Tandem Wittig – Reductive annulation decarboxylation approach for the synthesis of indole and 2-substituted indoles

Article abstract of DOI:10.1016/j.tetlet.2018.04.001

A simple tandem Wittig reaction-reductive decarboxylation route is established for the synthesis of indoles from commercially available o-nitrobenzaldehydes and a stable phosphorane. The method allows access to indoles in a very fast manner without involving any metal or expensive reagents or inert atmosphere. Also 2-substituted indoles are obtained which forms an important core of many biological active compounds.

Full text of DOI:10.1016/j.tetlet.2018.04.001

Accepted Manuscript
Tandem Wittig - reductive annulation decarboxylation approach for the syn-
thesis of indole and 2-substituted indoles
Prajesh S. Volvoikar, S.G. Tilve
PII:
S0040-4039(18)30432-5
https://doi.org/10.1016/j.tetlet.2018.04.001
TETL 49864
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
18 January 2018
31 March 2018
1 April 2018
Please cite this article as: Volvoikar, P.S., Tilve, S.G., Tandem Wittig - reductive annulation decarboxylation
approach for the synthesis of indole and 2-substituted indoles, Tetrahedron Letters (2018), doi: https://doi.org/
10.1016/j.tetlet.2018.04.001
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Graphical Abstract
Tandem Wittig - reductive annulation
decarboxylation approach for the synthesis
of indole and 2-substituted indoles
Leave this area blank for abstract info.
Prajesh S. Volvoikar a and S. G. Tilve a,b
*

1
Tetrahedron Letters
Tandem Wittig - reductive annulation decarboxylation approach for the synthesis of
indole and 2-substituted indoles
Prajesh S. Volvoikar a and S. G. Tilve a, b 
a Department of Chemistry, Goa University, Taleigao Plateau, Goa, 403206 (India)
b Organic Chemistry Department, RUDN University, 6 Miklukcho-Maklaya str., Moscow 117198, Russian Federation
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A simple tandem Wittig reaction-reductive decarboxylation route is established for the synthesis
of indoles from commercially available o-nitrobenzaldehydes and a stable phosphorane. The
method allows access to indoles in a very fast manner without involving any metal or expensive
reagents or inert atmosphere. Also 2-substituted indoles are obtained which forms an important
core of many biological active compounds.
Available online
Keywords:
Keyword_1:Indole
2009 Elsevier Ltd. All rights reserved.
Keyword_2: Wittig reaction
Keyword_3: Tandem
Keyword_4: Reductive cyclisation
Keyword_5: Phosphorane
1. Introduction
These reactions can be run in much shorter time if carried out
under microwave reactors.9 Palladium catalysed reductive
cyclisation using carbon monoxide is also known to be effective
way of construction of indole nucleus.10 Continuing our interest
in reductive cyclisation for the synthesis of nitrogen
heterocycles,11 we report herein one pot method for the synthesis
of 2,3-unsubstituted indoles, and 2-alkyl indoles using stable
Wittig reagents. These 2-alkyl indoles find their presence in
many of the bioactive frameworks, for example oxypertine A is
an antipsychotic agent, indomethacin10 B is a nonsteroidal
antiinflammetry agent and paraadoline C is an alazaric agent
(Fig. 1).1d
The indole ring constitutes large percentage of naturally
occurring heterocyclic compounds. It is of immense interest to
medicinal chemist due to its usage in synthetic pharmaceuticals
such as antimicrobial, antibacterial, anti-inflammatory, antitumor,
anticancer etc.1 Due to this indole scaffold has become target of
research for developing methodologies and large number of
methods have been accomplished. Synthesis of indole has been
reviewed several times.2 Recently several powerful strategies
utilizing metal catalysed cross coupling reactions have been
developed for this ring system.
functionalisation has attracted much interest amongst synthetic
organic chemist.3,4
The C-H insertion through nitrene
Very recently C-H
intermediates2g was developed by Cadgon, Sundberg and
Hessienberger.5 Cadgon’s initial studies indicated triethyl
phosphite to be better reagent for the reductive cyclisation
leading to carbazoles. Mali et al showed that the yield to 2-
carboethoxy indole increases when fivefold excess of triethyl
phosphite was used. From our laboratory use of
triphenylphosphine in refluxing diphenyl ether was reported for
the synthesis of 2-acyl indoles.6 The formation side product N-
ethyl indole in case of triethyl phosphite mediated reaction is
avoided using triphenylphosphine. Later Freener et al. refined
this reaction using refluxing o-dichlorobenzene.7 Subsequently
Sanz et al. developed a much milder procedure in refluxing
toluene using dioxomolybdenium catalyst.8 However, the latter
two procedures requires much longer time (16-18h).
Figure 1: Drugs containing 2-methyl indole
2. Results and discussion
Indoles and 2-substituted indoles can be conveniently
prepared by 2-step synthesis using Cadgon’s method or by other
———
 Corresponding author. Tel.: +91-832-651917; e-mail: stilve@unigoa.ac.in

