Reductive aromatization of oxindoles to 3-substituted indoles

Article abstract of DOI:10.1016/j.tetlet.2020.152109

A practical and scalable approach for the synthesis of 3-substituted indoles is delineated via hydride nucleophilic addition to 3-substituted-2-oxindoles. The reaction proceeds through reductive aromatization involving indolinium ion intermediate. A wide range of 3-functionalized indoles have been synthesized. The method is employed for the synthesis of 3,3?-bis-indoles and a dimeric 3-indole derivative. Moreover, this protocol is used to obtain naturally occuring amino acid tryptamine.

Full text of DOI:10.1016/j.tetlet.2020.152109

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Reductive aromatization of oxindoles to 3-substituted indoles
Tirtha Mandal, Gargi Chakraborti, Jyotirmayee Dash
PII:
S0040-4039(20)30560-8
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https://doi.org/10.1016/j.tetlet.2020.152109
TETL 152109
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Tetrahedron Letters
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1 June 2020
2 June 2020
Please cite this article as: Mandal, T., Chakraborti, G., Dash, J., Reductive aromatization of oxindoles to 3-
substituted indoles, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.152109
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Reductive aromatization of oxindoles to 3-
substituted indoles
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Tirtha Mandal, Gargi Chakraborti and Jyotirmayee Dash

1
Tetrahedron Letters
Reductive aromatization of oxindoles to 3-substituted indoles
Tirtha Mandala, Gargi Chakrabortia and Jyotirmayee Dasha
aSchool of Chemical Sciences, Indian Association for the Cultivation of Science, Jadavpur, Kolkata-700032, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A practical and scalable approach for the synthesis of 3-substituted indoles is delineated via
hydride nucleophilic addition to 3-substituted-2-oxindoles. The reaction proceeds through
reductive aromatization involving indolinium ion intermediate. A wide range of 3-functionalized
indoles have been synthesized. The method is employed for the synthesis of 3,3ʹ-bis-indoles and
a dimeric 3-indole derivative. Moreover, this protocol is used to obtain naturally occuring amino
acid tryptamine.
Available online
Keywords:
Bis-indoles;
Hydride transfer;
Indolinium ion;
3-Indole;
2009 Elsevier Ltd. All rights reserved.
Oxindole;
Reductive aromatization
Indole is the most common and widely studied heterocyclic
system. It is embodied in a myriad of natural products,
pharmaceuticals and polymers [1]. The widespread natural
occurrence of 3-substituted indoles in plants [2], fungi [3] and
marine organisms [4] as well as their medicinal applications have
stimulated continuing development of new methods for their
preparation [5, 6]. The neurotransmitter amino acids like
tryptophan [7], tryptamine [8], and serotonin contain the indole
skeleton (Figure 1). In higher plants, degradation of tryptophan
produces heteroauxin (indole-3-acetic acid), a plant hormone.
Bufotenine is used as hallucinogens in humans. Marine indole
alkaloids like (E)-methyl 3-(6-bromo-1H-indol-3-yl)acrylate
have been extracted from a number of sponges [9-11]. Alkaloid
(±)-chelonin A (Figure 1), isolated from a marine sponge of the
Chenolaplysilla sp [12] show potent antimicrobial and anti-
inflammatory activities. Similarly, discodermindol discovered in
discodermiapolydiscus shows moderate cytotoxicity [13].
Figure 1. Some biologically important 3-indole derivatives.
Scheme 1. Previous reports and our method.
———
 Corresponding author. E-mail: ocjd@iacs.res.in

