A facile and efficient synthesis of highly functionalised 3,3′-dispiropyrrolidine- and 3,3′-dispiropyrrolizidine bisoxindoles via [3+2] cycloaddition

Article abstract of DOI:10.1016/j.tetlet.2008.02.104

The [3+2] cycloaddition reaction of azomethine ylides with isomerised Morita-Baylis-Hillman adducts, both dipoles and dipolarophiles are derived from isatin, afforded highly functionalised 3,3′-dispiro pyrrolidine- and 3,3′-dispiropyrrolizidine bisoxindol

Full text of DOI:10.1016/j.tetlet.2008.02.104

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2611–2615
A facile and efficient synthesis of highly functionalised
0
0
3
,3 -dispiropyrrolidine- and 3,3 -dispiropyrrolizidine
bisoxindoles via [3+2] cycloaddition
*
Ponnusamy Shanmugam , Baby Viswambharan, Kodirajan Selvakumar,
Suchithra Madhavan
Chemical Sciences and Technology Division, National Institute for Interdisciplinary Science and Technology (NIIST),
Thiruvananthapuram 695 019, Kerala, India
Received 27 November 2007; revised 14 February 2008; accepted 16 February 2008
Available online 10 March 2008
Abstract
The [3+2] cycloaddition reaction of azomethine ylides with isomerised Morita–Baylis–Hillman adducts, both dipoles and dipolaro-
0
0
philes are derived from isatin, afforded highly functionalised 3,3 -dispiro pyrrolidine- and 3,3 -dispiropyrrolizidine bisoxindoles in high
yields.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Isatin; Azomethine ylides; Morita–Baylis–Hillman adduct; Dispiropyrrolidine oxindoles; Bispiropyrrolizidine oxindoles; Cycloaddition
1
. Introduction
O
Me
NH
H
O
H
0
N
3
-Spiro oxindoles and their derivatives have become
O
N
MeO
important synthetic targets as these structural frameworks
form the core units of many naturally occurring molecules
that possess significant biological activities (Fig. 1).
O
H
H
O
1
,2
N
O
N
Me
These derivatives have served as potential synthetic inter-
mediates for the total synthesis of alkaloids, drug interme-
diates and clinical pharmaceuticals. Hence, a number of
Alstonisine
Spirotryprostatin B
NH
1
MeO
Me
N
Me
synthetic routes have been developed for the preparation
Me
O
HO
3
–10
of these structural frameworks.
1,3-Dipolar cycloaddi-
N
O
N
H
tion reactions constitute one of the most fundamental reac-
tions for the stereoselective construction of five-membered
H
Horsfiline
Elacomine
1
1,12
heterocyclic compounds.
Azomethine ylides are a class
Fig. 1. Spirooxindole alkaloid natural products.
of powerful reagents used in [1,3]-dipolar cycloaddition
reactions which in general afford a range of pharmacologi-
cally important heterocyclic compounds.
1
3–20
Dispiro derivatives of heterocyclic systems are impor-
tant synthetic targets and only a few reports are
2
1,22
known.
The Morita–Baylis–Hillman (MBH) adducts
and their derivatives play an important role in synthetic
organic chemistry as they serve as synthons for the con-
struction of many complex molecular architectures. The
*
Corresponding author. Tel.: +91 471 2515275; fax: +91 471 2491712.
E-mail address: shanmu196@rediffmail.com (P. Shanmugam).
2
3
0
040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.104

