DBU-catalyzed [3 + 2] cycloaddition and Michael addition reactions of 3-benzylidene succinimides with 3-ylidene oxindoles and chalcones

Article abstract of DOI:10.1039/c9ob00385a

A metal-free DBU catalyzed protocol has been developed for the regioselective [3 + 2] cycloaddition reactions of 3-benzylidene succinimides with 3-ylidene oxindoles to furnish spirooxindole derivatives. The 3-benzylidene succinimides underwent Michael addition with chalcones to provide benzylidene succinimide-tethered propanones. All the reactions proceeded under mild conditions and the products were isolated by simple filtration and washing with ethanol in good yields. The current methodology utilizes simple precursors and provides functionally-rich succinimides with two to five contiguous stereocenters in excellent diastereoselectivity and with complete regioselectivity.

Full text of DOI:10.1039/c9ob00385a

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Biomolecular Chemistry
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DBU-catalyzed [3 + 2] cycloaddition and Michael
addition reactions of 3-benzylidene succinimides
with 3-ylidene oxindoles and chalcones†
Cite this: DOI: 10.1039/c9ob00385a
Piyush Tehri and Rama Krishna Peddinti
*
A metal-free DBU catalyzed protocol has been developed for the regioselective [3 + 2] cycloaddition
reactions of 3-benzylidene succinimides with 3-ylidene oxindoles to furnish spirooxindole derivatives.
The 3-benzylidene succinimides underwent Michael addition with chalcones to provide benzylidene suc-
cinimide-tethered propanones. All the reactions proceeded under mild conditions and the products were
isolated by simple filtration and washing with ethanol in good yields. The current methodology utilizes
simple precursors and provides functionally-rich succinimides with two to five contiguous stereocenters
in excellent diastereoselectivity and with complete regioselectivity.
Received 16th February 2019,
Accepted 27th March 2019
DOI: 10.1039/c9ob00385a
rsc.li/obc
In addition to this, cyclopentanes are a class of compounds
endowed with decisive biological and pharmacological activi-
Introduction
Succinimide and its derivatives are of great scientific interest ties, like antiviral, hepatitis B and significant antitumor activi-
in the family of nitrogen containing compounds because of ties.7 Moreover, cyclopentane scaffolds can serve as intermedi-
their remarkable pharmacological profiles. These compounds ates in natural product synthesis and as lead compounds in
are reported to have various biological activities such as anti- the development of new drugs.8 Owing to their wide spectrum
epileptogenic, antinociceptive and antagonistic activities.1 of biological activities, the synthesis of cyclopentane deriva-
Numerous efforts have been made by the researchers from tives attracted tremendous attention in the field of organic syn-
time to time to synthesize these moieties. There are many thesis and the construction of highly substituted derivatives
reports in the literature of maleimide being used as a Michael has been an important concern for organic chemists since
acceptor to furnish products with succinimide as an integral decades.9 When the oxindole moiety is spirocyclized to cyclo-
part of the structure.2 However, there are sporadic reports pentane, it upswings to a special class of biologically impor-
known in the literature where 3-benzylidene succinimides were tant natural alkaloids such as notoamide A, cirinalins A, citri-
used either in cycloaddition reactions or as Michael donors.3 nadin B, and cyclopiamine B and could lead to the synthesis
As a result, there exists a broad scope for the development of of highly stereocentric and more fertile bioactive compounds
user friendly, simple and environmentally benign approaches (Fig. 1).10,11 We utilized 3-ylidene oxindoles in the reactions
to synthesize more functionally-rich succinimides from easily with various electron-rich arenes and 1,4-benzoxazinones for
accessible succinimide derivatives. The functionalization of an the synthesis of 2,3-difunctionalized benzofuran, lactone
allylic centre has always been an important concern to organic bearing indolin-2-one scaffolds and multisubstituted pyrrole
chemists as it greatly contributes to the synthesis of various polyheterocycles.12 Recently, Du reported a similar kind of