2
Tetrahedron
Scheme 2. Preparation of 3-substituted oxindole derivatives.
The classical Fischer indole synthesis remains one of the most
Although a number of synthetic methods are available to
important approaches to obtain 3-substituted indoles [14]. Since
indole undergoes electrophilic substitution mainly on the C3-
position, several methods like Friedel Crafts alkylation or
acylation and Barbier type reaction have been developed over the
years [15]. Recently, Ackermann and co-workers reported an
efficient atom-economical method to synthesize C3-substituted
indoles based on intermolecular titanium chloride catalyzed
hydroamination of alkynes with hydrazine derivatives (Scheme
1) [16]. Kumar et al. developed Michael addition to synthesize 3-
substituted indoles using NbCl5 [17]. The preparation of various
functionalized 3-indoles was also reported via the formation of
reactive alkylideneindolenine intermediates [18]. Singh et al.
developed an electrochemical multicomponent reaction involving
indole, aldehyde and malononitrile for the construction of 3-
functionalized indoles (Scheme 1) [19]. Over the last decade, C-
H activation has also emerged as a method for regioselective
functionalization of indoles (Scheme 1) [2, 20]. Otha and co-
workers reported a palladium catalyzed highly selective C3-
arylation of N-tosyl indole using 2-chloropyrazine [21]. Sames
and Lamaire et al. developed a Heck-type cross coupling of
indole and 4-bromo-3-nitroanisole using palladium acetate and
triphenyl phosphine catalytic system for the C3-arylation [22].
Recently, Bellina and co-workers reported a palladium mediated
ligand free direct C3- arylation of free (NH)-indoles with
aromatic bromides [23]. Gaunt and co-workers demonstrated a
Cu catalyzed direct C3-arylation of indoles using aryliodonium
salts at room temperature employing the catalytic system
Cu(OTf)2/dtbpy [24]. Recently, KOtBu mediated metal free
approaches for the synthesis of C3-aryl indoles were developed
by Kumar et al and Lu et al independently by the reaction of NH-
free indoles and aryl halides in DMSO (Scheme 1) [25].
Oxindoles were also used to synthesize 3-indoles. Treatment of
3-oxindoles with POCl3 followed by hydrogenation on Pd/C and
triethylamine provided the corresponding 3-indoles (Scheme 1)
[26]. Kayaki et al. reported an example of the synthesis of a 3-
indole derivative from the corresponding 3-oxindole by
deoxygenative hydrogenation using pincer-Ru complexes
(Scheme 1) [27]. Further, a reductive strategy for the synthesis of
3-indoles from the corresponding 3-substituted-3-hydroxy
oxindoles was reported using boranes [28].
access 3-substituted indoles, given the importance of the C3-
functionalized indoles, the development of a rapid and scalable
method with high flexibility in substitution pattern is desirable.
Recently, we have reported the synthesis of 2-substituted and
2,3-disubstituted indole derivatives using Grignard addition via
dehydrative
aromatization
involving
indolinium
ion
intermediates (Scheme 1) [29]. We envisioned that instead of
Grignard reagent, addition of a hydride nucleophilic source to
C3-substituted oxindoles would lead to 3-substituted indoles via
the formation of indolinium ion intermediate using aromatization
as the driving force (Scheme 1). This methodology will allow an
easy access to 3-functionalized indoles from easily synthesizable
oxindole starting materials with wide substrate scope.
In order to examine the feasibility of our proposed work, a
variety of N-protected 3-substituted 2-oxindoles were prepared
from N-protected isatins (see Scheme S1, Supporting
Information, S.I.). The addition of alkyl or aryl Grignard reagents
to N-substituted isatins 1 followed by SnCl2 mediated reductive
deoxygenation of intermediate 3-alkyl/aryl-3-hydroxy oxindole 2
afforded the corresponding oxindoles 3a-i in good yields
(Scheme 2, a) [29, 30]. C3-allyl oxindole precursors 5a-b were
synthesized by allyl indium addition to isatin 1 followed by
subsequent reductive deoxygenation of the intermediate 4
(Scheme 2, b).
With the required 3-oxindole precursors in hand, a systematic
study was necessary to conduct for the development of the
reaction to obtain 3-indole derivatives. Since it is well known
that boron and aluminium based reagents are generally used for
the reduction of amides via hydride transfer, we began our
optimization studies by using LiAlH4, the most commonly used
reagent for reduction of amides to amines [31]. Previously,
Nishino and co-workers used LiAlH4 for the synthesis of a 3-
indole derivative from 3-oxindole [32]. To our delight, when the
reaction was performed in the presence of 2 equiv. of LiAlH4 in
THF at room temperature for 4 h, the desired product 6a was
obtained in acceptable yield (Table 1, entry 1). However, the
yield of the reaction decreased by using 4 equiv. of LiAlH4,
keeping other reaction parameters fixed (entry 2). The outcome
of the reaction did not alter upon increase of reaction time or

