Multiple Aryne Insertions into Oxindoles: Synthesis of Bioactive 3,3-Diarylated Oxindoles and Dibenzo[b,e]azepin-6-ones

Article abstract of DOI:10.1021/acs.orglett.6b03224

An aryne insertion cascade reaction on oxindoles has been observed and constitutes a convenient one pot preparation of bioactive di- and triarylated oxindoles in good yields under mild conditions. A temperature controlled reaction switch enables ready access to dibenzo[b,e]azepin-6-one derivatives employing the same reaction regime. This tactic has been extended to a short synthesis of potent antiulcer agent darenzepine.

Full text of DOI:10.1021/acs.orglett.6b03224

Letter
pubs.acs.org/OrgLett
Multiple Aryne Insertions into Oxindoles: Synthesis of Bioactive 3,3-
Diarylated Oxindoles and Dibenzo[b,e]azepin-6-ones
Ramesh Samineni,† Chandramohan Reddy C. Bandi,† Pabbaraja Srihari,*,† and Goverdhan Mehta*,‡
†Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad-500 007, India
‡School of Chemistry, University of Hyderabad, Hyderabad-500 046, India
S
* Supporting Information
ABSTRACT: An aryne insertion cascade reaction on
oxindoles has been observed and constitutes a convenient
“one pot” preparation of bioactive di- and triarylated oxindoles
in good yields under mild conditions. A temperature
controlled “reaction switch” enables ready access to dibenzo-
[b,e]azepin-6-one derivatives employing the same reaction
regime. This tactic has been extended to a short synthesis of
potent antiulcer agent darenzepine.
iversely substituted 3,3-diaryloxindole and dibenzo[b,e]-
azepin-6-one scaffolds are potentially useful pharmaco-
context, the most commonly pursued approach to 1 and its
derivatives are based on Friedel−Crafts type arylation using
various protic and Lewis acids on the corresponding isatins 2
and 3-hydroxyoxindoles 3.4 Similarly, aryl-α-ketoamides 4 on
exposure to superacid in the presence of another electron-rich
aromatic moiety furnishes the 3,3-diarylated oxindole sytem.5
Another approach to system 1 involves acid/thermal rearrange-
ment of O-aryl ethers 56 (Figure 2). Preformed 3-monoarylated
D
phoric constructs that display a broad range of interesting
biological activities (Figure 1).1,2 For example, 3,3-diarylated-2-
Figure 1. Bioactive 3,3-diarylated oxindoles and dibenzoazepinones.
Figure 2. Previous approaches for 3,3-diaryl-2-oxindoles 1.
oxindole derivatives are known to exhibit anticancer,
antioxidant, Ca2+-depleting translation initiation inhibitory,
and mineralocorticoid receptor antagonist activities among
others.1 On the other hand, dibenzo[b,e]azepin-6-one deriva-
tives possess antiulcer, central nervous system (CNS), and
anticonvulsant activities.2 These potentially useful bioactivity
attributes harbored by 3,3-diaryloxindole and dibenzo[b,e]-
azepin-6-one bearing structural motifs have drawn the attention
of organic and drug discovery communities to develop practical
synthetic methodologies for the construction of these scaffolds.
Although many approaches to 3,3-disubstituted oxindoles
have been reported in recent years,3 those specifically targeted
toward 3,3-diaryloxindoles 1 are relatively few, thus limiting
access to structural diversity around this scaffold. In this
oxindoles 6 too have been converted to 3,3-diaryloxindoles
through a Pd and chiral phase transfer catalyst (PTC) mediated
α-arylation reaction.7 Recently, a nontransition metal mediated
approach to 1 through montmorillonite K-10 driven cyclization
of 2,2-N-triarylacetamides 7 has been reported (Figure 2).8
Similarly, synthetic routes to the pharmacophoric dibenzo-
[b,e]azepin-6-ones 8 are limited, and besides some classical
approaches,9 the recent ones of general applicability consist of
Received: October 27, 2016
© XXXX American Chemical Society
A
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Letter
Pd-mediated intramolecular reductive Heck cyclization10 of 9
and intramolecular Pd-mediated benzylation of primary
benzamides11 10 (Figure 3).
Figure 3. Previous approaches for dibenzo[b,e]azepin-6-ones 8.
