Spiroannulation of Oxindoles via Aryne and Alkyne Incorporation: Substituent-Diverted, Transition-Metal-Free, One-Pot Access to Spirooxindoles

Article abstract of DOI:10.1021/acs.orglett.7b01233

A "product control via substrate design" strategy has been conceptualized and implemented to harness the potential of aryne and activated alkyne insertions into oxindoles to readily and efficiently furnish pharmacophoric indano- and cyclopentannulated spirooxindole scaffolds in an operationally straightforward, one-pot, transition-metal-free protocol.

Full text of DOI:10.1021/acs.orglett.7b01233

Letter
pubs.acs.org/OrgLett
Spiroannulation of Oxindoles via Aryne and Alkyne Incorporation:
Substituent-Diverted, Transition-Metal-Free, One-Pot Access to
Spirooxindoles
Ramesh Samineni,†,§ Jaipal Madapa,†,§ Pabbaraja Srihari,*,† and Goverdhan Mehta*,‡
†Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
‡School of Chemistry, University of Hyderabad, Hyderabad 500046, India
S
* Supporting Information
ABSTRACT: A “product control via substrate design” strategy has been
conceptualized and implemented to harness the potential of aryne and
activated alkyne insertions into oxindoles to readily and efficiently furnish
pharmacophoric indano- and cyclopentannulated spirooxindole scaffolds
in an operationally straightforward, one-pot, transition-metal-free
protocol.
pirooxindoles, constituted through a spiro-fusion of a
carbocyclic or heterocylic ring at the 3-position of an
oxindole, are well-recognized, privileged, three-dimensional
structural motifs, frequently encountered in diverse natural
products and pharmaceutically relevant entities.1−3 Representa-
tive examples of natural and unnatural spirooxindoles 1−8 are
collected in Figure 1 to capture their framework and functional
MI77301 (6) (for endocrine-resistant breast cancer), satavaptan
(7) (for hyponatremia), and gelsemine (8) (for CNS disorders)
are in various stages of clinical development. Consequently, there
is a widespread topical interest among synthetic organic and
medicinal chemists toward devising new and efficient methods
for accessing variegated spirooxindoles in order to explore the
chemical diversity space around this scaffold.3
S
While numerous synthetic approaches to access 3,3-hetero-
cycle-fused spirooxindole motifs have been devised,3 contem-
poraneous efforts toward accessing 3,3-carbocycle-fused spi-
rooxindoles are relatively few and of recent vintage.4−10 In this
context, metal-mediated activations/cyclizations on precrafted
advanced precursors have been a commonly pursued approach
toward 3,3-carbocycle-fused spirooxindoles. Notable examples
that have surfaced in recent years are Pd-mediated tandem Heck
reaction and C(sp3)−H bond activation (9 → 10),4 Pd-catalyzed
α-arylation of amides (11 → 12),5 Ni-catalyzed intramolecular
Heck cyclization (13 → 14),6 and Pd-catalyzed remote C−H
alkylation (15 → 16)7 (Figure 2). In addition, cationic
rearrangements (17 → 18)8 have also been harnessed to
generate the spirooxindole framework, among others.9 More
recently, organocatalytic protocols3b have been employed for
3,3-cyclopentaannulation (19 → 20, 21 → 22, and 23 → 24) and
3,3-cyclohexannulation of oxindoles to access spirooxindoles
(Figure 2).10
Figure 1. Representative examples for bioactive spirooxindole natural
products and synthetic compounds.
Although the aforementioned existing methods have met with
varying degrees of success, they necessitate use of either metal
catalyst or exotic organocatalyst and entail multistep substrate
acquisition, which is self-limiting. Thus, new, efficient approaches
diversity and complexity.2 These spirooxindole-based constructs
display an exceptionally broad range of biological activities that
include anticancer,1a,c antiviral,1b antifungal, contraceptive,
antimalarial, and antimigrane activity, to name a few. It is hardly
surprising, therefore, that several drug discovery programs in
industry and academia are anchored around a spirooxindole
scaffold, and compounds such as cipargamin (5) (for malaria),
Received: April 24, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01233
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Letter
better option to engage the ester group 31 (path b) and lead to
much desired spiroannulated oxindole 32 (Scheme 1). Many
variants of this conceptualization could be imagined, but initially,
we proceeded to test and demonstrate its validity with a few
diverse substituents as depicted in Schemes 2 and 3.
