Baylis-Hillman bromides as a source of 1,3-dipoles: Sterically directed synthesis of oxindole-fused spirooxirane and spirodihydrofuran frameworks

Article abstract of DOI:10.1002/chem.201203756

Poles apart: The sterically directed [3+2] cycloaddition reactions of dipoles that were generated from Baylis-Hillman bromides with isatin dipolarophiles provided a facile synthetic route to spirodihydrofuran oxindoles and spiroepoxy oxindoles (see scheme). a)-c) Me₂S, Cs ₂CO₃, DMF, 15-20 °C, N₂, 8 h. EWG: a) CO₂Me (Z), b) CO₂Me, and c) CN (E). Copyright

Full text of DOI:10.1002/chem.201203756

COMMUNICATION
DOI: 10.1002/chem.201203756
Baylis–Hillman Bromides as a Source of 1,3-Dipoles: Sterically Directed
Synthesis of Oxindole-Fused SpiroACTHNUGRTNEUNGoxirane and Spirodihydrofuran
Frameworks
Deevi Basavaiah,* Satpal Singh Badsara, and Bharat Chandra Sahu[a]
The spirooxindole moiety is one of the most important
structural frameworks and is frequently found in many natu-
ral products[1a–i] and clinical pharmaceuticals.[1d,j–l] Therefore,
the development of simple synthetic strategies for obtaining
spirooxindole derivatives has been and continues to be an
attractive area in synthetic and medicinal chemistry.[1f–i,2a–f]
As part of our ongoing research into the Baylis–Hillman
(BH) reaction, herein, we report the interesting sterically di-
rected cycloaddition reactions of the dipoles that are gener-
ated from Baylis–Hillman bromides with isatins as dipolaro-
philes, thus providing a facile strategy for the synthesis of
spiroepoxy oxindoles and spirodihydrofuran oxindoles in a
one-pot operation.
The Baylis–Hillman reaction provides diverse classes of
densely functionalized molecules, typically known as Baylis–
Hillman adducts, through the coupling of activated alkenes
with electrophiles under the influence of a catalyst in an op-
erationally simple atom-economical process.[3] The Baylis–
Hillman adducts and their derivatives (in particular, their
bromides and acetates) have become useful as synthons for
the development of a number of organic-transformation
methodologies that lead to the synthesis of various building
blocks and bioactive compounds.[3,4] These Baylis–Hillman
adducts and their derivatives have also been successfully
employed as dipolarophiles[3c,h] (with benzonitrile oxide,[5a]
azomethine ylides,[5b,c] etc. as dipoles) in [3+2] cycloaddition
reactions and also as a source for generating dipoles (with
methyleneindolinones,[4c] isatylidene malononitriles,[4d] N-
phenylmaleimide,[4a,6a] enones,[4g] diethyl azodicarboxylate
(DEAD)/diisopropyl azodicarboxylate (DIAD),[6b] pro-
(prepared from alkyl acrylates) and nitrile groups (prepared
from acrylonitrile) show remarkable opposite stereochemi-
cal directions in various chemical transformations.[7] This re-
versal has been mostly been attributed to the steric differ-
ence between the (smaller) nitrile and (larger) ester func-
tionalities. To the best of our knowledge, there has been no
systematic study in understanding the stereochemical direc-
tions in the cycloaddition reactions of Baylis–Hillman ad-
ducts (or their derivatives) that contain ester and nitrile
groups. It occurred to us that the dipoles that are generated
from Baylis–Hillman bromides that contain ester and nitrile
groups should, in principle, show different reactivities in
their cycloaddition reactions with isatin derivatives. Thus,
we selected three types of the Baylis–Hillman bromides (1–
3) and various isatin derivatives (4) as reaction partners for
our study (Figure 1).
Figure 1. Reaction partners Baylis–Hillman bromides and isatin deriva-
tives.
