Fe/Al pillared clay catalyzed solvent-free synthesis of bisindolylmethanes using diversely substituted indoles and carbonyl compounds

Article abstract of DOI:10.1039/c2ra22258b

A fast, solvent-free solid acid mediated synthetic strategy for the synthesis of bisindolylmethanes has been developed. The process is applicable to a wide range of substrates with different protecting group survival properties. Reusability of Fe/Al pilla

Full text of DOI:10.1039/c2ra22258b

View Article Online / Journal Homepage
RSC Advances
Accepted Manuscript
This is an Accepted Manuscript, which has been through the RSC Publishing peer
review process and has been accepted for publication.
Accepted Manuscripts are published online shortly after acceptance, which is prior
to technical editing, formatting and proof reading. This free service from RSC
Publishing allows authors to make their results available to the community, in
citable form, before publication of the edited article. This Accepted Manuscript will
be replaced by the edited and formatted Advance Article as soon as this is available.
To cite this manuscript please use its permanent Digital Object Identifier (DOI®),
which is identical for all formats of publication.
More information about Accepted Manuscripts can be found in the
Information for Authors.
Please note that technical editing may introduce minor changes to the text and/or
graphics contained in the manuscript submitted by the author(s) which may alter
content, and that the standard Terms & Conditions and the ethical guidelines
that apply to the journal are still applicable. In no event shall the RSC be held
responsible for any errors or omissions in these Accepted Manuscript manuscripts or
any consequences arising from the use of any information contained in them.
www.rsc.org/advances
Registered Charity Number 207890

RSC Advances
Page 1 of 6Journal Name
Dynamic Article Links ►
View Article Online
Cite this: DOI: 10.1039/c0xx00000x
www.rsc.org/xxxxxx
ARTICLE TYPE
Fe/Al pillared clay catalyzed solvent-free synthesis of
bisindolylmethanes using diversly substituted indoles and carbonyl
compounds
Deepak Kumar Sharma, a Altaf Hussain, a Mallikharjuna Rao Lambu, a Syed Khalid Yousuf,b Sudip
5
Maiety,c Baldev Singh a and Debaraj Mukherjee*a
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
efficiency in submolar scale and reusability are some of the
advantages of these catalysts over the conventional homogeneous
50 catalysts.9ꢀ12 Despite the fact that solid acid catalysts like
zeolites,13 clays14 and surface modified zirconia15 are well
reported for DIM preparation, longer reaction time and use of
toxic and volatile organic solvents as reaction media still demand
the need of new catalyst to fill the void between catalysis and
55 green chemistry. With our recent success in the development of
solid catalysts and their applications in organic synthesis,16,17
herein, we disclose the preparation and application of Fe/Al
pillared clay catalysts for the rapid synthesis of bis(indolyl)
methanes.
A fast, solvent free solid acid mediated synthetic strategy for
the synthesis of bisindolylmethanes has been developed. The
10 process is applicable to a wide range of substrate with
different protecting group survival properties. Reusability of
Fe/Al pillared clay for more than 5 cycles without significant
loss of catalytic activity adds to the features of the reaction.
The most ubiquitous of the known bioactive alkaloids are based
15 on the indole moiety. Particularly bis(indolyl)alkanes widely
occur in various natural products isolated from marine sponge
alkaloids.1 Diindolylmethanes (DIMs) and related compounds
exhibit
a wide range of biological activities including
antibacterial and antitumor.2 In a programme directed towards the
20 synthesis of indole based new chemical entities, in our earlier
communication, we designed synthesis of N,N’ꢀglycoside
derivatives of DIM’s for their antiproliferative potential against
various cancer cell lines.3 Owing to their unprecedented role in
biological chemistry, development of new catalytic processes for
25 the generation of DIM’s is always welcomed in organic
chemistry.
60
Fe/Al pillared clay catalysts were prepared by impregnation
method. FeCl3 and AlCl3 diluted in distilled ethanol, stirred
vigorously for one hour and then H+ form of Montmorillonite Kꢀ
10 clay added to the solution and stirred and refluxed for 15h
under N2 atomosphere and then dried under vacuum. Considering
65 on acidity, samples were further calcined at different
temperatures to get three different forms of catalyst (Table 1) and
stored in vacuum desiccators.
