First synthesis of bis(di(indolyl)aryl)methanes from bis(salicylaldehydes)

Article abstract of DOI:10.1002/jhet.2061

In this article, a simple method for the synthesis of bis(di(indolyl)aryl)methanes is described. The iodine-catalyzed (5 mol %) reaction of indoles with various bis(salicylaldehyde) derivatives affords the bis(di(indolyl)aryl)methanes in excellent yields. The reaction works well under mild reaction condition with shorter reaction time.

Full text of DOI:10.1002/jhet.2061

Month 2014 First Synthesis of Bis(di(indolyl)aryl)methanes From Bis(salicylaldehydes)
a
a
Manickam Bakthadoss,a,b Anthonisamy Devaraj, and Jayakumar Srinivasan
*
aDepartment of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600 025, India
bDepartment of Chemistry, Pondicherry University, Pondicherry 605 014, India
*
E-mail: bhakthadoss@yahoo.com
Additional Supporting Information may be found in the online version of this article.
Received July 9, 2012
DOI 10.1002/jhet.2061
Published online 00 March 2014 in Wiley Online Library (wileyonlinelibrary.com).
In this article, a simple method for the synthesis of bis(di(indolyl)aryl)methanes is described. The
iodine-catalyzed (5 mol %) reaction of indoles with various bis(salicylaldehyde) derivatives affords the bis
(di(indolyl)aryl)methanes in excellent yields. The reaction works well under mild reaction condition with
shorter reaction time.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
acids [7], heterogeneous acidic catalyst [8], and reagents
such as NBS [9], potassium hydrogen sulfate [10], and
CuSO4 [11]. Even then, these methods still suffer from
some drawbacks such as long reaction time, costly
reagents, low yields of products, and high catalyst loading,
and corrosive reagents would eventually result in the
production of large amounts of toxic waste that is threaten-
ing the environment to the greater extent. Because of these
reasons, superior catalysts, which are cheap, less toxic, and
easily available, are desirable. Even though a variety of
methods are reported for the synthesis of bis(indolyl)-
methanes, we found no report for the access of bis(di
(indolyl)aryl)methanes from bis(salicylaldehyde) derivatives.
Indole and its derivatives are known to exhibit several
biological properties including antibacterial, cytotoxic,
antioxidative, and insecticidal activities, and many indole
derivatives are used as antibiotics in pharmaceuticals [1].
Amongst many indole derivatives, bis(indolyl)alkanes are
an important class of bioactive metabolite [2]. Develop-
ment of an efficient method for accessing bis(indolyl)-
alkane has been of great interest in organic synthesis
because of their wide occurrence in nature. Few of the
representative examples for the naturally occurring
bisindoles [3] are shown in Figure 1.
The continuous discovery of new and more efficient
catalytic reactions is one of the major key steps in the
development of simpler, cheaper, and more environmen-
tally friendly syntheses of organic molecules. In particular,
electrophilic substitution reactions are important, because
they lead to the creation of new carbon–carbon bonds.
Generally, many carbon–carbon bond-forming electro-
philic substitution reactions employed in organic synthesis
are promoted by Lewis acid catalysts. In general, the
acid-catalyzed addition reaction of electron-rich
heterocycles such as pyrrole and indole components with
p-dimethylaminobenzaldehyde is known as the Ehrlich
test [4]. The very similar reaction of indoles with various
aromatic or aliphatic aldehydes and ketones produces
azafulvenium salts that in turn undergo further addition
with a second indole molecule to afford bis(indolyl)-
methanes [5].
Because
bis(di(indolyl)aryl)
methanes
from
bis
(salicylaldehydes) are not known in the literature, we were
prompted to synthesize this novel type of bis(di(indolyl)aryl)
methanes in our laboratory (see Supporting Information).