Scheme 2. Initial Experiment
Scheme 3. Reaction of various Substituted Oxindoles with
Arynes
Figure 2. Representative recent approaches for accessing 3,3-carbo-
cycle-fused spirooxindoles.
using readily available substrates with minimal processing
maneuvers should be a welcome addition to the repertoire of
methods for the synthesis of these valuable pharmacophoric
scaffolds. In this paper, we disclose a transition-metal-free, one-
pot access to 3,3-carbocylic spirooxindoles through incorpo-
ration of arynes and activated alkynes (as alkynones) into
strategically crafted oxindoles bearing an opportunistic sub-
stituent to efficiently access a diverse range of spirooxindoles.
In the preceding decade, aryne chemistry has re-emerged as a
powerful synthetic tool for generating complex and diverse
chemical entities.11,12 Our own recent efforts in the area have led
to some new opportunities through multiple aryne insertions13
that include reaction with oxindoles 25 to furnish diverse
dibenzoazepinones 28 (Scheme 1).13a This transformation
Scheme 1. Evolution of Aryne Approach to Spirooxindoles
In the event, reaction between an acetic acid side chain bearing
3-(carbethoxymethyl)oxindole 29a and aryne generated in situ
from Kobayashi14 precursor 33 under optimized conditions
(CsF, 2.5 equiv in THF, sealed tube at 100 °C for 24 h, Table 1,
Supporting Information) led to the formation of the projected
spirocyclized product 32a in 61% yield, Scheme 2. The structure
of 3,3-annulated spirooxindole 32a was confirmed unambigu-
ously through a single-crystal X-ray analysis (Scheme 2).
Gratifyingly, there was no trace of the ring-expanded
dibenzoazepinone 34, and only path b was operational.
Following this encouraging outcome, generality of the
spirocyclization protocol was demonstrated. Accordingly,
various 5-substituted N-methyl-3-(carbethoxymethyl)oxindoles
(29b−g) were reacted with aryne precursor 33 under optimized
conditions to furnish the respective spirooxindoles (32b−g) in
proceeds through initial aryne C(sp3)−H insertion to oxindole
to form anion 26, which adds to the amide carbonyl to form a
strained cyclobutenoid intermediate 27 and further fragments to
deliver dibenzoazepinones 28 (path a) (Scheme 1). We reasoned
that anion 26 is well poised for exploring an alternate reaction
path by engaging a favorably and strategically positioned
electrophilic ester substituent to eventuate in useful framework
diversification. This conceptualization is depicted for 29 bearing
an acetic acid side arm at the 3-postion (Scheme 1). Anion 30
formed through initial aryne C(sp3)−H insertion now has a
B
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decent yields. It is to be noted that even N-aryl-substituted
oxindole 29h reacted likewise to deliver the spirooxindole 32h in
71% yield. It was also considered useful to demonstrate the
spiroannulation with a substituted Kobayshi-type aryne
precursor 33a. Reaction of 33a with oxindole partners 29a,
29d, and 29i proceeded smoothly to result in spirooxindoles32i,
32j, and 32k, respectively (Scheme 3). A substrate 29j with a
methyl substituent at the methylene group of 29a also readily
engaged the aryne 33 to furnish an inseparable mixture (1:1) of
spiroannulated diastereomers 32l in 56% yield (Scheme 3).
Thus, the substitution on the methylene group is well tolerated,
but the outcome is nonstereoselective.
