NH4Cl-promoted synthesis of symmetrical and unsymmetrical triindolylmethanes under solvent-free conditions

Article abstract of DOI:10.3184/030823408X361101

The synthesis of various triindolylmethanes from indole-3-carboxaldehyde, using indole derivatives as reactants and NH₄Cl as catalyst under solvent-free conditions, is described. This methodology provides access to both symmetrical and unsymmetrical triindolylmethanes in excellent yields. With N-methylindole particularly, indole-3-carboxaldehyde appears to act as a formyl donor, leading to the exclusive formation of a symmetrically trisubstituted product. The novelty of the methodology lies in its operational simplicity, environment friendly reaction conditions, and inexpensive and easy availability of the catalyst. A plausible mechanism of formation of the products is suggested.

Full text of DOI:10.3184/030823408X361101

568 RESEARCH PAPER
OCTOBER, 568–571
JOURNAL OF CHEMICAL RESEARCH 2008
NH4Cl-promoted synthesis of symmetrical and unsymmetrical
triindolylmethanes under solvent-free conditions
Subhendu Naskar, Abhijit Hazra, Priyankar Paira, Krishnendu B. Sahu, Sukdeb Banerjee and
Nirup B. Mondal*
Indian Institute of Chemical Biology, Council of Scientific and Industrial Research, 4 Raja S. C. Mullick Road, Jadavpur,
Kolkata 700 032, India
The synthesis of various triindolylmethanes from indole-3-carboxaldehyde, using indole derivatives as reactants and
NH4Cl as catalyst under solvent-free conditions, is described. This methodology provides access to both symmetrical
and unsymmetrical triindolylmethanes in excellent yields. With N-methylindole particularly, indole-3-carboxaldehyde
appears to act as a formyl donor, leading to the exclusive formation of a symmetrically trisubstituted product.
The novelty of the methodology lies in its operational simplicity, environment friendly reaction conditions, and
inexpensive and easy availability of the catalyst. A plausible mechanism of formation of the products is suggested.
Keywords: triindolylmethanes, ammonium chloride, solvent free synthesis
Triindolylmethane (TRIM) has received considerable attention
due to its various biological activities1,2 and industrial
importance.3 It can be used as acceptor of hydride ions4 and
it also acts as an effective chloride ion receptor.5 Despite their
importance from the pharmacological, industrial and synthetic
points of view, comparatively few methods have been developed
for the preparation of triindolylmethanes. The formation of
triindolylmethane from indole and ethyl orthoformate in the
presence of ethanolic HCl first appeared in the literature in
1952.6 Bergman7 has reported the synthesis of TRIMs by using
substituted indoles and acetic formic anhydride. The preparation
of symmetrical TRIMs by the condensation of indoles with
orthoformate in presence of p-TSA was reported by Akgün
et al.8 Chakraborty and coworkers9 have proposed a useful
variation of this reaction using acid-washed montmorillonite
clay as catalyst. Other synthetic methods have appeared in the
literature.10,11 Recently, we reported the synthesis of TRIMs
using different Lewis acids and also molecular iodine as
catalyst.12 Despite the availability of different methodologies,
there is scope for the development of a clean and efficient
process with newer reagents, as one of the recent challenges
in organic synthesis is the demand for new methodologies that
afford products of structural complexity in fewer synthetic steps
and from simple starting materials.
synthetic processes such as aliphatic Claisen rearrangements,13
the Biginelli synthesis of 3,4-dihydropyrimidinones,14 in Ugi
four-component reactions,15 and also in a four-component
synthesis of pyrrolo[3,4-b]pyridinones.16 It is used in the
reduction of nitrophenols;17,18 the reduction of alkyl and
acyl azides to the corresponding amines and amides was
also achieved using Zn and NH4Cl.19 Azizian et al. claimed
the NH4Cl-catalysed one-pot synthesis of diindolylmethanes
(DIM) under solvent free conditions.20 But to the best of
our knowledge there appears to have been no report of the
synthesis of triindolylmethanes (TRIMs) using NH4Cl as
catalyst under solvent-free conditions.
Results and discussion
As with our previous work on the synthesis of triindolyl-
methane, we utilised indole-3-carboxaldehyde (1) as
substrate, indole (2a) as reactant and NH4Cl as catalyst in the
initial study. The reactions were carried out without solvent
in a reaction flask. Thus, the reaction with 1 and 2a using
NH4Cl at elevated temperature (120°C) under solvent-free
conditions yielded 5a as the only isolable product (Scheme 1).
