
phenylspiro[indoline-3,40-isoxazolidine]-2-one (5j).
Obtained as a light yellow solid (126 mg, 15%), mp 158–
160 8C (from petroleum ether–ethyl acetate), Rf: 0.32
(petroleum ether–ethyl acetate, 3:2); IR (KBr): 3304
(NH), 1733 (COOC2H5), 1617 (CONH), 1378, 1227, 1076
and 750 cmK1; 1H NMR (300 MHz; CDCl3): d 0.80 (3H, t,
JZ7.0 Hz, COOCH2CH3), 2.17 (3H, s, C6H4CH3), 3.80–
3.98 (2H, m, COOCH2CH3), 5.24 (1H, s, C-30H), 5.32 (1H,
s, C-50H), 6.64 (1H, d, JZ7.7 Hz, C-7H), 6.87–7.00 (3H, m,
C-400H, C-5000H and 00C-6000H), 7.03–7.10 (5H, m, C-200H,
C-300H, C-500H, C-6 00H0 and C-2000H), 7.22–7.28 (3H, m,
C-5H, C-6H and C-4 H) and 7.54–7.56 (2H, m, C-4H and
NH); d (75.5 MHz; CDCl3) 13.9 (COOCH2CH3), 21.6
(C6H4CH3), 61.6 (COOCH2CH3), 67.0 (C-40), 78.6 (C-30),
82.4 (C-50), 109.6 (C-400), 116.0 (C-200 and C-600), 122.7
(C-7), 123.2 (C-5), 124.0 0(00C-6), 125.5 (C-9), 127.5 (C-5000),
127.6 (C-6000), 128.4 (C-4 ), 129.1 (C-300 and C-500), 129.2
(C-2000), 129.4 (C-4), 135.6 (C-1000), 138.2 (C-8),
140.7 (C-100), 151.7 (C-3000), 166.2 (CONH) and 174.8
(COOC2H5); HRMS Calcd for C26H24N2O4: 428.1736.
Found: 428.1720.
5.4.17. 50-Ethoxycarbonyl-30-(3-florophenyl)-20-phenyl-
spiro[indoline-3,40-isoxazolidine]-2-one (5i). Obtained as
a light yellow solid (93 mg, 11%), mp 169–170 8C (from
petroleum ether–ethyl acetate), Rf: 0.35 (petroleum ether–
ethyl acetate, 3:2); IR (KBr): 3296 (NH), 1741 (COOC2H5),
1
1615 (CONH), 1484, 1379, 1296, 1024 and 904 cmK1; H
NMR (300 MHz; CDCl3): d 0.80 (3H, t, JZ7.0 Hz,
COOCH2CH3), 3.81–3.98 (2H, m, COOCH2CH3), 5.24
(1H, s, C-30H), 5.35 (1H, s, C-50H), 6.67 (1H, d, JZ7.7 Hz,
C-7H), 6.78–6.80 (1H, m, C-400H), 6.92 (1H, t,00JZ7.0 Hz,
5.4.20.
40-Ethoxycarbonyl-30-(3-methylphenyl)-20-
phenylspiro[indoline-3,50-isoxazolidine]-2-one (6j).
Obtained as a light yellow solid (287 mg, 36%), mp 139–
140 8C (from petroleum ether–ethyl acetate), Rf: 0.35
(petroleum ether–ethyl acetate, 3:2); IR (KBr): 3216
(NH), 1732 (COOC2H5), 1618 (CONH), 1470, 1377,
000
C-5 H), 7.04–7.06 (7H, m, C-4H, C-200H, C-3 H, C-500H,
00
C-6 H, C-4000H and C-6000H), 7.26–7.30 (2H, m, C-5H and
C-6H) and 7.50–7.52 (2H, m, C-2000H and NH); 13C NMR
(300 MHz; CDCl3):
d
13.6 (COOCH2CH3), 610.4
(COOCH2CH3), 66.5 (C-40), 77.7 (C-30), 82.2 (C-5 ),
1293, 1110, 1051 and 906 cmK1 1H NMR (300 MHz;
;
00
109.4 (C-4 ), 113.7 (d, JZ2.9 Hz, C-6000), 115.1 (d, JZ
CDCl3): d 0.70 (3H, t, JZ7.0 Hz, COOCH2CH3), 2.37 (3H,
s, C6H4CH3), 3.64–3.81 (2H, m, COOCH2CH3), 4.24 (1H,
d, JZ9.7 Hz, C-40H), 5.22 (1H, d, JZ9.7 Hz, C-30H), 6.87–
6.97 (5H, m, C-7H, C-200H, C-300H, C-500H and C-600H),
7.07–7.17 (4H, m, C-5H, C-6H, C-400H and C-5000H), 7.22–
7.29 (2H, m, C-4000H and C-6000H), 7.48–7.54 (2H, m, C-4H
and C-2000H) and 8.00 (1H, br s, NH); 13C NMR (75.5 MHz;
CDCl3): d 13.2 (COOCH2CH3), 21.3 (C6H4CH3), 61.0
(COOCH2CH3), 64.5 (C-40), 71.3 (C-30), 82.9 (C-50), 110.1
(C-400), 116.8 (C-200 and C-600), 122.8 (C-7), 122.9 (C-5),
124.9 (C-6), 1020 5.7 (C-9), 126.3 (C-4), 128.2 (C-6000), 128.3
000
8.2 Hz, C-5 ), 115.6 (C-200 and C-600), 122.1 (d, JZ22.9 Hz,
C-4000), 1220.07 (C-7), 123.2 (C-5), 124.8 (C-9), 127.8 (C-6),
129.0 (C-3 and C-500), 129.3 (C-4), 129.9 (d, JZ22.4 Hz,
C-2000), 138.3 (d, JZ7.9 Hz, C-1000), 140.2 (C-8), 151.0
(C-100), 162.7 (d, JZ246.8 Hz, C-3000), 165.6 (CONH) and
173.9 (COOC2H5); HRMS Calcd for C25H21FN2O4:
