A Convenient Modification of the Fischer Indole Synthesis with a Solid Acid

Article abstract of DOI:10.1080/00397911.2014.984854

(Chemical Equation Presented). A new one-pot version of the titled reaction involves heating a mixture of a carbonyl compound, a phenylhydrazine, and the cation exchange resin Amberlite IR 120 in refluxing ethanol. A variety of enolizable aldehydes, and ketones and several substituted phenylhydrazines could thus be converted to the corresponding indoles in excellent yields (70-88%). Reaction times were typically 6-10 h, with the resin being then filtered off and the product isolated after minimal workup.

Full text of DOI:10.1080/00397911.2014.984854

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A Convenient Modification of the Fischer Indole
Synthesis with a Solid Acid
Sosale Chandrasekhara & Somnath Mukherjeea
a Department of Organic Chemistry, Indian Institute of Science, Bangalore, India
Accepted author version posted online: 06 Jan 2015.
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To cite this article: Sosale Chandrasekhar & Somnath Mukherjee (2015): A Convenient Modification of the Fischer Indole
Synthesis with a Solid Acid, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
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A convenient modification of the Fischer indole synthesis with a solid acid
Sosale Chandrasekhar1, Somnath Mukherjee1
1Department of Organic Chemistry, Indian Institute of Science, Bangalore, India
Corresponding author. Sosale Chandrasekhar, Email: sosale@orgchem.iisc.ernet.in
Abstract
A new one-pot version of the titled reaction involves heating a mixture of a carbonyl
compound, a phenylhydrazine and the cation exchange resin Amberlite® IR 120 in
refluxing ethanol. A variety of enolizable aldehydes and ketones, and several substituted
phenylhydrazines could thus be converted to the corresponding indoles in excellent yields
(70-88%). Reaction times were typically 6-10 h, the resin being then filtered off and the
product isolated after minimal work-up.
INTRODUCTION
The indole skeleton is famously present in a very large number of biologically-active
molecules, both naturally-occurring and synthetically-engineered.[1-3] The essential amino
acid tryptophan and an eponymous group of alkaloids come easily to mind,[4] but there
also exists an expanding clutch of synthetic species covered by trade names that attest to
1

their commercial value. The skeleton has thus been the target of several synthetic
strategies and approaches spread over the preceding century. The vast majority of these
start from an aromatic precursor and fashion the fused pyrrole moiety by various tactics,
whether ingenious or deliberate.
One such, the Fischer synthesis, is a classical reaction that hails from the formative era of
modern organic chemistry,[1–3] but continues to be pursued for both its synthetic value
and mechanistic fascination.[5,6] (The key C-C bond forming step involves a symmetry-
allowed [3,3]-sigmatropic shift, vide infra.) Originally, the reaction was effected starting
from phenylhydrazones (1, Scheme 1), simple precursors that are indeed readily
prepared. Heating these in an appropriate solvent (e.g. EtOH) along with an acid catalyst
leads to the formation of the corresponding indoles (4).
The transformation is believed to occur via the initial isomerization of 1 to the ene-
hydrazine 2, which requires the presence of an α proton in the hydrazone moiety. The 2
then undergoes a [3,3]-sigmatropic rearrangement to form the di-imine 3, which re-
aromatizes and undergoes internal nucleophilic attack, to lead finally to the indole 4.
The acid catalyst is believed to facilitate the isomerisation of 1 to 2, a variety of Brønsted
and Lewis acids having been employed to effect the transformation. Interestingly, ZnCl2,
one of the earliest catalysts thus employed, often continues to be the catalyst of choice. A
problem with the reaction, however, is that the ammonia by-product neutralizes the acid
catalyst, which thus must be employed at stoichiometric levels.
2