RESULTS AND DISCUSSION
As part of our continued interest in the field of heterocy-
clic synthesis [12], herein we wish to report a novel
protocol toward the synthesis of bis(di(indolyl)aryl)-
methanes catalyzed by I2 using bis(salicylaldehydes)
and indoles. The precursor, (1a), needed for accessing
bis(di(indolyl)aryl) methanes was prepared using
salicylaldehyde and trioxane. Best results were obtained
when we treated compound 1a with indole (2) in THF with
a catalytic amount of iodine (5 mol %) over a period of
0.5 h that smoothly led to the 4,4′-methylenebis(2-(di(1H-
indol-3-yl)methyl) phenol) in excellent yield (93%). It is
An array of catalytic systems has been reported for the
bisindolylation reaction such as protic acids [6], Lewis
© 2014 HeteroCorporation

M. Bakthadoss, A. Devaraj, and J. Srinivasan
Vol 000
indole (4c), 3-methyl indole (4d), and 4-(1H-indol-3-yl)
butanoic acid (4e) for the synthesis of a novel type of bis
(di(indolyl)aryl)methanes under similar reaction condition
(Table 2). As mentioned earlier, we have treated compound
1b with N-methyl indole in acetonitrile with a catalytic
amount of iodine over a period of 0.5 h that successfully
afforded the anticipated bis(3-(bis(1-methyl-1H-indol-3-
yl)methyl)-4-methoxy phenyl)methane (5a) in excellent
yield (92%).
Delighted by this result, we have employed various bis
(salicylaldehydes) (1d, f, g, h) with a variety of indole
derivatives such as N-propargyl indole (4b), 2-methyl
indole (4c), 3-methyl indole (4d), and 4-(1H-indol-3-yl)
butanoic acid (4e) with a view to generate a novel class
of bis(di(indolyl)aryl)methanes. The desired products
5b–m were successfully obtained in excellent yields
(83–95%; Scheme 2).
Figure 1. Naturally occurring bisindoles.
important to mention here that this is the first report for
the synthesis of bis(di(indolyl)aryl)methanes.
Encouraged by the result, we have prepared various
O-alkylated precursors (1b and c, 1e–h) from compound
1a with various alkyl halides using K2CO3 in acetoni-
trile as a solvent (Scheme 1). The O-alkylated precur-
sors (1b–g) were reacted with indole under similar
reaction condition that successfully provided the bis(di
(indolyl)aryl)methanes (3b–g) in 82–92% yields
(Table 1). To check the role of an iodine catalyst and
its catalytic efficiency, we have treated compound 1a
with indole in the absence of iodine by using THF as
a solvent over a period of 24 h, but this did not yield
any desired product. The reaction conducted without
iodine using solvents such as acetonitrile and methanol
also did not provide any product. Furthermore, the
reaction carried out in the absence of iodine using
solvents such as THF, acetonitrile, and methanol under
reflux condition did not provide the desired product.
We have also carried out the reaction with different
loadings of iodine catalyst and found that the reaction
works well while using iodine in 5 to 15 mol % with
excellent yield. More than 25 mol % loading of iodine
results in the formation of many spots in the TLC,
and we were not able to isolate the desired product.
Therefore, 5 mol % of iodine is the optimized catalyst
loading for the reaction.
CONCLUSIONS
In summary, we have successfully developed a novel
and efficient protocol for the facile synthesis of bis(di
(indolyl)aryl)methanes catalyzed by I2 (5 mol %) using
bis(salicylaldehydes) and indole in excellent yields for
the first time. We have also utilized N-methyl indole,
N-propargyl indole, 2-methyl indole, 3-methyl indole,
and 4-(1H-indol-3-yl)butanoic acid in the indolylation
reaction to produce a novel class of bis(di(indolyl)aryl)
methanes in excellent yields. The salient features such as very
mild reaction condition, ease of workup, short reaction time,
and excellent yields make this protocol very attractive,
important, and useful in the field of organic synthesis.