The characterisation of 5a was accomplished by spectral
analysis (1H, 13C NMR, MS) and was confirmed as a
symmetrical triindolylmethane.12 The same reaction was
repeated varying the reaction time and proportion of
the catalyst to optimise the yield of the product. It was
observed that for 5a, the mole ratio with 1: 2: 1 of indole-
3-carboxaldehyde, indole and NH4Cl at 120°C provided
a maximum yield within 30 min. When similar reactions
were performed with substituted indoles (2b, 2c, 3 and 4) as
reactants, some variations were observed in the yield of the
products and also in reaction time with respect to 5a (Table1).
Progress in the field of solvent-free reactions is gaining much
importance from both an environmental and an economic
point of view, because solvent-free processes not only reduce
the use of potentially hazardous organic solvents, but also
minimise the formation of side products. Herein we report the
solvent-free synthesis of triindolylmethanes using ammonium
chloride as catalyst with better yields than hitherto.
Ammonium chloride (NH4Cl) is a cheap, eco-friendly and
easily available substance, which is used in various organic
HN
R''
R''
CHO
R''
NH Cl
4
CH
+
R'
N
H
120oC
N
H
NH
N
H
R'
R'
2,5, a: R' = R'' = H
b: R' = Me, R"= H
c: R' = H, R"= Br
2a–c
1
5a–c
Scheme 1 NH4Cl catalysed reaction of indole-3-carboxaldehyde (1) with indoles 2a–c.
* Correspondent. E-mail: nirup@iicb.res.in

JOURNAL OF CHEMICAL RESEARCH 2008 569
Table 1 Synthesis of TRIMs from 1 and indoles 2–4 using NH4Cl as catalyst under solvent free conditions
Indole
Product/s
Time/h
Catalyst/mmol
Yield(s)/%
2a
2a
2a
2b
2b
2b
2c
2c
2c
3
5a
0.5
0.5
1.5
1
0.5
1
74
5a
96
96
5a
2
5b
0.5
1
2
0.5
1
1
0.5
1
2
0.5
1
1
57
5b
2
87
5b
4
1
87
5c
74
5c
1.5
3
96
5c
96
6 + 2a
6 + 2a
6 + 2a
7a + 7b + 2a
7a + 7b + 2a
7a + 7b + 2a
1
30 + 10
45 + 25
45 + 25
15 + 35 + 5
20 + 55 + 10
20 + 55 + 10
3
3
3
5
4
1
4
3
4
5
aAll the reactions were performed at 120 °C; increase of temperature did not improve the yields.
bAll the products were characterised by IR, NMR and mass spectrometry.
cYield of isolated pure products.
Thus, from the reactions of 2b (2-methylindole) and 2c
(5-bromoindole) with 1, only the unsymmetrical products 5b
and 5c, respectively, were obtained. On the other hand, the
reaction using N-methylindole (3) as reactant yielded only the
symmetrical product 6,9 along with indole (2a) (Scheme 2).
However, when 3-methylindole (4) was the reactant the
formation of the products took a different turn; the reaction
yielded both the symmetrical (7a) and unsymmetrical (7b)
triindolylmethanes, along with 2a21 (Scheme 3). The yield of
the unsymmetrical product was appreciably higher than that
of the symmetrical product.
A plausible mechanism for the formation of symmetrical
and unsymmetrical TRIMs (7a and 7b), using NH4Cl as the
catalyst, is depicted in Scheme 4. It is presumed that in the
reaction NH4Cl may enhance the electrophilic character of
the carbonyl carbon of 1 by hydrogen bonding,20 facilitating
the nucleophilic attack of 3-methylindole (4) and thus
resulted in formation of the intermediate A, in equilibrium
with intermediate B. NH4Cl again might activate the
intermediate B to promote a Michael-type addition of 3-
methylindole (4) and finally facilitate the formation of the
unsymmetrical triindolylmethane 7b. On the other hand the
formation of symmetrical TRIM (7a) may take place through
the intermediate A, where in situ loss of indole (2a)
resulted the intermediate aldehyde C.22,23 Two moles of
4 then react with C, culminating in 7a. The formation of 2a in
this reaction indicated that there must be a mechanism for the
passing of the CHO group from 1 to 4 through the intermediate
A. We believe that the mechanism for the formation of 6
follows the same pathway as described for 7a. However,
the formation of an unsymmetrical triindolylmethane
from the reactions of 3 could not be detected even after
several attempts.
We attempted similar reactions using indole-2-carboxylic
acid, indole-3-acetic acid, 3-indolylacetonitrile, 1-methyl-
indole-3-acetic acid, and indole-3-carboxylic acid as the
reactants. In these cases, we were unable to isolate any
products from the reactions even after a longer reaction time
(10 h) and also using higher amounts of catalyst (10 mmol).