Synthetic strategies mediated through protic acids4 and Lewis
acids (BF3, AlCl3),5 ionic liquids,6 ion exchange resin7 and rare
earth metal8 have been reported in the literature for the
30 preparation of bis(indolyl)methanes. However use of harsh
conditions, long reaction times in several cases, limited substrate
scope and above all generation of harmful wastes are some of the
problems associated with existing methodologies. In some cases
use of microwave and ultrasonic irradiation have been used to
35 circumvent the problems, however, problems arise when large
scale production is needed. Thus, development of new, efficient
Surface properties of the catalysts were determined by Xꢀray
powder diffraction (Fig. 1) and ammoniaꢀTPD (Fig. 2 and 3). The
70 calcination temperature greatly affects the performance and the
physicoꢀchemical properties of the catalyst, as determined by
XRD studies. The XRD results are presented in Fig. 1. The
phases were identified by search match procedure with the help
of DIFFRACPLUS software using JCPDS databank. The
75 Montmorilonite (M) peak at 2θ = 19.600o is the peak for 001
plane which shows the pillaring effect. CAT-2 (Fe/Al pillared
clayꢀ250°C) has Chloraluminite phase (F, Fig. 1) and the TPD
(Fig. 2) results show that a desorption peak have appeared around
350°C which may be responsible for presence of Chloraluminite
80 phase. As per the XRD, the iron and aluminum species in CAT-3
do not have their independent phase and it is most probable that
Fe and Al have been hosted in the Montmorilonite phase.
and
ecoꢀfriendly
catalysts
for
the
synthesis
of
bis(indolyl)methanes is still needed. In recent years, solid acid
catalysts have evolved as potential candidates for organic
40 synthesis. Easy separation of product from reaction mixtures,
Although phases were generated for CAT-1 (Fe/Al pillared clayꢀ
110°C) but was not stable as found to be highly hygroscopic and
85 found difficult to handle. So we further continue our work with
CAT-2 (Fe/Al pillared clayꢀ250°C) and CAT-3 (Fe/Al pillared
clayꢀ425oC) as they are thermally robust and stable at room
*Corresponding Author. Tel.:+91-191-2569000; fax: +91-191-2569111;
e-mail: dmukherjee@iiim.ac.in
aNPC-microbes, Indian Institute of Integrative Medicine, (IIIM)-Jammu.
45 bMedicinal Chemistry Division, Indian Institute of Integrative Medicine,
(IIIM)-Branch Srinagar.
cCMFIR, Dhanbad, Jharkhand, India
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 | 1

RSC Advances
Page 2 of 6
View Article Online
temperature.
indicates that calcinations at high temperature show a strong
influence on the acidic properties of the FeꢀAl pillared clay and
also stability.
Prior to AmmoniaꢀTPD studies, samples were preheated at 250
°C for 2 h in a flow of pure nitrogen (99.9%), then cooled to room
temperature. After the pretreatment, the samples were saturated
To check the catalytic activity of Fe/Al pillared clay catalysts, in
5
with 10% anhydrous ammonia gas until saturated adsorption. The 30 a model reaction of 4ꢀhydroxybenzaldehyde (1equiv.) with 5ꢀ
°
temperature was increased to 80 C and kept there for 2 h to
remove the physisorbed ammonia. Finally the system was heated
bromoindole (2 equiv.) in the presence 0.5 mol % of catalysts
was used at room temperature with acetonitrile as solvent to yield
3a as the sole product (Scheme 1). The yield of product was
determined after 20 min. by HPLC and results are summerized in
°
°
from 80 °C to 1200 C at the rate of 10 C/min and the desorbed
gas was monitored with a T.C.D. detector. All the flow rates were
°
10 maintained at normal temperature and pressure (NTP).
35 Table 1. CAT-3 (Fe/Al pillared clayꢀ425 C) was found to be an
AmmoniaꢀTPD results revealed three temperature maximums for
effective catalyst for the electrophilic substitution reaction of
indole with aldehydes giving bis(indolyl)methanes 3a in excellent
yields as shown in Table 1. It clearly indicates that as the
ammonia desorption value increases, the yield of the product also
40 goes up.
°
the samples, CAT-2 (Fe/Al pillared clayꢀ250 C) and CAT-3
(Fe/Al pillared clayꢀ425oC) indicating the presence of three
OH
Br
Br
Br
catalyst (0.5mol%)
CH3CN, rt
CHO
OH
+
NH
(1eq.)
