Synthesis of some bis (Indolyl)methanes Catalyzed by Ascorbic Acid under Mild Conditions

Full text of DOI:10.1080/00304948.2015.1088755

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
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Synthesis of some bis(Indolyl)methanes Catalyzed
by Ascorbic Acid under Mild Conditions
Kandasamy Karthikeyan & Ganesabaskaran Sivaprasad
To cite this article: Kandasamy Karthikeyan & Ganesabaskaran Sivaprasad (2015)
Synthesis of some bis(Indolyl)methanes Catalyzed by Ascorbic Acid under Mild
Conditions, Organic Preparations and Procedures International, 47:6, 449-453, DOI:
10.1080/00304948.2015.1088755
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Date: 30 October 2015, At: 19:43

Organic Preparations and Procedures International, 47:449–453, 2015
Copyright Ó Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2015.1088755
Synthesis of some bis(Indolyl)methanes Catalyzed by
Ascorbic Acid under Mild Conditions
Kandasamy Karthikeyan and Ganesabaskaran Sivaprasad
Department of Chemistry, University College of Engineering Tindivanam,
Melpakkam, Tamil Nadu 604 001, India
1
,2
3
bis(Indolyl) derivatives exhibit tranquilizing, anti-bacterial and anti-fungal activity
and indoles themselves are useful in the treatment of fibromyalgia, chronic fatigue and
4
–6
irritable bowel syndrome. In addition bis-indoles are utilized as highly selective colori-
7
metric and ratiometric fluorescent molecular chemosensors and also in cancer
8
chemotherapy.
9
A wide variety of catalysts such as protic and Lewis acids,
10–12
13
clays, lithium
1
4
15
16
17
18
perchlorate, iodine, Amberlyst resins, trityl chloride, cyanuric chloride, as
1
9,20
well as ionic liquids
have been utilized for the electrophilic substitution reaction
of indoles with aromatic aldehydes to yield bis(indolyl)methanes. However, these
reagents are not only expensive, their preparation requires long reaction times and
results in low yields; furthermore, they are strongly acidic and may involve cumber-
some experimental and isolation procedures. Ascorbic acid has been used as a
2
1
C-nucleophile, as an intermediate for the synthesis of chiral oxetanes and chiral
23,24
2
2
polyols, as a reductant
in the preparation of chiral platinum-bis-phosphinite
and as a catalyst for the reductive desulfonylation of b-keto-
2
5,26
complex catalysts,
2
7
sulfones. Therefore it was decided to explore its potential as a catalyst and we
now report the successful condensation of indoles with several aromatic aldehydes.
The reaction, carried out at room temperature in ethanol, between indole and aro-
matic aldehydes in the presence of ascorbic acid, proceeded in better than 80% yield for
aromatic aldehydes bearing both electron-donating and electron-with-drawing substitu-
ents (Scheme 1). However, under the same conditions aliphatic aldehydes such as acetal-
dehyde and propionaldehyde did not yield bis-indoles; cinnamaldehyde and
crotonaldehyde only gave resinous products.
Ascorbic acid is economical and environmentally safe in contrast to Lewis
acids which are expensive, moisture sensitive, and can interact and be deactivated
by the NH of an indole. The use of this catalyst has the advantage of mild reaction
conditions, and simple experimental and isolation procedures. In conclusion, we
have developed a simple and efficient method for the preparation of bis(indolyl)-
methanes using ascorbic acid whose potential as a catalyst remains largely
unexplored.
Received March 7, 2105; in final form April 27, 2015.
Address correspondence to Ganesabaskaran Sivaprasad, Department of Chemistry, Univer-
sity College of Engineering Tindivanam, Melpakkam, Tamil Nadu 604 001, India. E-mail:
dr.g.sivaprasad@gmail.com
4
49