biologically active molecules.4 Michael addition is one of the cycloaddition of 3-benzylidene succinimides with enoates,
favourable ways to achieve C–C bond formation.5 Similarly though the reaction took a longer time.3a However, to the best
cycloaddition reactions have been considered as a major tool of our knowledge, the cycloaddition of 3-benzylidene succini-
to construct C–C bonds in organic synthesis and therefore mides with enones is not known in the literature. Later the
have attracted significant attention in recent years.6
same group reported the Michael addition of 3-benzilidine
succinimides with nitrostyrenes.3c In a report published by
Tan and co-workers in 2010, benzylidene succinimides were
used in Mannich-type allylic addition with imines.3d To the
best of our knowledge, no reports are available for the reac-
tions of 3-benzylidene succinimides with chalcones. We envi-
sioned that the base catalyzed reactions of 3-benzylidene succi-
nimides with enones such as 3-ylidene oxindoles and
Department of Chemistry, Indian Institute of Technology, Roorkee-247667,
Uttarakhand, India. E-mail: rkpedfcy@iitr.ac.in, ramakpeddinti@gmail.com
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, product characterization, and copies of 1H and 13C NMR spectra. CCDC
1863166 and 1890831. For ESI and crystallographic data in CIF or other elec-
tronic format see DOI: 10.1039/c9ob00385a
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Table 1 Optimization of conditions for the synthesis of spirooxindole
3aa
Entry
Reagent
Solvent
drb
Yieldc (%)
1
2
3
4
5
6
7
8
NEt3
DCE
DCE
DCE
DCE
—
—
—
—
—
—
—
98 : 02
86 : 14
93 : 07
90 : 10
91 : 09
93 : 07
Nr
Nr
Nr
Nr
Traces
Traces
Traces
43
60
28
DIPEA
DABCO
K2CO3
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DCE
DCM
Toluene
MeOH
EtOH
IPA
EtOH
EtOH
EtOH
9
Fig. 1 Biologically important spirooxindoles.
10
11d
12e
13f
75
80
71
DBU
DBU
chalcones would provide access to bioactive fragments in a
single structure via Michael addition and [3 + 2] cycloaddition
strategies. Herein, we report rapid protocols for the synthesis
of spirooxindoles and benzylidene succinimide-tethered pro-
panones with promising control over regioselectivity as well as
diastereoselectivity through DBU-catalyzed mild reactions with
no by-product formation.
a Reaction conditions: Unless otherwise specified, all reactions were
carried out using 2a (0.1 mmol), 1a (0.1 mmol), and a reagent
(0.1 mmol) in 2 mL solvent at room temperature for 40 min. b The dr
was determined by 1H NMR analysis of the crude product having 3a
and its diastereomer. c Isolated yield of 3a and its diastereomer after
column chromatography. Nr: No reaction. d 50 mol% of DBU was used.
e 20 mol% of DBU was used. f 10 mol% of DBU was used.
(entry 12). However, there was no appreciable variation in the
yield of the product on further diminishing the base to
Results and discussion
To establish the optimum reaction conditions, we commenced 10 mol% (entry 13). Thus, 20 mol% DBU in EtOH at room
our research by investigating the reaction of 3-ylidine temperature was considered as the optimized reaction con-
N-methyloxindole 1a and 3-benzylidene N-phenylsuccinimide dition for the model reaction. Gratifyingly, when the crude
(2a) as model substrates. When the reaction was performed in reaction mixture was subjected to filtration followed by simple
the presence of triethylamine in DCE at room temperature, no washing with ethanol, a single diastereomer 3a was isolated in
product was observed (Table 1, entry 1). To check the feasi- 70% chemical yield.
bility as per the mutual reactivity of the reactants, bases such
With the optimized reaction conditions in hand, we pro-
as DIPEA, DABCO and K2CO3 were examined and it was ceeded to study the functional group compatibility and scope
observed that these bases were unable to drive the reaction of the present DBU catalyzed protocol for the synthesis of
(entries 2–4) whereas the reaction involving DBU furnished spirooxindoles 3 using a variety of 3-ylidine oxindoles 1a–c and
trace amounts of 3a (entry 5). The spirooxindole 3a was 3-benzylidene succinimides 2a–d. Products 3a–l were obtained in
obtained via [3 + 2] cyclization of 3-ylidine oxindole 1a with good yields and excellent diastereoselectivities (Scheme 1).
