A novel MgI2 mediated unusual dimerization-spirocyclopropanation of bromo isomerised Morita-Baylis-Hillman adduct of isatin: A facile synthesis of 3-spirocyclopropane-2-oxindole derivatives

Article abstract of DOI:10.1016/j.tetlet.2011.05.009

A novel magnesium iodide mediated unusual dimerization- spirocyclopropanation of bromo isomerised Morita-Baylis-Hillman adducts of isatin afforded highly functionalized 3-spirocyclopropane-2-oxindole derivatives as regioisomers in good combined yield. It

Full text of DOI:10.1016/j.tetlet.2011.05.009

Tetrahedron Letters 52 (2011) 3610–3613
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A novel MgI2 mediated unusual dimerization–spirocyclopropanation
of bromo isomerised Morita–Baylis–Hillman adduct of isatin:
a facile synthesis of 3-spirocyclopropane-2-oxindole derivatives
Kandapalam Arun Prasath Lingam a, Asit Baran Mandal b, Ponnusamy Shanmugam a,
⇑
a Organic Chemistry Division, Central Leather Research Institute, Council of Scientific and Industrial Research (CSIR), Adyar, Chennai 600 020, India
b Chemical Laboratory, Central Leather Research Institute, Council of Scientific and Industrial Research (CSIR), Adyar, Chennai 600 020, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel magnesium iodide mediated unusual dimerization–spirocyclopropanation of bromo isomerised
Morita–Baylis–Hillman adducts of isatin afforded highly functionalized 3-spirocyclopropane-2-oxindole
derivatives as regioisomers in good combined yield. It has been observed that the regioselectivity is
dependent on the nature of electron withdrawing group at the activated position. A plausible mechanism
involving organomagnesium reagent has been proposed.
Received 6 April 2011
Revised 2 May 2011
Accepted 3 May 2011
Available online 11 May 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Isatin
Magnesium iodide
Morita–Baylis–Hillman adduct
Spirocyclopropane-2-oxindole
Dimerization–spirocyclopropanation
Construction of highly strained three membered carbocyclic
frameworks is a challenging task for synthetic chemists1 and it
has been used as a starting material for the synthesis of number
alkaloid natural products.2 Ring opening of the cyclopropanes in
a regio- and stereo-selective manner often provide interesting
and stereoselective products thereby gaining importance of both
theoretical and synthetic point of view.3 In view of their impor-
tance as synthons, numerous synthetic methods and synthetic
manipulation have been developed.4 Ring-expansion reaction of
spiro[cyclopropan-1,30-oxindoles]5 with a range of imines afforded
spiro[pyrrolidin-3,30-oxindoles] which are known to have iontrop-
ic6 and herbicidal7 and HIV-1 inhibiting properties.8 Further, cyclo-
propanes also provide access to useful synthetic intermediates
with reactivity that can be tuned by conjugation, substitution with
electron-withdrawing and/or donating groups.9 Magnesium iodide
(MgI2) as a powerful reagent has been used for the synthesis of
Baylis–Hillman adducts,10 cyclopropane ring opening reaction
and a number of synthetic transformations.11 In situ generation
of Grignard reagent by magnesium–halogen exchange reaction
has been used for efficient synthetic purposes and is a useful meth-
od for carbon–carbon bond formation reaction.12 The synthetic
utility of the Morita–Baylis–Hillman (MBH) reaction lies in the
dense functionality that is generated, providing handles for further
manipulation.13 As part of our research interest in the novel
synthetic applications of MBH adducts,14 recently we have re-
ported a simple method for the synthesis of spirocyclopropane-2-
oxindoles via reductive cyclization protocol.14d Further investiga-
tion on the reaction of bromo isomerised MBH adduct of isatin
with magnesium iodide resulted in an unusual dimerization fol-
lowed by spirocyclopropanation, thus providing allylic 3-spirocy-
clopropane-2-oxindole derivatives as
a separable mixture of
diastereomers and the details of the work is presented in this
manuscript.
According to a retrosynthetic analysis shown in Scheme 1, the
dimerized spirocyclopropane oxindole C can be synthesised from
the bromo isomerised MBH adduct B with MgI2, via Michael type
addition of in situ generated organomagnesium reagent to another
molecule of bromo isomerised MBH adduct followed by spirocycli-
zation. The MBH adduct A and bromo derivative B can be prepared
as per the literature.15
Our initial idea is to generate the organo magnesium reagent12a
using magnesium iodide with E- and Z-bromo isomerised MBH
Z
Z
Br
Z
HO
Z
O
O
N
R
N
R
O
N
R
O
N
R
A
C
B
⇑
Corresponding author. Tel.: +91 471 2515275; fax: +91 471 2491712.
E-mail address: shanmu196@rediffmail.com (P. Shanmugam).
Scheme 1. Retrosynthetic analysis of 3-spirocyclopropane-2-oxindoles.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.009