The available methods for accessing the scaffolds 1 and 8,
though variously successful, are self-limiting because of severe
reaction conditions, use of expensive transition metal catalysts,
multistep substrate preparation, and lack of functional group
tolerance in many cases. These limitations underscore the need
for a mild, efficient, and general method.
During the past decade, aryne chemistry12 has emerged as a
powerful synthetic tool for obtaining diverse arylated/
benzoannulated scaffolds in view of the ready availability of
Kobayashi aryne precursor13 11 (2-(trimethylsilyl) phenyl-
trifluoromethanesulfonate). Thus, aryne insertion into variously
activated C−H, C−C, and C−X (X = heteroatom) bonds and
commonly available heterocyclic systems continues to be an
area of intense scrutiny.14 As part of our continuing interest15 in
accessing diverse scaffolds through new aryne insertion
protocols, we report here an interesting variant of the aryne
insertion chemistry involving multiple aryne insertions into
oxindoles 12 to furnish either 3,3-diaryloxindoles or dibenzo-
[b,e]azepin-6-one, two seemingly diverse scaffolds, through a
common strategy involving a one-pot reaction and employing
reaction temperature as a product control switch (Scheme 1).
Scheme 1. Present Work: Temperature Controlled Aryne
Insertions Leading to Either 1 or 8
Figure 4. Reaction of diverse oxindoles with arynes.
was determined that 3-allyloxindole 12j, 3-carboethoxyoxindole
12k, and N-Me and N-Boc, 3-carboethoxymethyl-substituted
oxindole 12l and 12m reacted smoothly with aryne precursor
11 to furnish the corresponding N- and 3C-arylated oxindoles
1j−1m, respectively, in good yields (Figure 4). It was also
considered useful to demonstrate that substituted arynes
reacted likewise with oxindoles. Toward this end, substituted
arynes generated from Kobayashi-type precursor 11a was
reacted with N-substituted oxindoles 12h, i, n to furnish 3,3-
diarylated oxindoles 1n−p respectively. Similarly, reaction of N-
Me-3-carboethoxymethyl oxindole 12l with substituted aryne
precursor 11b led to the corresponding 3-arylated oxindole 1q
(Figure 4).
During our experiments to optimize the yield of 3,3-
diarylated oxindole 1a through aryne C−H insertions (Table
1 in the SI), it was observed that at elevated reaction
temperature an additional new product was being formed.
After some trials, it was found that when the aryne-oxindole
reaction was carried out with 11 and 12a at 90 °C, the yield of
this new product enhanced to 59% and was determined to be
dibenzo[b,e]azepin-6-one 8a (Figure 5).
Reaction of oxindole 12a with an in situ generated aryne in
the presence of CsF proceeded quite smoothly and after some
optimization efforts (see entry 5 in Table 1 in the Supporting
Information (SI)) furnished N-3,3-triphenylated compound 1a
in 85% yield at room temperature in the presence of 3.5 equiv
of the aryne precursor 11.
With the optimized reaction conditions, the scope of the
aryne insertion reaction was further explored with substituted
N-unprotected oxindoles (12b−g) to deliver the corresponding
triphenylated oxindoles (1b−g) in 75−81% yields (entry 1,
Figure 4). Formation of triphenylated oxindole products was
unambiguously secured by X-ray crystal structure determi-
nation of 1d.
To impart further substituent variation in accessing 3,3-
diphenyloxindoles, N-protected oxindoles (12h, N-Me and 12i,
N- Boc) were exposed to aryne 11 (2.5 equiv) under the
optimized reaction conditions to eventuate 1h and 1i,
respectively, in decent yields (Figure 4). In addition, it was of
interest to explore whether 3-monosubstituted oxindoles could
also be arylated through this aryl insertion protocol. Indeed, it
The generality of this new ring expansion reaction was
demonstrated employing diverse oxindoles 12b−g with aryne
B
DOI: 10.1021/acs.orglett.6b03224
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Letter
Scheme 2. Synthesis of Darenzepine
Scheme 3. Possible Mechanism for the Formation of 3,3-
Diaryl-2-oxindoles and Dibenzoazepinones
Figure 5. Accessing dibenzoazepinones from various oxindoles and
arynes.
11 to furnish N-phenyl-dibenzo[b,e]azepin-6-one 8b−g as the
major products along with varying amounts of corresponding
3,3-diarylated oxindoles 1b−1g as minor products (Figure 5).
