Intramolecular trapping of ammonium ylides with: N -benzoylbenzotriazoles in aqueous medium: Direct access to the pseudoindoxyl scaffold

Article abstract of DOI:10.1039/c8ob02683a

The present work documents an operationally simple, clean and practical method for accessing the 2,2-disubstituted indolin-3-one (pseudoindoxyl) scaffold. The rhodium carbenoid mediated reaction between N-o-alkylamino benzoylbenzotriazoles and aryl diazoacetates occurs smoothly in water and exploits the leaving group ability of the benzotriazole moiety to install the carbonyl function in the product. Other highlights of the methodology are a wide substrate scope and experimental practicality given the re-use of the benzotriazole byproduct for starting material preparation.

Full text of DOI:10.1039/c8ob02683a

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Intramolecular trapping of ammonium ylides with
N-benzoylbenzotriazoles in aqueous medium:
direct access to the pseudoindoxyl scaffold†
a,b
Cite this: Org. Biomol. Chem., 2019,
17, 135
Lalita Devi,a,b Rashmi Shuklaa and Namrata Rastogi
*
The present work documents an operationally simple, clean and practical method for accessing the 2,2-
disubstituted indolin-3-one (pseudoindoxyl) scaffold. The rhodium carbenoid mediated reaction between
N-o-alkylamino benzoylbenzotriazoles and aryl diazoacetates occurs smoothly in water and exploits the
leaving group ability of the benzotriazole moiety to install the carbonyl function in the product. Other
highlights of the methodology are a wide substrate scope and experimental practicality given the re-use
of the benzotriazole byproduct for starting material preparation.
Received 30th October 2018,
Accepted 30th November 2018
DOI: 10.1039/c8ob02683a
rsc.li/obc
An elegant cascade Fisher indolization-Claisen rearrangement
sequence employing aryl hydrazines and allyloxyketones was
Introduction
The 2,2-disubstituted indolin-3-one core is found in several developed by Yao and Xie.9 Recently, Zhu and co-workers
biologically active pseudoindoxyl spirocyclic alkaloids of plant reported a gold catalyzed heteroannulation reaction between
and fungal origin such as (+)-aristotelone, ervaoffines, duocar- α-amino imides and in situ generated arynes and further
mycins, (+)-austamide, brevianamides, etc. (Fig. 1).1
employed the strategy for the total synthesis of (+)-hinckden-
This is also a key starting subunit for several natural mole- tine A successfully.10
cules including hinkdentine A, isatisine A, grandilodine B, tri-
Furthermore, the asymmetric synthesis of the pseudoin-
gonoliimine C, etc.2 The 2,2-disubstituted-indolin-3-one oligo- doxyl core has also garnered significant attention. For
mers have also been found to be efficient synthetic mimetics instance, several methods for the enantioselective synthesis of
of the protein secondary structure.3
2,2-disubstituted indolin-3-ones based on asymmetric alkyl-
Several elegant protocols are known for the synthesis of 2,2- ation of 2-monosubstituted indolin-3-ones/indol-3-ones via the
disubstituted indolin-3-ones. Gagosz and co-workers described Michael reaction, Mannich reaction, Henry reaction, etc., have
a gold-carbenoid mediated Claisen rearrangement of 2-azido- been documented in the literature.11 Several groups reported
alkynes for accessing indolin-3-ones bearing an allyl group at enantioselective Friedal–Crafts alkylation of indoles with spiro
the 2-position.4 Xiao and co-workers subjected indoles to the indolin-3-ones,12a or with cyclic imines to access the pseudoin-
photocatalytic aerobic oxidation/semipinacol rearrangement to doxyl core.12b
afford 2,2-disubstituted indolin-3-ones.5 Okuma and co-
workers synthesized series of 2-phenylindolin-3-ones employing diazo compounds as the carbene precursor are
The transition metal catalyzed X–H insertion reactions
a
through the cycloaddition reaction of amino acid methyl esters among the most popular and practical methods for the con-
with the in situ generated arynes.6 Fan and co-workers pre-
pared several 2-acetoxy-indolin-3-ones from o-acyl anilines via
the cyclization–acetoxylation sequence mediated by hyperva-
lent iodine reagents.7 Shimizu and co-workers reported an
interesting aza-Brook rearrangement of α-imino esters followed
by Dieckmann condensation of the resulting aluminium eno-
lates for the construction of 2,2-disubstituted indolin-3-ones.8
aMedicinal and Process Chemistry Division, CSIR-Central Drug Research Institute,
Lucknow 226031, India. E-mail: namrata.rastogi@cdri.res.in
bAcademy of Scientific and Innovative Research, New Delhi, India
†Electronic supplementary information (ESI) available: 1H and 13C NMR spectra
of all new compounds. See DOI: 10.1039/c8ob02683a
Fig. 1 Natural products with the pseudoindoxyl core.
