Synthesis of pharmacologically active bis(indolyl) and tris(indolyl) derivatives using chlorotrimethylsilane

Article abstract of DOI:10.1002/jccs.201300467

Chlorotrimethylsilane is found to be a comparatively fast and efficient catalyst for carrying out electrophilic substitution reactions of indoles with various aldehydes/ketones/triethylorthoformate, yielding excellent amount of bis(indolyl)methanes/tris(indolyl)methanes. The merits of this protocol are avoidance of any external energy source, minimal reaction time, simple and easy procedure and high yield under solvent free room temperature condition. The versatility of this method has been tested with various aldehydes/ketones and received satisfactory results. A simple, fast, efficient, cheap and versatile method for the synthesis of bis(indolyl)methanes and tris(indolyl)methanes under solvent free room temperature condition using chlorotrimethylsilane as a catalyst has been developed. Thus, we have demonstrated the utility of TMSCl not only as a protecting group but also as catalyst in electrophilic substitution reactions. Copyright

Full text of DOI:10.1002/jccs.201300467

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
Synthesis of Pharmacologically Active Bis(indolyl) and Tris(indolyl) Derivatives Using
Chlorotrimethylsilane
Nongthombam G. Singh, Chingrishon Kathing, Jims W. S. Rani and Rishan L. Nongkhlaw*
Department of Chemistry, North Eastern Hill University, Shillong, Meghalaya-793022, India
(Received: Sept. 11, 2013; Accepted: Dec. 10, 2013; Published Online: Jan. 20, 2014; DOI: 10.1002/jccs.201300467)
Chlorotrimethylsilane is found to be a comparatively fast and efficient catalyst for carrying out electro-
philic substitution reactions of indoles with various aldehydes/ketones/triethylorthoformate, yielding ex-
cellent amount of bis(indolyl)methanes/tris(indolyl)methanes. The merits of this protocol are avoidance
of any external energy source, minimal reaction time, simple and easy procedure and high yield under sol-
vent free room temperature condition. The versatility of this method has been tested with various alde-
hydes/ketones and received satisfactory results.
Keywords: Indole; Chlorotrimethylsilane [TMSCl]; Bis(indolyl)methane [BIMS];
Tris(indolyl)methane [TIMS]; Solvent free.
INTRODUCTION
The compounds bearing indole moiety has generated
anes have recently gained importance for preparation of
cage compounds, photochemical transformations,22-26
physicochemical studies, and as dyes. Various research
groups have reported the preparation of TIMS using differ-
ent catalysts.27-30
immense interest nowadays due to its broad spectrum of bi-
ological activity.1 Indole plays an important role in the field
of drug design as well as synthesis and it has been exploited
to various ends in medicinal chemistry.2 Bis(indolyl)meth-
anes constitute an important class of indole derivative
which serve the purpose of antibiotics3 and also play a vital
role in cancer chemotherapy due to its apoptosis, growth
inhibition and antiangiogenic activities in various cancer
cell lines and tumors.
Hence, due to their broad spectrum of biological and
synthetic applications, the preparation of bis(indolyl)meth-
anes and tris(indolyl)methanes has instigated researchers
to develop improved protocols for milder and high-yield-
ing methods.
The process of carrying out energy efficient chemical
transformations involving coupling of two or more compo-
nents in a single catalytic step avoiding large amount of sol-
vents, and complex purification methods is the main target
of every synthetic chemist. Many methods have been re-
ported for the synthesis of BIMS using various Lewis ac-
ids4,6/protic acids5 such as InCl3,6 Ln(OTf)3,7 acetic acid,8
FeCl3,9 Dy(OTf)3,10 In(OTf)3,11 zeolites,12 LiClO4,13
KHSO4,14 NBS,15 NaHSO4.SiO2,16 clay,17 PPh3.HClO4
(TPP),18 InF3,19 I2,20 etc and some have even reported with
ionic liquids like 1-butyl-3-methylimidazolium tetrafluo-
roborate or 1-butyl-3-methylimidazolium hexafluorophos-
phate ionic liquids.21 However, these methods suffer from
various drawbacks such as longer reaction times,6,10,13,21
use of expensive reagents,7,8,11 use of large amount of sol-
vents,7,11,12,13 use of either conventional heating (reflux) or
microwave,12 low yields11 involvement of complicated pu-
rification processes, etc.