First, we investigated the cycloaddition reaction between
Baylis–Hillman bromide methyl-2-(bromomethyl)prop-2-
enoate (1) and 1-methylisatin (4a). In our initial studies, the
reaction between compounds 1 and 4a in the presence of
Me2S and K2CO3 in DMF gave spirodihydrofuran oxindole
5a in 74% yield (Table 1, entry 1). To optimize this reaction,
we tested various conditions (Table 1) and the best results
were obtained when the allyl bromide 1 (3 mmol) was treat-
ed with compound 4a (2 mmol) in DMF (5 mL) at 15–208C
in the presence of Me2S (4 mmol) and Cs2CO3 (4 mmol) for
8 h, thus providing the desired spirodihydrofuran oxindole
5a in 83% yield (Table 1, entry 5). To understand the scope
of this method, we used several N-substituted isatins (4a–g)
in the cycloaddition reaction with compound 1; the resulting
spirodihydrofuran oxindoles 5a–g[8a] were obtained in 78–
86% yield (Table 2).
ACHTUNGTRENNUNG
pargyl sulfones,[4e] etc. as dipolarophiles), thereby producing
a variety of heterocyclic and carbocylic compounds of me-
dicinal importance.[3c,d]
It has been well documented in the literature that Baylis–
Hillman adducts (or their derivatives) that contain ester
[a] Prof. D. Basavaiah, S. S. Badsara, B. C. Sahu
School of Chemistry, University of Hyderabad
Hyderabad-500 046 (India)
Fax : (+91)40-23012460
E-mail: dbsc@uohyd.ernet.in
Supporting information for this article, including experimental details,
Next, we directed our attention to examining the potential
of Baylis–Hillman bromide[9] methyl-(2Z)-2-bromomethyl-3-
phenyl-prop-2-enoate (2a) in the cycloaddition reaction
with 1-methylisatin (4a) under similar conditions.[10]
1
spectroscopic data, H and 13C NMR spectra for compounds 5, 6, 7,
and 8, and X-ray crystallographic data for compounds 5a, 6a, 7a, 6h,
7h, 8d, and 8e, is available on the WWW under http://dx.doi.org/
10.1002/chem.201203756.
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2961

Table 1. Optimization: treatment of methyl-2-(bromomethyl)prop-2-
enoate (1, 3 mmol) with 1-methylisatin (4a, 2 mmol) in the presence of
Me2S (4 mmol) and base (4 mmol) to provide the spirodihydrofuran oxin-
dole 5a.
Table 2. Synthesis of spirodihydrofuran oxindoles 5a–g.[a]
Entry
R1
R2
Isatin
Product[b]
Yield [%][c]
1
2
3
4
5
6
7
H
H
Me
Et
Me
Et
Me
Et
Bn
4a
4b
4c
4d
4e
4 f
4g
5a[d]
5b
5c
5d
5e
5 f
83
78
78
82
86
81
80
Entry
Base
Solvent (5 mL)
t [h]
Yield [%]
Cl
Cl
Br
Br
Me
1
2
3
4
5
6
7
8
9
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
NaOH
DMF
CHCl3
CH3CN
THF
DMF
THF
DMF
CH3CN
DMF
48
72
36
60
8
24
12
24
14
74
38
43
38
83
65
78[a]
71
76
5g
[a] All reactions were performed on a 3 mmol scale with respect to
Baylis–Hillman bromide 1 with isatins 4a–g (2 mmol) in the presence of
Me2S (4 mmol) and Cs2CO3 (4 mmol) in DMF (5 mL) at 15–208C. [b] All
of these compounds were obtained as solids and were fully characterized
(see the Supporting Information). [c] Yield of isolated product, based on
the isatin. [d] The structure of this compound was further confirmed by
single-crystal X-ray analysis (see the Supporting Information).[8b] Bn=
benzyl.
[a] 1 equiv of base was used.