3-benzylidene succinimide 2a. After screening of various The reactions of 3-benzylidene succinimides 2a–d bearing
bases, DBU was found to be a promising base to furnish electron-withdrawing and electron-donating groups proceeded
product 3a. Subsequently, to assess the solvent effect, the reac- well.
tion was studied by performing it in different solvents (entries
We tested the applicability of the present methodology for
6–10). EtOH was identified as the optimal solvent furnishing 3-ylidine oxindoles with a bulky protecting group to ascertain
the spirooxindole 3a in 40 min in 60% yield with 86 : 14 its effect on the stereochemical outcome of the reaction. When
diastereoselectivity (entry 9). Encouraged by this promising N-benzyl protected oxindoles were used in the reaction, no sig-
result, we further varied the amount of DBU and found that on nificant changes in the yield and diastereoselectivity of the
decreasing the amount of base to 50 mol% the product was products were noticed. The reaction proceeded smoothly to
obtained in an increased yield of 75% with very good furnish the desired products 3m–x in 50–80% yield with excel-
diastereoselectivity (entry 11). When 1a was treated with 2a in lent diastereoselectivity (Scheme 1). In the case of 3-ylidine oxi-
the presence of 20 mol% of DBU, the reaction afforded spir- ndoles, the ones bearing electron-donating groups participated
ooxindole 3a in 80% yield with 91 : 09 diastereoselectivity in the cycloaddition smoothly. When the unsubstituted/parent
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Scheme 1 Reaction of 3-benzylidene succinimides 2a–d with N-protected 3-ylidene oxindoles 1a–f. All reactions were carried out using 2a
(0.1 mmol), 1a (0.1 mmol), and DBU (0.02 mmol) in 2 mL of EtOH at room temperature for 40 min. The dr was determined by 1H NMR analysis of the
isolated product.aNo minor diastereomer was observed in the 1H NMR spectrum.
3-ylidine N-methyl oxindole (1a) was treated with various sub-
stituted 3-benzylidene succinimides 2a–d, the cyclized pro-
ducts 3a–d were obtained in 57–70% yield with diastereo-
selectivity up to >99%. Similarly, the reaction of 4-methyl and
4-methoxy substituted 3-ylidine N-methyloxindoles 1b,
c and 3-benzylidene succinimides afforded the corresponding
products
diastereoselectivities.
3e–l
in
51–72%
yield
with
excellent
Fig. 2 Selected 1H NMR chemical shifts (ppm) and NOE correlations in
3a.
The structures of spirooxindoles were confirmed by detailed
spectral analysis obtained from H and 13C NMR, and HRMS
1
1
experiments of the isolated products. For instance, in the H
NMR of 3a, the protons Ha and Hd appear as doublets at δ 4.10 COSY and H–13C COSY experiments, respectively (Fig. S6 and
1
and 4.90 ppm, respectively, and the protons Hb and Hc appear S7, ESI†).
as doublet of doublets at δ 4.21 and 5.04 ppm, respectively
The results obtained from NMR studies were further con-
(Fig. 2). The connectivity of the protons that are firmed by the single crystal X-ray analysis of compound 3a
coupled with each other and between protons and carbons of (Fig. 3, also see the ESI†).13 The crystals were grown by a slow
spirooxindole 3a was identified by two-dimensional 1H–1H evaporation process from dichloromethane.
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Fig. 3 The ORTEP plot of the crystal structure of 3a (the trapped di-
chloromethane is also shown).
To further explore the scope of 3-benzylidene succinimide
2a, we carried out its reaction with chalcone 4a, and it was
observed that the reaction proceeded through Michael
addition to furnish Michael adduct 5a in 64% yield and
excellent diastereoselectivity. To evaluate the substrate scope
of the reaction, chalcones 4a–f were treated with 3-benzylidene
succinimides 2a–d. As shown in Scheme 2, a variety of
chalcones bearing electron-rich and electron-deficient groups
on both the phenyl rings were amenable for the reaction, and
produced 5a–p in 8 h with yields up to 83%. Notably,
the donors 2b–d bearing 4-chloro, 4-methyl and
3-methoxy groups on the benzylidene moiety could also be
well tolerated.
Then we explored the scope of N-aryl benzylidene succina-
mide 2e with chalcone derivatives 4a and 4b. The reaction pro-
ceeded smoothly under the optimized reaction conditions to
provide the corresponding Michael adducts 5q and 5r, each in
67% yields. Interestingly, the cyclization of initial Michael
adducts did not take place. Similarly, benzyl protection also
worked well towards this protocol and furnished 5s in 65%
yield (Scheme 3).
Furthermore, we extended the scope of this protocol to
benzoylmethylidene malonate 6a. To our delight, the reaction
of 3-benzylidene succinimide 2a with 6a showed good compat-
ibility and produced Michael adduct 7a in high yield with
excellent diastereoselectivity (Scheme 4).