4
50
Karthikeyan and Sivaprasad
Scheme 1 Synthesis of bis(Indolyl)methanes Catalyzed by Ascorbic Acid
Experimental Section
Ascorbic acid, substituted benzaldehydes, indoles, silica gel (100–200 mesh),
petroleum ether, ethyl acetate and ethanol were purchased from S. D. Fine Chemi-
cals and used as received. Macherey-Nagel pre-coated plastic sheets coated with
silica gel G/UV-254 of 0.2 mm thickness were used to perform analytical TLC. A
mixture of petroleum ether-ethyl acetate (80:20) was used as the solvent system
for elution. Mps were determined in capillary tubes on a Concord melting point
apparatus and are uncorrected. A Perkin-Elmer Spectrum One FTIR/ATR spec-
trometer was used to obtain Fourier transform infrared spectra as KBr pellets.
NMR spectra were acquired in CDCl solutions (with TMS as an internal standard)
3
1
13
on a Bucker Avance III instrument ( H NMR at 500 MHz and C NMR at
25 MHz). Mass spectra were measured using a Jeol GCMATE II GC-MS in EI
mode. Combustion analyses were carried out using a Thermo Finnigan Flash EA
112 series.
1
1
Typical Procedure
A mixture of indole (0.29 g, 2.5 mmol), benzaldehyde (0.13 g, 1.2mmol) and ascorbic
acid (0.03 g, 0.17 mmol) in 10 mL of ethanol was stirred at room temperature in a round-
bottomed flask for 30 min. The progress of the reaction was monitored by TLC [petro-
leum ether-ethyl acetate (80:20) Rf value D 0.169 for bis(indolyl)methane]. After that
time, the reaction mixture was poured into crushed ice and the precipitated product was
collected and purified using column chromatography on silica gel [elution with a mixture
of ethyl acetate and petroleum ether (1:9)] to give 0.35g (89%) of 3a as a pink solid. All
the products are known compounds whose mps matched those reported in the literature
(
see Table 1).

Synthesis of bis(Indolyl)methanes Catalyzed
451
Table 1
Synthesis of bis(Indolyl)methanes Catalyzed by Ascorbic Acid
ꢀ
Product
Compound
Yield (%)
89
mp. C (lit.)
Ref.
28
3a
125–127(125–126)
3
b
82
80
81
90
89
87
80
84
86
259–261(261–263)
75–76(76–77)
32
29
33
29
30
34
28
28
31
3
c
3d
73–75(75–77)
3
e
188–190(187–189)
196–197(197–198)
94–96(95–97)
3
f
3
3
g
h
221–222(220–222)
343–345(342–344)
179–180(180)
3
3
i
j
1
13
All compounds were characterized by H NMR, C NMR, IR and mass spectra.