3
Table 1. Optimization of the reactiona
Entry
1
Hydride source (equiv.)
Solvent
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
Et2O
Diglyme
THF
T (° C)
Time (h)
Yield (%); 6ab
LiAlH4 (2.0)
LiAlH4 (4.0)
LiAlH4 (2.0)
LiAlH4 (2.0)
LiAlH4 (2.0)
LiAlH4 (1.5)
LiAlH4 (1.5)
LiAlH4 (1.0)
LiAlH4 (0.5)
AlH3 (1.5)
Rt
Rt
Rt
70
0
4
4
8
4
4
2
1
2
2
2
2
2
2
2
2
2
65
2
50
3
55
4
40
5
74
6
0
80
7
0
64
8
0
40
20
9
0
10
11
12
13
14
15
16c
0
trace
DIBAL-H (1.5)
Li(OtBu)3AlH (1.5)
BH3-Me2S (1.5)
LiAlH4 (1.5)
LiAlH4 (1.5)
LiAlH4 (1.5)
0
No reaction
No reaction
62
0
0
0
40
0
Trace
78
0
aReaction conditions: 3a (1.0 equiv, 0.3 mmol). bYield calculated are isolated yields. cPreparative scale experiment.
temperature (entry 3 and 4). Yield of 6a increased by carrying
out the reaction at 0 °C (entry 5). 6a was produced in 80% yield
when the reaction was performed using 1.5 equivalent of LiAlH4
at 0 °C for 2 h (entry 6). However, the yield of 6a dropped to
40%, when the reaction was carried out for 1 h (entry 7).
Moreover, use of catalytic amount or 1 equiv. of LiAlH4 (Table
1, entry 8 and 9) was detrimental to the reaction. We next
screened different reducing agents under optimized reaction
conditions (Table 1, entry 6). Reaction did not proceed with
AlH3, DIBAL-H, Li(OtBu)3AlH as the hydride nucleophilic
source (Table 1, entry 10-12). However, in the presence of BH3-
Me2S, 6a was obtained in 62% yield (Table 1, entry 13). Further
optimization studies were then carried out in different solvents
generally used for LiAlH4. The yield of 6a was found to be
decreased considerably in diethyl ether and diglyme instead of
THF (entry 14-15). It is worth noting that the reaction was scaled
(1.0 g of 3a) without loss of yield under the optimized conditions
(entry 16).
different alkyl and aryl C3-substituents such as methyl, ethyl,
allyl, benzyl, phenyl and 4-methoxy phenyl were converted to the
corresponding 3-substituted indoles (Table 2, 6a-h) in excellent
yields. Oxindoles containing both electron donating and
withdrawing substituents in the aromatic ring provided the
corresponding C3-indoles in excellent yields (Table 2, 6i-k). The
oxindoles bearing different halo substituents were effectively
converted to the corresponding indoles (6i and 6j) in good yields.
These halo indoles can be used as precursors for further synthetic
transformations by cross-coupling reactions. Electron donating
methoxy and electron withdrawing fluoro functional groups are
well tolerated under the reaction conditions to furnish the
corresponding indoles 6k and 6i in good yields (Table 2). The N-
Ts protected 3-indole derivative 6l was obtained in 72% yield,
whereas reaction with N-Boc protected 3-oxindole 3k failed to
provide the corresponding 3-indole 6m (Table 2).
It is intriguing to find that the NH-free oxindole precursor 7
provided the product 3-methyl indole 6n in good yield. The
reaction was performed in gram scales (see Scheme S6 and S7,
Supporting Information, S.I.) successfully affording 3-substituted
indoles 6a and 6i in good yields (78% and 70% respectively).
With the optimal reaction conditions (Table 1, entry 6), the
scope and generality of this methodology was subsequently
explored with respect to substitution in the C3-position as well as
aromatic ring of the oxindole moiety. The oxindoles containing