2
Tetrahedron
reductive cyclisation5,12 methods wherein first 2-vinyl
also provided ester 5a in comparatively lower yield. Freemen’s
method for nitrene formation with triphenylphosphine in
refluxing o-dichlorobenzene resulted in mixture of indole 4a and
indole-2-carboxylic acid 6a in 29% and 27% yield respectively.
As in none of the above cases we could get the required parent
indole except partly in the last method we chose our protocol for
further studies.
nitrobenzene is prepared from 2-nitrobenzaldehydes via
appropriate unstable Wittig reagent or other reagents under
anhydrous conditions in inert atmosphere and then are
reductively cyclised to get the parent indole in 25 to 55% yield
(Scheme 1).
Scheme 1: Literature synthesis
We were interested in developing reactions condition which does
not involve the problem of handling unstable Wittig reagents and
get the product in a single step. In order to do that we thought
that if we use appropriate stable phosphorane 2, we may be able
to achieve Wittig reaction, reductive cyclisation, hydrolysis and
decarboxylation in one pot as shown in Scheme 2.
Scheme 4. Stepwise approach
The isolation of acid 6a under Sanz’s condition suggested that in
our one step protocol the corresponding ester 5a is formed first
which then undergoes hydrolysis followed by decarboxylation
and not via decarboxylative reductive cyclisation as proposed in
scheme 2. Hence, we compared the yield of one pot protocol with
step wise reaction sequence with isolation product at every step
(Scheme 4). Cinnamate ester 3a was isolated in 90% yield;
reductive cyclisation of 3a with triethyl phosphite in xylene gave
indole ester 5a in 73% yield. Hydrolysis of the ester with
trifluroacetic acid and decarboxylation at high temperature
fetched the acid 6a and the indole 4a in 90 and 80% yield
respectively. The overall yield of the stepwise sequence was
found to be 47% and required three chromatographic purification
steps.
Scheme 2: Retrosynthetic pathway.
To test the hypothesis, a mixture of o-nitrobenzaldehyde 1a (1
equiv), phosphorane 2a (1 equiv) and triphenylphosphine (2.4
equiv ) were refluxed in diphenyl ether for 1 h. Usual workup
provided parent indole 4a in 66% yield (table 1, entry 1).
Table 1. One pot synthesis of indoles
Sr. No.
R
H
5-Cl
1
R1, R
H, H
H, 5-Cl
4
4a
4b
4c
4d
4e
4f
4g
4h
4i
Yield % a
66
1
2
3
4
5
6
7
8
9
10
11
12
13
1a
1b
1c
1d
1e
1f
1g
1a
1b
1c
1d
1e
1g
50
46
51
52
62
45
43
47
45
48
47
36
5-Br
H, 5-Br
5-OMe
4,5-OMe
4,5,6-OMe
4,5-OCH2O
H
5-Cl
5-Br
5-OMe
4,5-OMe
4,5-OCH2O
H, 5-OMe
H, 5,6-OMe
H, 4,5,6-OMe
H, 5,6-OCH2O
CH3, H
CH3, 5-Cl
CH3, 5-Br
CH3, 5-OMe
CH3, 5,6-OMe
CH3, 5,6-OCH2O-
4j
4k
4l
Scheme 3. One pot Wittig reductive cyclisation studies
After confirming that the required product could be obtained by
the reaction conditions reported from our laboratory,6 we
evaluated the other reaction conditions employed for reductive
cyclisation known in literature (Scheme 3). Cadgon’s method in
refluxing triethyl phosphite showed complete conversion of
starting in just 30 minutes, resulting in ester 5a in 68% yield. The
same result was obtained in refluxing xylene in presence of
triethyl phosphite. Sanz’s condition with molybdenum catalyst
4m
a isoated yields
As the one pot protocol gave better yield in shorter reaction time,
this protocol was then explored on variety of nitrobenzaldehydes
to fetch the corresponding indoles (table 1). Nitrobenzaldehydes
with one, two and three methoxy groups were easily converted to