K. A. P. Lingam et al. / Tetrahedron Letters 52 (2011) 3610–3613
3611
adduct of isatin 3a/3a0 and to trap it with methyl acrylate to syn-
CO2Me
Br
(Z)
thesise 3-spirocyclopentane-2-oxindole derivative 4 via cycloaddi-
tion reaction. However, the reaction did not afford any expected
product 4, instead it furnished the unexpected dimerized 3-spiro-
cyclopropane-2-oxindoles 5a and 5b as a mixture of separable dia-
stereomers in good combined yield. The reaction is shown in
Scheme 2.
CO2Me
CO2Me
O
N
3a
Optimised
condition
+
Br
CO2Me
O
O
+
N
O
N
N
O
N
(E)
5a
5b
O
N
3a'
The structure of the new compounds 5a and 5b were estab-
lished by the analysis of spectroscopic data such as FT-IR, 1H, 13C
NMR, DEPT 135, FAB-mass and single crystal X-ray data. Thus,
the observed coupling constants of methylene protons (d = 2.44
and 2.07, J = 5.35 Hz) and allylic methylene protons (d = 4.51 and
4.10, J = 16.05 Hz) of the spirocyclopropane are sufficient evidence
to assign the structure of compound 5a. Besides, the dimerization
of the product was established from the 1H NMR spectrum as it
showed two ester methoxy proton at d = 3.94, d = 3.56 and two
N-methyl protons at d = 3.29, d = 3.21 and was further supported
by FAB mass spectrum. Final proof of the structure and relative
configuration has been arrived from single crystal XRD data16
shown in Figure 1.
Interestingly, when the mixture of E and Z isomers of bromo
isomerised MBH derivatives 3a and 3a0 in dry THF with 1 equiv
of MgI2 afforded functionalized 3-spirocylopropyl-2-indolones 5a
and 5b as a diastereomeric mixture in 32% combined yield in the
product ratio of 1:1.2 as evidenced by 1H NMR (Scheme 3).
Remarkably, the reactions of individual E and Z isomers of bromo
isomerised MBH derivatives under conditions described above
have also afforded functionalized 3-spirocylopropyl-2-indolones
5a and 5b almost in the same yield and ratio indicating that both
the isomers undergo product formation through a common inter-
mediate. Hence, mixture of isomers was used for the rest of
experiments.
Scheme 3. Synthesis of spirocyclopropane derivatives of oxindole 5a and 5b from E
and Z isomers 3a and 3a0.
Table 1
Optimization of synthesis of 3-spirocyclopropane-2-oxindole derivatives 5a and 5b
Entry
Reagent
Equivalents
reagent
Time (h)
Combined
yield 5a/5ba (%)
1
2
3
4
5
6
7
8
Mg turnings
Mg/cat. I2
Mg/cat. I2
MgI2
MgI2
MgI2
2
2
1
0.5
1
1.5
0.2
2
6
2.5
3
2
3
2
4
2
—
22
15
10
35
52
Trace
32
MgI2
MgI2
a
Isolated yield after column chromatography.
Z
Z
Br
MgBr
MgI2
dry THF
O
O
O
N
N
3a/3a'
D
Z= CO2Me
Br
In order to optimise the reaction condition, experiments with
change in the number of equivalents of MgI2, use of magne-
sium turnings and varied reaction time have been carried out
(Table 1). Thus, an experiment with magnesium turnings under re-
flux condition did not provide the desired 3-spiroyclopropane-2-
oxindole (Table 1, entry 1). Experiment with Mg-turnings and a
MgBr
Z
N
Z
O
N
Path B
Path A
Br
Br
OMgBr
N
OMgBr
N
Z
Z
Z
MeO2C
MeO2C
CO2Me
MeO2C
Br
MgI2, dry THF,
Z
CO2Me
O
°
0
C to rt
O
O
N
O
N
O
O
N
4
N
E-I
N
E-II
N
CO2Me
5a and 5b
1:1.2 diastereomers
3a/3a'
Not formed
Z
via cycloaddition
Z
Z
Z
Scheme 2. Synthesis of 3-spirocyclopropane derivatives 5a and 5b.
O
O
N
N
O
O
N
N
1:1.2
5a
5b
Scheme 4. Proposed mechanism for the formation of 5a and 5b.
NC
NC
N
Br
CN
O
MgI2, Ar
O
O
dryTHF, RT
O
N
N
N
3e/3e'
9a
Single diasteromer
9b
E or Z isomer
Scheme 5. Synthesis of 9a and 9b.
catalytic amount of iodine furnished the expected spirocyclopro-
pane in 30% yield (Table 1, entry 2). When the number of equiva-
lents of MgI2 gradually increased (up to 1.5 equiv), yield of the
product improved and the reaction time considerably reduced.
However, excess use of the MgI2 in the reaction resulted in the
decomposition of the products. Thus, an optimum yield (52%)
Figure 1. ORTEP diagram of compound 5a.