EXPERIMENTAL
All reagents were purchased from commercial sources and
used without further purification. Solvents were distilled prior to
use. Column chromatography was performed on silica gel. IR
spectra were recorded on an FTIR-8300 Shimadzu spectrometer
(Chennai, Tamilnadu (India)). 1H (300 MHz) and 13C NMR
(75 MHz) were recorded on a Bruker spectrometer (Chennai,
Tamilnadu (India)) using CDCl3 as solvent and TMS as an
internal standard [chemical shift in (δ) parts per million (ppm)].
The mass spectra were recorded on a JEOL-JMS-DX 303 mass
spectrometer (ESI–MS, Chennai, Tamilnadu (India)). Elemental
To further demonstrate the generality of this protocol,
we have planned to utilize various indole derivatives such
as N-methyl indole (4a), N-propargyl indole (4b), 2-methyl
Scheme 1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
First Synthesis of Bis(di(indolyl)aryl)methanes from Bis(salicylaldehydes)
Table 1
Synthesis of bis(di(indolyl)aryl)methanes from bis(salycylaldehydes).
Entry
1
Substrate
Producta
Yield (%)b
93
2
3
90
91
4
88
5
89
6
92
7
82
aAll reactions were carried out on a 1-mmo1 scale of aldehydes with 4 mmo1 of indole with 5 mol % of I2 in THF for 0.5 h.
bIsolated yields of the pure products (3a–g) obtained after column chromatography (silica gel 60–120 mesh, 20% EtOAc in hexanes).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Bakthadoss, A. Devaraj, and J. Srinivasan
Vol 000
Table 2
Synthesis of bis(di(indolyl)aryl)methanes from 1, 2, 3-alkyl indoles.
Entry
1
Substrate
Producta
Yield (%)b
92
95
2
3
83
94
4
5
6
86
89
7
93
(Continued)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
First Synthesis of Bis(di(indolyl)aryl)methanes from Bis(salicylaldehydes)
Table 2
Continued
Entry
Substrate
Producta
Yield (%)b
8
96
9
87
10
90
11
12
92
89
13
84
aAll reactions were carried out on a 1-mmol scale of aldehydes with 4 mmol of indole with 5 mol % of I2 in THF for 0.5 h.
bIsolated yields of the pure products (5a–m) obtained after column chromatography (silica gel 60–120 mesh, 20% EtOAc in hexanes).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Bakthadoss, A. Devaraj, and J. Srinivasan
Vol 000
Scheme 2
analyses were recorded on a Perkin-Elmer 240C-CHN analyzer
(Chennai, Tamilnadu (India)). Melting points are uncorrected.
TLC was performed using glass plates coated with silica gel
(ACME Synthetic Chemicals, 254F). Spots were visualized using
iodine vapor and UV lamp.
128.08, 132.90, 136.23, 159.29, 190.27; IR (neat): ν 1255,
1677, 2839, 2967 cmÀ1; MS (m/z): 341 (M+ + 1).
5,5′-Methylenebis(2-(benzyloxy)benzaldehyde) (1f). Yield:
1
90%; reaction time: 24 h; mp: 175–177°C; H NMR (300 MHz,
CDCl3): δ 3.89 (s, 2H), 5.15 (s, 4H), 6.96–7.66 (m, 16H), 10.52
(s, 2H); 13C NMR (75 MHz, CDCl3): δ 39.76, 70.65, 113.47,
125.09, 127.31, 128.30, 128.75, 133.44, 136.12, 136.27,
159.78, 189.74; IR (neat): ν 1268, 1688, 2865, 2949 cmÀ1; MS
(m/z): 437 (M+ + 1).
General procedure for the O-alkylation of bis
(salicylaldehydes) (1b–h).
