Stereoselective synthesis of 3-spiro-α-methylene-γ-butyrolactone oxindoles from Morita-Baylis-Hillman adducts of isatin

Article abstract of DOI:10.1016/j.tet.2008.02.002

A concise stereoselective synthesis of 3-spiro-α-methylene-γ-butyrolactone oxindoles from Morita-Baylis-Hillman adducts of isatin in excellent yield has been achieved following a three-step reaction sequences viz. (1) Isomerisation of the Morita-Baylis-Hi

Full text of DOI:10.1016/j.tet.2008.02.002

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 3322e3330
www.elsevier.com/locate/tet
Stereoselective synthesis of 3-spiro-a-methylene-g-butyrolactone
oxindoles from MoritaeBayliseHillman
adducts of isatin
*
Ponnusamy Shanmugam , Vadivel Vaithiyanathan
Chemical Sciences and Technology Division, National Institute for Interdisciplinary Science and Technology (NIIST),
Thiruvananthapuram 695 019, Kerala, India
Received 30 November 2007; received in revised form 30 January 2008; accepted 1 February 2008
Available online 6 February 2008
Abstract
A concise stereoselective synthesis of 3-spiro-a-methylene-g-butyrolactone oxindoles from MoritaeBayliseHillman adducts of isatin in
excellent yield has been achieved following a three-step reaction sequences viz. (1) Isomerisation of the MoritaeBayliseHillman adducts of
isatin with trimethyl orthoformate and montmorillonite K10 clay catalyst, (2) a second MoritaeBayliseHillman reaction with formaldehyde,
and (3) an acid catalysed lactonization. The structure and stereochemistry of the products were assigned by X-ray crystallographic and
NMR spectroscopic studies. Formation and mechanism of the minor product spirofuran oxindoles and a one-pot base promoted second
MoritaeBayliseHillman adduct formationelactonization reaction have also been achieved.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: BayliseHillman adduct; Spirolactone; Spirooxindole; Isatin; Lactonization
1. Introduction
exploiting MoritaeBayliseHillman adducts of isatin is un-
known. Thus, as part of our research in the area of novel syn-
thetic applications of MoritaeBayliseHillman adducts, in
particular with MoritaeBayliseHillman adduct of isatin,31e36
herein we report a short and efficient stereoselective synthesis
Oxindoles functionalised at C3 as spirolactones,1e4 spirocy-
clicethers and spirocarbo- and heterocyclics are elegant targets
in organic synthesis due to their significant biological activiti-
es.5e7 These derivatives have been served as potential interme-
diates for the synthesis of alkaloids, drug intermediates and
clinical pharmaceuticals.5e7 A few examples of natural prod-
ucts having spirooxindole core structure are shown in Figure 1.
Hence, a number of synthetic methods have been developed for
expedition of these structural frameworks.8e26 The synthetic
versatility of isatin and its derivatives has led to the extensive
use of this compound in synthetic organic chemistry.27 Among
various carbonecarbon bond forming reactions, the Moritae
BayliseHillman reaction is an important reaction giving rise
to densely functionalized molecules and is considered to be
atom economic.28e30 The synthesis of title compounds
O
Me
H
H
O
N
O
N
NH
MeO
O
H
H
O
N
O
N
H
Me
Alstonisine
Spirotryprostatin B
NH
MeO
Me
N
Me
Me
HO
O
N
H
O
N
H
Horsfiline
Elacomine
* Corresponding author. Tel.: þ91 471 2515275; fax: þ91 471 2491712.
E-mail address: shanmu196@rediffmail.com (P. Shanmugam).
Figure 1. Spirooxindole alkaloid natural products.
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.02.002

P. Shanmugam, V. Vaithiyanathan / Tetrahedron 64 (2008) 3322e3330
3323
OMe
of 3-spiro-a-methylene-g-butyrolactone oxindoles from
MoritaeBayliseHillman adduct of isatin.
5.04
MeO2C
OMe
H
H
CO2Me
4.64
O
O
2. Results and discussion
N
N
Compound 2 (Z)
Figure 2. Distinction of E and Z isomers of 2.
Compound 2 (E)
The target compounds were synthesized according to
retrosynthetic analysis shown in Scheme 1. 3-Spiro-a-methyl-
ene-g-butyrolactone oxindoles A could be obtained from Mor-
itaeBayliseHillman adduct derivative B by an acid catalysed
lactonization reaction. The MoritaeBayliseHillman adduct
derivative B could be obtained through a second Moritae
BayliseHillman reaction with isomerised adducts of Moritae
BayliseHillman adduct of isatin C and formaldehyde. The
isomerised adduct C could be prepared by isomerisation reac-
tion of MoritaeBayliseHillman adducts of isatin D with
trimethyl orthoformate/AreH and a solid acid clay catalyst.
methylene protons of E-isomer appeared as a singlet at
d 4.64 whereas Z-isomer showed the methylene peak at
d 5.04 due to ring current of aryl ring (deshielding zone) as
shown in Figure 2.
The column purified E/Z mixture 2 in acetone was sub-
jected to a second MoritaeBayliseHillman adduct formation
with 40% aqueous formaldehyde and 1.5 equiv DABCO at
room temperature for 2 h to afford adduct 3 in excellent yield
(98%). To our surprise, attempts to form the second Moritae
BayliseHillman adduct from the isomerised compound 2 with
benzaldehyde, p-chloro benzaldehyde, p-nitrobenzaldehyde,
acetaldehyde, heptanaldehyde and E-crotonaldehyde under
optimised condition failed. Thus, we preceded further investi-
gation with formaldehyde derived second MoritaeBaylise
Hillman adduct 3. Exposure of the compound 3 in benzene
with p-toluenesulfonic acid (PTSA) for 30 min furnished
excellent combined yield of 3-spiro-a-methylene-g-butyrolac-
tone oxindoles 4a (Z-isomer major, 75%) and 4b (E-isomer
minor, 15%) and the compounds were separated by column
chromatography. The structure of the lactones 4a and 4b
was confirmed by a single crystal X-ray analysis (Fig. 3).41
The assigned geometry of compounds 4a and 4b was further
supported by the analysis of chemical shifts of vinylic olefin
R3
O
R3
R2
R2
CO2Me
OH
O
Acid catalysed
lactonization
O
O
N
N
R1
R1
B
A
Morita-Baylis-Hillman
Reaction
R2
MeO2C
R3
R2
HO
CO2Me
Isomerisation
O
N
O
N
R1
D
R1
C
1
Scheme 1. Retrosynthetic analysis.
protons in H NMR spectra. Accordingly, the Z-vinyl proton
of major isomer 4a was observed as a singlet at d 7.27 whereas
E-vinyl proton of minor isomer 4b observed at d 6.14 as
a singlet.
