Domino Corey-Chaykovsky Reaction for One-Pot Access to Spirocyclopropyl Oxindoles

Article abstract of DOI:10.1021/acs.orglett.8b01840

The development of the sequential Corey-Chaykovsky reactions of isatins, spiroepoxy-, or spiroaziridine oxindoles with sulfur ylide has led to the discovery of a unique reaction mode that allows easy and direct one-pot access to a range of spirocyclopropyl oxindoles.

Full text of DOI:10.1021/acs.orglett.8b01840

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Domino Corey−Chaykovsky Reaction for One-Pot Access to
Spirocyclopropyl Oxindoles
Saumen Hajra,* Sayan Roy, and SK Abu Saleh
Centre of Biomedical Research, Sanjay Gandhi Post-Graduate Institute of Medical Sciences, Campus Raebareli Road, Lucknow
226014, India
S
* Supporting Information
ABSTRACT: The development of the sequential Corey−Chaykovsky reactions of isatins, spiroepoxy-, or spiroaziridine
oxindoles with sulfur ylide has led to the discovery of a unique reaction mode that allows easy and direct one-pot access to a
range of spirocyclopropyl oxindoles.
pirocyclic oxindoles have garnered considerable research
enthusiasm for their unique structures and diverse but
However, the reports suggest that the unsubstituted
spirocyclopropyl oxindoles/indolines 1 have received more
attention than the mono- and disubstituted spirocyclopropyl
oxindoles.6
S
target-specific pharmacological profiles.1 In particular, spiro
3,3′-cyclopropyl oxindole, integrating two significant pharma-
cophores quaternary oxindole and the smallest three-member
cyclopropane ring, has been treated as an attractive framework
for both medicinal as well as synthetic chemistry research.2
The unusual bonding with characteristic angular as well as
torsional strain make the cyclopropane ring an exceptional
among various carbocycles. Significant pharmaceutical proper-
ties including intrinsic lipophilicity, metabolic stability, and
alteration of pKa have been imposed by the cyclopropane ring.
For instance, molecules shown in Figure 1 containing
Regarding the C−C bond forming reaction, the Corey−
Chaykovsky reaction (CCR) is efficient for organic synthesis.
It involves the addition of sulfur ylide to the electrophiles such
as carbonyl, imine, and enone, leading to the formation of
corresponding 3-membered rings such as epoxide, aziridine,
and cyclopropane, respectively (Scheme 1, eq 1).7 Mono- and
disubstituted spirocyclopropyl oxindoles have been frequently
synthesized by CCR using a suitable sulfur ylide.5a,8 However,
the synthesis of spirocyclopropyl oxindoles 1 is not successful
by CCR, which may be due to the instability of the 3-
methylene-2-oxindole and the lack of a suitable method for its
generation (Scheme 1, eq 2).9 Thus, spirocyclopropyl oxindole
1 is mostly synthesized by base-promoted double alkylation of
N-protected 2-oxindole using 1,2-dibromoethane.10 There are
other notable routes, but the use of costly reagents and
substrates make them less attractive (Scheme 1, eq 3).11
Scrutinizing all the importance of spirocyclopropyl oxindoles
and their reported routes, the development of an effective
synthetic method, in particular for spirocyclopropyl oxindole 1,
is highly appealing. Herein, we report the domino Corey−
Chaykovsky reaction of isatins, spiroepoxides, and spiroazir-
idines with sulfur ylide derived from trimethylsulfoxonium
iodide for the direct one-pot synthesis of spirocyclopropyl
oxindoles 1 (Scheme 1, eq 4).
Figure 1. Representative bioactive spirocyclopropyl oxindoles and
-indolins.
Our continuous research interest in the ring-opening
reaction of spiroepoxide and spiroaziridine oxindoles12 led us
to wonder whether spiroepoxides 2 could undergo a ring-
opening reaction with sulfur ylide derived from trimethyl
sulfoxonium iodide (TMSOI). It was also envisioned that
spirocyclopropyl oxindole have emerged as potential drug
candidates because of its conformational restraint and
lipophilicity.3 Spirocyclopropyl indolines also exhibit signifi-
cant biological activity acting as an EP4 receptor antagonist
and selective adrenaline α1A receptor agonist.4 Moreover,
from a synthetic point of view, spirocyclopropyl oxindoles have
also been considered to be a donor−acceptor cyclopropane.5
Received: June 13, 2018
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.8b01840
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Scheme 1. Corey−Chaykovsky Reaction (CCR) for the
Synthesis of Spirocyclopropyl Oxindoles
Table 1. Optimization of Reaction Conditions
a
ylide source
(equiv)
base
temp
t
yield
(%)
(equiv)
solvent
MeCN
(°C)
(h)
1
2
3
Me3SOI (2)
Me3SOI (2)
Me3SOI (2)
Cs2CO3
(3)
Cs2CO3
(3)
Cs2CO3
(3)
50
50
25
12
DMSO
DMSO
4
22
40
4
4
5
6
7
Me3SOI (2)
Me3SOI (3)
Me3SOI (3)
Me3SI (3)
NaH (3)
NaH (4)
NaH (4)
NaH (4)
DMSO
DMSO
DMF
25
25
25
25
1
1
2
2
56
76
46
55
DMSO
a
Isolated yield.
