Mild, efficient Fischer indole synthesis using 2,4,6-trichloro-1,3,5- triazine (TCT)

Article abstract of DOI:10.1016/j.tetlet.2013.07.157

Mild and efficient protocol for the Fischer indole synthesis using TCT has been described. TCT serves as a mild and inexpensive catalyst. Under these conditions several functional groups such as ester, cyano, sulfone, amides, and ethers are tolerated. By this method, many functionalized analytically pure indoles were prepared easily without the need of purification.

Full text of DOI:10.1016/j.tetlet.2013.07.157

Tetrahedron Letters 54 (2013) 5591–5596
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Tetrahedron Letters
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Mild, efficient Fischer indole synthesis using 2,4,6-trichloro-1,3,5-
triazine (TCT)
⇑
Eranna Siddalingamurthy, Kittappa M. Mahadevan , Jagadeesh N. Masagalli, Hosanagara N. Harishkumar
Department of Post Graduate Studies and Research in Chemistry, School of Chemical Sciences, Kuvempu University, Shankaraghatta 577 451, Karnataka, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Mild and efficient protocol for the Fischer indole synthesis using TCT has been described. TCT serves as a
mild and inexpensive catalyst. Under these conditions several functional groups such as ester, cyano, sul-
fone, amides, and ethers are tolerated. By this method, many functionalized analytically pure indoles
were prepared easily without the need of purification.
Received 22 June 2013
Revised 28 July 2013
Accepted 31 July 2013
Available online 8 August 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
2,4,6-Trichloro-1,3,5-triazine
Cyanuric chloride
Fischer indole synthesis
Mild catalyst
Carbazole
2,4,6-Trichloro-1,3,5-triazine (TCT) is an inexpensive, readily
available chemical in the laboratory. This compound was used as
a starting material for the synthesis of various heterocycles.1,2 Re-
cently TCT has served as an inexpensive, nonvolatile, and easy to
handle reagent for various organic transformations.3–6 For in-
stance, TCT promotes Beckman rearrangement,7 sulfide to sulfone
oxidation,8 Swern oxidation,9 Lossen rearrangement,10 sulfonyl
chloride preparation,11 and Friedel–Craft acylation.12 TCT is often
used for functional group transformations such as carboxylic acid
into esters, amides, and peptides,13 and sulfonic acids into sulfon-
amides.14 Furthermore, it has been used in the construction of het-
erocyclic ring like 1,3,4 oxadiazoles,15 2-aryl benzothiazoles,16 and
bisindoles17 and in the multicomponent reaction.18–20 TCT is also
employed in the solid support reactions.21,22 Interestingly, in all
the above examples the product isolation was easy and yields were
ranging from good to excellent. Hence prompted by these results,
we applied TCT for the Fisher indole synthesis.
catalysts. Unfortunately, most of the methods suffer due to the use
of excessive reagent, strong acidic media, and often long reaction
time. Hence mild and expedient protocol is of a significant impor-
tance. In continuation of our interest in new organic transforma-
tions in indole29–31 and quinoline32 synthesis, herein we wish to
report the mild and efficient catalyst, TCT for the first time in the
synthesis of indoles via Fischer indolization.
As a preliminary study we carried out a reaction between a
mole equivalent of phenyl hydrazine hydrochloride (1 equiv),
cyclohexanone (1 equiv) in the presence of TCT (0.5 equiv) in dry
EtOH as solvent and the reaction mixture was heated to 80 °C
(Scheme 1). To our surprise, the reaction gave complete conversion
to tetrahydrocarbazole, after 2 h. Encouraged by these results we
planned to optimize the reaction conditions. Consequently, a mix-
ture of phenyl hydrazine hydrochloride (1a) and cyclohexanone
(2a) were heated in different solvents and at reduced equivalence
of TCT. The results are summarized in Table 1. As shown in the
Indole is a versatile heterocyclic structure available in variety of
compounds with vast biological activities.23–25 Due to this, indole
and its preparation continue to capture the attention of organic
and medicinal chemists. Although, many methods are available
for the synthesis of indole ring,26 the Fisher indole synthesis using
ketones and arylhydrazines remains the most widely employed
synthetic procedure.27,28 Over here, the acid catalyzed 3,3 sigma-
tropic rearrangement of aryl hydrazones followed by elimination
of ammonia results in an indole skeleton in the presence of various
Cl
N
N
TCT
Cl
O
Cl
N
NH2
NH
+
N
H
EtOH, 80° C
2a
1a
3a
⇑
Corresponding author.
E-mail address: mahadevan.kmm@gmail.com (K.M. Mahadevan).
Scheme 1. Reaction of phenyl hydrazine with cyclohexanone in the presence of
TCT.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.157