Encouraged by preliminary results, we then turned our
attention to investigate and to generalize the synthesis of
spiro-a-methylene-g-butyrolactone oxindoles with a number
of MoritaeBayliseHillman adducts of isatin substituted at
aryl and N-alkyl positions as shown in Scheme 3.
Hence, we first prepared isomerised MoritaeBayliseHill-
man derivatives from various MoritaeBayliseHillman
adducts. The MoritaeBayliseHillman adducts of isatin
substituted at aryl and N-alkyl positions 5e10 with trimethyl
The preliminary study is depicted in Scheme 2. Initially, the
reaction of MoritaeBayliseHillman adduct of N-methylisatin
1 with excess of trimethyl orthoformate and montmorillonite
K10 clay37e40 catalyst at 110 ꢀC for 0.5 h afforded a 1:3 mix-
ture of E- and Z-isomer 2 in excellent overall yield (75%).
OMe
MeO
CO2Me
OH
HO
N
CO2Me
CO2Me
b
a
98%
75%
O
O
O
N
N
Z:E = 3:1
2
1
3
c
O
OMe
O
MeO
O
O
+
O
O
N
N
15%
4b(E-minor)
75%
4a(Z-major)
Scheme 2. Synthesis of 3-spiro-a-methylene-g-butyrolactone-N-methyl oxin-
doles 4a and 4b. (a) CH(OMe)3/Mont. K10, neat, 110 ꢀC, 30 min; (b) aq
HCHO, DABCO, rt, acetone, 1.5 h; (c) PTSA/benzene, 30 min.
The E and Z isomers were inseparable by column chroma-
tography. However, the ratio and distinction of E and Z
isomers were found based on 1H NMR study. Thus, the
Figure 3. X-ray crystal structure of compounds 4a and 4b.

3324
P. Shanmugam, V. Vaithiyanathan / Tetrahedron 64 (2008) 3322e3330
R3
N
R3
O
R3
CO2Me
OH
O
R2
R2
R2
R2
HO
N
O
CO2Me
CO2Me
c
a
b
O
70-97%
O
O
30-75%
80-95%
N
R1
N
R1
1, 5-10
R1
(27-34) ab
R1
11-18
19-26
R1= Me, Et, Propargyl, Bz,Allyl, CO2Me; R2=H, Br; R3= OMe, Ph, O-Propargyl
Scheme 3. Synthesis of 3-spiro-a-methylene-g-butyrolactone-N-alkyl oxindoles (27a/be34a/b). (a) CH(OMe)3 (or) AreH (or) propargyl alcohol/Mont. K10, neat,
110 ꢀC, 30 min; (b) aq HCHO, DABCO, acetone, rt, 2 h; (c) PTSA/benzene, 80 ꢀC, 30 min.
orthoformate, and montmorillonite K10 clay catalyst at 110 ꢀC
for 1.5 h afforded the corresponding isomerised compounds
11e16 in moderate to good yields (Table 1 entries 1e6).
The isomerisation of MoritaeBayliseHillman adduct 1 with
propargyl alcohol and benzene afforded the corresponding iso-
merised compounds 17 and 18. It should be noted that the iso-
merisation reaction with benzene provided poor yield (30%) of
compound 18 (Table 1, entry 8). However, the isomerisation
with propargyl alcohol furnished very good yield of 17
(68%, Table 1, entry 7).
In continuation of the target compound synthesis, the second
MoritaeBayliseHillman adduct formation from isomerised
derivatives 11e18 with aqueous formaldehyde and DABCO
in acetonewas performed and the reactions underwent smoothly
to afford the corresponding second MoritaeBayliseHillman
adducts 19e26 in very good to excellent yields.
Table 1
Generality for the synthesis of 3-spiro-a-methylene-g-butyrolactone-N-alkyl oxindoles
Entry
Substrate
Products
Yieldb
(A)
%
Isomerised product (A)
Lactone producta (B)
(B) (Z/E)c
O
OMe
OMe
O
O
CO2Me
1
5
63
90 (2:1)
N
O
N
27a and 27b
11
OMe
O
OMe
O
O
CO2Me
O
N
N
2
3
6
7
65
75
80 (1:0.2)
12
28a and 28b
OMe
O
OMe
O
O
CO2Me
95
O
N
N
Ph
Ph 29a
13
O
OMe
OMe
Br
O
O
Br
CO2Me
N
4
5
8
9
60
67
70 (1:0.3)
77 (1:0.7)
O
N
Ph
30a and 30b
Ph
14
O
OMe
OMe
O
CO2Me
O
N
O
N
15
31a and 31b

P. Shanmugam, V. Vaithiyanathan / Tetrahedron 64 (2008) 3322e3330
3325
Table 1 (continued)
Entry
Substrate
Products
Yieldb
(A)
%
Isomerised product (A)
Lactone producta (B)
(B) (Z/E)c
O
OMe
OMe
O
CO2Me
O
N
O
N
6
10
57
67 (2:1)
CO2Me
CO2Me
32a and 32b
16
O
O
O
O
O
CO2Me
7
1
1
68
30
84 (2:1)
N
O
N
17
33a and 33b
Ph
O
Ph
O
O
CO2Me
8
97 (1:0.6)
O
N
N
18d
34a and 34be
a
Separable by column chromatography.
b
c
Yield/ratio were determined after column purification.