2612
P. Shanmugam et al. / Tetrahedron Letters 49 (2008) 2611–2615
synthetic versatility of isatin and its derivatives has led to
the extensive use of this compound in synthetic organic
furnished a library of highly functionalised dispiropyrrol-
idine oxindole derivatives in excellent yield in a single step.
The results of the study are the content of this Letter.
As shown in Scheme 1, the preliminary experiment was
carried out between the bromo-isomerised MBH adduct 1
of N-methylisatin and azomethine ylide C (generated
in situ from sarcosine and isatin) in refluxing toluene using
montmorillonite K10 clay as catalyst. The reaction affor-
2
4
and natural product chemistry.
We have been exploring the novel synthetic applications
2
5–28
of MBH adducts.
Recently, we focussed our attention
to MBH adducts derived from isatin for the synthesis of
2
9–31
novel heterocycles.
Our recent report reveals the syn-
thesis of 3-spiropyrrolizidine and 3-spiropyrrolidine oxin-
doles from MBH-adducts of isatin and heteroaldehydes
0
ded highly substituted 3,3 -dispiropyrrolidine bisoxindole
7 in 40% yield.
3
1
via [3+2] cycloaddition of azomethine ylides. However,
there is no report on the [3+2] cycloaddition reaction of
bromo- and methoxy isomerised MBH adducts of isatin
which in general would afford structurally different dispiro
bisoxindoles derivatives in a stereoselective manner. In this
context, we were interested in exploring the reactivity pat-
tern of isomerised MBH adducts of isatin with azomethine
ylides (C or E) generated in situ from isatin and sarcosine/
proline by a thermal decarboxylative route as per the retro-
synthetic analysis shown in Figure 2. The reaction
The bromo isomerised MBH adducts 1 and 1a were
prepared from the MBH adduct of N-methylisatin by
treatment with aqueous HBr in the presence of silica gel
(100–200 mesh) and under solvent free microwave irradia-
tion. The E-isomer 1a was converted to the Z-isomer 1 by
increasing microwave irradiation time (ca. 10min). The
geometries of isomers 1a (E) and 1 (Z) were established
1
based on H NMR chemical shift studies. Thus, the
methylene proton of the E-isomer was observed at d 5.23
R1
R1
N
N
N
N
O
O
Z
Z
R2
Z
R2
N
H
O
O
R2
N
C
H E
N
N
O
O
N
R
O
[
3+2]
[3+2]
N
1
N
H
H
B
Dispiropyrrolidine oxindole A
Dispiropyrrolizidine oxindole F
Isomerization
HO
O
+
O
Z
MBH reaction
Z
O
N
R
N
1
1
R
D
Fig. 2. Retrosynthetic analysis of dispiro bisoxindoles A and F.
mw, 70% Power
Level, 5 min.
Br
HO
N
MeO C
2
Br
CO Me
(E)
N
2
(
Z)
CO Me
2
aq. HBr/neat,mw, SiO2,
O
+
7
0% Power Level, 5 min.
O
O
N
1:1
E isomer, 1a
Z isomer, 1
C, Montmorillonite K10
Methanol, reflux, 2 h
N
O CO Me
2
Br
N
O
N
H
7
Scheme 1. Optimization of the reaction conditions.