We presume that the nucleophilicity of indole, which is highly
Me
N
CHO
NH Cl
4
CH
2a
+
+
120oC
N
N
H
N
N
Me
Me
Me
1
3
6
Scheme 2 NH4Cl catalysed reaction of indole-3-carboxaldehyde with N-methylindole.
Me
NH
HN
CHO
CH3
N
H
CH
NH4Cl
120oC
Me
Me
Me
2a
+
+
+
Me
CH
HN
N
H
N
H
NH
HN
1
4
7b
7a
Scheme 3 NH4Cl catalysed reaction of indole-3-carboxaldehyde with 3-methylindole.

570 JOURNAL OF CHEMICAL RESEARCH 2008
OH
CH
H3N-H
O
H
N
H
N
H
N
H
HCO
+
2a
N
H3C
H3C
H
H3C
N
H
A
C
1
4
4
NH4Cl
OH
CH
H3C
H
C
H
N
H
N
4
4
7a
NH
7b
NH4Cl
N
NH4Cl
H3C
H3C
B
Scheme 4 Route to the symmetrical and unsymmetrical triindolylmethanes 7a and 7b.
Bis-(5-bromoindol-3-yl)-(3-indolyl)methane (5c): Colourless needles,
m.p. 239–241°C (acetone–pet. ether) (lit.12 238–240°C). IR: 3420,
1451, 1336, 1213 cm-1. NMR (DMSO-d6): dH 6.07 (s, 1H, Ar3CH),
6.88 (m, 1H), 6.96 (s, 1H), 7.02 (bs, 3H), 7.15 (m, 2H), 7.34 (m,
4H), 7.53 (bs, 2H), 10.79 (1H, NH-indole), 11.01 (2H, NH-5-
bromoindole); dC 30.5 (Ar3CH), 110.7 (C), 110.8 (C), 111.5 (CH),
113.5 (CH), 113.6 (CH), 117.4 (C), 117.6 (C), 117.7 (C), 118.1 (CH),
119.3 (CH), 120.7 (CH), 120.8 (CH), 121.4 (CH), 123.2 (CH), 123.3
(CH), 125.0 (CH), 126.6 (C), 126.7 (C), 128.4 (C), 128.5 (C), 135.3
(C), 136.6 (C). ESI-MS: m/z 542 [M + Na]+.
Tris-(1-methylindol-3-yl)methane (6): Orange needles, m.p. 255–
256°C(acetone–pet.ether)(lit.9256–258°C).IR:1612,1471,1331cm-1.
NMR (Py-d5): dH 3.40 (s, 9H, CH3), 6.52 (s, 1H, Ar3CH), 6.94 (s, 3H,
CH), 7.10 (t, 3H, J = 7.2 Hz, CH), 7.26 (t, 3H, J = 7.8 Hz, CH), 7.35
(d, 3H, J = 8.1 Hz, CH), 7.77 (d, 3H, J = 8.1 Hz, CH). ESI-MS: m/z
404 [M + H]+.
reduced by the electron withdrawing groups at the 2 or 3
positions, plays a vital role in the reactions.
In summary, we have developed a simple, efficient,
and environmentally acceptable synthetic method for the
preparation of triindolylmethanes using NH4Cl as catalyst
under solvent free conditions. The mild reaction conditions,
ease of product separation, ready availability of the catalyst,
and excellent yields of products, makes this procedure an
acceptable one for the synthesis of triindolylmethanes. The
formation of products by apparent migration of the formyl
group from one indole nucleus to another is an interesting
sideline of these reactions.
Experimental
Tris-(3-methylindol-2-yl)methane (7a): Colourless prisms, m.p.
318–320°C (acetone–pet. ether) (lit.9 319–320°C). IR: 3383, 1624,
1429 cm-1. NMR (Py-d5): dH 2.13 (s, 9H, CH3), 6.29 (s, 1H, Ar3CH),
7.04 (m, 6H), 7.37 (d, 3H, J = 7.8 Hz), 7.48 (d, 3H, J = 7.8 Hz), 10.50
(s, 3H, NH); dC 9.1 (CH3), 34.6 (Ar3CH), 107.4 (C), 112.1 (CH),
118.7 (CH), 119.1 (CH), 121.5 (CH), 129.6 (C), 133.9 (C), 136.4 (C).
ESI-MS: m/z 404 [M + H]+.