Stereochemistry was assigned based on 1H NMR and single crystal X-ray studies.
The combined yield of the mixture 18 from 1 for 12 h was only 30%.
Inseparable by column chromatography.
d
e
Subsequent to the second MoritaeBayliseHillman adduct
Duringthecourse oflactonizationofsecond MoritaeBaylise
Hillman adducts 3, 20 and 22 in benzene with PTSA, in addition
to the desired lactone products 4a/b, 28a/b and 30a/b, a minor
amount of spirofuran oxindole derivatives (<10%) 4c, 28c and
30c were also isolated. The synthetic transformation and results
are shown in Table 2.
formation, reactions for the lactonization of the silica gel col-
umn purified compounds 19e26 using PTSA were performed
and the results are collected in Table 1. In consequence, the
second MoritaeBayliseHillman adduct 19 upon lactonization
using PTSA afforded Z- and E-isomer of 3-spiro-a-methylene-
g-butyrolactone-N-ethyl oxindoles 27a/b, separable by col-
umn chromatography, in excellent combined yield (Table 1,
entry 1). Similarly, under optimised conditions, highly
functionalised second MoritaeBayliseHillman adducts of N-
propargyl and N-benzyl isatin derivatives 20 and 21 afforded
3-spiro-a-methylene-g-butyrolactone-N-propargyl and benzyl
oxindoles 28a/b and 29a, respectively, in excellent yield (Ta-
ble 1, entries 2 and 3). The bromo derivative 22 under lactoni-
zation reaction condition furnished spirolactones 30a/b in very
good yield (Table 1, entry 4). Likewise, the N-allyl compound
23 furnished the corresponding lactone derivatives 31a/b in
good yield (Table 1, entry 5). The MoritaeBayliseHillman
adducts bearing carbo methoxy functional group at NeH posi-
tion 24 also furnished the desired spirolactones 32a/b in 67%
combined yield (Table 2, entry 6). The second MoritaeBayl-
iseHillman adducts 25 and 26 upon lactonization using
PTSA furnished the corresponding spirooxindole lactone de-
rivatives 33a/b and 34a/b in excellent combined yield (Table
1, entries 7 and 8). All the Z/E isomers of spirolactone com-
pounds 27a/be33a/b were separable by column chromatogra-
phy and thoroughly characterized by spectroscopic methods
The structures of 3-spiro dihydrofuran compounds were es-
1
tablished unambiguously using FTIR and H NMR spectro-
scopic studies. Thus, in the FTIR spectrum of compounds 4a/
b, the lactone and amide carbonyl absorptions were observed
at 1753, 1714 and 1755, 1704 cmꢁ1, respectively. However,
the IR spectrum of compound 4c showed the only a merged am-
ide and ester carbonyl absorption at 1714 cmꢁ1. Due to the ab-
sence of lactone carbonyl absorption at w1755 cmꢁ1 for
compound 4c, the structure was assigned as 3-spiro dihydro-
1
furan 4c. Further structural evidence was arrived from the H
NMR spectrum of compound 4c. Accordingly, the olefinic pro-
ton in the spiro dihydrofuran ring appeared as a singlet at
d 7.58, the ester eOMe appeared as a singlet at d 3.53 whereas
in the spirolactones 4a/b, the olefinic proton appeared at d 7.27/
6.14 and eOMe substituent in exocyclic double bond appeared
at d 3.67 and 3.82, respectively.
A plausible mechanism for the formation of minor amounts
of dihydro spirofuran oxindole derivatives is depicted in
Scheme 4. It is assumed that the protonation of second Mori-
taeBayliseHillman adduct forms a methoxy-stabilised carbo-
cation E. The hydroxyl group of the intermediate E undergoes
cyclisation with stabilised carbocation by loss of a proton to
1
(IR, H NMR, 13C NMR and HRMS).

3326
P. Shanmugam, V. Vaithiyanathan / Tetrahedron 64 (2008) 3322e3330
Table 2
Synthesis of 3-spirolactone and 3-spiro dihydrofuran-N-alkyl oxindoles
Table 3
One-pot base promoted MoritaeBayliseHillman adduct formatione
lactonization
O
OMe
R3
MeO2C
OMe
OH
O
R2
R3
R3
O
R2
R2
O
O
R2
R2
R2
PTSA
CO2Me
OH
CO2Me
O
+
CO2Me
a
benzene, 80 °C
O
O
O
N
N
N
30 min.
80-95%
R1
4a/b, 28a/b
R1
N
R1
R1
O
O
N
N
4c, 28c and 30c
R1
3, 19-23
3, 20 and 22
R1
(4, 27-31)a
and 30a/b
2, 11-15
R1=Me, Propargyl and Bn; R2=H, Br
(z-isomer)
a. aq. HCHO, DABCO, RT, acetone, 12h
(z-isomer)
Entry
Adduct
Product
Yield (%)
Entry
Substrate
Product
Yield %
Lactone A
Furan B
A
B
1
2
3
4
5
6
3
11
12
13
14
15
4a
90
92
90
95
80
85
O
27a
28a
29a
30a
31a
CO2Me
1
3
4a/b
90
8
O
O
N
4c
O
mixture was stirred overnight (12 h). A one-pot base promoted
second MoritaeBayliseHillman adduct formation followed
by lactonization occurred smoothly and provided a single
Z-isomer of the lactone 4a in excellent yield (90%, Table 3,
entry 1).