An interesting variant of the Fischer indole synthesis involves the in situ formation of the
phenylhydrazone from a carbonyl precursor and phenylhydrazine. This ‘one-pot’ reaction
is feasible because hydrazone formation is also promoted by acid; and the reaction can be
run without removal of the water by-produced with the intermediate hydrazone, as the
aromatic stability of the final indole product shifts this initial equilibrium.
The increasing importance of environmentally-friendly ‘green’ methodologies has led to
the use of aqueous media, or even solvent-free conditions, for effecting the Fischer indole
synthesis.[7,8] The catalysts employed, however, are not always easily obtained; in fact,
the solvent-free versions often employ the acid catalyst in excess, possibly to overcome
poor diffusion of the reactants in the semi-solid or viscous reaction medium.
It was thus of interest to explore alternative acid catalysts that are both readily available
and easily recovered from the reaction medium upon work-up. This led to the possibility
of using resin-based acids, the results of our studies being described in detail below.
Interestingly, although such polymer-bound cation exchangers have been known for long,
they have not been employed extensively in the Fischer indole synthesis.[7]
RESULTS AND DISCUSSION
In exploratory studies, a mixture of phenylhydrazine, a ketone (typically, cyclohexanone)
and a cation exchange resin (e.g. Dowex® or Amberlite®) was refluxed in a solvent
(MeOH, EtOH, MeCN, CHCl3, EtOAc and dioxane) over several hours. The reaction was
3

monitored by thin layer chromatography, which also indicated the formation of the
expected indole product. Reaction conditions were then optimized in terms of catalyst,
solvent and the time taken for completion of the reaction. The optimized conditions and
yields are shown in Table 1 (full characterization data can be found in the supplementary
information file).
The reaction has been performed herein with a variety of ketones (5, Scheme 2) and
several para substituted phenylhydrazines (6), the final indole product (8) being isolated
in generally excellent yields in a reasonable period of time (typically ~ 80% in 6-10 h).
Interestingly, cyclic ketones (items 8-17) generally took longer for completion of
reaction, as did certain aromatic ketones (items 19-26). The cyclic ketones are possibly
sterically hindered, with the derived indole products also possibly strained because of the
ring fusion; the aromatic ketones would be unreactive because of conjugation between
the carbonyl and aromatic moieties. Also, in the case of ketones with two different α-
acidic sites, the indole regio-isomer derived from the more stable ene-hydrazine (I) was
apparently formed.
The effect of the para substituent (R3) in the phenylhydrazone on the reaction time was
unpredictable. However, the time taken was apparently enhanced in many cases,
regardless of the nature of R3. This may be due to competing kinetic and thermodynamic
factors, electron- donating R3 enhancing the nucleophilicity of 6, but electron-
withdrawing R3 possibly stabilizing 8 (and vice-versa). (These conclusions are clearly
tentative, but they are apparently similar to previous observations.[9,10] Also, attempts to
4

recycle the catalyst led to considerably lower yields, so were not pursued further in view
of its ready availability and minimal requirements at laboratory scales.)
The replacement of the normally employed soluble acid catalysts by a solid acid herein is
a significant improvement, as the catalyst is generally employed at stoichiometric levels
(often in large excess) in the Fischer indole synthesis.[11] This is because of the liberation
of ammonia as a by-product, which neutralizes a large part of the acid catalyst. The
advantages of a solid acid catalyst are clearly greater on larger scales, thus leading to
environmentally sustainable (‘green’) processes.
CONCLUSIONS
A convenient modification of the conventional Fischer indole synthesis has been
developed, essentially characterized by simplicity of operation and work-up. These derive
from the fact that the normally employed soluble acid catalyst has been replaced by a
solid acid (the Amberlite® cation exchange resin). Excellent yields have been realized
with a wide range of reactants, with reasonable reaction times. Additional benefits,
particularly on large scales, involve environmental concerns, as the acid catalyst is
normally employed in excess in the Fischer indole synthesis.
SUPPORTING INFORMATION
Supporting Information: Full characterization data for all compounds reported herein.
This material can be found via the ‘‘Supplementary Content’’ section of this article’s
webpage.
5