3612
K. A. P. Lingam et al. / Tetrahedron Letters 52 (2011) 3610–3613
was obtained with 1.5 equiv of MgI2, dry THF as solvent at room
temperature under argon atmosphere.
Based on the product formation, a plausible mechanism has
been proposed as outlined in Scheme 4. Accordingly, in situ gener-
ated common reactive intermediate alkyl magnesium derivative D
obtained from reaction of both E- and Z-bromo isomerised MBH
adduct with MgI2 is believed to undergo a Michael type conjugate
addition with another molecule of bromo isomerised MBH deriva-
tive to afford intermediates E-I and E-II. Intermediates E-I and E-II
upon spirocyclization by the elimination of bromide via path A and
Table 2
Synthesis of 3-spirocyclopropane-2-oxindole derivatives 5(a–b)–12(a–b)
Entry
Reactant (E and Z)a
Time (h)
1.5
Products
Ratio
1:1.2
Combined yieldb
MeO2C
Br
e
M
O
CO2Me
CO2Me
C
O
N
1
52
O
O
O
N
N
O
N
N
3a/3a’
5b
5a
MeO2C
Br
2 CO2Me
2
CO2Me
O
N
O
O
2
2
1:1.3
41
N
O
N
N
O
N
6a
6b
3b/3b’
MeO2C
MeO2C
CO2Me
Br
CO2Me
O
N
O
N
O
N
O
3
3.5
1:1
40
N
O
N
3c/3c’
7a
7b
MeO2C
Br
e
e
M
M
O
C
O
CO2Me
C
CO2Me
O
N
4
2.5
1:1.5
40
O
O
N
O
N
N
O
N
Ph
Ph
Ph
Ph
Ph
3d/3d’
8a
8b
NC
Br
NC
N
CN
O
O
O
O
N
5
6
2
1:0.5
1:0.3
40
29
N
N
9b
NC
9a
3e/3e’
NC
N
C
Br
CN
O
N
O
N
O
N
O
3.5
N
Ph
Ph
Ph
Ph
10b
3f/3f’
10a
NC
NC
N
Br
CN
O
C
O
O
N
N
O
N
N
7
1.5
1:0.4
39
3g/3g’
11b
11a
NC
NC
Br
N
CN
C
O
O
N
N
O
O
N
N
8
1
1:0.5
38
12b
3h/3h’
12a
a
E and Z mixture used as a starting material.
Isolated yield after column chromatography.
b

K. A. P. Lingam et al. / Tetrahedron Letters 52 (2011) 3610–3613
3613
Supplementary data
MeO2C
CO2Me
OH
MeO2C
MeO2C
Br
R-CHO
MgI2, Ar
R
Supplementary data (general experimental procedure, com-
plied spectroscopic data of new compounds and scanned copies
of spectra) associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2011.05.009.
dryTHF, RT
O
O
N
O
N
O
N
N
3a / 3a'
Not formed
5a and 5b
R= C6H5, Fc, 2-(N-Me-pyrrole)
Scheme 6. Attempted allylation reaction of 3a/3a0 with aldehydes.
References and notes
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Interestingly, when the nitrile substituted bromo isomerised
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afforded only one diastereoisomeric product 9a along with reduced
product 9b (<10%) as shown in Scheme 5. The reduction product 9b
is formed due to high reactivity of cyano bromo isomerized MBH
adduct during the magnesium metal insertion. It should be noted
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Z mixture of bromo isomerised MBH adduct may be due to a free
rotation of the C–C bond in the intermediate.
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afforded diastereomeric mixture of products whereas the nitrile
derivatives afforded single diastereomer along with reduced prod-
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alkyl magnesium derivative from bromo isomerised MBH adduct
of isatin using MgI2 and dimerization–cyclopropanation. The forma-
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To understand the reactivity pattern, nature of reactive inter-
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envisaged to trap the organomagnesium reagent thus formed ini-
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ferrocenealdehyde to get the corresponding allylated product.17
However, to our dismay, all the reactions provided only the 3-spi-
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allylated product was observed (Scheme 6). The reason for not
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towards dimerization–spirocyclopropanation than the Grignard
addition to the aldehydes.
In conclusion, we have demonstrated a novel MgI2 mediated
short and efficient synthesis of highly functionalised strained 3-
spirocyclopropane-2-oxindole derivatives from E- and Z-bromo
isomerised derivatives of MBH adduct of isatin. A plausible mech-
anism for the formation of diastereomeric 3-spirocyclopropane-2-
oxindole systems has been explained via formation of organomag-
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comparison and evaluation of 1H NMR chemical shifts, coupling
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Acknowledgments
K.A.P.L. thanks the Council of Scientific and Industrial Research
(CSIR), New Delhi, for the award of Junior Research Fellowship
(JRF).