CO2Me
N
2
3
20
22
28a/b
30a/b
80
70
7
9
28c
O
The formation of E-isomer was not observed as per the
1
analysis of crude and purified H NMR spectra of the com-
Br
CO2Me
pounds. In order to show the generality of this observation,
reactions with isomerised Z-isomers 11e15 with 1.5 equiv
DABCO and aqueous formaldehyde in acetone for 12 h
afforded the expected Z-isomers of 3-spiro-a-methylene-
g-butyrolactone-N-alkyl oxindoles 27ae31a in excellent
yields (80e95%) (Table 3, entries 2e6).
O
N
Ph
30c
H+
3. Conclusion
O
OMe
OMe
O
OMe
R2
MeO
OMe
MeO
HO
R2
R2
O H
In conclusion, we have developed a short and efficient ste-
reoselective synthesis of highly functionalised 3-spiro-a-meth-
ylene-g-butyrolactone oxindoles along with minor amounts of
spirofuran oxindole derivatives from MoritaeBayliseHillman
adducts of isatin for the first time. A one-pot procedure for the
second MoritaeBayliseHillman adduct formation followed
by lactonization has been achieved. Further studies in this
area are under way in this laboratory.
O
H
O
H
O
O
O
N
N
N
R1
R1
R1
-H+
E
R1=Me, Propargyl, Bn
R2=H, Br
R2
O
O
OMe
R2
-MeOH
9-7%
CO2Me
CO2Me
H
O
O
N
N
R1
4c, 28c and 30c
R1
F
4. Experimental section
Scheme 4. A plausible mechanism for the formation of spiro dihydrofuran
derivatives.
4.1. General consideration
form the intermediate F, which upon elimination of methanol
affords the spirofuran derivatives.
All the experiments were carried out in oven-dried glass-
ware. Analytical thin layer chromatography was performed
on silica gel TLC plates. Purification by gravity column chro-
matography was carried out using silica gel (100e200 mesh).
Mixture of ethyl acetate, hexane and pure ethyl acetate were
used as eluent as required. IR spectra were run on a Nicolet
(impact 400D FT-IR) spectrophotometer. NMR spectra were
obtained using chloroform-d as solvent on Bruker DPX
300 MHz NMR spectrometer. Chemical shifts are given in
On further examination on the lactonization studies, we
have developed a base promoted one-pot procedure for the
second MoritaeBayliseHillman adducts’ formation followed
by lactonization reaction. The reaction and the results are
collected in Table 3. Thus, as a preliminary experiment, the
isomerised Z-isomer of adduct 2 was treated with 1.5 equiv
DABCO and aqueous formaldehyde in acetone and the

P. Shanmugam, V. Vaithiyanathan / Tetrahedron 64 (2008) 3322e3330
3327
d scale with TMS as internal reference. HRMS were measured
4.3.5. Compound (Z)-13
Rf (20% EtOAcehexanes) 0.47; IR (CH2Cl2): nmax 1717,
1667, 1603 cmꢁ1 1H NMR (CDCl3/TMS, 300.1 MHz):
d 3.45 (s, 3H), 3.98 (s, 3H), 4.92 (s, 2H), 5.10 (s, 2H), 6.69
(d, J¼7.8 Hz, 1H), 6.96 (t, J¼7.8 Hz, 1H), 7.16e7.33 (m,
7H); 13C NMR (CDCl3/TMS, 75.3 MHz): d 44.2, 52.8, 53.9,
62.6, 106.2, 109.3, 122.7, 123.5, 126.8 (2C), 127.6, 128.5
(2C), 129.0, 131.2, 135.4, 142.6, 143.6, 174.8, 175.7; HRMS
calcd for C20H19NO4: 337.1314; found: 337.1303.
at the JMS 600 JEOL Mass Spectrometer. Yields refer to quan-
tities obtained after chromatography. Solvents used are of
reagent grade and were purified before use according to the
literature procedure.42
;
4.2. General experimental procedure for isomerisation
Isomerisation: A mixture of MoritaeBayliseHillman ad-
ducts (100 mg, 0.404 mmol), excess of trimethyl orthoformate
(3 mL) (or) AreH (3 mL) (or) propargyl alcohol (3 mL) and
montmorillonite K10 clay (50% w/w) without any solvent
was heated at 110 ꢀC for 1.5 h. After the reaction (TLC), the
crude mixture was purified by a silica gel column chromatog-
raphy using gradient elution with hexane and hexaneeEtOAc
(80:20) mixture to afford isomerised products in good yields
(68e75%).
4.3.6. Compound (Z)-14
Rf (20% EtOAcehexanes) 0.43; IR (CH2Cl2): nmax 1721,
1667, 1605 cmꢁ1
;
1H NMR (CDCl3/TMS, 300.1 MHz):
d 3.43 (s, 3H), 3.87 (s, 3H), 4.92 (s, 2H), 5.04 (s, 2H), 6.63
(d, J¼8.4 Hz, 1H), 7.28e7.34 (m, 8H); 13C NMR (CDCl3/
TMS, 75.3 MHz): d 44.4, 52.9, 62.9, 73.8, 105.8, 110.5,
116.2, 126.1, 127.3 (2C), 128.2, 128.8 (2C), 131.8, 132.6,
135.1, 141.7, 143.6, 170.4, 172.8; HRMS calcd for
C20H18BrNO4: 415.0419; found: 415.0417.
4.3. Spectral data for isomerised BayliseHillman adducts
4.3.7. Compound (Z)-15
Rf (20% EtOAcehexanes) 0.47; IR (CH2Cl2): nmax 1715,
4.3.1. Compound (Z)-2
Rf (20% EtOAcehexanes) 0.42; IR (CH2Cl2): nmax 1710,
1659, 1608 cmꢁ1; 1H NMR (CDCl3/TMS, 300.1 MHz): d 3.22
(s, 3H), 3.43 (s, 3H), 3.96 (s, 3H), 5.04 (s, 2H), 6.78 (d,
J¼7.8 Hz, 1H), 6.98 (t, J¼7.8 Hz, 1H), 7.22e7.31 (m, 2H);
13C NMR (CDCl3/TMS, 75.3 MHz): d 25.9, 52.6, 59.1, 68.2,
108.3, 119.7, 122.4, 122.6, 124.9, 130.4, 141.6, 143.6, 166.9,
167.5; HRMS calcd for C14H15NO4: 261.1001; found:
261.0988.