EXPERIMENTAL
Typical Procedure
A mixture of the carbonyl compound (5, 1.0 mmol), arylhydrazine (6, 1.2 mmol) and the
solid acid (7, Amberlite®, 1.5 g, obtained from Aldrich Chemical Co.) was refluxed in
absolute ethanol (10 ml) for 8 h. The reaction was monitored by tlc, and upon completion
the mixture was cooled to room temperature, the catalyst filtered off and washed
thoroughly with ethyl acetate (30 ml). The combined organics were washed with water,
dried (Na2SO4) and concentrated in vacuo. The resulting residue was chromatographed
on a silica gel column eluting with ethyl acetate-hexane mixtures, to obtain the purified
indole (8). This was fully characterized by IR, 400 MHz 1H NMR and HRMS, and
melting point (solids).
ACKNOWLEDGMENTS
We are grateful to CSIR (New Delhi) for fellowship support to S.M.
REFERENCES
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376.
[2] Joule, J. A.; Mills, K. Heterocyclic Chemistry 4th ed.; Blackwell Science Ltd.:
Oxford, 2000; pp. 353-370.
[3] Smith, M. B.; March, J. March’s Advanced Organic Chemistry: Reactions,
Mechanisms and Structure, 6th ed.; John Wiley: Hoboken, 2007; pp. 1674-1676.
6

[4] Barbour, P. M.; Marholz, L. J.; Chang, L.; Xu, W.; Wang, X. Chem. Lett. 2014, 43,
572–578. doi:10.1246/cl.131230.
[5] Razzaq, T.; Glasnov, T. N.; Kappe, C. O. Eur. J. Org. Chem. 2009, 1321–1325. doi:
10.1002/ejoc.200900077.
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2727–2735. doi: 10.1080/00397910600764766.
[7] Xu, D-Q.; Wu, J.; Luo, S-P.; Zhang, J-X.; Wu, J-Y.; Du, X-H.; Xu, Z-Y.; Green
Chem., 2009, 11, 1239–1246. doi: 10.1039/b901010f.
[8] Matsumoto, K.; Tanaka, A.; Yukio, I.; Hayashi, N.; Toda, M.; Bulman, R. A.
Heterocycl. Commun. 2003, 9, 9-12. doi: 10.1515/HC.2003.9.1.9.
[9] Ishii, H. Acc. Chem. Res. 1981, 14, 275-283.
[10] Robinson, B. Chem. Rev. 1969, 69, 227-250.
[11] Ishii, H.; Murakami, Y.; Furuse, T.; Hosoya, K.; Ikeda, N. Chem. Pharm Bull. 1973,
21, 1495-1505.
7

Table 1. Conditions and yields (of 8) for the Fischer indole synthesis in Scheme 2
Item
1
R1
Me
Et
R2
Me
R3
Time (h)
8
Yield (%)
80
H
2
Me
H
8
75
3
Me
H
Et
MeO
H
10
8
75
4
Me2CH
70
5
Me
H
Me2CH
H
10
6
82
6
n-C5H11
H
72
7
Me
n-C5H11
MeO
H
10
10
12
10
14
12
10
8
84
8
Cyclopentanone
Cyclohexanone
Cyclohexanone
Cyclohexanone
Cyclohexanone
4-Methylcyclohexanone
4-t-Butylcyclohexanone
Cycloheptanone
Cyclooctanone
Cyclododecanone
PhCH2
84
9
H
85
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
MeO
CN
Br
85
80
88
H
82
MeO
Br
90
10
12
12
7
88
H
80
H
78
Me
Ph
MeO
MeO
Br
85
Me
6
88
p-Cl-C6H4-
Ph
Me
10
12
12
14
10
10
7
82
Ph
H
74
PhCH2
Ph
H
80
p-(MeO)-C6H4-
p-(NO2)-C6H4-CH2
β-Tetralone
β-Tetralone
p-(NO2)-C6H4-
p-(NO2)-C6H4-
H
72
H
64
H
86
MeO
90
8

Scheme 1. The Fischer indole synthesis with the accepted mechanism
9

Scheme 2. The one-pot Fischer indole synthesis starting from a carbonyl compound (5)
and a phenylhydrazine (6) catalyzed by Amberlite® IR 120 (7) to yield the indole 8; the
pattern of substitution observed in 8 implies that the reaction occurs via the ene-
hydrazine I
10