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E. Siddalingamurthy et al. / Tetrahedron Letters 54 (2013) 5591–5596
Table 1
table the best result was obtained when we used 0.1 equiv of TCT
Optimization of reaction condition
at 80 °C temperature in EtOH solvent. Further the decrease in the
quantity of TCT slows down the reaction rate. Thus unlike aq HCl
which gives unwanted side products (i.e., hydrolysis of hydra-
zones) TCT is found to be mild and optimum to catalyze the Fischer
indolization.
Alternately, we also performed the same reaction without add-
ing TCT. As expected, heating the phenyl hydrazine and ketone in
EtOH did not give even traces of indolization but subsequent addi-
tion of TCT to the same reaction mixture and further heating for
another 2 h afforded the indole product. This confirms the role of
TCT in promoting the Fisher indolization (Scheme 1).
Solvent
TCT in equiv Temperature in
Time in h Conversiona
(%)
°C
EtOH
EtOH
EtOH
MeOH
Moist ACN
Anhyd.ACN 0.1
Anhyd THF 0.1
EtOH
EDC
0.5
0.1
0.05
0.1
0.1
80
80
80
Reflux
Reflux
Reflux
Reflux
80
2
2
4
100
100
80
4
90
4
95
>6
>6
>6
>6
10b
20b
0b
0
0.1
Reflux
0b
a
With this optimized condition and further to evaluate the scope
of this protocol, we attempted Fisher indolization with permutations
Based on LC–MS.
Hydrazones were observed as major product.
b
Table 2
Reaction of phenyl hydrazine with different ketones and aldehydes (3a–3n)
R1
O
NH2.HCl
TCT
EtOH, 80 o
R1
R
NH
+
R
N
H
C
2 a- n
1a
3 a- n
Entry
1
Ketones/Aldehydes
Product
Yield (%)
Time in h
2
M.P/Litr (°C)
O
99a
118–117/116–11833
2a
NH
3a
O
2b
2
98
2
Gummy
N
H
3b
3c
Gummy34
Gummy
O
3
4
98
2
2
2c
N
H
F
F
100a
O
2d
N
H
3d
O
59–61/60–6235
2e
5
95
3
N
H
3e
O
2f
6
7
94
95
2
2
45–46 (41–42)36
84–86/85–8637
N
H
3f
O
2g
N
H
3g

E. Siddalingamurthy et al. / Tetrahedron Letters 54 (2013) 5591–5596
5593
Table 2 (continued)
Entry
Ketones/Aldehydes
Product
Yield (%)
50
Time in h
M.P/Litr (°C)
O
O
8
9
5
138–139/14238
N
O
H
3h
3i
2h
O
H
N
O
98
2.5
142–144
O
N
H
2i
N
H
NH.HCl
O
O
N
10
11
95
2
2
Gummyb
O
N
H
3j
2j
O
O
O
S
N
O
S
98a
18539
N
O
2k
N
3k
CN
H
NC
O
2l
12
13
100a
2
170
N
H
3l
O
O
O
95a
2.5
Gummy40
N
H
O
3m
O
2m
O
O
O
N.HCl
N
14
90
3
Gummyb
Ph
O
2n
N
H
O
3n
a
Isolated without purification.
Hygroscopic.
b
of various phenyl hydrazines and ketones. The results are summa-
rized in Tables 2 and 3.
reaction with 4-chromanone (2h) took longer reaction time with
a moderate yield (entry 8) and a relatively low yield of 8 attributes
to the destruction of ether linkage by the nascent HCl. It was nota-
ble that several functional groups especially esters (2m and 2n),
amides (2i), sulfone (2k), ether (2h) in the ketone substrates (en-
tries 9, 11, 13, and 14), and halogens (1e, 1f, and 1h) in phenyl
hydrazines were tolerated during the course of the reaction (en-
tries 18, 19, and 21). Particularly in the case of 4-(40-cyano-
The reaction with symmetric ketones such as cyclohexanone
(2a) and neopentylcyclohexanone (2b) gave complete conversion,
yielding more than 90% of the corresponding indoles (entries 1
and 2). Interestingly, reaction with unsymmetrical ketones such
as 5-methyl 2-hexanone (2c) affords single regio isomers through
the cyclization of the most substituted ene hydrazine (entry 3),
which emphasizes the role of TCT as a mild acid catalyst for Fischer
indolization. Due to this, the reaction remains incomplete (stopped
at hydrazone) in the case of acetophenone. However, the interest-
phenyl)cyclohexanone (2l),
a good yield of carbazole was
observed without any solvolysis on the nitrile group (entry 12),
but in the case of ethyl-1-benzyl-4-oxopiperidine-3-carboxylate
(2n) hydrolysis of the product to corresponding acid was observed
when we kept the reaction for a longer time. However, in the case
of ethyl 2-oxocyclopentanecarboxylate (2m) no such hydrolysis
was observed.
In continuation, we further studied the scope of this reaction
with substituted phenyl hydrazines and the results are summarized
in Table 3. The phenyl hydrazines possessing electron donating
groups such as methyl (1b, 1d) and isopropyl (1c) (entries
15–17), electron withdrawing groups such as chloro (1e), fluoro
(1h), and methoxy (1g) are well tolerated to furnish good to
ing reaction with 4-Boc piperidone (2j) gave cyclized
with simultaneous deprotection of boc group (entry 10). This in
situ deprotection of boc gives directly -carboline which is further
c -carboline
c
useful for the derivatization of the amine functionality. The reac-
tion with aldehydes such as heptanal (2f) and phenyl acetaldehyde
(2g) gave an excellent yield of corresponding indoles (entries 6 and
7). Even the less reactive aromatic ketone hexanophenone (2e)
gave an excellent yield (entry 5). Interestingly, 1-(2-fluorophenyl)
acetone (2d) reacted faster giving an almost quantitative yield of
corresponding indole without any purification (entry 4), while