RESULTS AND DISCUSSION
Our present study gives emphasis on the synthesis of
bis(indolyl)methanes and tris(indolyl)methanes using
TMSCl as a catalyst under solvent free condition. The reac-
tions were carried out by simple mixing of indole and alde-
hyde/ketone/triethtylorthoformate at room temperature
and extraction was done with ethyl acetate. Our method
(Scheme I) minimizes the reaction time and avoids usage of
additional energy source. The yield is found to vary from
good to excellent yield depending on the aldehyde/ketone
used.
The versatility of our method was tested using differ-
ent aromatic and aliphatic aldehydes/ketones. Effect of the
substituents on the aromatic ring did not have profound ef-
fect on the yield; however electron withdrawing groups on
the aromatic ring gave slightly better yield. The reaction
seems to proceed via formation of azafulvenium salt (7)
which reacts with another molecule of indole to give the
3-alkylated bis(indolyl) derivative (3) as the predominant
Another derivative of indole i.e. tris(indolyl)meth-
* Corresponding author. E-mail: rlnongkhlaw@nehu.ac.in
442
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JOURNAL OF THE CHINESE
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A Novel Synthesis of BIMS and TIMS Using TMSCl
Table 1. Screening for the optimum amount of TMSCl required
Scheme I Synthesis of various derivatives of indole
under different solvent conditions for the synthesis of 3c
TMSCl
Indole
Reaction Yield
time (min) (%)
Conditions Solvent
(Eq. mol) (Eq. mol)
0.2
0.3
0.5
1
2
2
2
2
2
2
2
2
2
2
rt mixing
rt mixing
rt mixing
rt mixing
rt mixing
rt stirring
rt stirring
rt stirring
rt stirring
-
*
*
47
65
96
96
90
95
30
89
94
95
-
-
-
*
*
2
-
*
0.5
0.5
0.5
0.5
0.5
CH2Cl2
H2O
CH3CN
EtOH
15
15
15
15
2
Reflux (80 oC) EtOH
*Product formed immediately on addition of catalyst.
product without formation of any N-alkylated product. The
most plausible pathway or mechanism is depicted in the
figure (Figure 1) below.
tion of 3c was done as shown in Table 1 and it was found
that 0.5 mole equivalent of TMSCl per 2 mole equivalent of
indole was the ideal amount for excellent yield. On further
increasing the quantity of the catalyst, the yield was found
to decrease. This may be due to over saturation of the de-
sired product by the catalyst.
The reaction of indole with a,b-unsaturated aldehyde
such as cinnamaldehyde produced the normal bis(indolyl)
1,2-addition product, however the reaction with a,b-unsat-
urated ketone such as chalcone did not form the expected
1,2-addition product but instead gave the 1,4-addition
product as shown in Scheme I.
Tris(indolyl)methanes were also prepared under sol-
vent-free room temperature condition using 1:3 TMSCl-
Indole ratio. Here we replaced the aldehyde/ketone by
triethylorthoformate. The schematic representation is given
in Scheme I.
Optimization of the quantity of TMSCl for prepara-
EXPERIMENTAL
All the concerned chemicals were purchased from Merck
and S.D.-Fine and were used without any further purification.
Products were confirmed by IR, 1H NMR, 13C NMR, Mass spec-
tra, elemental analysis and melting point data. Melting points
were determined in open capillary tubes and are uncorrected. In-
frared spectra were recorded on a BOMEM DA-8 FTIR instru-
ment and the frequencies are expressed in cm-1. 1H and 13C NMR
spectra were recorded on a Bruker Avance II-400 and DRX-300
MHz Bruker spectrometer. Mass spectral data were obtained with
a JEOL D-300 (EI) mass spectrometer. Elemental analyses were
carried out on a Heraeus CHN-O-Rapid analyzer. All reactions
were monitored by thin layer chromatography (TLC) using
precoated aluminum sheets (silica gel 60 F 254 0.2 mm thickness)
and developed in an iodine chamber. Column chromatographic
separations were carried out using ACME silica gel (60–120
mesh).
