Ultrasound assisted green synthesis of bis(indol-3-yl)methanes catalyzed by 1-hexenesulphonic acid sodium salt

Article abstract of DOI:10.1016/j.ultsonch.2009.08.015

1-Hexenesulphonic acid sodium salt as catalyst for green synthesis of bis(indol-3-yl)methanes was described. The reaction of indole with various aldehydes in water using ultrasound irradiation at ambient temperature for appropriate time using 1-hexenesulp

Full text of DOI:10.1016/j.ultsonch.2009.08.015

Ultrasonics Sonochemistry 17 (2010) 298–300
Contents lists available at ScienceDirect
Ultrasonics Sonochemistry
journal homepage: www.elsevier.com/locate/ultsonch
Short Communication
Ultrasound assisted green synthesis of bis(indol-3-yl)methanes catalyzed
by 1-hexenesulphonic acid sodium salt
*
Ratnadeep S. Joshi, Priyanka G. Mandhane, Santosh D. Diwakar, Charansingh H. Gill
Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431 004, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 July 2009
Received in revised form 23 August 2009
Accepted 25 August 2009
Available online 29 August 2009
1-Hexenesulphonic acid sodium salt as catalyst for green synthesis of bis(indol-3-yl)methanes was
described. The reaction of indole with various aldehydes in water using ultrasound irradiation at ambient
temperature for appropriate time using 1-hexenesulphonic acid sodium salt furnish the desired product
in good to excellent yield. Utilization of aqueous medium, simple reaction conditions, isolation, and puri-
fication makes this manipulation very interesting from an economic and environmental perspective.
Ó 2009 Elsevier B.V. All rights reserved.
Keywords:
1-Hexenesulphonic acid sodium salt
Bis(indol-3-yl)methanes
Ultrasonication
Green synthesis
Aza-Michael
Indole
1. Introduction
dures involving simplified work-up. Organic reactions in water or
aqueous media have attracted great interest [11–13]. With tight-
Interest in indole-containing structures stems from their wide-
spread occurrence in molecules that exhibit significant activity
against several bacteria and viruses [1]. In addition, bis-indolylal-
kane derivatives have been used as bioactive metabolites of terres-
trial and marine origin [2]. Various oxyindole derivatives are used
as potential anticancer agents [3]. Medicinal chemists repeatedly
twirl indole based compounds as a target pharmacophores for the
development of therapeutic agents [4]. Bis(indolyl)-methanes are
most active cruciferous substances for promoting beneficial estro-
gen metabolism and inducing apoptosis in human cancer cell [5].
The acid-catalyzed reaction of electron rich heterocyclic com-
pounds with p-dimethyl amino benzaldehyde knowns as the Ehr-
ened regulatory pressure focusing on organic solvents, the search
for alternatives is of increasing importance. In this respect, the
development of water-tolerant catalyst has rapidly become an area
of intense research. Surprisingly however, there are only four re-
ports for synthesis of indole and its derivatives in net water using
oxalic acid [14], Meldrum’s acid [15], [Cu(3,4-tmtppa)(MeSO4)4]
[16] and H3PW12O40 [17].
Ultrasound irradiation has been established as an significant
technique in synthetic organic chemistry [18–21]. Shorter reaction
time is the main benefit of ultrasound-assisted reactions. Simple
experimental procedure, high yields, improved selectivity and
clean reaction of many ultrasound induced organic transforma-
tions offers additional convenience in the field of synthetic organic
chemistry. Also bis(indol-3-yl)methanes synthesis under ultra-
sound irradiation [22–24] but all these method having some draw-
backs like prolonged reaction time, lower yield and expensive
catalyst due to this we have expand this method in under ultra-
sound irradiation in aqueous media with our catalyst.
lich test [6–8] for
p-electron rich heterocycles such as pyrroles
and indoles. Analogous to Ehrlich test, indoles with other aromatic
or aliphatic aldehydes and ketones produces azafulvenium salts.
The azafulvenium salts can undergo further addition with a second
indole molecule to afford bis(indol-3-yl)methanes [9].
In the organic synthesis and reactions, increasing attention is
being focused on green chemistry using environmentally benign
reagents and conditions, particularly solvent-free procedures [10]
which often lead to clean, eco-friendly and highly efficient proce-
We herein, report an eco-friendly, facile and efficient methodol-
ogy for the synthesis of bis(indol-3-yl)methanes. The 1-hexenesul-
phonic acid sodium salt [25,26] liberates corresponding acid with
extreme wide applications such as sulphonation of alkanes [27]
etc. However, there are no examples of 1-hexenesulphonic acid
sodium salt as a catalyst in the organic transformation.