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E. Siddalingamurthy et al. / Tetrahedron Letters 54 (2013) 5591–5596
Table 3
Reaction of various phenyl hydrazines with different ketones (3o–3x)
Cl
N
N
N
TCT
R4
R1
R2
Cl
Cl
NH2.HCl
O
R3
R2
NH
R4
+
R3
2a-c, e, i
N
EtOH, 80 oC
H
R1
1b-h
3o-x
Entry
15
Phenyl hydrazines
Ketones
Product
Yield (%)
80
Time in h
Mp/Litr (°C)
NHNH2.HCl
O
O
2
Gummyb
2c
1b
N
H
3o
NHNH2.HCl
16
17
96
2
55–58
64–67
2c
1c
3p
N
H
NHNH2.HCl
O
90a
3.5
2e
2e
1d
Ph
N
H
3q
NHNH2.HCl
O
18
19
90
3
2
82–85
Cl
Cl
1e
Ph
3r
Cl
N
H
NHNH2.HCl
Cl
O
98a
Gummy
2c
1f
N
H
Cl
Cl
3s
NHNH2.HCl
O
O
O
20
21
97
98
2
2
87–89/88–9033
94–95/93–9533
2a
N
3t
H
1g
O
NHNH2.HCl
F
2a
3u
N
H
1h
F
NHNH2.HCl
O
H
N
O
22
23
99
98
3
2
200
Cl
1e
O
Cl
N
3v
N
H
H
2i
NHNH2.HCl
O
2b
Gummy
1d
N
3w
H

E. Siddalingamurthy et al. / Tetrahedron Letters 54 (2013) 5591–5596
5595
Table 3 (continued)
Entry
Phenyl hydrazines
Ketones
Product
Yield (%)
Time in h
Mp/Litr (°C)
NHNH2.HCl
O
24
90
3
60
2e
1c
N
H
3x
a
Isolated without purification.
Unstable.
b
H
N
Cl
N
OEt
OEt
O
N
2 EtOH
-HCl
EtOH
Cl
N
N
N
N
N
N
N
+
3HCl
Cl
Cl
EtO
N
OEt
Cl
N
Cl
Cl
Cl
H
H
Cl
N
OH
OH
O
Moist ACN
Cl
N
N
N
N
N
N
N
N
+
3HCl
2H2O
Cl
Cl
HO
N
OH
Cl
N
Cl
Cl
N
Cl
Scheme 2. Plausible mechanism in which TCT generates nascent HCl to induce Fischer indolization.
excellent yields of substituted indoles (entries 18, 20, and 21). In
addition 2,4 disubstituted phenyl hydrazine (1f) also gave an
excellent yield of the corresponding indole (entry 19). Even the ste-
ric factor due to ortho substitutions (1b and 1f) did not reduce the
reaction rate (entries 15 and 19).
It has been noticed that TCT promotes the Fischer indolization
via slow liberation of nascent HCl. This happens when nucleophilic
EtOH displaces the chloride ion from 1 mol of TCT to give 3 mol of
nascent HCl (Scheme 2). Thus liberated HCl catalyzes the hydra-
zone formation and subsequent cyclization to yield the desired in-
dole product, whereas in the case of anhydrous THF, EDC, and ACN,
HCl liberation was not found to catalyze the indolization (Table 1).
However, we noticed that the moment we used moist ACN we
found indolization. This can be attributed to the moisture in ACN
which reacts with TCT to liberate HCl and catalyzes the indoliza-
tion (Scheme 2).
In summary, we have developed a mild, efficient, and high
yielding protocol for the Fischer indolization using TCT as a cata-
lyst. Because of the mild nature of TCT, several functional groups
such as ester, amides, sulfone, ethers, and cyano are tolerated. An-
other significant feature is the ease of product isolation. Pure prod-
ucts are obtained by just evaporation of the solvent, after work-up.
Thus a wide variety of biologically active functionalized pure in-
doles can be prepared by adopting these conditions.
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