1664, 1612 cmꢁ1
;
1H NMR (CDCl3/TMS, 300.1 MHz):
d 3.54 (s, 3H), 4.08 (s, 3H), 4.45e4.52 (m, 2H), 5.18 (s,
1H), 5.29e5.35 (m, 2H), 5.5 (m, 1H), 6.91 (d, J¼7.5 Hz,
1H), 7.09 (t, J¼7.4 Hz, 1H), 7.35e7.341 (m, 2H); 13C NMR
(CDCl3/TMS, 75.3 MHz): d 42.6, 52.77, 52.9, 62.6, 106.20,
109.3, 117.5, 122.8, 123.2, 128.7, 130.63, 131.2, 142.5,
158.4, 173.9, 174.6; HRMS calcd for C16H17NO4: 287.1158;
found: 287.1150.
4.3.2. Compound (E)-2
Rf (20% EtOAcehexanes) 0.42; IR (CH2Cl2): nmax 1710,
4.3.8. Compound (Z)-16
Rf (20% EtOAcehexanes) 0.39; IR (CH2Cl2): nmax 1702,
1659, 1608 cmꢁ1
;
1H NMR (CDCl3/TMS, 300.1 MHz):
1659, 1607 cmꢁ1
;
1H NMR (CDCl3/TMS, 300.1 MHz):
d 3.20 (s, 3H), 3.48 (s, 3H), 3.95 (s, 3H), 4.64 (s, 2H), 6.82
(d, J¼7.8 Hz, 1H), 7.10 (t, J¼6.9 Hz, 1H), 7.30e7.42 (m, 2H).
d 3.43 (s, 3H), 3.98 (s, 3H), 4.04 (s, 3H), 5.00 (s, 2H),
7.13e7.44 (m, 3H), 7.98 (t, J¼7.8 Hz, 1H); 13C NMR
(CDCl3/TMS, 75.3 MHz): d 52.8, 53.4, 59.3, 67.8, 105.7,
108.4, 122.3, 123.6, 129.4, 131.7, 143.3, 143.8, 167.5,
174.9, 175.3; HRMS calcd for C15H15NO6: 305.0899; found:
305.0900.
4.3.3. Compound (Z)-11
Rf (20% EtOAcehexanes) 0.38; IR (CH2Cl2): nmax 1713,
1665, 1614 cmꢁ1
;
1H NMR (CDCl3/TMS, 300.1 MHz):
d 1.26 (t, J¼7.0 Hz, 3H), 3.43 (s, 3H), 3.77 (q, J¼7.0 Hz,
2H), 3.96 (s, 3H), 5.04 (s, 2H), 6.79 (d, J¼7.8 Hz, 1H), 6.96
(t, J¼7.6 Hz, 1H), 7.22e7.30 (m, 2H); 13C NMR (CDCl3/
TMS, 75.3 MHz): d 12.3, 35.0, 53.2, 54.8, 63.5, 109.2,
119.5, 122.3, 123.2, 125.3, 130.2, 142.5, 143.5, 167.3,
167.8; HRMS calcd for C15H17NO4: 275.1158; found:
275.1147.
4.4. General experimental procedure for second
BayliseHillman adduct formation and lactonisation
Second MoritaeBayliseHillman adduct formation: A mix-
ture of isomerised MoritaeBayliseHillman adducts (100 mg,
0.382 mmol) was treated with 40% aqueous formaldehyde
(0.5 mL) and DABCO (1.5 equiv) in acetone (3 mL) and
stirred for 2 h at room temperature. The crude mixture was
passed through a silica gel column using gradient elution
with hexane and hexaneeEtOAc (70:30) mixture to afford
pure adducts as inseparable mixture (combined yield:
80e90%). Lactonisation: The mixture of second Moritae
BayliseHillman adducts (100 mg, 0.343 mmol) in benzene
(5 mL) and PTSA (cat. 0.3 equiv) was refluxed at 80 ꢀC for
30 min. The reaction mixture in CH2Cl2 (50 mL) was washed
with saturated NaHCO3, brine and water. The organic layer
4.3.4. Compound (Z)-12
Rf (20% EtOAcehexanes) 0.41; IR (CH2Cl2): nmax 2146,
1716, 1666, 1613 cmꢁ1
;
1H NMR (CDCl3/TMS,
300.1 MHz): d 2.22 (t, J¼2.4 Hz, 1H), 3.43 (s, 3H), 3.95 (s,
3H), 4.49 (s, 2H), 5.05 (s, 2H), 7.03e7.10 (m, 2H), 7.26e7.37
(m, 2H); 13C NMR (CDCl3/TMS, 75.3 MHz): d 29.6, 52.7,
57.54, 62.7, 72.2, 97.6, 111.3, 119.77, 122.51, 123.2,
125.27, 130.24, 142.06, 143.51, 166.89, 167.40; HRMS calcd
for C16H15NO4: 285.1001; found: 285.0992.

3328
P. Shanmugam, V. Vaithiyanathan / Tetrahedron 64 (2008) 3322e3330
was separated, dried (Na2SO4) and concentrated under vac-
uum. The crude mixture was purified by a column chromatog-
raphy using gradient elution with hexane and hexaneeEtOAc
(80:20) mixture to afford 3-spiro-a-methylene-g-butyrolac-
tone-N-alkyl oxindoles in 70e97% isolated yields.