* Corresponding author. Tel.: +91 240 2403311; fax: +91 240 2400491.
E-mail address: prof_gill@rediffmail.com (C.H. Gill).
1350-4177/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.ultsonch.2009.08.015

R.S. Joshi et al. / Ultrasonics Sonochemistry 17 (2010) 298–300
299
phonic acid sodium salt to afford the corresponding bis(indol-3-
yl)methanes (3a). Using lower amount of catalyst resulted in lower
yields, while higher amount of catalyst did not affect the reaction
times and yields and in the absence of catalyst, the yield of the
product was not found. The best results were obtained using
10 mol% of catalyst (yield = 94%). The reaction proceeds smoothly
at ambient temperature with 10 mol% of catalyst and completes
within 45 min (Table 2, entry 6). We kept catalyst concentration
constant and used different solvents like toluene, dichlorometh-
ane, acetonitrile:water (8:2), methanol, and ethanol afforded a
lower yields. We have also studied the sonochemical effect on
model reaction by using different solvents. In all cases, the exper-
imental results show that the reaction times are shorter and the
yields of the products are higher under sonication. Based on the re-
sults of this study, it seems that the ultrasound irradiation im-
proves the reaction times and yields. The obtained results
summarized in (Table 1, entries 1–6). These results suggest that
water is the best solvent for synthesis of bis(indol-3-yl)methanes;
it may be due to catalyst having greater solubility in water than in
any organic solvent.
Furthermore, effect of catalyst load on reaction time and yield is
explored in Table 2. The best result is obtained with 10 mol% of the
catalyst. After optimizing the conditions, the generality of this
method was examined by the reaction of several substituted aryl
aldehydes with indol. The results are shown in Table 3. The newly
synthesized compounds were compared (melting point, MS, NMR,
and IR) with compounds that were prepared by using the literature
method [32] (Scheme 1. This comparison revealed that the com-
pounds synthesized by this newly developed method were exactly
similar in all aspects to the reference compounds.
2. Experimental
Melting points were determined on a Veego apparatus and are
uncorrected. Infrared spectra were recorded on a Bruker spectro-
photometer in a KBr disc, and the absorption bands are expressed
in cmÀ1 1H NMR spectra were recorded on a Varian AS 400 MHz
.
spectrometer in CDCl3/DMSO-d6, chemical shifts (d) are in ppm rel-
ative to TMS, and coupling constants (J) are expressed in Hertz
(Hz). Mass spectra were taken on a Macro mass spectrometer
(Waters) by electro-spray method (ES). Bandelin Sonorex (with a
frequency of 35 kHz and a nominal power 200 W) ultrasonic bath
was used for ultrasonic irradiation. Built-in heating, 30–80 °C ther-
mostatically adjustable. The reaction vessel placed in side the
ultrasonic bath containing water.
3. General procedure
A mixture of 1H-indole (1 mmol), aldehyde (2 mmol) and 1-
hexenesulphonic acid sodium salt (10 mol%) was dissolved in min-
imum quantity of water with constant stirring. Further the reaction
mass was irradiated under ultrasonic irradiation at ambient tem-
perature for appropriate time (Table 3). The progress of reaction
was monitored by TLC. After the completion of reaction the col-
oured product obtained was filtered and recrystallized from etha-
nol to get the pure product.
4. Results and discussion
In the continuation of our research work of developing methods
in various organic transformations [28–31]. Herein, we have devel-
oped methodology for the synthesis of bis(indol-3-yl)methanes
using 1-hexenesulphonic acid sodium salt, which makes use of
milder condition over the reported procedure as depicted in
Scheme 1.
The methodology developed is simple with good to excellent
yields. We first compared the catalyst effect on different solvents
for synthesis of bis(indol-3-yl)methanes using 1-hexenesulphonic
acid sodium salt and the results are summarized in Table 1.
In a typical experiment, the reaction of indole (1) and benzalde-
hyde (2a) in water was carried in the presence of 1-hexenesul-
The probable mechanism [23,33] of the reaction is shown in
Scheme 2. The mechanistic part shows 1-hexenesulphonic acid so-
dium salt liberates corresponding acid when dissolved in water,
which activates the aldehyde towards electrophilic attack of indole
to generate aza-Michael intermediate. Later on aza-Michael of 1H-
indole furnishes desired bis(indol-3-yl)methanes.
Table 2
Screening of catalyst concentration on model reactiona.