However, we did not obtain the expected spirodihydrofuran
oxindole; instead, spiroepoxy oxindoles 6a and 7a[8a] were
obtained in a 27:46 ratio (separated by column chromatogra-
phy) and an overall 73% yield (Table 3, entry 1). Interest-
ingly, allyl bromide 1 provided spirodihydrofuran oxindoles
5, whereas sterically more demanding allyl bromide 2a gave
spiroepoxy oxindoles 6a and 7a.[11] These reactions clearly
indicated the influence of steric factors in directing the reac-
tion pathway, thus leading to the formation of different
products. Then, we extended this strategy to the use of
Baylis–Hillman bromides 2a–e in cycloaddition reactions
with representative isatin derivatives 4a,c, and e; the result-
ing spiroepoxy oxindoles 6a–j and 7a–j[8a,11] were
case of allyl bromides 2a–e, spirodihydrofuran oxindoles
were not formed. This result is probably due to the Z stereo-
chemistry of the bromide, which might prevent the attack of
the oxygen anion on the olefinic carbon atom a to the aryl
group (owing to steric hindrance), thus leading to the forma-
tion of an oxirane ring. In the case of allyl bromides 3a and
b, E stereochemistry might facilitate the formation of the
spirodihydrofuran oxindole framework, (Æ)-8, with high dia-
stereoselectivity (see transition states T-1 and T-2,
Scheme 3). Path A3, which leads to the formation of com-
obtained as separable mixtures of diastereomers in
65–75% yield (Table 3).
Table 3. Synthesis of spiroepoxy oxindoles 6a–j and 7a–j.[a,b,c]
The significant differences in reactivity between
allyl bromides 1 and 2 in these reactions led us to
investigate the reaction of (2E)-2-bromomethyl-3-
(4-methylphenyl)prop-2-enenitrile (3a)[9] with 5-
chloro-1-methylisatin (4c) under similar conditions.
In this case, the spiroepoxy oxindole was not ob-
tained; instead spirodihydrofuran oxindole 8a [3R-
Entry Isatin R1 BH
bromide
Ar1
Product Yield Product Yield
6
[%]
7
[%]
A
ACHTUNGTRENNUNG(2’S),5’S]-(1-methyl-5-chloroindolin-2-
1
2
3
4
5
6
7
8
9
4a
4e
4a
4a
4c
4a
4e
4a
4c
4e
H
2a
C6H5
C6H5
6a[d]
6b
6c
6d
6e
6 f
27
30
19
30
25
25
26
41
36
41
7a[d]
7b
7c
7d
7e
46
43
52
43
42
50
42
29
31
24
Br 2a
AHCTUNGTRENNUNG
H
H
Cl
H
Br 2d
H
2b
2c
2c
2d
4-ClC6H4
4-MeC6H4
4-MeC6H4
2-ClC6H4
2-ClC6H4
(Table 4, entry 1).[12] We were pleased to observe
high stereoselectivity in this reaction. To understand
the applicability of this strategy, we subjected allyl
bromide 3a to the reaction with isatin derivatives
4d and e, which gave spirodihydrofuran oxindoles
8b and c in 73% and 67% yield, respectively.[8a,12]
Similarly, the reactions of allyl bromide 3b with
4a,c, and e provided the desired spirodihydrofuran
oxindoles 8d–f in 65–71% yield.[8a,12]
7 f
6g
7g
2e
2e
4-MeOC6H4 6h[d]
4-MeOC6H4
4-MeOC6H4
7h[d]
7i
Cl
Br 2e
6i
10
6j[e]
7j
[a] All reactions were performed on a 3 mmol scale with respect to Baylis–Hillman
bromides 2a–e with isatins 4a,c and e (2 mmol) in the presence of Me2S (4 mmol) and
Cs2CO3 (4 mmol) in DMF (5 mL) at 15–208C. [b] Pure diastereomers 6 and 7 were
separated and obtained as solids and were fully characterized (see the Supporting In-
formation). [c] Yield of isolated product, based on the isatin. [d] The structure of this
compound was further confirmed by single-crystal X-ray analysis (see the Supporting
The different reactivities of allyl bromides 1–3
might be attributed to steric factors, as shown in the
mechanistic pathway (Schemes 1–3). Thus, in the Information).[8b] [e] This compound was obtained as a viscous liquid.