Once armed with the optimized conditions, we began an
exploration of the scope of this domino cyclopropanation
reaction with a wide range of spiroepoxides (Scheme 3).
Irrespective of the N-protection on spiroepoxides, we acquired
high yields in all cases. Substituted spiroepoxyoxindoles
participated in this transformation with good yield. Electron-
donating as well as electron-withdrawing groups on oxindoles
Scheme 3. One-Pot Synthesis of Spirocyclopropyl
Oxindoles 1 from Spiroepoxides 2
alkoxide intermediate 3 could undergo a retro-aldol reaction,
and a subsequent elimination of DMSO and formaldehyde
might bestow 3-methylene-2-oxindole 4.13 This reactive enone
4 could produce spirocyclopropyl oxindoles 1 by CCR with an
excess sulfur ylide (Scheme 2). Alternatively, we anticipated
that the cyclization of alkoxide 3 by analogy with the known
homologous CCR of epoxide would give spirooxetanes.7d
Scheme 2. Proposed Domino CCR of Spiroepoxy Oxindole
2
As a proof of concept, we commenced our journey with the
model substrate N-methyl spiroepoxyoxindole 2a altering
solvents, temperature, ylide sources, bases, and their
stoichiometry (Table 1). Gratifyingly, exclusive formation of
spirocyclopropyl oxindole 1a was achieved when spiroepoxide
2a was treated with trimethyl sulfoxonium iodide (TMSOI; 3
equiv) and NaH (4 equiv) in DMSO at rt within 1 h (entry 5).
Interestingly, no spirooxetane was detected by the MS analysis
of the crude reaction mixture. Other conditions mostly
afforded low yields with incomplete conversion.
B
DOI: 10.1021/acs.orglett.8b01840
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did not hamper the cyclopropanation reaction. With an
additional equiv of NaH, we also accomplished the reaction
with unprotected spiroepoxyoxindoles to yield the correspond-
ing spirocyclopropyl oxindoles 1u−w.
found to be a better solvent over DMSO for the synthesis of
spiroaziridine oxindoles.12b Thus, changing the solvent to
DMF and further lowering the temperature to 0 °C eventually
optimized the cyclopropanation of spiroaziridine 6a with a
high yield of 75%. The scope of this cyclopropanation reaction
of spiroaziridines was also generalized. Satisfyingly, a wide
range of spiroaziridineoxindoles with electron-donating or
-withdrawing substituents on the oxindole ring participated
smoothly to afford the corresponding spirocyclopropyl
oxindole with moderate to good yields (Scheme 5).
The spiroepoxides are commonly synthesized by CCR of
isatins.12 Thus, we desired to explore the cyclopropanation
reaction directly from isatin. Similar reaction conditions were
established for the domino CCR of isatin as well. Because it
begins with one-step back, the reaction required additional
amounts of ylide source as well as base. Reaction of isatin with
5 equiv of TMSOI and 6 equiv of NaH at rt (25 °C) in DMSO
was found to be the optimum conditions for the complete
conversion of isatin to spirocyclopropane oxindole. As
expected, the formation of intermediate spiroepoxide was
observed during the course of the reaction. It diminished with
the complete transformation to the spirocyclopropyl oxindole.
The scope of this direct cyclopropanation reaction was further
generalized with a wide range of isatins through complete
displacement of the oxygen atom in a one-pot fashion (Scheme
4). With N-methyl, N-benzyl, or N-PMB isatins, we obtained
Scheme 5. One-Pot Synthesis of Spirocyclopropyl
Oxindoles 1 from Spiroaziridines 6
Scheme 4. One-Pot Synthesis of Spirocyclopropyl
Oxindoles 1 from Isatins 5
To reinforce our presumption, we performed two control
experiments. Initially, the domino CCR of substituted spiro-
epoxyoxindoles 7 was executed under the standardized
conditions. Interestingly, these afforded spirocyclopropane 1a
exclusively. No substituted spirocyclopropyl oxindole 9 was
obtained. Moreover, epoxides 8, which were actually generated
by the CCR of the corresponding expelled aldehydes, were
detected in the mass spectrometry analysis (for details, see
Supporting Information) of the crude reaction mixture
(Scheme 6).