Entry
Catalyst (mol%)
Yieldb (%)
1
2
3
4
5
6
7
0
2
4
6
8
10
12
No reaction
24
36
58
80
94
94
Scheme 1. Synthesis of bis(indol-3-yl) methanes.
a
Reaction of benzaldehyde with 1H-Indole in presence of 1-hexanesulphonic
acid sodium salt (10 mol%) in water under ultra sonic waves for 45 min.
Table 1
b
Isolated yield.
Optimization of solvent effect on the model reaction.
Entry Solvent
With USa
Without USb
Time
(min)
Yieldc
(%)
Time
(min)
Yieldc
(%)
1
2
3
Toluene
45
45
45
25
34
65
120
120
120
20
28
53
Dichloromethane
Acetonitrile:water
(8:2)
4
5
6
Methanol
Ethanol
Water
45
45
45
72
78
94
120
120
120
60
70
85
a
Reaction of benzaldehyde with 1H-Indole in presence of 1-hexenesulphonic
acid sodium salt (10 mol%) under ultrasonic waves for 45 min.
b
Reaction of benzaldehyde with 1H-Indole in presence of 1-hexanesulphonic
acid sodium salt (10 mol%) under reflux condition for 120 min.
c
Isolated yield.
Scheme 2. Proposed mechanism of reaction.

300
R.S. Joshi et al. / Ultrasonics Sonochemistry 17 (2010) 298–300
Table 3
Characterization dataa of bis(indol-3-yl)methanes (3a–3n).
Entry
Aldehyde
Time (min)
Yieldb,c (%)
MP (°C)
Found
Lit.
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
Benzaldehyde
45
55
60
40
60
60
40
65
60
65
50
45
60
60
94
88
92
92
82
85
90
84
88
90
83
80
87
90
123–124
73–75
74–75
124 [34]
74 [34]
74 [35]
78 [32]
111 [35]
124 [32]
220[32]
96[35]
189 [32]
102 [36]
322[32]
68 [34]
97 [32]
152 [35]
2-Chlorobenzaldehyde
3-Chlorobenzaldehyde
4-Chlorobenzaldehyde
4-Hydroxy-3-methoxy benzaldehyde
4-Hydroxybenzaldehyde
4-Nitrobenzaldehyde
4-Methylbenzaldehyde
4-Methoxybenzaldehyde
Benzo[1,3]dioxale-5-benzaldehyde
Furan-2-carbaldehyde
Heptanal
76–77
109–111
122–123
221–222
97–98
188–189
100–102
320–321
68–70
Piconaldehyde
Thiophene-2-carbaldehyde
99–100
150–153
a
b
c
Reaction of aldehyde with 1H-Indole in presence of 1-hexenesulphonic acid sodium salt (10 mol%) in water under ultrasound irradiation.
Isolated yield.
Compounds were characterised by 1H NMR, MS spectral data and were compared with the reference compounds [37].
[15] S.Y. Wang, S.J. Ji, X.M. Su, Chinese J. Chem. 26 (1) (2008) 22.
[16] S. Sobhani, E. Safaei, A. Hasaninejad, S. Rezazadeh, J. Org. Meta. Chem. 694 (18)
(2009) 302.
5. Conclusion
1-Hexenesulphonic acid sodium salt in aqueous media was
found to be mild and effective catalyst in green synthesis of bis(in-
dol-3-yl)methanes under ultrasonic irradiation. This catalyst pro-
vides clean, conversion; greater selectivity and easy work-up
make this protocol practical and economically attractive.
[17] N. Aziz, L. Torkian, M.R. Saidi, J. Mol. Catal. A: Chem. 275 (2007) 109.
[18] T.J. Mason, J.P. Lorimer, In Sonochemistry: Theory, Application and Uses of
Ultrasound in Chemistry, John Wiley and Sons, New York, 1988.
[19] K.S. Suslick, In Ultrasound its Chemical, Physical and Biological Effects, VCH,
Weinheim, 1988.
[20] A. Gaplovsky, M. Gaplovsky, S. Toma, J. Luche, J. Org. Chem. 65 (2000)
8444.
[21] R.R. Deshmukh, R. Rajagopal, K.V. Srinivasan, Chem. Commun. (2001)
1544.
Acknowledgements
[22] X. Zeng, S. Ji, S. Wang, Tetrahedron 61 (2005) 10235.
[23] J. Li, H. Dai, W. Xu, T. Li, Ultrason. Sonochem. 13 (2006) 24.
[24] M. Iraj, R.M. Hamid, R.K. Ahmed, N. Kobra, Lett. Org. Chem.
768.
[25] J. Weiss, VCH Verlags Gesellschaft mbH, second ed., VCH Publisher, Inc., New
York, Weinheim, Germany, 1995, p. 239.
[26] H. Small, Ion Chromatography, Plenum Press, New York and London, 1989. p.