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Baylis–Hillman Bromides as a Source of 1,3-Dipoles
COMMUNICATION
Table 4. Synthesis of spirodihydrofuran oxindoles 8a–f.[a]
Entry Isatin R1 R2
BH
bromide
Ar2
Product[b] Yield[c]
[%]
1
2
3
4
5
6
4c
4d
4e
4a
4c
4e
Cl Me 3a
Cl Et 3a
Br Me 3a
Me 3b
Cl Me 3b
Br Me 3b
4-MeC6H4 8a
4-MeC6H4 8b
4-MeC6H4 8c
66
73
67
69
65
71
H
2-ClC6H4
2-ClC6H4
2-ClC6H4
8d[d]
8e[d]
8 f
[a] All reactions were performed on a 3 mmol scale with respect to
Baylis–Hillman bromides 3a and b with isatins 4a and c–e (2 mmol) in
the presence of Me2S (4 mmol) and Cs2CO3 (4 mmol) in DMF (5 mL) at
15–208C. [b] All of these compounds were obtained as solids and were
fully characterized (see the Supporting Information). [c] Yield of isolated
product, based on the isatin. [d] The structure of this compound was fur-
ther confirmed by single-crystal X-ray analysis (see the Supporting Infor-
mation).[8b]
Scheme 1. Plausible mechanism for the formation of spirodihydrofuran
oxindole 5.
ed with water (3 mL) and extracted with EtOAc (3ꢁ10 mL). The com-
bined organic layer was washed with water (2ꢁ5 mL) and dried over an-
hydrous Na2SO4. The solvent was evaporated and the crude product was
purified by column chromatography on silica gel (EtOAc/hexanes, 20%)
to provide compound 5a as a white solid (0.431 g, 83% yield).
pound (Æ)-8, is probably favored, owing to the possible
steric repulsions in path B3.
In conclusion, we have demonstrated that steric factors
direct the cycloaddition reactions between dipoles that are
generated from Baylis–Hillman bromides 1–3 and isatins 4
as dipolarophiles, thus providing an interesting method for
the synthesis of spiroepoxy oxindoles and spirodihydrofuran
oxindoles.
Acknowledgements
We thank the DST (New Delhi) for funding this project. S.S.B. thanks the
CSIR (New Delhi) for a fellowship and B.C.S. thanks the UGC (New
Delhi) for a Kothari fellowship. We thank the UGC for providing some
instrumental facilities. We thank the National Single-Crystal X-ray and
HRMS Facility funded by the DST. We also thank Professors T. P. Rad-
hakrishnan and S. Pal at the School of Chemistry, the University of Hy-
derabad, for their helpful discussions regarding analysis of the X-ray
data.
Experimental Section
To
a stirring solution of methyl-2-(bromomethyl)prop-2-enoate (1,
3 mmol, 0.537 g) in DMF (5 mL) were added Me2S (4.0 mmol, 0.248 g,
0.3 mL), Cs2CO3 (4.0 mmol, 1.303 g), and 1-methylisatin (4a, 2.0 mmol,
0.322 g) at 15–208C. After stirring for 8 h, the reaction mixture was dilut-
Scheme 2. Plausible mechanism for the formation of spiroepoxy oxindoles 6 and 7.
Chem. Eur. J. 2013, 19, 2961 – 2965
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Keywords: cycloaddition · dipoles · fused-ring systems ·
heterocycles · spiro compounds
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Baylis–Hillman Bromides as a Source of 1,3-Dipoles
COMMUNICATION
proton) for compounds 6a–j appeared in the range of d=6.74–
6.97 ppm, whereas in the case of compounds 7a–j, it was deshielded
and appeared at d>7.00 ppm. Although this observation is not sig-
nificant, it is worth noting that in the 13C NMR spectra of com-
pounds 6a–j the ester cabonyl carbon atom appeared in the range
of d=170.56–171.44 ppm, whereas in the case of compounds 7a–j,
the same atom appeared in the range of d=169.09–169.74 ppm.
[12] a) The stereochemistry was assigned on the basis of the single-crys-
tal X-ray structures of compounds 8d and e.[8] b) We have retained
“[3R
and “[3R
N
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
8d–f to indicate their racemic nature and also their stereochemistry.
The difference in configuration (R versus S) at the 5’ position was
due to a change in priority groups.
Received: October 20, 2012
Published online: February 1, 2013
Chem. Eur. J. 2013, 19, 2961 – 2965
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2965