To a stirred solution of bis
(salicylaldehyde) (1a) (0.50 g, 1.95 mmol) in CH3CN (20 mL),
K2CO3 (1.35 g, 9.76 mmol) was added, and the solution was stirred
for 15 min. To the reaction mixture, alkyl halides (4 mmol) was
added and allowed to stir at RT for 24 h. After the completion of
the reaction as indicated by TLC, the reaction mixture was
concentrated, and the resulting crude mass was diluted with water
(15 mL) and extracted with ethyl acetate (3 × 15 mL). The
combined organic layer was washed with brine (2 × 10 mL) and
dried over anhydrous Na2SO4. The organic layer was concentrated,
and the solid thus obtained was washed with ethyl acetate–hexanes
(1:9) to afford the compounds 1b–h as colorless solids.
5,5′-Methylenebis(2-(allyloxy)benzaldehyde) (1g).
Yield:
96%; reaction time: 24 h; mp: 130°C; 1H NMR (300 MHz,
CDCl3): δ 3.89 (s, 2H), 4.63 (d, 4H, J = 5.1 Hz), 5.33 (dd,
2H, J1 = 1.2 Hz, J2 = 10.5 Hz), 5.44 (dd, J = 1.2, 17.1 Hz, 2H),
6.00–6.13 (m, 2H), 6.89–7.65 (m, 6H), 10.49 (s, 2H); 13C
NMR (75 MHz, CDCl3): δ 39.72, 69.30, 113.26, 118.09,
124.91, 128.24, 132.42, 133.28, 136.25, 159.64, 189.80.; IR
(neat): ν 1274, 1567, 1672, 2855, 2952 cmÀ1; MS (m/z): 337
(M+ + 1).
5,5′-Methylenebis(2-(prop-2-ynyloxy)benzaldehyde) (1h). Yield:
5,5′-Methylenebis(2-methoxybenzaldehyde) (1b).
Yield:
95%; reaction time: 24 h; mp: 146–148°C; 1H NMR (300 MHz,
CDCl3): δ 2.58 (t, 2H, J = 2.4 Hz), 3.95 (s, 2H), 4.83 (d, 4H,
J = 2.4 Hz), 7.06–7.69 (m, 6H), 10.46 (s, 2H); 13C NMR
(75 MHz, CDCl3): δ 39.79, 56.52, 77.70, 77.45, 113.65,
125.41, 128.44, 134.04, 136.06, 158.47, 189.49; IR (neat): ν
1274, 1688, 2230, 2850, 2951 cmÀ1; MS (m/z): 333 (M+ + 1).
1
97%; reaction time: 24 h; mp: 135–137°C; H NMR (300 MHz,
CDCl3): δ 3.90 (s, 8H), 6.90–7.63 (m, 6H), 10.42 (s, 2H); 13C
NMR (75 MHz, CDCl3): δ 39.68, 55.75, 112.04, 124.68,
128.35, 133.12, 136.32, 160.54, 189.81; IR (neat): ν 1264,
1682, 2847, 2946 cmÀ1; MS (m/z): 285 (M+ + 1).
5,5′-Methylenebis(2-ethoxybenzaldehyde) (1c).
Yield:
94%; reaction time: 24 h; mp: 159°C; 1H NMR (300 MHz,
CDCl3): δ 1.46 (t, 6H, J = 6.9 Hz), 3.89 (s, 2H), 4.12 (q, 4H,
J = 6.9 Hz), 6.88–7.63 (m, 6H), 10.46 (s, 2H); 13C NMR
(75 MHz, CDCl3): δ 14.68, 39.44, 64.28, 112.90, 124.69,
128.07, 133.25, 137.62, 160.31, 189.99; IR (neat): ν 1252,
1674, 2861, 2960 cmÀ1; MS (m/z): 313 (M+ + 1).
General procedure for compound 3a.
A mixture of bis
(salicyaldehyde) (1a) (0.256 g, 1 mmol), indole (2) (0.468 g,
4 mmol), and cat.I2 (catalytic iodine) (5 mol %) in THF (10 mL)
was stirred at RT for 30 min. After the completion of the reaction as
indicated by TLC, THF was removed under reduced pressure, and
the crude mass thus obtained was purified by column
chromatography using ethyl acetate–hexanes (2:8) to afford the
5,5′-Methylenebis(2-propoxybenzaldehyde) (1d).