106.
The authors are thankful to University Grants Commission, New
Delhi, for awarding the fellowship and to The Head, Department of
Chemistry, Dr. Babasaheb Ambedkar Marathwada University,
Aurangabad, for valuable support and laboratory facility.
3 (2006)
References
[27] J.L. Boyer, B. Gilot, J.P. Canselierm, Phosphorus, Sulphur, Silicon Relat. Elem. 20
(1984) 259.
[28] G.R. Jadhav, M.U. Shaikh, R.P. Kale, C.H. Gill, Chinese Chem. Lett. 20 (2009) 292.
[29] S.S. Sonar, A. Kategaokar, M. Ware, B. Shingate, C.H. Gill, M.S. Shingare, Arkivoc
(ii) (2009) 138.
[30] R.P. Kale, G.R. Jadhav, M.U. Shaikh, C.H. Gill, Tetrahedron Lett. 50 (2009) 1780.
[31] G.R. Jadhav, M.U. Shaikh, R.P. Kale, C.H. Gill, Chinese Chem. Lett. 20 (2009) 535.
[32] S.A. Sadaphal, S.S. Sonar, M.N. Ware, M.S. Shingare, Green Chem. Lett. Rev. 1
(2008) 191.
[33] D. Cao, H. Kolshorn, H. Meier, Tetrahedron Lett. 37 (1996) 4487.
[34] R.R. Nagawade, D.B. Shide, Bull. Korean Chem. Soc. 26 (2005) 12.
[35] S.A. Sadaphal, K.F. Shelke, S.S. Sonar, M.S. Shingare, Cent. Eur. J. Chem. 6 (2008)
622.
[1] R.J. Sundberg, The Chemistry of Indoles, Academic, New York, 1996.
[2] B.P. Bandgar, K.A. Shaikh, Tetrahedron Lett. 44 (2003) 1959.
[3] N. Sirisoma, A. Pervin, J. Drewe, B. Tseng, S.X. Cai, Bioorg. Med. Chem. Lett. 9
(2009) 2710.
[4] G.W. Gribble, In Comprehensive Heterocyclic Chemistry, vol. 2, second ed.,
Pergamom Press, New York, 1996, p. 211.
[5] X. Ge, S. Yannai, G. Rennert, N. Gruener, F.A. Fares, Biochem. Biophys. Res.
Commun. 228 (1996) 153.
[6] P. Ehrlich, Med. Woche (1901) 151.
[7] L. Morgan, R. Schunior, J. Org. Chem. 27 (1962) 3696.
[8] D. Dolphin, J. Heterocycl. Chem. 7 (1979) 275.
[36] B.P. Bandgar, K.A. Shaikh, J. Chem. Res. Synop. (2004) 34.
[37] Spectral data of reprehensive compounds (3d) 1H NMR (400 MHz, CDCl3): 5.86
(s, 1H, Ar–CH), 6.65 (s, 2H), 7.02 (t, 2H, J = 7.6 Hz), 7.18 (t, 2H, J = 7.6 Hz), 7.26–
7.38 (m, 8H), 7.93 (br s, 2H, NH); MS m/z. 357 (M+) 359 (M+2). (3j) 1H NMR
(400 MHz, CDCl3): 5.80 (s, 1 H), 5.90 (s, 2 H), 6.66 (d, 2 H, J = 1.2 Hz), 6.72 (d, 1
H, J = 8.6 Hz), 6.83 (d, 2 H, J = 7.8 Hz), 7.01 (t, 2H, J = 7.8 Hz), 7.16 (t, 2 H,
J = 7.2 Hz), 7.35 (d, 2 H, J = 8.4 Hz), 7.4 (d, 2 H, J = 8.1 Hz), 7.89 (br, s, 2 H, NH).
ES-MS m/z = 356 (M+).
[9] W. Remers, Chem. Heterocycl. Compd. 25 (1972) 1.
[10] G. Bram, A. Loupy, in: P. Laszlo (Ed.), In Preparative Chemistry Using Supported
Reagents, Academic Press, San Diego, 1987, p. 387.
[11] S. Narayan, J. Muldoon, M.G. Finn, V.V. Fokin, H.C. Kolb, K.B. Sharpless, Angew.
Chem. Int. Ed. 44 (2005) 3275.
[12] U.M. Lindstrom, Chem. Rev. 102 (2002) 2751.
[13] C. Wei, C.J. Li, J. Am. Chem. Soc. 125 (2003) 9584.
[14] N.D. Kokare, J.N. Sangshetti, D.B. Shinde, Chinese Chem. Lett. 19 (2008) 1186.