NH
(2eq.)
NH
(a)
(b)
(3a)
Scheme 1 Condensation of 5ꢀbromoindole with 4ꢀhydroxybenzꢀ
aldehyde using CAT-2 and CAT-3.
45 Table 1 Effect of ammonia desorption value of catalysts on the yield of
product for the reaction of 5ꢀbromoindole and 4ꢀhydroxybenzaldehyde
using acetonitrile as solvent.
15 Fig. 1. CAT-1 (Fe/Al pillared clayꢀ110 °C): M, Q; CAT-2 (Fe/Al pillared
clayꢀ250 °C): M, Q, F; CAT-3 (Fe/Al pillared clayꢀ425oC): M, Q.
M: Montmorillonite, Q: Quartz, F: Chloraluminite (AlCl3.6H2O)
Entry
Catalyst
Strength of Site/
NH3
BET
surface
area,
Yield
%
Peak temps (° C)/ desorꢀ
Temp. range
n.d.a
bed
(ꢁmol
/g)
different types of acids sites with different acid strength
distribution. The total amount of ammonia desorbed in case of the
(m2gꢀ1)
°
20 sample heated at 425 C is much higher than that of sample
1
2
CAT-1
(Fe/Al
n.d.a
n.d.a
n.d.a
87
heated at 250 °C ( Fig. 2 and 3, Table 1, entries 2 and 3). It clearly
pillared clayꢀ
TCD Signal (a.u.) vs. Temperature
110 °C)
TCD Signal (a.u.) - TPD-1000C
2.4
2.3
2.2
2.1
CAT-2
(Fe/Al
Weak/ 207/ 40ꢀ
400
395
142
pillared clayꢀ
250 °C)
Medium/ 580/
400ꢀ630
Strong/ 682/ 630ꢀ
1000
186
201
3
CAT-3
(Fe/Al
Weak/ 105/ 40ꢀ
360
1486
156
91
100
200
300
400
500
600
700
800
900
1,000
Temperature (°C)
Fig. 2 Ammonia desorption curve of CAT-2 (Fe/Al pillared clayꢀ250 °C)
pillared clayꢀ
425 °C)
TCD Signal (a.u.) vs. Temperature
Medium/ 494/
360ꢀ585
Strong/ 627/ 585ꢀ
1000
1322
793
TCD Signal (a.u.) - TPD-1000C
2.3
2.2
2.1
a n.d.: not determined
The efficacy of the CAT-3 was checked in different organic
solvents and it was found the acetonitrile is best in terms of yield
50 and reaction time. The progress of the reaction was monitored in
solvent free conditions as well and to our delight the reaction
proceeded smoothly leading to the formation of the desired
product in >93 % yield (Table 2, entry 8, Scheme 2) making the
process more environmentally viable.
100
200
300
400
500
600
700
800
900
1,000
Temperature (°C)
25 Fig. 3 Ammonia desorption curve of CAT-3 (Fe/Al pillared clayꢀ425 °C)
2
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 3 of 6
RSC Advances
View Article Online
3b, R1= 4ꢀBrꢀphenyl, 93%
1e, R1 =2,3ꢀ(OMe)2ꢀphenyl, 91%
1f, R1 =2,4ꢀ(OMe)2ꢀphenyl, 88%
Table 2 Effect of different solvents on the yield of the product.
3c, R1 = nꢀC3H7, 89%
Entry
Solvent
Time (hr)
Yielda %
1g, R1 =3,4ꢀ(OMe)2ꢀphenyl, 90% 3d, R1 = nꢀC7H15, 86%
1h, R1 =2,5ꢀ(OMe)2ꢀphenyl, 87%
35 1i, R1 =4ꢀNMe2ꢀphenyl, 88%
1j, R1 = cyclohexyl, 84%
1
2
3
4
5
6
7
CH3CN
AcOEt
CH2Cl2
MeOH
EtOH
DMF
0.20
0.45
1
1
1.30
2
91
87
84
81
78
78
60
1k, R1 = 2ꢀnaphthyl, 87%
THF
Solvent freeb
2.45
1l, R1 = 4ꢀClꢀphenyl, 95%
8
0.15
94
1m, R1 = 4ꢀBrꢀphenyl, 94%
a Yield determined through HPLC
40 1n, R1 =4ꢀNO2ꢀphenyl, 92%
1o, R1 = nꢀC3H7, 85%
b Indole (2 equiv.), 4ꢀhydroxy benzaldehyde (1 equiv.), Cat-3 (0.5mol%),
90°C
1p, R1 = nꢀC7H15, 80%
5
The catalyst could be separated from the reaction mixture by
dissolving the product in dichloromethane, filtering, washing
with dichloromethane, and drying at 120 C. Reusability of the
a Characterized through spectroscopic analysis.