4
Tetrahedron
Table 2. Synthesis of 3-substituted indolesa.
entry
1
Substrate
Product
entry
8
Substrate
Product
2
3
9
10
4
5
11
12
6
7
13
14
aThe reactions were performed using 3-oxindole (0.3 mmol, 1 equiv.) with LiAlH4 (1.5 equiv.) in THF (4
mL) for 2 h at 0 °C. bYields refer to the gram scale experiment.
mediated reductive deoxygenation of intermediate 9 afforded
oxindole derivatives 10a-b (Scheme 3) [29]. To our delight,
reaction of 10a-b with LiAlH4 under the standard conditions
produced the corresponding 3,3´-bisindoles 11a-b in 74% and
72% yields, respectively (Scheme 3).
Furthermore, the synthesis of a dimeric indole derivative 13
was achieved using the developed protocol. Reaction of dimeric
oxindole 12, prepared using our developed method [29], with
LiAlH4 provided 13 in 75% yield (Scheme 4; Scheme S8, S.I.).
Scheme 3. Synthesis of bis-indoles.
Next the method was used for the synthesis of bis-indoles [33]
11 (Scheme 3) from C3-indolyl oxindoles 10. Base mediated
addition of indole 8 to isatin 1 [34] followed by subsequent SnCl2
Scheme 4. Synthesis of a dimeric 3-substituted indole derivative.

5
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Next, the utility of the developed method was demonstrated by
the synthesis of naturally occurring amino acid tryptamine [8].
Reaction of oxindole 14 with LiAlH4 provided tryptamine 15 in
62% isolated yield (Scheme 5).
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Scheme 5. Synthesis of tryptamine.
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We presume that the addition of LiAlH4 to oxindoles
generates the intermediate A via hydride transfer to the amide
carbonyl of the oxindole (Scheme 6). Elimination of ŌAlH2 leads
to the formation of indolinium ion intermediate B [29, 35].
Subsequent aromatization provides the desired indole derivatives
(Scheme 6). As aromatization is the driving force, C3-hydrogen
elimination is faster than another hydride transfer from LiAlH4 to
the indolinium ion intermediate B.
(c) Alex, K.; Tillack, A.; Schwarz, N.; Beller, M. Angew. Chem.
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Scheme 6. Plausible mechanism for the formation of 3-indoles
via hydride transfer.
In summary, we have developed a general protocol for the
synthesis of 3-substituted indoles using an optimized amount of
LiAlH4. The synthetic pathway proceeds via hydride transfer to
the oxindole moiety involving indolinium ion intermediate
followed by aromatization. Various 3-functionalized alkyl and
aryl indoles were obtained in excellent yields. The 3,3ʹ-bis-
indoles were also obtained in high yields using this method. The
synthesis of a dimeric indole derivative further highlights the
efficiency of the developed protocol. The method described
herein is mild, simple and efficient, providing a convenient
synthetic access to a wide variety of 3-substituted indoles.
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2015, 17, 82;
Declaration of competing interests
The authors declare no competing financial interests or personal
relationships that could have appeared to influence the work
reported in this paper.
(b) Chen, J.; Wu, J. Angew. Chem. Int. Ed. 2017, 56, 3951.
26. Kubo. A.; Nakai, T. Synthesis 1980, 365.
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Acknowledgments
We thank CSIR-India for financial support. TM and GC thank
CSIR-India for research fellowships.
29. Mandal, T.; Chakraborti, G.; Karmakar, S.; Dash, J. Org. Lett.
2018, 20, 4759.
Supplementary Material
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1H NMR and 13C NMR data and spectra and HRMS data of the
products are available. Supplementary data to this article can be
found online at https://doi.org/
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2019, 21, 8044.

6
Tetrahedron
Highlight


Practical and scalable synthetic route to 3-indoles
Partial reduction-aromatization of oxindoles to 3-
indoles using LiAlH4



The reaction proceeds via an indolinium ion
intermediate
Synthesis of a diverse class of 3-indoles and bis-
indoles
A quick access to tryptamine
Graphical Abstract
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Reductive aromatization of oxindoles to 3-
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Leave this area blank for abstract info.
Tirtha Mandal, Gargi Chakraborti and Jyotirmayee Dash