4
52
Karthikeyan and Sivaprasad
Acknowledgements
The authors thank the SAIF-IIT for instrumental analyses and gratefully acknowledge the
Executive Editor, Professor J.-P. Anselme, for his patience, corrections and continuous
suggestions in writing this manuscript.
References
1. S. Foldeak, J. Czombas, and B. Matkovis, Acta Univ. Sjeged Acta Phys. Chem., 11, 115 (1965).
2
. J. Povszasz, G. P. Katalin, S. Foleat, and B. Malkovics, Acta Phys. Acad. Sci. Hung., 29, 299
(
1996).
3. G. Sivaprasad, P. T. Perumal, V. R. Prabavathy, and N. Mathivanan, Bioorg. Med. Chem. Lett.,
16, 6302 (2006).
4
5
6
. A. Kathleen and A. G. Merrill, PCT Int. Appl. WO 99, Chem. Abstr., 130, 276, 765 (1999).
. C. A. Bradfield and L. F. Bjeldanes, J. Toxicol. Environ. Health., 21, 311 (1987).
. R. H. Dashwood, L. Uyetake, A. T. Fong, J. D. Hendricks, and G. S. Bailey, Food Chem. Toxi-
col., 27, 385 (1989).
7. R. Martınez, A. Espinosa, A. Alberto T aꢀ rraga and P. Molina, Tetrahedron., 64, 2184 (2008).
8. S. Safe, S. Papineni, and S. Chintharlapalli, Cancer Lett., 269, 326 (2008).
9. A. Kamal and A. A. Qureshi, Tetrahedron., 19, 513 (1963).
10. A. Chatterjee, S. Manna, J. Banerji, C. Pracard, T. Prange, and J. Shoolery, J. Chem. Soc., Per-
kin Trans. 1, 553 (1980).
1
1
1
1
1. D. Chen, L. Yu and P. G. Wang, Tetrahedron Lett., 37, 4467 (1996).
2. P. J. Ji, M. F. Zhou and D. G. Qu, S. V. Wang, T. P. Loh, Synlett, 2077 (2003).
3. J. S. Yadav, B. V. S. Reddy and G. Satheesh, Tetrahedron Lett., 45, 3673 (2004).
4. J. S. Yadav, B. V. S. Reddy, V. S. R. Murthy, G. M. Kumar and C. Madan, Synthesis, 783
(2001).
1
1
1
5. S.-J. Ji, S.-Y. Wang, Y. Zhang and T.-P. Loh, Tetrahedron., 60, 2051 (2004).
6. S. A. Farhanullah, P. R. Maulik and V. J. Ram, Tetrahedron Lett.,45, 5099 (2004).
7. A. Khalafi-Nezhad, A. Parhami, A. Zare, A. R. Zare, A. Hasaninejad Moosavi, and F. Panahi,
Synthesis, 617 (2008).
1
8. G. V. M. Sharma, J. J. Reddy, P. S. Lakshmi, and P. R. Krishna, Tetrahedron Lett., 45, 7729
(
2004).
1
2
2
2
2
2
2
9. S.-J. Ji, M.-F. Zhou, S.-Y. Wang, and T.-P. Loh, Synlett, 2077 (2003)
0. D.-G. Gu, S.-J. Ji, Z.-Q. Jiang, and T.-P. Loh, Synlett, 959 (2005).
1. R. K. Belter and A. J. Poss, J. Org. Chem., 53, 1535 (1988).
2. S. R. Thopate, M. G. Kulkarni, and V. G. Puranik, Angew.Chem. Int. Ed., 37, 1110 (1998).
3. V. D. Bock, H. Hiemstra, and J. H. van Maarseveen, Eur. J. Org. Chem., 51 (2006).
4. Y. Yu, J.Srogl, and L. S. Liebeskind, Org. Lett., 6, 2631 (2004).
5. R. K. Sharma and A. G. Samuelson, Tetrahedron: Asym., 18, 2387 (2007).

Synthesis of bis(Indolyl)methanes Catalyzed
453
2
2
2
2
3
3
3
3
6. R. K. Sharma, M. Nethaji, and A. G. Samuelson, Tetrahedron: Asym., 19, 655 (2008).
7. Q. Liu, B. Han, Z. Liu, L. Yang, Z.-L. Liu, and W. Yu, Tetrahedron Lett., 47, 1805 (2006).
8. Z. H. Zhang, L. Yin and Y. M. Wang, Synthesis, 1949 (2005).
9. J. Shun-Jun, W. Shun–Yi and L. Teck-Peng, Tetrahedron., 60, 2051 (2004).
0. V. T. Kamble et al. Catal. Commun., 8, 498 (2007).
1. K.L. Dhumaskar and S.G. Tilve, Green Chem. Lett. and Rev., 5, 353 (2012).
2. R. G. -Vaghei and S. M. Malaekehpoor, Org. Prep. Proced. Int., 42, 175 (2010).
3. A. Zare, F. Bahrami, M. Merajoddin, M. Bandari, A. R. M.-Zare, M. AliZolfigol, A. Hasanine-
jad, M. Shekouhy, M. H. Beyzavi, V. Khakyzadeh, M. Mokhlesi, and Z. Asgari, Org. Prep.
Proced. Int., 45, 211 (2013).
34. M. A. Zolfigol, A. Khazaei, A. R. M.-Zare and A. Zare, Org. Prep. Proced. Int., 42, 95 (2010).