b % HPLC yield.
°
45 substituted indoles at 90 °C in absence of organic solvent in an oil
bath for 10ꢀ30 min. In all cases the corresponding DIM
derivatives were obtained in good to excellent yield. (Table 3).
catalyst was checked for several times and product 3a was
obtained in good to excellent yields with substantial (>15%) loss
10 of activity after more than five cycles Fig. 4.
Table 4 Synthesis of DIMs by condensations of diversly substituted
indoles and carbonyl compounds catalyzed by CATꢀ3 (Fe/Al pillared
50 clayꢀ425 °C) via Scheme 3.
Indole
Carbonyl
compound
Compounda
Yield
%
b,c
F
Br
F
Br
Br
N
87
89
N
N
CHO
(4a)
(4)
F
Br
F
Br
Br
N
Fig. 4 Effect of reusability of Fe/Al pillared clay catalyst on the yield of
product 3a.
N
N
CHO
Br
(5)
(5a)
Br
Br
To check the substrate scope of the reaction, various aldehydes
15 including aliphatic (Table 3, entries 1j, 1oꢀ1p and 3cꢀ3d) and,
aromatic (Table 3, entries 1aꢀ1i, 1kꢀ1n, 2b and 3aꢀ3b), having
both electron withdrawing (Table 3, entries 1lꢀ1n and 3b) and
electron donating (Table 3, entries 1dꢀ1h) were reacted with
Cl
Br
Br
Br
Cl
N
88
O
N
OAc
OAc
N
AcO
O
O
(6a)
CHO
OAc
OAc
AcO
OAc
AcO
OAc
(6)
Table 3 Synthesis of DIMs by condensations of indoles and carbonyl
OAc
OAc
OAc
°
20 compounds catalyzed by CAT-3(Fe/Al pillared clayꢀ425 C) via Scheme
Br
Br
Br
2.
F
N
87
89
N
N
N
"Solvent Free"
N
N
X
N
X
N
N
N
CHO
CAT-3
N
R1 R2
N
X
O
(Fe/Al pillared clay-425 οC)
(7a)
+
R1
R2
N
90oC, 10-30min.
(7)
NH
1a - 3d,a 81-96%b
H
HN
F
Br
F
Br
Br
N
S
O
Scheme 2 Condensation of substituted indoles with different carbonyl
compound using CAT-3 (Fe/Al-pillared clay-425 °C).
O
N
N
25
CHO
S
O
S
O
O
(8a)
O
F
(8)
F
F
1a-1p, R2 = X = H,
2a-2b, X = H,
a Compound characterize through spectroscopical analysis.
1a, R1 = phenyl, R2 = X = H, 96% 2a, R1 = CH3, R2 = CH3, 86%
b Isolated yield after column chromatography. c % HPLC yield: 85ꢀ94%
1b, R1 = 4ꢀOHꢀphenyl, 95%
1c, R1= 3ꢀOHꢀphenyl, 93%
2b, R1= Phenyl, R2=CH3, 81%
3a-3d, R2 = H, X = Br
In general aldehydes with electron withdrawing groups react
faster than their counter ones. Compared to aldehydes, ketones
55 reacted in much sluggish manner and best conversions for the
30 1d, R1 =4ꢀOMeꢀphenyl, 92%
3a, R1 = 4ꢀOHꢀphenyl, 95%
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 3

RSC Advances
Page 4 of 6
View Article Online
products (2a-2b) were obtained after 20 min with a 1:2:0.5 ratios 40 1260 infinity). The compounds (1a-3d, 6a and 7a) are already
of ketone/ indole/CAT-3.