3
2.
(a) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127-
its corresponding indole derivatives in moderate yield. The
method was then successfully extended to synthesize 5-chloro
and 5-bromo indoles in 50 and 46% yields respectively, which
can be potentially exploited for further functionalisation of indole
nucleus. For the synthesis of 2-methyl indoles phosphorane 2b
was required. This was synthesized by alkylating 2a with methyl
iodide. Following the same protocol the phosphorane 2b was
reacted with nitroaldehydes 1a-f to fetch all important 2-methyl
indole derivatives in slightly lower yields than the corresponding
unsubstituted indoles. Lower yields of 2-alkyl indoles were
attributed to their higher reactivity. The 2-methyl indoles are
important starting intermediates for preparing pharmaceutically
active compounds (Scheme 5).13
2198; (b) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873-
2920; (c) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106,
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J. J.; Reeves, J. T.; Fandrick, D. R.; Tan, Z.; Yee, N. K.;
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Scheme 5. Application to bioactive compounds
Conclusions
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W.; Rector, S. R.; O'Neil, S. N. Tetrahedron 2005, 61, 3637-3649;
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Soderberg, B. C. G. Tetrahedron 2010, 66, 1800-1805;
In conclusion a practical metal free synthesis of indole and 2-
methyl indoles in one pot from easily available substituted o-
nitrobenzaldehydes and stable phosphoranes was achieved. The
reactions involved in this one step protocol are Wittig reaction,
reductive cyclisation, hydrolysis and decarboxylation. The
important feature of this methodology is its ease of handling of
substrates, short reaction time and no requirements of inert
atmosphere.
(g) Motohiro, A.; Teruyuki, K.; Yoshihisa, W. Chem.Lett. 1992,
769-772;(h) Crotti, C.; Cenini, S.; Rindone, B.; Tollari, S.;
Demartin, F. Chem. Commun. 1986, 784-786.
Acknowledgments
11. (a) Kadam, H. K.; Parvatkar, P. T.; Tilve, S. G. Synthesis 2012,
44, 1339-1342; (b) Volvoikar, P. S.; Parvatkar, P. T.; Tilve, S. G.,
Eur. J. Org. Chem. 2013, 2172-2178.
We are grateful to the DST (EMR/2016/00091) New Delhi
and Ministry of Education and Science of the Russian Federation
(the Agreement № 02.А03.21.0008) for the financial assistance.
Prajesh S. Volvoikar thanks the CSIR, New Delhi for the Junior
Research Fellowship and Senior Research Fellowship.
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References and notes
1.
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Chem. Soc., Perkin Trans. 1 2001, 2491-2515; (d) Kaushik, N.
K.; Kaushik, N.; Attri, P.; Kumar, N.; Kim, C. H.; Verma, A. K.;
Choi, E. H. Molecules 2013, 18, 6620-6662; (e) Kawasaki, T.;
Higuchi, K. Nat. Prod. Rep. 2005, 22, 761-793; (f) Ishikura, M.;
Abe, T.; Choshi, T.; Hibino, S. Nat. Prod. Rep. 2013, 30, 694-752;
(g) Toyota, M.; Ihara, M. Nat. Prod. Rep. 1998, 15, 327-340; (h)
Cacchi, S.; Fabrizi, G.; Goggiamani, A. Org. Biomol. Chem. 2011,
9, 641-652. (a) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004,
104, 2127-2198; (b) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105,
2873-2920; (c) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006,
106, 2875-2911; (d) Shiri, M. Chem. Rev. 2012, 112, 3508-3549;
(e) Vicente, R. Org. Biomol. Chem. 2011, 9, 6469-6480;
13. Gong T-J.; Cheng, W-M.; Su, W.; Xiao, B.; Fu, Y., Tetrahedron
Lett. 2014, 1859-1862.
14. General
procedure
for
synthesis
of
indoles
from
nitrobenzaldehyde: In a 50 ml round bottom flask containing
magnetic stir bar was charged with o-nitro benzaldehydes (2
mmol), phosphorane (2.2 mmol), triphenyl phosphine (4.6 mmol)
and diphenyl ether (10 mL) and heated at 260 oC for 1 h. The
reaction massl was then cooled to room temperature and poured
on silica column. Products were isolated by eluting with pet ether
to 3:1 pet ether: ethyl acetate.

4
Tetrahedron
Highlights
 One pot synthesis of indoles and 2-alkyl
indoles.
 Metal free synthesis.
 Tandem Wittig reaction, reductive
cyclisation, hydrolysis and decarboxylation.
 No requirements of special experimental
conditions.
 A general and convenient method.