Fig. 1. Proposed mechanism for the formation of bis-
(indolyl) alkane via azafulvene. In case of 3-
substituted indole, alkylation occurs at C-2 and
the mechanism proceeds by rearrangement
pathway (Figure 2).
General procedure for preparation of 3a-p, 4a-d, 6a-c,
8a-c: To a mixture of Indole and aldehyde/ketone, TMSCl was
added and thorough mixing was done. The formation of the prod-
Fig. 2. Rearrangement of substituent from position C3
to C2.
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Article
Singh et al.
uct was noticed by the appearance of a coloured solid and was fur-
ther confirmed by TLC. Extraction of the compound was done us-
ing ethyl acetate and then washed with water (3 ´ 15 mL) and
brine solution (1 ´ 15 mL). Finally the product was triturated with
hexane as a precautionary measure in order to remove any indole
or aldehyde remnants. The products obtained were further puri-
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JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
A Novel Synthesis of BIMS and TIMS Using TMSCl
Table 3. Comparative study of preparation of 3c under different
38.2, 45.2, 111.1, 119.3, 119.4, 119.5, 121.4, 122.1, 126.2, 127.8,
128.1, 128.4, 128.5, 133.8, 136.6, 137.1, 144.2, 198.5; MS: m/z
326 [M+1]; Anal. Calcd. for C23H19NO: C, 84.89; H, 5.89; N,
4.30%; Found: C, 84.76; H, 5.70; N, 4.50%. tris(1H-indol-3-
catalyst condition. Yields are approximately the same
Reaction
Catalyst
Conditions
Solvent
References
time (min)
Cu(BF4)2.SiO2 reflux 80 oC
CH2Cl2
---
30
45
[31]
[32]
[33]
[34]
[10]
[7]
o
yl)methane (8a): Red solid, Yield: 95%, mp: 241-243 C, IR
ZnO
Heat 80 oC
(KBr): 3395, 3045, 1484, 1454, 1418,1348, 1228, 1029, 804, 744
cm-1; 1H NMR (300 MHz, Acetone-d6): d 6.19 (s, 1H), 6.86 (m,
6H), 7.04 (t, J = 7.5 Hz, 3H), 7.36 (d, J = 8.1 Hz, 3H) ArC-H),
7.47 (d, J = 8.1 Hz, 3H), 9.92 (s, 3H); 13C NMR (75 MHz, Ace-
tone-d6): d 32.2, 112.1, 119.1, 120.0, 120.5, 121.9, 124.3, 128.2,
138.1; ESI-MS (positive mode): 360 [M-1].
Polyindole salt rt stirring
EtOH
180
90
FeCl3.6H2O
Dy(OTf)3
Ln (OTf)3
InF3.H2O
TMSCl
rt stirring [omim]PF6
rt stirring [BMIM]BF4
rt stirring EtOH/H2O
60
720
600-900
*
rt stirring
rt mixing
Aqueous
---
[19]
-
*Product formed immediately on addition of catalyst.
ACKNOWLEDGEMENTS
The authors would like to thank UGC for financial as-
sistance in the form of fellowship, to SAIF-NEHU-
Shillong and SAIF-CDRI-Lucknow for analytical assis-
tance.
fied by column chromatography using Ethyl acetate-Hexane as
eluent.
For products 3a-o, 3p, 4a-d, 6a-c and 8a-c the same proce-
dure is followed with the variations in mole percentage as shown
below:
For 3a-o, 4a-d: Indole (2 mmol) and aldehyde/ketone (1
mmol), TMSCl (0.5 mmol). For 3p: Indole (4 mmol), terephth-
aldehyde (1 mmol), TMSCl (1 mmol). For 6a-c: Indole (1 mmol),
chalcone (1 mmol), TMSCl (0.5 mmol). For 8a-c: Indole (3
mmol), triethylorthoformate/trimethylortho-formate (1 mmol),
TMSCl (1 mmol).
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