Structures of newly formed dibenzo[b,e]azepin-6-ones were
secured through their characteristic spectral features and single
crystal X-ray structure determination of one of them, 8b.
Further variations of this interesting reaction were demon-
strated through aryne insertion to N-substituted oxindoles 12h,
i, k to deliver corresponding dibenzo[b,e]azepin-6-ones 8h, i, j.
Also, the reaction of N-Me-3-carboethoxymethyl oxindole 12l
with naphthyne derived from 11c eventuated in the
corresponding dibenzo[b,e]azepin-6-one 8k (Figure 5).
As a practical application of our new dibenzo[b,e]azepin-6-
one synthesis, a four-step synthesis of potent antiulcer
muscarinic antagonist darenzepine16,2 15 embodying this
framework is outlined here. Accordingly, N-Boc protected 3-
carboethoxymethyl oxindole partner 12m was reacted with
aryne precursor 11 at elevated temperature (90 °C) to furnish
N-Boc-dibenzoazepinenone 13 and was further subjected to
dehydrogenation with 2,3-dichloro-5,6-dicyano-1,4-benzoqui-
none (DDQ) to stereoselectively deliver the E-isomer of α,β-
unsaturated ester 14 (Scheme 2). The ester functionality in 14
was hydrolyzed with base, and the resulting acid was directly
subjected to amidation with N-methylpiperzine which also
resulted in concomitant N-Boc deprotection to furnish
darenzepine 15. Since full characterization data for 15 were
not available in the patent and other literature, we confirmed its
structure by single crystal X-ray structure determination
(Scheme 2).
aryne results in the formation of an intermediate aryl anion A,
which after intramolecular protonation leads to N-arylated
oxindole B. The carbanion of B adds further to another aryne
to form intermediate anion C, which through an intra-
molecular1,3-hydride shift generates carbon anion D. Anion
D reacts with one more equivalent of aryne and forms aryl
anion E that on protonation (path ‘a’) delivers triarylated
oxindole 1. Alternately, at higher temperature E can attack the
amide carbonyl group (path ‘b’) to give cyclobutanoid
intermediate F which fragments to deliver a ring expanded
dibenzoazepinone 8 through an overall C−C insertion. The
reaction temperature based dichotomous behavior of inter-
mediate anion D, though intriguing, has precedence17 in aryne
chemistry.
In conclusion, an efficient “one-pot” multiple aryne insertion
approach of general applicability to furnish either 3,3-diarylated
or N-3,3-triarylated oxindoles from readily available precursors
is disclosed. We have also found that ‘reaction temperature
control’ can be deployed to divert this arylation reaction on
oxindoles to deliver dibenzo[b,e]azepin-6-ones. A short syn-
thesis of darenzepine, an antiulcer agent from substituted
oxindole, is reported using this aryne insertion strategy.
ASSOCIATED CONTENT
* Supporting Information
■
S
A possible mechanism for the formation of triarylated
oxindole 1 and dibenzoazepinone 8 from oxindole 12 via a
convergent aryne insertion pathway is depicted in Scheme 3.
Initial nucleophilic attack of amide nitrogen of oxindole 1 on
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03224.
C
DOI: 10.1021/acs.orglett.6b03224
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Organic Letters
Detailed experimental procedures and spectral data for
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all new compounds (PDF)
Crystallographic data for compound 15 (CIF)
Crystallographic data for compound 8b (CIF)
Crystallographic data for compound 1d (CIF)
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: srihari@iict.res.in.
*E-mail: gmehta43@gmail.com.
ORCID
(8) Lim, J. W.; Kim, K. H.; Moon, H. R.; Kim, J. N. Tetrahedron Lett.
2016, 57, 784.
Pabbaraja Srihari: 0000-0002-1708-6539
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was conducted under the auspices of Indo-French
“Joint Laboratory for Sustainable Chemistry at Interfaces”. R.S.,
C.R.B., and P.S. thank CSIR-New Delhi for funding from the
XII Five Year Plan project ORIGIN (under budget head CSC-
0108). G.M. wishes to thank Dr. Reddy’s Laboratory (DRL) for
the award of Dr. Kallam Anji Reddy Chair Professorship. The
authors thank Dr. N. Jagadeesh Babu (CSIR-IICT) and Mr.
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