well known in the literature.3-11, 20
To check the applicability of this catalyst in synthesis of various
Nꢀsubstituted DIM’s, Nꢀalkylated,18 Nꢀbenzylated,18 Nꢀ
glucoside3, Nꢀtriazole19 and Nꢀsulphonyl18 derivatives of indole
Preparation of catalyst: Fe/Al pillared clay catalysts were
prepared by impregnation method. anhydrous FeCl3 (1g, 6.17
mmol) and AlCl3 (1g, 7.49 mmol) diluted in distilled ethanol (90
5
were allowed to react with carbonyl compound under 45 mL), stirred vigorously for one hour and then H+ form of
standardised reaction conditions (Scheme 3) to yield the
Montmorillonite Kꢀ10 clay (2g) was added to the solution, stirred
with reflux for 15h under N2 atomosphere and then dried under
vacuum. Considering on acidity, samples were further calcined at
different temperatures to get three different forms of catalyst
50 (Table 1) and stored in vacuum desiccators.
corresponding DIM derivatives (Table 4).
X
"Solvent Free"
Br
Br
Br
CAT-3, 0.5mol%
(Fe/Al pillared clay-425oC)
CHO
+
X
90oC, 10-30min.
N
General procedure for synthesis of compounds from 1a-8a
A mixture of aldehyde or ketone (1 equiv.), indole (2 equiv.) and
CAT-3 (0.5 mol%) in test tube was heated with stirring at 90oC
for the appropriate time 10ꢀ30 min. After cooling,
55 dichloromethane was added to the reaction mixture, filtered and
washed (2x20 mL) to recover the catalyst. The filtrate was
purified by column chromatography (ethylacetate: petroleum
ether/3:7) to afford the pure product.
HPLC Method: purity of the samples 1aꢀ3d were measured by
60 and 4a-8a were measured by HPLC methods A and B,
respectively. Complete description of both HPLC methods are
given in supporting information.
R
N
R
N
R
10
Scheme 3 Condensation of Nꢀsubstituted indoles with carbonyl
compound using CAT-3 (Fe/Alꢀpillared clayꢀ425 °C).
Finally a comparison was made between various known catalyst
and our newly synthesised catalyst (Table 5). It was found that
15 catalytic efficiency of our catalyst is superior to other one in
terms of catalyst loading and reaction time.
Table 5. Comparison of the catalytic efficiency of Fe/Al pillared clay
with various reported catalyst for reaction of indole with benzaldehyde.
Spectral data of selected compounds
Entry
ReactionCondition/
Time
Catalyst
content
Yield
%
Ref.
Compound 3a: 1H NMR (500MHz, CDCl3): δ 5.68 (s, 1H), 6.63
65 (s, 2H), 6.77 (d, J=8.5Hz, 2H), 7.13 (d, J = 8.5Hz, 2H), 7.23 (d, J
= 8.7, 2H), 7.25 (d, J = 8.7Hz, 2H), 7.47 (s, 2H) ; 13C NMR
(CDCl3): 154.13, 135.3, 129.6, 128.6, 124.9, 124.7, 124.5, 122.3,
119.2, 115.2, 112.6, 112.5, 39.04; MS m/z (M++Na): 519. HPLC
method A, retention time: 34.254, Peak area: 95%.
1
2
Zeokarbꢀ225/CH3CN
0.5 g
95
11
15
7.5 h
ZrO2(400oC)
1h
ꢀ
70
3
4
ZrOCl2.8H2O, Solventꢀ
free, 50 °C
5mol%
84
89
12
1
70 Compond 3b: H NMR (200MHz, CDCl3): δ 5.70 (s, 1H), 6.62
40min.
SO4ꢀ2/ZrO2(500oC)
50min.
1.5 N
1.5 N
15
15
(s, 2H), 7.13ꢀ7.28 (m, 8H), 7.45 (s, 2H), 8.07 (s, 2NH); 13C NMR
(CDCl3): 141.6, 135.3, 132.2, 129.8, 128.0 ,125.1, 124.8, 122.1,
118.5, 112.7, 112.7, 39.3; MS m/z (M++Na): 582.7. HPLC
method A, retention time: 37.551, Peak area: 93%.
5
6
PO4ꢀ3/ZrO2 (500oC)
92
94
20min.
Fe/Al pillared clay
(425oC)/solvent free,
15min.