(3-Indolyl)-bis-(3-methylindol-2-yl)methane (7b): Colourless
needles, m.p. 229–230°C (acetone–pet. ether) (lit.12 228–230°C). IR:
3404, 1623, 1454 cm-1. NMR (Py-d5): dH 2.44 (s, 6H, CH3), 5.09 (s,
1H, Ar3CH), 6.69 (s, 1H), 7.03 (t, 1H, J = 6 Hz), 7.21 (m, 4H), 7.31
(d, 2H, J = 7.8 Hz), 7.42 (d, 1H, J = 8.1 Hz), 7.61 (d, 1H, J = 7.8 Hz),
7.73 (d, 2H, J = 6 Hz), 11.27 (s, 2H, NH-3-Me-Indole), 11.86 (s, 1H,
NH-Indole); dC 9.1 (CH3), 34.1 (Ar3C), 107.2 (C), 111.7 (CH), 112.2
(CH), 115.6 (C), 118.8 (CH), 119.2 (CH), 119.7 (CH), 121.3 (CH),
122.1 (CH), 125.2 (CH), 128.1 (C), 130.4 (C), 136.5 (C) 136.9 (C),
138.2 (C).ESI-MS: m/z 390 [M + H]+.
IR spectra were recorded in KBr pellets on a JASCO FTIR (model
410) instrument.1H and 13C NMR spectra were recorded in pyridine-
d5 or DMSO-d6 with tetramethylsilane as internal standard on a
Bruker 300 MHz DPX spectrometer operating at 300 and 74.99
MHz respectively. ESI-MS (positive-ion) was recorded using LC-
ESI-Q-TOF micro mass spectrometer. Indole-3-carboxaldehyde and
other indole derivatives were purchased from Aldrich Chemicals
Ltd (USA). Organic solvents for chromatographic purification were
purchased from E. Merck (India) and were of analytical grade.
All chromatographic purifications were performed with silica gel
(100–200 mesh) obtained from SRL (India).
Triindolylmethane synthesis using NH4Cl: general procedure
A mixture of indole-3-carboxaldehyde (1, 0.145 g, 1 mmol), indole
(2–4, 2 mmol) and NH4Cl (0.055 g, 1 mmol) in a conical flask
was heated in an oil bath with occasional stirring with a glass rod
at 120°C for the appropriate time (see Table 1). The progress of the
reaction was monitored by TLC. After completion of the reaction, the
mixture was cooled and cold water was added to dissolve NH4Cl.
The product was filtered off and the residue was purified by column
chromatography, eluting with petroleum ether/ethyl acetate.
Tri-(3-indolyl)methane (5a): Colourless prisms, m.p. 241°C
(acetone–pet. ether) (lit.24 245–247°C). IR: 3386, 1624, 1428 cm-1.
NMR (DMSO-d6): dH d 6.11 (s, 1H, Ar3CH), 6.88 (t, 3H, J = 7.2 Hz),
6.98 (s, 3H), 7.04 (t, 3H, J = 7.2 Hz), 7.37 (d, 3H, J = 7.8 Hz), 7.44
(d, 3H, J = 7.8 Hz), 10.74 (s, 3H, NH); dC 31.0 (Ar3CH), 111.4 (CH),
118.0 (CH), 118.3 (C), 119.3 (CH), 120.7 (CH), 123.2 (CH), 126.8
(C), 136.6 (C). ESI-MS: m/z 362 [M + H]+.
We are extremely grateful to the Director, IICB, for laboratory
facilities, the Council of Scientific and Industrial Research
(CSIR) for awarding fellowship to S. Naskar, A. Hazra,
P. Paira and K. B. Sahu and also to Dr V. S. Giri, Dr. R.
Mukherjee and Mr K. Sarkar for recording the spectra.
Received 18 March 2008; accepted 18 July 2008
Paper 08/5166 doi:10.3184/030823408X361101
Published online: 10 October 2008
(3-Indolyl)-bis-(2-methylindol-3-yl)methane (5b): Colourless
needles, m.p. 260–262°C (acetone–pet. ether) (lit.12 260–262°C).
IR: 3397, 1458, 1343, 1297 cm-1. NMR (DMSO-d6): dH 2.09 (s, 6H,
CH3), 6.07 (s, Ar3CH), 6.14 (s, 1H), 6.67 (m, 2H), 6.84 (m, 5H), 7.06
(m, 2H), 7.22 (m, 2H), 7.37 (d, J = 7.8 Hz, 1H), 10.65 and 10.70
(m, 3H, NH); dC 12.8 (CH3), 31.1 (Ar3CH), 111.1(CH), 112.2 (CH),
113.2 (C), 113.5 (C), 118.6 (CH), 118.7 (CH), 118.9 (CH), 119.1
(CH), 119.3 (CH), 119.8 (CH), 120.2 (CH), 121.7 (CH), 124.2 (CH),
128. (C), 129.3 (C), 129.7 (C), 132.2 (C), 132.6 (C), 135.8 (C), 135.9
(C), 137.5 (C). ESI-MS: m/z 390 [M + H]+.
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