P. Shanmugam et al. / Tetrahedron Letters 49 (2008) 2611–2615
2613
while the Z-isomer was observed at d 4.49. The major iso-
mer 1 was purified using column chromatography on silica
gel and used for the cycloaddition study.
doles can be modified further. However, the [3+2] cyclo-
addition of adducts 1–6 with azomethine ylide E, failed
to provide the expected products probably due to the steric
effect of the bulky bromine atom at the allylic position. All
the new compounds were thoroughly characterised by the
Optimization of the reaction was carried out in different
solvents (methanol, toluene, acetonitrile and dioxane), with
and without montmorillonite K10 clay. When toluene was
used as the solvent, we isolated a 40% yield of the desired
product 7. A remarkable increase in the yield (75%) of
compound 7 was observed with methanol as the solvent
and freshly activated 100% w/w montmorillonite K10 clay
catalyst under reflux for 2 h. The reactions in acetonitrile
and dioxane provided none of the desired product.
1
13
spectroscopic methods (IR, H, C NMR and FAB-mass
spectra). The results are summarised in Table 1.
The excellent results obtained from the bromo isomer-
ised MBH adducts 1–6, prompted us to explore the [3+2]
cycloaddition reactivity pattern of the methoxy isomerised
MBH adducts 13–16 of isatin with azomethine ylides C and
E. The MBH adducts 13–16 were prepared from the corres-
ponding MBH adducts of isatin in refluxing acetonitrile
with a small excess of trimethyl orthoformate and mont-
morillonite K10 clay as the catalyst for 30 min. The reac-
tions furnished only Z isomers 13–16 in 75–80% yields.
The geometry of the isomers was assigned based on our
The structure of compound 7 was determined based on
the spectroscopic studies. Thus, the proton NMR spectrum
of compound 7 showed two doublets centred at d 3.54 and
d 3.72 with coupling constants J = 9 Hz indicating the
presence of two pyrrolidine ring protons. Two doublets
centred at d 4.44 and d 4.88 indicated two mutually coupled
protons (J = 9 Hz) at the carbon attached to bromine. A
singlet at d 7.64 was due to the free hydrogen attached to
3
3
recent report. All the cycloaddition reactions of com-
pounds 13–16 with dipole C under optimised conditions
afforded the corresponding dispiropyrrolidine bisoxindole
derivatives 17–20 in excellent yields (Table 2, entries 1–4).
However, adducts 13 and 14 on reaction with ylide E affor-
ded only moderate yields of the dispiropyrrolizidine deriv-
atives 21 and 22, respectively (Table 2, entries 5 and 6).
It should be noted that, in contrast to our previous
1
3
the nitrogen of the oxindole moiety. In the C NMR
spectrum, two signals at d 65.6 and d 79.3 indicated the
presence of two spiro carbons and signals at d 175.2,
1
77.3 and 180.1 correspond to the carbonyl groups of
the oxindole moiety and the ester group. The endo/exo
selectivity of product 7 was assigned based on the literature
3
1
report, the reactions of methoxy isomerised MBH-
adducts of isatin with dipole E derived from proline and
isatin showed less reactivity towards the isomerised MBH
adducts, possibly due to the steric effects of the two bulky
functional groups present on the isomerised adducts which
hinders the approach of the dipole. It should be noted that
the cycloaddition reaction reported herein proceeds to the
products with the formation of two quaternary carbons
(two spiro centres) in a one-pot reaction. The compounds
reported herein may serve as synthons for alkaloid natural
product synthesis.
3
1,32
analogy.
To show the general nature of the reaction, bromo isom-
erised MBH adducts of isatins 2–6 bearing different substit-
uents (ester, sulfone, nitrile) and various saturated,
unsaturated, aromatic substituents on the isatin nitrogen
(
methyl, benzyl, propargyl and allyl) were reacted with azo-
methine ylide C, under optimised conditions (Table 1,
entries 1–6). The reaction afforded highly functionalised
dispiro bisoxindole compounds 7–12 in excellent yields
(
75–85%). The functional groups on the dispiro bisoxin-
Table 1
Table 2
Synthesis of dispiropyrrolidine bisoxindoles 7–12 from E-bromo isomer-
ised MBH adducts 1–6 and dipole C
Synthesis of dispiropyrrolidine and dispiropyrrolizidine bisoxindoles from
MBH adducts 13–16
R
N
R
N
R
N
Br
Z
O
O
Z
N
MeO
Z
Z
O
a
Z
Br
a
OMe
+
C/E
OMe +
O +
O
O
N
O
N
O
N
R
N
H
N
O
N
R
N
H
17-20
N
H
21-22
N
H
1-6
C
1
3-16
7
- 12
Entry
Z
R
Product
Yield (%)
Entry
Z
R
Dipole C/E
Product
Yield (%)
1
2
3
4
5
6
CO
CO
CO
CO
2
2
2
2
Me
Me
Me
Me
Methyl
Benzyl
Allyl
Propargyl
Methyl
Methyl
7
8
75
85
82
80
75
78
1
2
3
4
5
6
CO
CO
CO
2
2
2
Me
Me
Me
Methyl
Allyl
Benzyl
Methyl
Methyl
Allyl
C
C
C
C
E
E
17
18
19
20
21
22
75
85
80
82
45
9
10
11
12
CN
SO
2
Ph
CO
CO
2
Me
Me
b
CN
2
40
a
Reagents and condition: (a) Montmorillonite K10 clay, methanol, reflux,
h.
Reagents and condition: Montmorillonite K 10, methanol, reflux, 2 h.
b
2
12 h.