Scheme 2 Reactions of 3-benzylidene succinimides 2a–d with chal-
cones 4a–f. All reactions were carried out with 2a (0.1 mmol), 1a
(0.1 mmol), and DBU (0.02 mmol) in 2 mL of EtOH at room temperature
for 8 h. No minor diastereomer was observed in the 1H NMR spectra of
the isolated products.
The structures of Michael adducts were confirmed by
1
detailed analysis obtained from H and 13C NMR, and HRMS
1
spectral data of the isolated products. For instance, in the H
NMR of Michael adduct 5b, protons Ha and Ha′ appear at
δ 3.27 and 4.68 ppm, respectively, each as doublet of doublets
and proton Hb appears at δ 4.14 as doublet of triplets
and proton Hc appears at 4.51 ppm as doublet of doublets
(Fig. 4).
The connectivity of the protons that are coupled with each
other and between the protons and carbons of Michael adduct
5b was identified by two-dimensional 1H–1H COSY and 1H–13C
COSY experiments, respectively (Fig. S9 and S10, ESI†).
The results obtained from NMR studies were further con-
firmed by the single crystal X-ray analysis of compound 5h
(Fig. 5, also see the ESI†).14
Scheme 3 Reactions of 3-benzylidene succinimides 2e,f with chal-
cones 4a,b. All reactions were carried out using
2 (0.1 mmol), 4
(0.1 mmol), and DBU (0.02 mmol) in 2 mL of EtOH at room temperature
for 8 h. No minor diastereomer was observed in the 1H NMR spectra of
The plausible mechanism for the formation of spirooxin-
dole is depicted in Fig. 6. Firstly, the anion generated from the isolated products.
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3-benzylidene N-phenylsuccinimide (2a) by the abstraction of a
proton with DBU attacks on the β-carbon of the amide func-
tionality in 1a to produce anion A. The electron-donation by
the nitrogen atom of oxindole reduces the electron-withdraw-
ing ability of both ketone as well as amide functionalities.
Consequently the steric factor would greatly facilitate the
attack at a sterically less hindered β-position. The carbanion A,
being benzylic and α- to carbonyl, is highly stabilized and acts
as a soft nucleophile. The aromatic ring of the benzylidene
moiety may participate in resonance to the benzyl carbonium
ion centre that facilitates 5-exo-trig cyclization at a soft electro-
philic centre of B leading to tetracyclic system C. The hydroxye-
namine C tautomerises to more stable imide 3a. In the case of
chalcone 4 or benzoylmethylidene malonate 6a, the ketone
enolates and the malonate enolates are more stable than
amide enolates derived from 3-vinylidene oxindoles due to the
resonance effect and relatively strong electron-withdrawing
groups present in the former acceptors. Thus the enolates
from 4 and 6a, being more stable, do not take part in the
second Michael addition. The excellent diastereoselectivity
realised in the reactions of 3-benzylidene succinimides with
the enones studied may be attributed to the presence of steric
bulk in the vicinity of reacting sites.
Scheme 4 Reaction of 3-benzylidene succinimide 2a with benzoyl-
methylidene malonate 6a. The reaction was carried out using 2a
(0.1 mmol), 6a (0.1 mmol), and DBU (0.02 mmol) in 2 mL of EtOH at
room temperature for 5 h. No minor diastereomer was observed in the
1H NMR spectrum of the isolated product.
Fig. 4 Selected 1H NMR chemical shifts (ppm) in 5b.
Conclusions
In conclusion, we have successfully demonstrated DBU-cata-
lyzed regioselective reactions of a series of enones viz. 3-ylidine
oxindole, chalcones and benzoylmethylidene malonate with
3-benzylidene succinimides; the reaction proceeded via a
[3 + 2] cycloaddition strategy and when treated with 3-ylidine
oxindole 1 it followed Michael addition with other enones
chalcones 4 and benzoylmethylidene malonate 6a. The current
rapid protocol offers valuable functionalized succinimides
with two to five contiguous stereocenters in excellent diastereo-
selectivities and with complete regioselectivities from easily
accessible starting materials. Moreover, this methodology is
simple and does not require purification steps such as column
chromatography and recrystallization.
Fig. 5 The ORTEP plot of the crystal structure of 5h.
Fig. 6 Plausible reaction mechanism for the formation of spirooxindole.
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We sincerely thank the SERB (research grant No. EMR/2017/
000174), New Delhi for financial support and the DST-FIST
program for HRMS facility. P. T. thanks the MHRD for a
research fellowship.
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