(CDCl3/TMS, 300.1 MHz): d 2.55 (t, J¼2.5 Hz, 1H), 3.68
(s, 3H), 4.36e4.70 (m, 4H), 7.06 (d, J¼7.8 Hz, 1H), 7.13 (t,
J¼7.6 Hz, 1H), 7.25 (d, J¼6.9 Hz, 1H), 7.28 (s, 1H); 13C
NMR (CDCl3/TMS, 75.3 MHz): d 29.6, 52.7, 62.7, 72.2,
73.6, 98.0, 103.7, 109.2, 122.8, 123.8, 128.9, 130.7, 141.4,
158.7, 170.5, 174.3; HRMS calcd for C16H13NO4: 283.0845;
found: 283.0837.
4.5. Spectral data for 3-spiro-a-methylene-g-butyrolactone
oxindoles compounds
4.5.6. Compound 28b
Rf (20% EtOAcehexanes) 0.37; IR (CH2Cl2): nmax 2143,
4.5.1. Compound 4a
Rf (20% EtOAcehexanes) 0.38. IR (CH2Cl2): nmax 1753,
1752, 1715, 1667, 1612, 1487, 1049 cmꢁ1 1H NMR
;
1
1714, 1667, 1612, 1470, 1048 cmꢁ1; H NMR (CDCl3/TMS,
(CDCl3/TMS, 300.1 MHz): d 2.28 (t, J¼2.5 Hz, 1H), 3.85
(s, 3H), 4.32e4.63 (m, 4H), 6.61 (s, 1H), 6.91e7.41 (m,
4H); 13C NMR (CDCl3/TMS, 75.3 MHz): d 29.9, 53.2, 63.7,
73.1, 73.2, 77.4, 109.7, 111.3, 115.5, 116.6, 123.8, 124.5,
129.7, 158.3, 168.9, 178.3; HRMS calcd for C16H13NO4:
283.0845; found: 283.0835.
300.1 MHz): d 3.26 (s, 3H), 3.67 (s, 3H), 4.34 (d, J¼8.8 Hz,
1H), 4.59 (d, J¼8.8 Hz, 1H), 6.86 (d, J¼7.8 Hz, 1H), 7.09
(t, J¼7.5 Hz, 1H), 7.22 (d, J¼7.4 Hz, 1H), 7.27 (s, 1H), 7.32
(t, J¼7.7 Hz, 1H); 13C NMR (CDCl3/TMS, 75.3 MHz):
d 26.6, 52.8, 62.9, 73.8, 106.2, 108.2, 122.7, 123.4, 128.9,
130.8, 143.3, 158.6, 170.8, 175.2; HRMS calcd for
C14H13NO4: 259.0845; found: 259.0845.
4.5.7. Compound 29a
Rf (20% EtOAcehexanes) 0.35; IR (CH2Cl2): nmax 1747,
1
4.5.2. Compound 4b
Rf (20% EtOAcehexanes) 0.28. IR (CH2Cl2): nmax 1755,
1714, 1667, 1607, 1486, 1050 cmꢁ1; H NMR (CDCl3/TMS,
300.1 MHz): d 3.62 (s, 3H), 4.38 (d, J¼8.8 Hz, 1H), 4.64 (d,
J¼8.8 Hz, 1H), 4.65 (d, J¼15.6 Hz, 1H), 5.22 (d,
J¼15.6 Hz, 1H), 6.75 (d, J¼7.7 Hz, 1H), 7.05 (t, J¼6.9 Hz,
1H), 7.18e7.33 (m, 8H); 13C NMR (CDCl3/TMS,
75.3 MHz): d 44.2, 52.8, 62.6, 74.1, 106.2, 109.2, 122.8,
123.4, 127.4 (2C), 127.7, 128.7 (2C), 128.8, 130.9, 135.5,
142.4, 158.6, 170.7, 175.3; HRMS calcd for C20H17NO4:
335.1158; found: 335.1153.
1
1704, 1657, 1607, 1465, 1071 cmꢁ1; H NMR (CDCl3/TMS,
300.1 MHz): d 3.24 (s, 3H), 3.82 (s, 3H), 4.29 (d, J¼8.8 Hz,
1H), 4.55 (d, J¼8.8 Hz, 1H), 6.14 (s, 1H), 6.88 (d,
J¼7.7 Hz, 1H), 7.12 (t, J¼7.5 Hz, 1H), 7.27 (d, J¼7.4 Hz,
1H), 7.34 (t, J¼7.7 Hz, 1H); 13C NMR (CDCl3/TMS,
75.3 MHz): d 26.7, 53.1, 63.3, 73.2, 105.6, 108.7, 122.3,
123.4, 129.4, 131.6, 143.0, 158.1, 167.2, 176.5; HRMS calcd
for C14H13NO4: 259.0845; found: 259.0840.
4.5.8. Compound 30a
Rf (20% EtOAcehexanes) 0.36; IR (CH2Cl2): nmax 1744,
4.5.3. Compound 27a
Rf (20% EtOAcehexanes) 0.37. IR (CH2Cl2): nmax 1750,
1
1722, 1668, 1602, 1484, 1053 cmꢁ1; H NMR (CDCl3/TMS,
1
1715, 1667, 1611, 1486, 1051 cmꢁ1; H NMR (CDCl3/TMS,
300.1 MHz): d 3.66 (s, 3H), 4.37 (d, J¼8.9 Hz, 1H), 4.60 (d,
J¼15.7 Hz, 1H), 4.63 (d, J¼8.9 Hz, 1H), 5.22 (d,
J¼15.7 Hz, 1H), 6.62 (d, J¼8.4 Hz, 1H), 7.28e7.34 (m,
8H); 13C NMR (CDCl3/TMS, 75.3 MHz): d 44.4, 52.9, 62.9,
73.8, 105.8, 110.8, 116.1, 126.2, 127.4 (2C), 128.0, 128.9
(2C), 131.8, 132.9, 135.1, 141.5, 159.0, 170.4, 174.9; HRMS
calcd for C20H16BrNO4: 413.0263; found: 413.0263.
300.1 MHz): d 1.27 (t, J¼7.1 Hz, 3H), 3.67 (s, 3H), 3.62e
3.98 (m, 2H), 4.35 (d, J¼8.8 Hz, 1H), 4.59 (d, J¼8.8 Hz,
1H), 6.87 (d, J¼7.8 Hz, 1H), 7.07 (t, J¼7.4 Hz, 1H), 7.22e
7.34 (m, 3H); 13C NMR (CDCl3/TMS, 75.3 MHz): d 12.3,
35.0, 52.9, 62.5, 73.7, 106.7, 108.3, 122.9, 123.1, 128.9,
131.2, 142.4, 158.4, 170.71, 174.6; HRMS calcd for
C15H15NO4: 273.1001; found: 273.1006.
4.5.9. Compound 30b
Rf (20% EtOAcehexanes) 0.27; IR (CH2Cl2): nmax 1751,
4.5.4. Compound 27b
Rf (20% EtOAcehexanes) 0.26. IR (CH2Cl2): nmax 1755,
1
1712, 1668, 1605, 1486, 1054 cmꢁ1; H NMR (CDCl3/TMS,
1
1715, 1652, 1612, 1468, 1073 cmꢁ1; H NMR (CDCl3/TMS,
300.1 MHz): d 3.85 (s, 3H), 4.34 (d, J¼8.9 Hz, 1H), 4.62 (d,
J¼8.9 Hz, 1H), 4.84 (d, J¼15.4 Hz, 1H), 4.94 (d,
J¼15.4 Hz, 1H), 6.11 (s, 1H), 6.70 (d, J¼8.2 Hz, 1H),
7.28e7.41 (m, 7H); 13C NMR (CDCl3/TMS, 75.3 MHz):
d 44.3, 53.1, 63.6, 72.88, 105.4, 111.2, 116.4, 126.8, 127.4
(2C), 128.2 (2C), 129.1 (2C), 132.2, 135.1, 141.1, 158.3,
176.6, 178.4; HRMS calcd for C20H16BrNO4: 413.0263;
found: 413.0263.
300.1 MHz): d 1.30 (t, J¼7.1 Hz, 3H), 3.77 (q, J¼7.1 Hz,
2H), 4.31 (d, J¼8.8 Hz, 1H), 4.56 (d, J¼8.8 Hz, 1H), 6.13
(s, 1H), 6.92 (d, J¼7.8 Hz, 1H), 7.12 (t, J¼7.5 Hz, 1H), 7.29
(d, J¼6.8 Hz, 1H), 7.35 (t, J¼7.7 Hz, 1H); 13C NMR
(CDCl3/TMS, 75.3 MHz): d 12.7, 35.1, 53.0, 63.3, 73.1,
105.8, 108.8, 123.6 (2C), 129.3, 131.8, 142.1, 157.9, 167.1,
176.1; HRMS calcd for C15H15NO4: 273.1001; found:
273.1003.
4.5.10. Compound 31a
Rf (20% EtOAcehexanes) 0.36; IR (CH2Cl2): nmax 1752,
4.5.5. Compound 28a
Rf (20% EtOAcehexanes) 0.34. IR (CH2Cl2): nmax 2146,
1
1714, 1668, 1611, 1471, 1047 cmꢁ1; H NMR (CDCl3/TMS,
1747, 1716, 1666, 1613, 1489, 1051 cmꢁ1
;
1H NMR
300.1 MHz): d 3.68 (s, 3H), 4.18 (dd, J¼5.2, 16.6 Hz, 1H),

P. Shanmugam, V. Vaithiyanathan / Tetrahedron 64 (2008) 3322e3330
3329
4.38 (d, J¼8.8 Hz, 1H), 4.54e4.62 (m, 2H), 5.22e5.28 (m,
2H), 5.79e5.85 (m, 1H), 6.84 (d, J¼7.8 Hz, 1H), 7.08 (t,
J¼7.5 Hz, 1H), 7.25e7.31 (m, 3H); 13C NMR (CDCl3/TMS,
75.3 MHz): d 42.6, 52.7, 62.6, 74.0, 106.3, 109.1, 117.3,
122.8, 123.3, 128.8, 130.8, 130.9, 142.4, 158.5, 170.7,
174.8; HRMS calcd for C16H15NO4: 285.1001; found:
285.0992.
13C NMR (CDCl3/TMS, 75.3 MHz): d 26.8, 29.8, 53.2, 61.8,
73.2, 77.9, 106.4, 107.7, 123.5, 123.8, 129.5, 131.4, 143.2,
154.3, 166.5, 176.1.
4.6. Spectral data for 3-spiro dihydrofuran compounds
4.6.1. Compound 4c
Rf (20% EtOAcehexanes) 0.47; IR (CH2Cl2): nmax 1714,
1615, 1492, 1471 cmꢁ1
;
1H NMR (CDCl3/TMS,
4.5.11. Compound 31b
Rf (20% EtOAcehexanes) 0.29; IR (CH2Cl2): nmax 1756,
300.1 MHz): d 3.27 (s, 3H), 3.53 (s, 3H), 4.64 (d, J¼9.5 Hz,
1H), 4.90 (d, J¼9.5 Hz, 1H), 6.86 (d, J¼7.7 Hz, 1H), 7.08
(t, J¼7.5 Hz, 1H), 7.21 (d, J¼7.2 Hz, 1H), 7.30 (t,
J¼7.7 Hz, 1H), 7.58 (s, 1H); 13C NMR (CDCl3/TMS,
75.3 MHz): d 26.6, 51.0, 56.7, 85.2, 108.0, 112.7, 113.1,
122.9, 129.0, 131.4, 143.4, 159.4, 162.9, 176.6; HRMS calcd
for C14H13NO4: 259.0845; found: 259.0842.