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Table 1 Optimization of reaction conditionsa
struction of C–X bonds.13 In particular, the N–H and O–H
insertion reactions have been developed extensively over other
X–H insertion reactions, attributable to the significance of
these functional groups in organic synthesis.14 Liang and co-
workers reported a palladium catalyzed cross-coupling reaction
of aryldiazoacetates with N-substituted-2-iodoanilines in the
presence of carbon monoxide leading to the 2,2-disubstituted
indolin-3-one scaffold.15 The reaction involves the formation
of palladium carbenoid with aryldiazoacetates after palladium
catalyzed carbonylation of aryl iodide with CO initially. The
usual acyl migratory insertion and isomerization followed by
the intramolecular nucleophilic substitution reaction affords
the 2,2-disubstituted indolin-3-one. The limited substrate
scope and moderate yields along with the use of CO as the
source of the carbonyl group are major limitations of this
otherwise elegant synthetic methodology. We hereby report a
simple strategy to achieve the synthesis of the 2,2-disubstituted
indolin-3-one core via the Rh2(OAc)4 catalyzed reaction of dia-
zoesters with o-amino benzoylbenzotriazoles in aqueous
medium. The reaction takes advantage of the benzotriazole
group’s leaving abilities to install the carbonyl function after
the nucleophilic addition of the transient ammonium ylide
species onto the carbonyl carbon (Scheme 1).16
Entry
1a : 2a
Catalyst (mol % w.r.t. 2a)
Solvent
3ab (%)
1
2
3
4
5
6
7
8
1 : 1
1 : 1
1 : 1.5
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
Rh2(OAc)4 (1)
Rh2(OAc)4 (1)
Rh2(OAc)4 (1)
Rh2(OAc)4 (1)
Cu(acac)2 (1)
Pd(OAc)2 (1)
Rh2(OAc)4 (1)
Rh2(OAc)4 (1)
Cu(acac)2 (1)
Rh2(OAc)4 (1.5)
Rh2(OAc)4 (0.5)
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DCE
H2O
H2O
H2O
H2O
NRc
58 (51)d
64
95
93 (80)d
65
85
88
26
9
10
11
75
96 (86)d
a Unless otherwise noted, all reactions were performed with 0.5 mmol
of 1a, specified amount of 2a and catalysts in 5 mL of solvent at reflux
temperature. b NMR yields. c No reaction at room temperature.
d Isolated yield in parentheses.
to be the better catalyst in terms of yield so far, it was used for
the optimization of the solvent used in the reaction. The reac-
tion when carried out with Rh2(OAc)4 in DCE provided 3a in
85% NMR yield (entry 7). The catalyst Rh2(OAc)4 worked
efficiently in aqueous medium as well affording 3a in 88%
NMR yield but surprisingly the product was obtained in poor
yield when Cu(acac)2 was used as the catalyst in H2O (entries 8
and 9).18 Although the product yield was approximately 7%
better in the reaction carried out with Rh2(OAc)4 in toluene as
compared to the reaction in the aqueous medium (compare
entries 4 and 8), water was selected as the reaction solvent due
to its innocuous character. Moreover, the product was isolated
in excellent yield upon reducing the catalyst loading to half in
the aqueous reaction (entry 11). Therefore, the 1 : 2 ratio of
substrates 1 and 2 in the presence of 0.5 mol% of Rh2(OAc)4 in
water at reflux temperature was established as the optimum
condition for the reaction.
After optimizing the reaction conditions, we decided to
examine the scope of o-amino benzoylbenzotriazoles 1 in the
reaction. A variety of differently substituted o-amino benzoyl-
benzotriazoles 1, bearing electron withdrawing as well as
electron donating substituents, were reacted with ethyl
2-diazo-2-phenylacetate 2a under the optimized reaction
conditions (Table 2).