0.5
mol%
75 Compound 3c: 1H NMR (200MHz, CDCl3): δ 0.95 (t, J=7.2, 7.4,
3H), 1.22ꢀ1.44 (m, 2H), 2.05ꢀ2.15 (m, 2H), 4.34 (t, J = 7.3 Hz,
7.5 Hz, 1H), 6.82 (s, 2H), 7.16ꢀ7.26 (m, 4H), 7.65 (s, 2H), 8.19
(s, 2NH); 13C NMR (CDCl3): 135.2, 128.6, 124.6, 122.6, 122.0,
119.6, 112.5, 112.3, 37.5, 33.7, 21.3, 14.1; MS m/z (M++Na):
80 469.1. HPLC method A, retention time: 36.552, Peak area: 89%.
Compound 3d: 1H NMR (200MHz, CDCl3): δ 0.83ꢀ0.86 (m,
3H), 1.23ꢀ1.34 (m, 10H), 2.1ꢀ2.3 (m, 2H), 4.32 (t, J = 7.5 Hz,
1H), 6.92 (s, 2H), 7.21ꢀ7.26 (m, 4H), 7.65 (s, 2H), 7.98 (s, 2NH) ;
13C NMR (CDCl3): 135.2, 128.6,124.6, 122.6, 122.0, 119.6,
85 112.5, 112.3, 35.2, 33.9, 31.8, 29.6, 29.3, 28.2, 22.6, 14.1; MS
m/z (M++Na): 525.7. HPLC method A, retention time: 39.268,
Peak area: 86%.
20 Conclusions
In conclusion, we have developed an efficient synthetic protocol
for the synthesis of BIMs from various aldehydes and diversly
substituted indoles using 0.5 mol% Fe/Al pillared clay as a
catalyst. Key features of the protocol include mild reaction
25 conditions, reduced reaction times, high yields and wide substrate
scope. Above all the recyclability of the catalyst for more than 5
cycles without significant loss in catalytic activity adds to the
merits of the process.
Compound 4a: 1H NMR (400MHz, CDCl3): δ 0.85 (t, J = 8
Hz,3H), 1.21ꢀ1.31 (m, 8H), 1.72ꢀ1.76 (m, 4H), 3.98 (t, J = 8 Hz,
90 1H), 5.71 (s, 1H), 6.49 (s, 2H), 6.98 (t, J = 8Hz, 2H), 7.17ꢀ7.23
(m, 6H), 7.42(s, 2H); 13C NMR (CDCl3): 139.2, 135.4, 129.9,
129.8, 128.9, 128.3, 124.3, 122.3, 117.2, 115.4, 115, 112.1,
110.9, 46.4, 39.1, 29.8, 28.9, 22.2, 13.9; MS m/z (M++Na): 659.9.
HPLC method B, retention time: 4.139, Peak area: 94%.
30 Experimental
All chemicals and reagents required for the reactions were
procured from SigmaꢀAldrich with purity 98% and used without
further purification. The products were characterized using 1H
NMR, 13C NMR spectra. NMR spectra of the products were
35 obtained using Bruker 200,400 and 500 MHz spectrometers with
TMS as the internal standard. Column chromatography was
performed on silica gel, Merck grade 60–120 mesh size. TLC was
performed on 0.25 mm E. Merck precoated silica gel plates (60
F254 ). % Purity of the samples were measured by HPLC(Agilent
95 Compound 5a: 1H NMR (400MHz, CDCl3): δ 5.14 (s, 4H), 5.76
(s, 1H), 6.56 (s, 2H), 6.88 (m, 4H), 7.00ꢀ7.05 (m, 4H), 7.20ꢀ7.25
(m, 4H), 7.43ꢀ7.45 (m, 6H); 13C NMR (CDCl3): 136.1, 135.6,
4
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 5 of 6
RSC Advances
View Article Online
3687. (b) M. Karthik, A. K. Tripathi, N. M. Gupta, M.
132, 129.9, 129.8, 129.1, 128.7, 128.0, 125.0, 122.5, 121.6,
118.0, 115.4, 115.2, 112.8, 111.3, 49.6, 39.3; MS m/z (M++Na):
Palanichamy, V. Murugesan, Catal. Commun., 2004, 5, 371.