432.1485. Found: 432.1492.
5.4.18. 40-Ethoxycarbonyl-30-(3-florophenyl)-20-phenyl-
spiro[indoline-3,50-isoxazolidine]-2-one (6i). Obtained as
a light yellow solid (185 mg, 23%), mp 144–145 8C (from
petroleum ether–ethyl acetate), Rf: 0.38 (petroleum ether–
ethyl acetate, 3:2); IR (KBr): 3210 (NH), 1730 (COOC2H5),
000
(C-300 and C-5 ), 128.7 (C-5000), 129.0 (C-4000), 130.5 (C-2 ),
000
138.1 (C-1000), 138.6 (C-8), 141.1 (C-100), 149.8 (C-3 ),
167.3 (CONH) and 175.1 (COOC2H5); HRMS Calcd for
C26H24N2O4: 428.1736. Found: 428.1718.
1618 (CONH), 1473, 1341, 1229, 1132, 1090 and 961 cmK1
;
1H NMR (300 MHz; CDCl3): d 0.71 (3H, t, JZ7.0 Hz,
COOCH2CH3), 3.67–3.80 (2H, m, COOCH2CH3), 4.19
(1H, d, JZ9.3 Hz, C-40H), 5.27 (1H, d, JZ9.3 Hz, C-300H0 ),
6.87 (1H, d, JZ7.7 Hz, C-7H), 6.90–7.01 (4H, m, C-2 H,
6. X-ray crystallography
00
C-3 H, C-500H and C-600H), 7.03–7.08 (2H, m, C-400H and
000
C-5 H), 7.14–7.19 (2H, m, C-5H and C-6H), 7.31–7.38
The crystallographic measurements on compounds 3, 5a
and 6c were made using a Siemens SMART area-detector
diffractometer. Graphite monochromated Mo-Ka radiation
was used in all cases. The structures were solved using
SHELXTL-PLUS32 and refined with SHELXL-96.33
(1H, m, C-4000H) and 7.42–7.50 (3H, m, C-4H, C-2000H and
C-6000H); 13C (75.5 MHz; CDCl3): d 13.3 (COOCH2CH3),
61.3 (COOCH2CH3), 64.4 (C-40), 70.7 (C-30), 83.1 (C-50),
110.3 (C-400), 114.8 (d, JZ2.9 Hz, C-6000), 115.4 (d, JZ

Raunak et al. / Tetrahedron 61 (2005) 5687–5697
5697
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Acknowledgements
Financial support from Danish International Development
Agency (DANIDA, Denmark) and the Council for Scientific
and Industrial Research (CSIR, New Delhi, India) is
gratefully acknowledged. We thank Professor Alan R.
Katritzky (Director, Institute for Heterocyclic Compounds,
University of Florida, Gainesville, FL 32611-7200, USA)
and Professor Dr. Jesper Wengel (Department of Chemistry,
University of Southern Denmark, DK-5230 Odense,
Denmark) for helpful discussions in arriving at the
mechanism of these reactions. We also thank Dr. Robert
C. Reynolds (Manager, Medicinal Chemistry at TAACF,
Southern Research Institute, Birmingham, Alabama 35255-
5305, USA) for his help in the evaluation of anti-
mycobacterial activities of our compounds, Professor Dr.
Marc E. Bracke (Laboratory of Experimental Cancerology,
University Hospital, De Pintelaan, B-9000 Gent, Belgium)
for testing the anti-invasive activities of our compounds and
Dr. Ravi Mosurkal (University of Massachusetts, Lowell) is
thanked for carrying out the molecular modeling studies.
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