Scheme 5. Synthesis of Cyclopentane-Fused Spirooxindoles
from Various Substituted Oxindoles and Alkynones
In the backdrop of the successful spiroannulation of oxindoles
through aryne incorporation, it was natural to ponder over the
question whether such substitutent diverted annulations could
be replicated by employing alkyne partners for oxindoles. An
encouraging cue in this regard emerged from the recent work of
Li et al.,15 who showed that activated alkynes like the α,β-
unsaturated alkynone 36 insert into the C−C bond of β-keto
esters like 35 in the presence of Cs2CO3 to deliver ring-expanded
product 38 via the intermediacy of cyclobutene intermediate 37
(Scheme 4). This outcome, reminiscent of the response of
Scheme 4. Alkynone Reactivity with Activated Carbonyl
Compounds and Our Hypothesis
oxindole without a substituent in 3-position (Scheme 1),
indicated that a 3-carbethoxymethyl group in 29 could be
leveraged to induce diversion to 40 in the intermediate 39 (path
a) obtained through initial Michael addition and thus circumvent
the formation of benzoazepinone 42 via cyclobutene inter-
mediate 41 (path b) (Scheme 4).
To validate this proposition, a reaction between 3-
(carbethoxymethyl)oxindole 29a and α,β-unsaturated alkynone
36a (1,3-diphenylprop-2-yn-1-one) was performed using
Cs2CO3 as base in DMF at room temperature. Pleasingly,
exclusive formation of cyclopenteno-annulated spirooxindole
40a was observed in very good yield (89%).The structure of 40a
was secured by a single-crystal X-ray structure determination
(Scheme 5). As we had contemplated, the bystander 3-
substituent steered the reaction between oxindole 29 and
alkynone 36 along the preferred pathway b (Scheme 4), and no
leakage to benzoazepinone 42 could be detected. Spiroannulated
40 is endowed with an interesting enedione moiety suitable for
further elaboration of this interesting pharmacophoric scaffold.
Given such utilitarian prospects of 40, it was of interest to
demonstrate the generality of the one-pot spiro-cyclopentannu-
lation of oxindoles through reaction between diverse α,β-
unsaturated alkynones and 3-(carbethxymethyl)oxindoles. In-
deed, reactions between various α,β-unsaturated alkynone 36a−i
(readily prepared from the corresponding aldehydes via TMS-
acetylene addition and oxidation) were treated with 3-
(carbethoxymethyl)oxindoles 29. The o-bromo-substituted
alkynone (36b), heterocyclic alkynones (36c, 36d, 36e), and
methoxy-substituted alkynones (36f, 36g, 36h) reacted
smoothly with 3-(carbethoxymethyl)oxindoles 29 under the
optimized reaction conditions and provided the corresponding
substituted spirooxindoles (40a−q) in excellent yields (Scheme
5). Alkyl-substituted ynone 36i also smoothly reacted with
oxindole 29a to furnish the spiroannulated product 40r. The
ynone 36h reacted with oxindole 29j bearing a methyl
substituent at the α-position to ester to furnish the
spiroannulated 40s (diastereomeric mixture)(Scheme 5).
C
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In summary, a “product control via substrate design” strategy
in which a tactically placed 3-carbethoxymethyl group on the
oxindole framework steers and deviates the reaction course of
aryne and activated alkyne incorporation into oxindoles to
furnish indano- and cyclopentannulated spirooxyindoles in a
one-pot, transition-metal-free operation has been developed.
The generality of this protocol and its efficacy in creating
diversity have been demonstrated.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b01233.
Detailed experimental procedures and spectral data for all
new compounds (PDF)
Crystallographic data for compounds 32a (CIF)
Crystallographic data for compounds 40a (CIF)
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: srihari@iict.res.in.
*E-mail: gmehta43@gmail.com.
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ORCID
Pabbaraja Srihari: 0000-0002-1708-6539
Author Contributions
§R.S. and J.M. contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This research was initiated under the Indo-French “Joint
Laboratory for Natural Products and Synthesis towards
Affordable Health (NPSAH)” and supported jointly by the
CSIR and DST, New Delhi, under project code GAP-584. J.M.
thanks CSIR for a fellowship. G.M. thanks Dr. Reddy’s
Laboratory (DRL) for the award of the Dr. Kallam Anji Reddy
Chair Professorship.
Garg, N. K. Chem. Commun. 2015, 51, 34. (d) Per
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