Yield:
1
96%; reaction time: 24 h; mp: 153–155°C; H NMR (300 MHz,
CDCl3): δ 1.06 (t, 6H, J = 7.2 Hz), 1.74–1.92 (m, 4H), 3.89 (s,
2H), 4.01 (t, 4H, J = 6.3 Hz), 6.88–7.63 (m, 6H), 10.45 (s, 2H);
13C NMR (75 MHz, CDCl3): δ 10.56, 22.49, 39.73, 70.12,
112.91, 124.75, 128.02, 132.97, 136.30, 160.26, 189.91.; IR
4,4′-methylenebis(2-(di(1H-indol-3-yl)methyl)phenol) (3a) as a
pink solid.
4,4′-Methylenebis(2-(di(1H-indol-3-yl)methyl)phenol) (3a). Yield:
93%; reaction time: 0. 5 h; mp: 156°C; 1H NMR (300 MHz,
CDCl3): δ 3.67 (s, 2H), 5.33 (s, 2H), 5.87 (s, 2H), 6.39 (s, 4H),
6.66–7.47 (m, 26H); 13C NMR (75 MHz, CDCl3): δ 35.90,
40.39, 117.27, 116.56, 117.30, 119.49, 119.84, 122.25, 123.64,
126.76, 128.20, 128.85, 130.45, 134.15, 136.74, 152.51; IR
(neat): ν 1457, 1612, 1704, 3251, 3393 cmÀ1; MS (m/z): 689
(M+ + 1); Anal. Calcd for C47H36N4O2: C, 81.95; H, 5.27; N,
8.13. Found: C, 81.99; H, 5.24; N 8.16.
(neat): ν 1257, 1670, 2852, 2960 cmÀ1; MS (m/z): 341 (M+ + 1).
5,5′-Methylenebis(2-isopropoxybenzaldehyde) (1e). Yield:
93%; reaction time: 24 h; mp: 180°C; 1H NMR (300 MHz,
CDCl3): δ 1.38 (d, 12H, J = 6 Hz), 3.87 (s, 2H), 4.63 (sep, 2H,
J = 4.8 Hz), 6.90–7.64 (m, 6H), 10.45 (s, 2H); 13C NMR
(75 MHz, CDCl3): δ 22.02, 39.77, 71.24, 114.42, 125.55,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
First Synthesis of Bis(di(indolyl)aryl)methanes from Bis(salicylaldehydes)
General procedure for compound 5a. A mixture of bis
(salicyaldehyde) derivative (1b) (0.284 g, 1 mmol), N-methyl
indole (4a) (0.524 g, 4 mmol), and cat.I2 (5 mol %) in THF
(10 mL) was stirred at RT for 30 min. After the completion of
the reaction as indicated by TLC, THF was removed under
reduced pressure, and the crude mass thus obtained was purified
by column chromatography using ethyl acetate–hexanes (2:8)
to afford the bis(3-(bis(1-methyl-1H-indol-3-yl)methyl)-4-
methoxyphenyl)methane (5a) as a pink solid.
M.; Yukawa, H. J Nat Prod 2000, 63, 596; (d) Shiri, M.; Mohammad, A.
Z.; Hendrik, G. K.; Zahra, T. Chem Rev 2010, 110, 2250.
[2] Sundberg, R. J The Chemistry of Indoles; Academic: New York, 1996.
[3] (a) Bifulco, G.; Bruno, I.; Riccio, R. J Nat Prod 1995, 58,
1254; (b) Yadav, J. S.; Gupta, M. K.; Jain, R.; Yadav, N. N.; Reddy, B.
V. S. Monatsh Chem 2010, 141, 1001.
[4] (a) Ehrlich, P. Med Woche 1901, 151; (b) Morgan, L.;
Schunior, R. J Org Chem 1962, 27, 3696; (c) Dolphin, D. J Heterocycl
Chem 1979, 7, 275.