14 (a) M. Chakrabarty, N. Ghosh, R. Basak, Y. Harigaya,
Tetrahedron Lett., 2002, 43, 4075. (b) G. PnieresꢀCarrillo, J.
G. GarciaꢀEstrada, J. L. GutierrezꢀRamirez, C. Alvarezꢀ
Toledano, Green Chem. 2003, 5, 337. (c) A. K. Maiti, P.
Bhattacharyya, J. Chem. Research (S), 1997, 424.
15 S. V. Nadkarni, M. B. Gawande, R. V. Jayaram, J. M.
Nagarkar, Catal. Commun., 2008, 9, 1728.
16 S. Mohammed, A. K. Padala, B. A. Dar, B. Singh, B.
Sreedhar, R. A. Vishwakarma, S. B. Bharate, Tetrahedron,
2012, 68, 8156.
65
70
75
80
85
90
95
857.7. HPLC method B, retention time: 4.160, Peak area: 91%.
1
Compound 6a: H NMR (400 MHz, CDCl3): δ 1.51, 1.55, 1.92,
5
1.94, 1.97, 1.98, 1.99, 2.04( 8s, 24H, CH3CO), 3.8ꢀ3.9 (m, 2H),
4.09ꢀ4.16 (m, 4H), 5.1ꢀ5.2 (m, 2H), 5.3ꢀ5.4 (m, 6H), 5.6 (s,1H),
6.6, 6.7 (d, J = 7.2Hz, 2H),7.08 (d, J = 8.4Hz , 2H), 7.20 (d, J =
8.4, 2H), 7.19 (d, J = 8.4 Hz, 2H), 7.23ꢀ7.28( m, 5H), 7.4 (s, 1H).
13C NMR (CDCl3): 169.1, 168.4, 167.5, 167.4, 140.4, 134.3,
10 134.1, 131.5, 128.7, 128.6, 128.4, 127.7, 125.1, 124.6, 123.9,
121.4, 121.2, 118.7, 118.1, 112.8, 112.7, 110.8,110.5, 82.9, 82.5,
73.8, 73.7, 71.9, 71.8, 69.9, 69.3, 67.0, 60.9, 60.7, 37.6, 19.7,
19.6, 19.53, 19.50, 19.4, 19.0, 18.9. MS m/z(M++Na):1195.1.
HPLC method B, retention time:11.880, Peak area: 88%.
17 A. Hussain, S. K. Yousuf, D. Kumar, M. Lambu, B. Singh, S.
Maity and D. Mukherjee, Adv. Synth. Catal., 2012, 354, 1933.
18 To a mixture of powdered potassiun hydroxide (4mmol) in
dimethylsulphoxide (5ꢀ7ml) was added the appropriate
alkyl/aryl and sulphonyl halides
(1.2 mmol) and
15 Compound 8a: 1H NMR (400MHz, CDCl3): δ 5.45 (s, 1H), 6.85
(s, 2H), 7.05ꢀ7.18 (m, 8H), 7.25 (d, J = 4Hz), 7.45 (dd, J = 4Hz,
4Hz), 7.71ꢀ7.74 (m, 4H), 7.85 (s, 1H), 7.88 (s, 1H); 13C NMR
(CDCl3): 166.9, 164.8, 163.1, 161.1,134.9, 134.8, 134.3, 133.4,
131.3, 129.7, 129.5, 129.4, 126.2, 123.8, 122.6, 117.2, 117.1,
20 116.9, 116.2, 116.0, 115.4, 38.7; MS m/z (M++Na): 849.9. HPLC
method B, retention time: 4.405, Peak area: 85%.
indole(1mmol) with stirring at room temperature. The reaction
was monitored by TLC. After the completion of the reaction,
the reaction mixture was diluted by water and extracted with
ethyl acetate. The organic layer was dried over anhydrous
sodium sulphate and concentrated in vacuo to get the crude
product. The crude product was purified by column
chromatography.
19 To a mixture Nꢀpropargyl derivative of indole (1mmol) of CuI
(10 mol%) in PEGꢀ400 (5ꢀ7ml) was added benzyl azide (1.2
mmol) with stirring at room temperature. The reaction was
monitored by TLC. After the completion of the reaction, the
reaction mixture was diluted by water and extracted with ethyl
acetate. The organic layer was dried over anhydrous sodium
sulphate and concentrated in vacuo to get the crude product.