1
1702, 1659, 1606, 1464, 1071 cmꢁ1; H NMR (CDCl3/TMS,
300.1 MHz): d 3.85 (s, 3H), 4.32e4.38 (m, 3H), 4.58 (d,
J¼9.0 Hz, 1H), 5.26e5.29 (m, 2H), 5.85 (m, 1H), 6.15 (s,
1H), 6.90 (d, J¼7.8 Hz, 1H), 7.13 (t, J¼7.5 Hz, 1H), 7.25e
7.35 (m, 2H); 13C NMR (CDCl3/TMS, 75.3 MHz): d 43.2,
52.8, 62.6, 74.0, 106.2, 109.2, 117.4, 122.8, 123.4, 129.3,
131.3, 131.7, 142.4, 158.6, 167.87, 175.7; HRMS calcd for
C16H15NO4: 285.1001; found: 285.0993.
4.6.2. Compound 28c
Rf (20% EtOAcehexanes) 0.48; IR (CH2Cl2): nmax 2186,
1715, 1615, 1486 cmꢁ1
;
1H NMR (CDCl3/TMS,
4.5.12. Compound 32a
Rf (20% EtOAcehexanes) 0.37; IR (CH2Cl2): nmax 1756,
300.1 MHz): d 2.27 (t, J¼2.5 Hz, 1H), 3.51 (s, 3H), 4.51
(dd, J¼17.6, 2.5 Hz, 1H), 4.62 (dd, J¼17.6, 2.5 Hz, 1H),
4.80 (d, J¼9.6 Hz, 1H), 4.91 (d, J¼9.6 Hz, 1H), 7.07e7.26
(m, 3H), 7.32 (t, J¼7.7 Hz, 1H), 7.59 (s, 1H); HRMS calcd
for C16H13NO4: 283.0845; found: 283.0838.
1
1702, 1659, 1606, 1464, 1071 cmꢁ1; H NMR (CDCl3/TMS,
300.1 MHz): d 3.68 (s, 3H), 4.04 (s, 3H), 4.36 (d, J¼8.9 Hz,
1H), 4.63 (d, J¼8.9 Hz, 1H), 7.23e7.40 (m, 4H), 7.93 (t,
J¼8.4 Hz, 1H); 13C NMR (CDCl3/TMS, 75.3 MHz): d 52.8,
59.3, 67.8, 74.0, 105.7, 108.6, 122.1, 123.5, 129.2, 132.4,
143.3, 158.5, 167.4, 174.8, 175.7; HRMS calcd for
C15H13NO6: 303.0743; found: 303.0732.
4.6.3. Compound 30c
Rf (20% EtOAcehexanes) 0.48; IR (CH2Cl2): nmax 1717,
1621, 1485 cmꢁ1
;
1H NMR (CDCl3/TMS, 300.1 MHz):
4.5.13. Compound 32b
Rf (20% EtOAcehexanes) 0.27; IR (CH2Cl2): nmax 1756,
d 3.53 (s, 3H), 4.66 (d, J¼9.6 Hz, 1H), 4.77 (d, J¼15.8 Hz,
1H), 4.95 (d, J¼9.6 Hz, 1H), 5.11 (d, J¼15.8 Hz, 1H), 6.57
(d, J¼8.2 Hz, 1H), 7.27e7.35 (m, 7H), 7.62 (s, 1H); 13C
NMR (CDCl3/TMS, 75.3 MHz): d 44.5, 51.4, 57.0, 82.3,
110.8, 112.4, 115.8, 126.5, 127.3 (2C), 127.8, 128.8 (2C),
131.9, 133.2, 135.0, 141.6, 160.3, 163.0, 176.8; HRMS calcd
for C20H16BrNO4: 413.0263; found: 413.0254.
1
1702, 1659, 1606, 1464, 1071 cmꢁ1; H NMR (CDCl3/TMS,
300.1 MHz): d 3.68 (s, 3H), 4.13 (s, 3H), 4.36 (d, J¼8.9 Hz,
1H), 4.61 (d, J¼8.9 Hz, 1H), 6.19 (s, 1H), 6.89 (d,
J¼7.7 Hz, 1H), 7.07e7.42 (m, 3H), 7.92 (t, J¼8.3 Hz, 1H);
13C NMR (CDCl3/TMS, 75.3 MHz): d 53.2, 58.5, 66.9, 73.5,
105.6, 109.7, 122.5, 124.3, 129.3, 132.3, 143.6, 158.5,
168.4, 174.4, 175.8; HRMS calcd for C15H13NO6: 303.0743;
found: 303.0734.
Acknowledgements
The authors thank Prof. Dr. T.K. Chandrashekar, Director,
for providing infrastructure facilities. Financial support (SR/
S1/OC-38/2005) from the DST (New Delhi) is gratefully ac-
knowledged. V.V. thanks CSIR (New Delhi) for the award of
a Senior Research Fellowship. Thanks are due to Mrs. Viji
and Mrs. Soumini Mathew for providing HRMS and NMR
data, respectively.
4.5.14. Compound 33a
Rf (20% EtOAcehexanes) 0.36; IR (CH2Cl2): nmax 2120,
1747, 1715, 1668, 1048 cmꢁ1
;
1H NMR (CDCl3/TMS,
300.1 MHz): d 2.42 (t, J¼2.3 Hz, 1H), 3.14 (s, 3H), 4.24e
4.27 (m, 3H), 4.50 (d, J¼8.9 Hz, 1H), 6.75 (d, J¼7.8 Hz,
1H), 6.97 (t, J¼7.5 Hz, 1H), 7.13 (d, J¼7.3 Hz, 1H), 7.21 (t,
J¼7.6 Hz, 1H), 7.35 (s, 1H); 13C NMR (CDCl3/TMS,
75.3 MHz): d 26.9, 53.0, 61.9, 74.1, 76.2, 78.1, 108.5, 108.6,
123.0, 123.6, 129.2, 130.79, 143.6, 155.4, 170.5, 175.2;
HRMS calcd for C16H13NO4: 283.0845; found: 283.0843.
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