[5] (a) Hosseini Sarvari, M.; Sharghi, H. J Org Chem 2004, 69,
6953; (b) Sharghi, H.; Hosseini Sarvari, M. Synthesis 2002, 8, 1057; (c)
Hosseini Sarvari, M. Synthesis 2005, 5, 787; (d) Hosseini Sarvari, M.;
Sharghi, H. Tetrahedron 2005, 61, 10903.
Bis(3-(bis(1-methyl-1H-indol-3-yl)methyl)-4-methoxyphenyl)
methane (5a).
Yield: 92%; mp 228–230°C; 1H NMR
(300 MHz, CDCl3): δ 3.57 (s, 12H), 3.61 (s, 2H), 3.78 (s, 6H),
6.31 (s, 2H), 6.43–7.37 (m, 26H); 13C NMR (75 MHz, CDCl3):
δ 31.76, 32.54, 40.19, 55.94, 108.89, 110.70, 118.26, 118.40,
120.19, 121.19, 127.06, 127.69, 128.11, 130.52, 132.38,
133.64, 137.41, 154.93; IR (neat): ν 1621, 1658, 2899,
[6] (a) Maciejewska, D.; Rasztawicka, M.; Wolska, I.;
Anuszewska, E.; Gruber, B. Eur J Med Chem 2009, 4136; (b) Ji, S.-J.;
Zhou, M.-F.; Gu, D.-G.; Wang, S.-Y.; Loh, T.-P. Synlett 2003, 2077.
[7] (a) Maiti, A. K.; Bhattacharyya, P. J Chem Res 1997, 424; (b)
Sharma, G. V. M.; Reddy, J. J.; Lakshmi, P. S.; Krishna, P. R. Tetrahe-
dron Lett 2004, 45, 7729; (c) Firouzabadi, H.; Iranpoor, N.; Jafari, A. A.
J Mol Catal A Chem 2005, 244, 168.
3110 cmÀ1
;
MS (m/z): 774 (M+ + 1); Anal. Calcd for
C53H48N4O2: C, 82.35; H, 6.26; N, 7.25. Found: C, 82.27; H,
6.35; N, 7.18.
[8] (a) Firouzabadi, H.; Iranpoor, N.; Jafarpour, M.; Ghaderi, A. J
Mol Catal A Chem 2006, 253, 249.
Acknowledgments. We thank the CSIR, UGC (New Delhi) for
the financial support. We also thank the DST-FIST for the NMR
facility. A. D and J. S thank the CSIR for their Senior Research
Fellowship (SRF).
[9] Koshima, H.; Matsuaka, W. J Heterocycl Chem 2002, 1089.
[10] Niknam, K.; Zolfigol, M. A.; Sadabadi, T.; Nejati, A. J Iran
Chem Soc 2006, 3, 318.
[11] Moghaddam, F. M.; Bardajee, G. R.; Ismaili, H. Asian J Chem
2008, 20, 1063.
REFERENCES AND NOTES
[12] (a) Bakthadoss, M.; Murugan, G. Eur J Org Chem 2010, 5825;
(b) Bakthadoss, M.; Sivakumar,G; Kannan, D.. Org Lett 2009, 11, 4466;
(c) Bakthadoss, M.; Sivakumar, N. Synlett 2009, 1014; (d) Bakthadoss,
M.; Sivakumar, N.; Sivakumar, G.; Murugan, G. Tetrahedron Lett 2008,
49, 820.
[1] (a) Bell, R.; Carmeli, S.; Sar, N. J Nat Prod 1994, 57, 1587; (b)
Fahy, E.; Porn, B. C. M.; Faulkner, D. J.; Smith, K. J Nat Prod 1991, 54,
564; (c) Garbe, T. R.; Kobayashi, M.; Shimizu, N.; Takesue, N.; Ozawa,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet