TBHP Mediated Substrate Controlled Oxidative Dearomatization of Indoles to C2/C3-Quaternary Indolinones

Article abstract of DOI:10.1002/ejoc.201800167

Oxidative dearomatization of indoles with 70 % aqueous tert-butylhydroperoxide (TBHP) in the absence of any metal salts/organic solvents gave the corresponding C2/C3-quaternary indolinones under open-air reaction conditions. The nature of substituent on the indole nitrogen dictates the type of product formed in these reactions. Free (NH)-indoles gave C2-quaternary indolinone derivatives whilst (NR)-indoles yielded C3-quaternary indolinones as the major product. Moreover, the addition of an excess amount of TBHP also facilitated the one-pot transformation of (NR)-indoles to the corresponding isatin derivatives.

Full text of DOI:10.1002/ejoc.201800167

A Journal of
Accepted Article
Title: TBHP mediated substrate controlled oxidative dearomatization of
indoles to C2/C3-quaternary indolinones
Authors: Jagatheeswaran Kothandapani, Singarajanahalli Mundarinti
Krishna Reddy, Subbiah Thamotharan, Shankar Madan
Kumar, Kullaiah Byrappa, and Subramaniapillai Selva
Ganesan
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800167
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800167
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201800167
COMMUNICATION
TBHP mediated substrate controlled oxidative dearomatization of
indoles to C2/C3-quaternary indolinones
[
a]
[a]
Jagatheeswaran Kothandapani, Singarajanahalli Mundarinti Krishna Reddy, Subbiah
[
b]
[c]
[d]
[a]
Thamotharan, Shankar Madan Kumar, Kullaiah Byrappa and Subramaniapillai Selva Ganesan*
Dedication ((optional))
Abstract: Oxidative dearomatization of indoles with 70% aqueous t-
butylhydroperoxide (TBHP) in the absence of any metal salts/organic
solvents gave the corresponding C2/C3-quaternary indolinones
under open-air reaction conditions. The nature of substituent on the
for completion. Ceric ammonium nitrate on silica gel also has the
ability to convert N-methylindole to the corresponding C2-
[
11]
quaternary indolinone derivative, albeit in very poor yields.
It
was previously reported that atmospheric air itself is sufficient for
[
6]
indole nitrogen dictates the type of product formed in these reactions. the oxidative dimerization of oxindole derivatives. Hence, it is
Free (NH)-indoles gave C2-quaternary indolinone derivatives whilst of interest to study the t-butylhydroperoxide (TBHP) assisted
NR)-indoles yielded C3-quaternary indolinones as the major product. one-pot transformation of indole to the corresponding C2/C3-
(
Moreover, the addition of excess amount of TBHP also facilitated the
one-pot transformation of (NR)-indoles to the corresponding isatin
derivatives.
quaternary indolinone derivatives under open-air reaction
conditions.
Results and discussion
Introduction
During the course of our investigation, we have identified the
excellent potential of 70% aqueous TBHP reagent to perform
oxidative dearomatization of indoles. Interestingly, the reaction
proceeds in the absence of any organic solvents and metal salts.
(Scheme 1).
Indole and its derivatives are considered as one of the privileged
structural motifs present in several biologically relevant
[
1-5]
molecules.
Oxidative dearomatization reaction of indole leads
to the formation of a diverse class of products such as 2/3-
[
6]
oxoindoles, indirubin, indigo, isatin and indoline derivatives.
Among them, the transformation of indoles to C2/C3-quaternary
indolinone derivatives is synthetically quite valuable since it
converts structurally simpler, planar indole skeleton to a complex
three-dimensional architecture. In addition to their structural
elegance, they are also highly biologically relevant molecules.
Kobayashi et al., isolated trisindoline,
a
C3-quaternary
[
7]
indolinone derivative from the culture of Vibrio spp. Kim and
co-workers identified that trisindoline derivatives inhibited the
growth of both parental and multidrug-resistant uterine sarcoma
[
8]
and colorectal adenocarcinoma cell lines.
In spite of such
biological significance, only limited number of reports are
available for the one-pot transformation of indole to the
corresponding C2/C3-quaternary indolinone derivatives.
Guchhait et al., reported expensive PdCl
2
/TBHP/MnO
2
[
9]
reagent system
to convert free (NH)–indoles to the
.
corresponding C2-quaternary indolinone derivatives. Liu and co-
workers reported the TEMPO (2,2,6,6-Tetramethylpiperidin-1-
yl)oxyl) mediated synthesis of C2-quaternary indolinones from
Scheme 1. TBHP assisted syntheses of C2/C3-quaternary indolinones
[10]
free (NH)-indoles. However, the reaction required three days
To our surprise, free (NH)-indole 1a gave the
corresponding C2-quaternary indolinone derivative 2a whilst
(
NMe)-indole 1b yielded the corresponding C3-quaternary
[
[
a]
b]
Department of Chemistry, School of Chemical and Biotechnology,
SASTRA Deemed University, Thanjavur-613401, Tamil Nadu, India,
Fax: +91 (4362) 264120; E-mail: selva@biotech.sastra.edu
Biomolecular Crystallography Laboratory, Department of
Bioinformatics, School of Chemical and Biotechnology, SASTRA
Deemed University, Thanjavur 613 401, India.
PURSE Laboratory, Mangalagangotri, Mangalore University,
Mangalore 574 199, India.
Department of Materials Science, Mangalore University, Mangalore
indolinone derivative 3a as the major product. Along with 3a, the
minor product 2b was also formed in the reaction medium. The
formation of the major products 2a and 3a can be explained as
given below.
TBHP mediated C3-oxygenation of free (NH)-indole could
[
[
c]
d]
[
12]
result in the in situ formation of indolones.
successive nucleophilic addition of free (NH)-indole onto the
indolones transform them into structurally complex C2-
Further, two
574 199, India.
a
Supporting information for this article is given via a link at the end of
the document.
quaternary indolinone derivative 2a. Unlike C3-oxygenation, C2-
oxygenation of N-methylindole is quite intriguing. It was
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European Journal of Organic Chemistry
10.1002/ejoc.201800167
COMMUNICATION
2
previously reported in the literature that TBHP/I reagent system
18
19
20
21
22
23
3a
3a
3a
3a
3a
3a
---
---
---
---
---
---
H
2
O (3)
Reflux
Reflux
100
3
39
68
facilitated the C2-oxygenation of (NMe)-indoles through 3-iodo
iminium intermediate which eventually yielded isatin as the final
CH
3
CN (3)
3
3
3
3
3
[
13]
product.
However, during our investigation with TBHP in the
, the formation of C3-quaternary indolinone 3a was
DMSO (3)
Toluene (3)
MeOH (3)
DMF (3)
---
absence of I
2
100
Traces
44
observed instead of isatin derivative. We surmise that in the
absence of iodine, the nucleophilicity of C3-position of (NMe)-
indole is retained and hence the product 3a was formed in
appreciable yields. Also, a careful review of literature revealed
Reflux
100
---
that TEMPO in the presence of AgNO
3
/Brønsted acid in pyridine
[
a] Unless otherwise mentioned all the reactions were performed with 1 mmol
solvent gave C3-quaternary indolinone derivative 3 as a minor
of (NH)-indole 1a or (NMe)-indole 1b and 70% aqueous solution of TBHP (400
µL). [b] Yields are for the isolated products. [c] 70% aqueous solution of TBHP
(400 µL) was used as reagent cum solvent. [d] Presence of unreacted starting
material was observed on TLC for the reactions performed less than 3 h.
Reaction performed for 4 h didn’t improved the yield of the product. [e]
Reaction performed with 200 µL of TBHP required 5.5 h for completion of the
reaction.
[
14]
product. In a similar manner, organic peroxide mediated C2-H
oxygenation of indoles in presence of PdCl and MnO was
2
2
[
9]
reported earlier. However, in both cases, free (NH)-indole was
used as a substrate. Apart from these methods, C3-quaternary
indolinones 3 can also be prepared by the nucleophilic addition
[
15-17]
of indole on to isatin derivatives.
In order to maximize the yield of products 2a and 3a, the
reaction conditions such as solvents, temperature, time, molar
ratio of reagent, and nature of additives were optimized. The
results obtained from the optimization studies are given in Table
Reaction performed with polar protic solvents such as
water and methanol gave the corresponding product 2a in
moderate yield (Table 1, Entries 1, 2). A sharp decrease in the
yield of 2a was observed when the reaction was performed in
polar aprotic or non-polar solvents (Entries 3-6). Since water
gave appreciable yield among the screened solvents, it is of
interest to perform the reaction with only 70% aqueous TBHP
medium in the absence of any externally added organic solvents
or water. To our delight, we have got the product 2a in 84% yield
1.
[
a]
Table 1. Optimization of reaction conditions
2
or
a
Additive
Solvent
mL)
Temp
( C)
Time
(h)
Yield
(%)
(
Entry 9). The use of additives didn’t alter the reaction outcome
S. No
o
[b]
(
3a
(Entries 12-16). Under similar organic solvent-free reaction
conditions, (NMe)-indole also gave the corresponding product
1
2
2a
2a
---
---
H
2
O (3)
Reflux
Reflux
3
3
53
47
3a in good yields (Entry 17).
MeOH (3)
Under the optimized condition, we explored the scope and
limitation of the TBHP mediated oxidative dearomatization
reaction of indole derivatives (Table 2). The electronic effects of
the substituent on the indole ring and the nature of substituent
on the indole nitrogen play a pronounced role in determining the
type and yield of the product. Presence of electron donating 5-
OMe group on the free (NH)-indole produced the corresponding
trimer 2c in appreciable yields. Conversely, electron withdrawing
3
4
5
6
7
8
2a
2a
2a
2a
2a
2a
---
---
---
---
---
---
CH
3
CN (3)
Reflux
100
100
100
80
3
3
3
3
3
3
34
28
---
---
79
54
DMSO (3)
DMF (3)
Toluene (3)
5-cyano group drastically affected the yield of the product 2g.
The 2-methylindole gave the corresponding unsymmetrically
substituted C2-quaternary indolinone product 2f in 80% yield. It
is noteworthy to mention here that the N-allylindole derivative
gave the corresponding N-deallylated C2-quaternary indolinone
product 2a by C-N bond cleavage followed by C-C bond
formation (Table 2, Entry 8). Interestingly, inductively electron
withdrawing 5-bromoindole gave the corresponding C3-
quaternary indolinone 2h instead of expected C2-quaternary
product. A similar reversal in product selectivity for the electron
[
c]
c]
---
---
[
60
[
c,d]
[e]
9
2a
---
---
100
3
84
[
[
c]
c]
10
11
12
13
14
15
16
17
2a
2a
2a
2a
2a
2a
2a
3a
---
---
---
120
120
RT
RT
RT
80
3
4
81
83
---
---
---
---
---
---
---
[10]
withdrawing substituents was reported earlier. The products 2f
Copper
acetate
Copper
triflate
[c]
[c]
3
and 2b were further confirmed by single crystal XRD studies
(
Figure 1).
1
---
[
c]
ZnCl
2
12
3
---
Benzoic
acid
[c]
54
---
[
c]
PTSA
80
3
[
c]
---
---
100
3
73
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European Journal of Organic Chemistry
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COMMUNICATION
.
[
18]
Figure 1. ORTEP diagrams of compounds 2f and 2b
The oxidative dearomatization reaction of N-alkylated
indole derivative was found to be general for diverse alkyl
derivatives. The presence of lipophilic alkyl chain did not deter
the course of reaction (3c, 3d). The presence of electron
donating –OMe group also facilitates the formation of C3-
quaternary indolinone derivative 3d in acceptable yields. The
scope of substrate is given in Table 2.
Table 2. Substrate scope for C2/C3-quaternary indolinone derivative
[
a]
synthesis
[a] Unless otherwise mentioned all the reactions were performed with 1 mmol
of (NH)-indole or (NR)-indole and 70% aqueous solution of TBHP (400 µL).
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European Journal of Organic Chemistry
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COMMUNICATION
Figure 2. Variable time NMR analyses of TBHP mediated oxidation of N-
methylindole.
MacMillan and co-workers had previously reported that the
amount of oxidant in the reaction medium affected the position
[
19]
of oxygenation of N-alkylated indole derivatives. Based on this
report, we investigated the effect of varying the amounts of
oxidant in the reaction medium. Our observations showed that
increasing the quantum of TBHP oxidant from 0.4 mL to 1 mL
led to the formation of corresponding isatin derivatives (Scheme
The NMR studies confirmed the formation of C3-
quaternary indolinone 3a in the reaction medium. Kobayashi and
co-workers stated that under oxidative reaction environment, the
presence of C3 substitution in the free (NH)-indole is detrimental
2). Surprisingly, the reaction carried out with free (NH)-indole did
[
12]
and it leads to the oxidative cleavage of the substrate.
We
not yield the expected isatin derivative.
presume that oxidative cleavage could be one of the reasons
behind the lack of formation of isatin product by the TBHP
mediated oxidation of C2-quaternary indolinones 2a (Scheme
2(ii)). These observations imply that the substituent on indole
nitrogen determines the course of the reaction.
In order to confirm whether the oxidative dearomatization
of indoles proceeds via radical intermediate, the TBHP mediated
oxidation of N-methylindole was performed in presence of
radical quencher TEMPO (Scheme 3(i)). The lack of formation of
isatin confirms that the reaction is driven via
a radical
intermediate. The use of either nitrogen or oxygen atmosphere
did not influence the yield of the product significantly (Scheme
3(ii)). Hence, it is not required to perform the reaction under inert
Scheme 2. One-pot synthesis of isatin derivatives
reaction conditions. In Scheme 3(ii), the use of excess amount
of TBHP (1 mL) resulted in the one-pot transformation of (NMe)-
indole to the corresponding isatin derivative.
A careful analysis of the reaction mixture (Scheme 2(i))
revealed that the formation of trace quantities of C3-quaternary
indolinone derivative 3a along with expected isatin 4b. The
formation of 3a was further confirmed by quenching the reaction
mixture within
1 h prior to complete conversion. These
observations indicate that the transformation of (NMe)-indole to
isatin 4b could progress via C3-quaternary indolinone
intermediate 3a. This surmise was further confirmed by
performing TBHP assisted one-pot transformation of C3-
quaternary indolinone 3a to 4b (Scheme 2(ii)). To further
substantiate the formation of 3a in the reaction medium, the
following NMR experiment was performed at different time
intervals (Fig. 2).
Scheme 3. Mechanistic investigations
To substantiate the role of water solvent in the 70% TBHP
solution in the oxidative dearomatization reaction, we have
performed the reaction with TBHP solution in decane (5.0-6.0 M).
The isatin product was obtained in appreciable yields (Scheme
3(iii)). This observation indicates that the type of solvent in
which TBHP is dissolved also does not play a significant role.
We also carried out the oxidative dearomative cross-coupling
reaction of 2-methylindole with 5-cyanoindole and indole.
However, both the reaction yielded only homocoupled product 2f
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European Journal of Organic Chemistry
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COMMUNICATION
instead of expected, cross-coupled reaction product. Based on
the results obtained from the control experiments, we outline a
plausible mechanism for the TBHP mediated formation C2/C3-
quaternary indolinone and isatin derivatives (Fig. 3).
derivatives. The substituent effect on the indole nitrogen on the
product selectivity was demonstrated using free (NH)-indole and
(NR)-indole derivatives.
Experimental Section
Materials and methods:
Materials:
Substituted Indoles were purchased from Sigma Aldrich and Avra
chemicals. tert-Butyl hydroperoxide solution 70% in H O and tert-Butyl
2
hydroperoxide solution in decane (5.0-6.0 M) were purchased from
1
Sigma Aldrich. Melting points were uncorrected. H-NMR was recorded in
13
Bruker model avance-II 300 MHz & 400 MHz and C-NMR in 75 MHz &
00 MHz spectrometer using TMS as an internal standard and CDCl or
DMSO-d as a solvent. The JEOL GCMATE II GC-MS with data system
1
3
6
is a high resolution, Electron impact (EI) methods were used for
analyzing mass of molecules. FT-IR spectrum recorded using Perkin
Elmer Spectrum RX I model.
Methods:
Synthesis of Indole trimer and isatin derivatives: To a stirred mixture
2
of indole (1 mmol) and TBHP solution 70% in H O (400 µL for indole
o
trimer or 1 mL for isatin synthesis) was heated at 100 C under air
atmosphere for 3 or 5 hours. The progress of the reaction was monitored
by TLC. After completion of the reaction, the reaction mixture was diluted
with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The
.
combined organic layer was dried with anhydrous Na
concentrated under reduced pressure. The residue was purified by flash
column chromatography on silica gel (Eluent: Ethyl acetate: hexane 1:2).
2
SO
4
and
Figure 3. Plausible mechanism
The C3 peroxygenation of free (NH)-indole followed by the
[
12]
elimination of t-BuOH lead to the formation of 3H-indol-3-one.
Acknowledgements
Further, two consecutive nucleophilic addition of free (NH)-
indoles on to the 3H-indol-3-one could have resulted in the
formation of C2-quaternary indolinone 2a. Unlike free (NH)-
indoles, peroxygenation of (NMe)-indole took place at C2 carbon.
The C2-peroxygenated indole on elimination of t-BuOH followed
by the addition of two molecules of (NMe)-indole led to the
formation of 3a which on further oxidation yielded 4b. To
address the reviewers comment, C3-quaternary indolinone 3a
was synthesized separately by closely following a previously
Financial support from the Science and Engineering Research
Board, DST-SERB (No. EMR/2016/000317) and Council of
Scientific and Industrial Research, CSIR (80(0085)/16/EMR-II) is
gratefully acknowledged by S.S.G. The authors thank the
SASTRA Deemed University for providing lab space and NMR
facility and J.K thanks SASTRA University for financial
assistance. S.S.G. thanks Dr. Sai Subramanian for his valuable
suggestions.
[
17]
reported literature procedure.
3a on subject to the TBHP
mediated oxidation reaction condition also gave the product 4b
in quantitative yields. Although, at this juncture, the reason for
preferential C2 vs C3 peroxygenation is not understood
completely.
Keywords: Indole; Oxidative dearomatization; Isatin; Peroxide;
Green synthesis
[
[
1]
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J.-H. Lee, T. K. Wood, J. Lee, Trends Microbiol. 2015, 23, 707-718.
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H. Preut, S. Ziegler, D. Rauh, H. Waldmann, Nat. Chem. 2010, 2, 735-
Thus, we have demonstrated the metal and organic solvent free,
one-pot oxidative dearomatization reaction of indole leading to
the formation of biologically important diverse oxindole
7
40.
P. S. Prathima, R. Bikshapathi, V. J. Rao, Tetrahedron Lett. 2015, 56,
385-6388 and references cited therein.
6
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European Journal of Organic Chemistry
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COMMUNICATION
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[
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Key Topic*
Jagatheeswaran Kothandapani, Singarajanahalli Mundarinti
[
a]
[
a]
[b]
Krishna Reddy, Subbiah Thamotharan, Shankar Madan
[
c]
[d]
Kumar, Kullaiah Byrappa and Subramaniapillai Selva
[
a]
Ganesan*
Page No. – Page No.
TBHP mediated substrate controlled oxidative
dearomatization of indoles to C2/C3-quaternary indolinones
An efficient metal-free oxidative dearomatization reaction of indoles was reported for the synthesis of diverse C2/C3-
quaternary indolinones. The nature of substituent on the indole nitrogen dictates the type of product formed in the reaction.
[
[
a]
b]
Department of Chemistry, School of Chemical and Biotechnology,
SASTRA Deemed University, Thanjavur-613401, Tamil Nadu, India,
Fax: +91 (4362) 264120; E-mail: selva@biotech.sastra.edu
Biomolecular Crystallography Laboratory, Department of
Bioinformatics, School of Chemical and Biotechnology, SASTRA
Deemed University, Thanjavur 613 401, India.
[
[
c]
d]
PURSE Laboratory, Mangalagangotri, Mangalore University,
Mangalore 574 199, India.
Department of Materials Science, Mangalore University, Mangalore
574 199, India.
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.