The crude product was purified by column chromatography.
20 M. Damodiran, D. Muralidharan, Paramasivan T. Perumal,
Bio. Org. Med. Chem. Lett.,, 2009, 19 3611.
Acknowledgement
Authors are highly thankful to Director IIIM Jammu for support
25 and DST for funding under the project GAPꢀ1145.
Notes and references
† Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
30
35
40
45
50
55
60
1
K. B. Oh, W. Mar, S. Kim, J. Y. Kim, T. H. Lee, J. G. Kim, D.
Shin, C. J. Sim, J. Shin, Biol. Pharm. Bull. 2006, 29, 570.
A. Kamal, M. Naseer, A. Khan, K. S. Reddy, Y. V. V.
Srikanth, S. K. Ahmed, K. P. Kumar, U. S. N. Murthy, J.
Enzym. Inhib. Med. Chem. 2009, 24, 559.
D. K. Sharma, B. Rah, M. R. Lambu, A. Hussain, S. K.
Yousuf, A. K. Tripathi, B. Singh, G. Jamwal, Z. Ahmed, N.
Chanauria, A. Nargotra, A. Goswami,D. Mukherjee, Med.
Chem. Commun., 2012, 3, 1082.
K. Niknam, M. A. Zolfigol, T. Sadabadi, A. Nejati, J. Iran
Chem. Soc., 2006, 3, 318.
V. Murugesan, K. K. Cheralathan, M. Karthik, Bull.
Catal. Soc. India, 2004, 3, 23.
(a) J. S. Yadav, B. V. S. Reddy, S. Sunitha, Adv. Synth.
Catal., 2003, 345, 349. (b) S. J. Ji, M. F. Zhou, D. G. Gu, S. Y.
Wang, T. P. Loh, Synlett, 2003,13, 2077. (c) S. J. Ji, M. F.
Zhou, D. G. Gu, Z. Q. Jiang, T. P. Loh, Eur. J. Org. Chem.,
2004,7, 1584. (d) S. A. Sadaphal, S. S. Sonar, M. S. Shingare,
Central Euro. J. Chem. 2008, 6, 622.
X. L. Feng, C. J. Guan, C. X. Zhao, Synth. Commun., 2004,
34, 487.
L. M. Wang, J. W. Han, H. Tian, J. Sheng, Z. Y. Fan, X. P.
Tang, Synlett, 2005, 2, 337.
2
3
4
5
6
7
8
9
M. Luo, D. Bowden, P. Brimblecombe, Appl. Catal. B:
Environ.,2009, 85, 201.
10 A. K. Ladavos, P. N. Trikalitis, P. J. Pomonis, J. Mol. Catal.
A: Chem. 1996, 106, 241.
11 C. J. Magesh, R. Nagarajan, M. Karthik, P. T. Perumal,
Applied Catal. A: General , 2004, 266, 1.
12 H. Firouzabadi, N. Iranpoor, M. Jafarpour, A. Ghaderi, J.
Mol. Cat. A:chem., 2006, 253, 249.
13 (a) A. V. Reddy, R. Ravinder, V. L. N. Reddy, T. V. Goud, V.
Ravikanth, Y. Venkateswarlu, Synth. Commun., 2003, 33,
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 5

RSC Advances
Page 6 of 6
View Article Online
Fe/Al pillard clay catalyzed solvent-free synthesis of
bisindolylmethanes using diversly substituted indoles and
carbonyl compounds.
Deepak Kumar Sharma, a Altaf Hussain, a Mallikharjuna Rao Lambu, a Syed Khalid
Yousuf, b Sudip Maiety,c Baldev Singh a and Debaraj Mukherjee a*
A fast, solvent free solid acid mediated synthetic strategy for the synthesis of bisindolylmethanes has been developed. The
process is applicable to a wide range of substrate with different protecting group survival properties. Reusability of Fe/Al
pillard clay for more than 5 cycles without significant loss of catalytic activity adds to the features of the reaction.
Y
Y
R1 R2
"Solvent Free"
Y
O
0.5mol%
(Fe/Al pillard clay-425oC)
+
R1
R2
N
R
N
R
N
R
90oC, 10-30min.
Aldehyde/ketone
Indoles
R= H, alkyl, benzyl, glucosyl,
triazole, sulphonyl