Scheme 6. Domino CCR of Substituted Spiroepoxy
Oxindoles 7
good yields of the corresponding spirocyclopropyl oxindoles 1.
On the other hand, substituted isatins also rendered the
corresponding spirocyclopropyl oxindoles with good yields
irrespective of the protecting group on the nitrogen atom. We
could also synthesize unprotected spirocyclopropyl oxindoles
1u and 1w from the corresponding isatins with good yields.
For unprotected isatins, an additional equiv of NaH was
needed.
Next, we performed the CCR of spiroepoxide 2a and
spiroaziridine 6a with tetrahydrothiophene-derived substituted
sulfur ylide and obtained disubstituted spirocyclopropane 10
from both substrates. Here, monosubstituted spirocyclopro-
pane 9c was also not detected in the crude reaction mixture by
MS analysis. When CCR of 3-benzylidene oxindole 11 was
again performed with substituted sulfur ylide under similar
conditions, it also furnished the substituted spirocyclopropane
10 with the same selectivity (Scheme 7). These experimental
outcomes strongly supported our presumption of in situ
Our interest12 in ring-opening reactions of small spirocyclic
oxindoles further motivated us to utilize this unique cyclo-
propanation reaction on analogous spiroaziridineoxindole,
which may provide insight into the reaction mechanism.
Standardized conditions for the cyclopropanation of spiroe-
poxy oxindoles was executed on N-methyl spiroaziridineox-
indole 6a, but only a moderate yield was obtained. DMF was
C
DOI: 10.1021/acs.orglett.8b01840
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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Scheme 7. Domino CCR of Spiroepoxide 2a and
Spiroaziridine 6a with Substituted Sulfur Ylide vs CCR of 3-
Alkylidene Oxindole 11
Scheme 9. Gram-Scale Domino CCR of Isatin 5u and Their
Late Stage Functionalizations
generation of 3-alkylidene oxindole as an intermediate for the
cyclopropanation of isatin, spiroepoxide, and spiroaziridine.
To demonstrate the general applicability and robustness of
the method, the domino CCR of both spiroepoxide and isatin
were extended up to gram-scale under the optimized
conditions. Spiroepoxide 2j (1 g, 3.3 mmol) underwent
smooth reaction with TMSOI in DMSO and endowed
spirocyclopropyl oxindole 1j in high yield (78%). This
compound 1j was employed for the Suzuki coupling reaction
with 1-methylindole-2-boronic acid, furnishing the correspond-
ing 5-indolyl spirocyclopropane 12 in 85% yield (Scheme 8).
iodide. This protocol provides a unique and facile one-pot
access of spirocyclopropyl oxindoles with diversity under
ambient conditions. The gram-scale reactions followed by late
stage modifications further prove its flexibility. Thus, the
present development can unfold a new route for the
spirocyclopropyl oxindole and -indoline based drug discovery
and medicinal chemistry research.
Scheme 8. Gram-Scale Domino CCR of Spiroepoxide 2j
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01840.
General procedures and standardization tables for
cyclopropanation reactions, spectroscopic data of the
products, mass spectrometry analysis of compound 8,
and copies of NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: saumen.hajra@cbmr.res.in.
ORCID
On the other hand, N-unprotected spirocyclopropyl
oxindole 1u was directly obtained in good yield by gram-
scale domino CCR of isatin 5u (1.0 g, 6.8 mmol) (Scheme 9).
Subsequently, a late stage base-promoted N-alkylation of
spirocyclopropane 1u was also achieved with 2-(bromometh-
yl)-1-butyl-1H-benzo[d]imidazole, providing the correspond-
ing N-alkylated spirocyclopropyl oxindole 13, a similar motif to
anti-RSV compound with quantitative yield. Spirocyclopro-
pane 1u could also be an important antecedent for the
synthesis of other substituted spirocyclopropyl oxindoles.
Hence, it was utilized for electrophilic substitution reactions
giving 5-bromo and 5,7-dibromo spirocyclopropyl oxindoles
(Scheme 9), which were difficult to obtain from the
corresponding isatins or by other means.
Saumen Hajra: 0000-0003-0303-4647
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank SERB, New Delhi (EMR/2016/001161) for
providing financial support. S.R. and S.A.S. thank CSIR and
UGC, New Delhi, respectively, for their fellowships. We thank
the Director of CBMR for providing research facilities.
REFERENCES
■
In conclusion, we present a novel domino Corey−
Chaykovsky reaction of isatin, spiroepoxy-, and spiroaziridine
oxindoles, which reveals mechanistically new reaction pathways
with the in situ generation of 3-methylene oxindole upon
reaction with sulfur ylide derived from trimethylsulfoxium
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