Results and discussion
For preliminary investigations, we selected ethyl 2-diazo-2-phe-
nylacetate 2a as the carbene precursor and N-o-methylamino
benzoylbenzotriazole 1a as the nucleophile in 1 : 1 ratio, after
an initial unsuccessful attempt to use o-amino benzoylbenzo-
triazole in the reaction.17
The reaction carried out in toluene in the presence of
Rh2(OAc)4 at room temperature was ineffective but provided
the expected product in moderate yield at reflux temperature
(entries 1 and 2; Table 1). There was only a slight enhancement
of yield upon increasing the amount of 2a to 1.5 equivalents;
however yield increased enormously upon doubling the
amount of 2a in the reaction (entries 3 and 4). Furthermore,
screening of catalysts revealed that Cu(acac)2 works equally
well in the reaction, whereas Pd(OAc)2 resulted in a much
lower product yield (entries 5 and 6). Since Rh2(OAc)4 proved
It was satisfying to note that the desired products were iso-
lated in high yields in all the cases except with the fluorine
substituted o-amino benzoylbenzotriazole 1c. Additionally,
different substitutions on the amine nitrogen including the
ethyl group and benzyl group were tolerated well and the
corresponding products 3i and 3j were isolated in 57% and
60% yields, respectively. However, the cyclopropyl substitution
on nitrogen resulted in lower yield of the product 3k, viz. 24%.
Notably, this is quite a clean and practical reaction methodo-
logy since the byproducts are nitrogen gas and benzotriazole,
Scheme 1 Pseudoindoxyl core from diazo compounds.
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Table 2 Scope of the reaction: variation of o-amino benzoylben-
zotriazoles 1a
Table 3 Scope of the reaction: variation of diazoacetatesa
a Reaction conditions: 1 (0.5 mmol), 2a (1.0 mmol), Rh2(OAc)4
(0.005 mmol), H2O (5 mL), reflux
which could be isolated conveniently and reused for the
synthesis of the starting material.
After utilizing the wide range of o-amino benzoylbenzotri-
azoles 1 in the reaction, we aimed to investigate the scope of
diazoacetates 2 in the reaction (Table 3). Therefore, variously
substituted diazophenylacetates were prepared from the
corresponding phenylacetates via the diazo transfer reaction.19
The reaction of several o-amino benzoylbenzotriazoles
1 with a range of diazoacetates 2, bearing substituents with
different electronic characters, proceeded smoothly under the
reaction conditions. The products were isolated in moderate to
good yields ranging from 42% to 72%. Notably, the heteroaryl-
diazoacetate 2f too participated well in the reaction with
1a providing product 3x in 50% yield. Furthermore, the
reaction of N-o-methylamino benzoylbenzotriazole 1a with
ethyl 2-diazopropanoate 2g as well as diethyl 2-diazomalonoate
2h (with acceptor–acceptor group substitution on diazo
carbon) furnished the desired products 3zb and 3zc, respect-
ively, albeit in low yields.
a Reaction conditions: 1 (0.5 mmol), 2 (1.0 mmol), Rh2(OAc)4
(0.005 mmol), H2O (5 mL), reflux
Mechanistically, the reaction plausibly follows the carbe-
noid generation → ylide formation → nucleophilic addition →
proton transfer and elimination sequence (Scheme 2). The
rhodium carbenoid A derived from diazoacetate 2 upon inter-
action with the lone pair of electrons on nitrogen of sec-amine
1 results in the generation of rhodium ylide species B.20 The
transient rhodium ylide B dissociates to provide the resonance
stabilized ammonium ylide C. The intramolecular nucleophilic
addition of the ylide C onto the amide carbonyl group followed
by “delayed proton transfer” and benzotriazole elimination
ultimately leads to the 2,2-disubstituted indolin-3-one
product 3.21
Scheme 2 Plausible mechanism.
Conclusions
In summary, we devised an efficient strategy for the synthesis
of the 2,2-disubstituted indolin-3-one or pseudoindoxyl
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scaffold through the Rh-carbenoid mediated reaction between
N-o-alkylamino benzoylbenzotriazoles and aryl diazoacetates.
The method elegantly exploits the leaving group ability of the
benzotriazole moiety to lodge the carbonyl function in the pro-
ducts. The reaction takes place in aqueous medium and offers
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
LD and RS thank the CSIR, New Delhi and DST, New Delhi,
respectively for the Ph. D. and project fellowships. We thank
the SAIF division of CSIR-CDRI for the analytical support.
CDRI Communication No: 9775.
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