2614
P. Shanmugam et al. / Tetrahedron Letters 49 (2008) 2611–2615
2
. Conclusion
4.33 (d, 1H, J = 9 Hz), 4.65 (d, 1H, J = 9 Hz), 6.48–6.59
m, 2H), 6.78–6.79 (m, 1H), 6.93–6.94 (m, 1H), 7.09–7.13
(m, 2H), 7.23–7.28 (m, 1H), 7.49 (d, 1H, J = 9 Hz), 8.11
(
In conclusion, we have synthesised a library of pharma-
1
3
cologically important highly functionalised dispiropyrrol-
idine and dispiropyrrolizidine oxindoles starting from
E-bromo and Z-methoxy isomerised MBH adducts of isatin
with azomethine ylides using eco-friendly montmorillonite
K10 clay as a catalyst. Further studies using this reagent
are underway in this laboratory.
(s, 1H); C NMR (CDCl /TMS, 75.3 MHz): d 25.8, 34.6,
3
51.9, 58.0, 59.1, 60.3, 63.5, 78.5, 107.5, 107.0, 109.2, 121.5,
121.8, 124.1, 124.8, 127.2, 128.1, 129.6, 130.5, 141.8,
143.3, 171.5, 172.6, 177.1; FAB mass: calcd for
+
C H N O is 435.47; found: M = 435.35.
2
4
25
3
5
3
.1.4. Compound 18
FTIR (CH Cl ): m : 753, 1222, 1359, 1459, 1469, 1614,
3
. General experimental procedure for cycloaddition
2
2
max
ꢀ1
1
1723, 2951, 3272 cm
;
H
NMR (CDCl /TMS,
3
A mixture of isomerised Morita–Baylis–Hillman adduct
300.1 MHz): d 2.24 (s, 3H), 3.33 (s, 6H), 3.46 (d, 1H,
J = 9 Hz), 4.12 (d, 1H, J = 9 Hz), 4.28 (d, 1H, J = 9 Hz),
4.66 (d, 1H, J = 9 Hz), 4.91–4.95 (m, 1H), 5.35–5.42 (m,
1H), 6.51 (d, 1H, J = 6 Hz), 6.59 (d, 1H, J = 6 Hz), 6.78
(t, 1H, J = 6 Hz), 6.92 (t, 1H, J = 6 Hz), 7.05–7.13 (m,
2H), 7.22 (d, 1H, J = 6 Hz), 7.29 (d, 1H, J = 6 Hz), 7.50
of isatin (100 mg, 0.404 mmol), L-(ꢀ) proline or sarcosine
1.2 equiv), isatin (1.2 equiv) and montmorillonite K-10
clay (100% w/w) in methanol (1 mL) was refluxed for
–12 h. After completion of the reaction (TLC), the crude
mixture was filtered through a pad of Celite and then puri-
fied by silica gel column chromatography to afford the
desired products (40–85%).
(
2
1
3
(d, 1H, J = 6 Hz), 8.01 (s, 1H); C NMR(CDCl /TMS,
3
75.3 MHz): d 35.2, 47.7, 51.4, 58.1, 58.4, 59.2, 60.3, 63.4,
7
6.5, 78.4, 108.1, 109.2, 116.8, 121.6, 122.1, 124.3, 125.1,
127.2, 128.5, 129.4, 130.7, 141.9, 142.4, 171.5, 172.2,
77.3; FAB mass: calcd for C H N O is 461.51; found:
3
3
1
.1. Spectral data for selected compounds
1
2
6
27
3
5
+
.1.1. Compound 7
FTIR (CH Cl ): m : 1225, 1355, 1480, 1470, 1614,
M = 461.89.
2
2
max
ꢀ1
1
731, 1735, 2124, 2928, 3210 cm
;
H NMR (CDCl3/
Acknowledgements
TMS, 300.1 MHz): d 2.2 (s, 3H), 2.97 (s, 3H), 3.54 (d,
H, J = 9 Hz), 3.60 (s, 3H), 3.73 (d, 1H, J = 9 Hz), 4.45
d, 1H, J = 9 Hz), 4.89 (d, 1H, J = 9 Hz), 6.53–6.60 (m,
1
(
P.S. thanks Professor Dr. T. K. Chandrashekar,
Director-NIIST, for providing infrastructure facilities.
Financial support from the DST (New Delhi) vide sanction
No.SR/S1/OC-38/2005 is acknowledged. B.V. and K.S.
thank CSIR and UGC (New Delhi) for the award of Senior
and Junior Research Fellowships, respectively. P.S. thanks
the reviewer of this manuscript for constructive sugges-
tions. Thanks are due to Mrs. Viji and Mrs. Saumini
Mathew for providing Mass and NMR spectra.
2
1
H), 6.92–6.95 (m, 2H), 7.10–7.12 (m, 1H), 7.22–7.38 (m,
H), 7.38–7.47 (m, 2H), 7.64 (s, 1H); C NMR (CDCl3/
1
3
TMS, 75.3 MHz): d 26.7, 35.3, 51.9, 53.7, 59.5, 65.6, 79.3,
1
1
07.8, 108.3, 110.2, 122.4, 122.8, 124.1, 126.6, 128.5,
31.2, 133.3, 141.4, 144.8, 175.2, 177.3, 180.1; FAB mass:
+
calcd for C H BrN O is 484.34; found: M = 484.29
2
3
22
3
4
and M+2 = 486.21.
3
.1.2. Compound 10
FTIR (CH Cl ): mmax: 750, 1470, 1488, 1614, 1731, 1730,
References and notes
2
2
1
2
3
1
4
6
924,
3287;
H
NMR
(CDCl /DMSO-d /TMS,
3 6
1
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.39 (d, 2H, J = 9.8 Hz), 4.97 (d, 1H, J = 8.6 Hz), 6.51–
.53 (m, 2H), 6.80–6.86 (m, 2H), 7.02–7.06 (m, 2H), 7.25
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3
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3
7
7
1
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.1.3. Compound 17
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ꢀ1
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3
1
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