Heterocycl. Commun.

2015; 21(2): 89–92

Tayebeh Jari, Mohammad Ali Amrollahi* and Zohreh Kheilkordi

ZrOCl2·SiO2-catalyzed synthesis of bis(indoles)

via conjugate addition of indole with electron-
deficient alkenes in water
Abstract: This report provides a description of an efficient Aqueous phase organic synthesis has attracted the atten-
and environmentally benign procedure for the synthesis tion of chemists as it overcomes the harmful effects asso-
of bis(indole) derivatives via reaction of indole with elec- ciated with the organic solvents and is environmentally
tron-deficient alkenes. The remarkable advantages of this benign [19].
method for obtaining bis(indoles) are the simplicity of the In recent years, zirconium salts have been used as
experimental procedure, short reaction times, and high catalysts in organic synthesis because these solid acids
yields with the green aspects by avoiding toxic catalysts are relatively nontoxic, easy to handle, inexpensive, and
and solvents. possess good stability [20–23]. Among these, ZrOCl2 has
been reported to be an efficient catalyst for many impor-
Keywords: aqueous media; bis(indole); Michael addition; tant organic transformations [24–29]. In continuation
oxidative dehydrogenation; zirconium oxychloride. of our previous work on the development of new syn-
thetic methodologies [30, 31], we report the synthesis of
DOI 10.1515/hc-2015-0014
bis(indole) derivatives via reaction of indole with elec-
Received December 13, 2014; accepted March 2, 2015; previously tron-deficient alkenes in the presence of ZrOCl2·SiO2 in
published online March 26, 2015 H2O under reflux conditions (Scheme 1).

Introduction Results and discussion

Michael addition is one of the most important reactions
For optimizing the experimental conditions, the reac-
for the construction of carbon-carbon bonds in organic
tion between 1 and 2a was used as a model reaction. To
reactions [1, 2]. Among the Michael acceptors, (arylmethyl-
find the best catalyst, several Lewis acids such as ZrCl4,
idene)malononitriles are attractive because nitrile moiety
Ni(NO3)2, ZrOCl2, P2O5, Cu(I)Cl, and Cu(OAc)2 were used.
is an electron-withdrawing group that can be readily
The highest yield was achieved with ZrOCl2. The forma-
transformed into a range of different functionalities.
tion of the product was more facile and proceeded in
Bis(indole) derivatives have received much attention
shorter time when the reaction was performed in the pres-
because of their synthetic as well as biological applica-
ence of ZrOCl2·SiO2. Similar reactions were then attempted
tions [3, 4]. The synthesis of this important class of nitro-
in the presence of 10, 15, 20, and 25 mol% of ZrOCl2·SiO2.
gen heterocycles has been reported via condensation
The results show that the use of 20 mol% of ZrOCl2·SiO2
reactions of indole with different carbonyl compounds.
at reflux in water is sufficient. Greater amounts of the
A variety of reagents such as I2 [5, 6], hexamethylenete-
catalyst had no significant influence on the reaction
tramine-bromine [7], ZrOCl2 [8], p-toluenesulfonic acid
yield. To find the optimum temperature, the reaction was
[9], [bnmim][HSO4] [10], NH4Cl [11], AlPW12O40 [12], TPA-
conducted with 20 mol% of ZrOCl2·SiO2 at room tempera-
ZrO2 [13], Zr(DS)4 [14], ZrCl4 [15], trichloro-1,3,5-triazine
ture, 60°C, and at reflux, which resulted in the isolation
[16], ZrOCl2 silica gel [17], and N-bromosuccinimide
of product in a trace amount, 70 and 92% yields, respec-
[18] have been used to accomplish this transformation.
tively. In addition, CH2Cl2, CHCl3, MeCN, and AcOEt were
also tested as solvents. In all these cases, product 3a was
*Corresponding author: Mohammad Ali Amrollahi, Department
formed in lower yields. Solvent-free conditions at differ-
of Chemistry, Yazd University, PO Box 89195-741, Yazd, Iran,
e-mail: [email protected]
ent temperatures did not accelerate the reaction. Thus,
Tayebeh Jari and Zohreh Kheilkordi: Department of Chemistry, Yazd the reaction is optimally conducted in the presence of
University, PO Box 89195-741, Yazd, Iran 20 mol% of ZrOCl2·SiO2 under reflux conditions.
90      T. Jari et al.: ZrOCl2·SiO2-catalyzed synthesis of bis(indoles)

R2
R1 CN

CN ZrOCl2 . SiO2(20 mol%) X

N R1
X H2O, ∆ N
H H
1 2a-k 3a-k

2a: R1 = Ph; X = CN 3a: R1 = Ph; R2 = 3-indolyl; X = CN

2b: R1 = 4-NO2-C6H4; X = CN 3b: R1 = 4-NO2-C6H4; R2 = 3-indolyl; X = CN
2c: R1 = 4-F-C6H4; X = CN 3c: R1 = 4-F-C6H4; R2 = 3-indolyl; X = CN
2d: R1 = 4-Cl-C6H4; X = CN 3d: R1 = 4-Cl-C6H4; R2 = 3-indolyl; X = CN
2e: R1 = 3, 4-diMe-OC6H3; X = CN 3e: R1 = 3,4-diMeO-C6H3; R2 = 3-indolyl; X = CN
2f: R1 = 4-OH-C6H4; X = CN 3f: R1 = 4-OH-C6H4; R2 = 3-indolyl; X = CN
2g: R1 = 4-Me-C6H4; X = CN 3g: R1 = 4-Me-C6H4; R2 = 3-indolyl; X = CN
2h: R1 = 3-pyridyl; X = CN 3h: R1 = 3-pyridyl; R2 = H; X = CN
2i: R1 = 4-pyridyl; X = CN 3i: R1 = 4-pyridyl; R2 = H; X = CN
2j: R1 = 3-pyridyl; X = CO2Et 3j: R1 = 3-pyridyl; R2 = H; X = CO2Et
2k: R1 = 4-pyridyl; X = CO2Et 3k: R1 = 4-pyridyl; R2 = H; X = CO2Et

Scheme 1 

Bis(indole) derivatives 3a-g were synthesized under General procedure for the synthesis of bis(indole)
the optimized conditions. It can be observed that the ­compounds 3a–g and mono adducts 3h–k
process tolerates both electron-donating and electron-
withdrawing substituent R1 in the substrates 2a-k. In all A mixture of indole (1, 1 mmol), an electron-deficient alkene [(2a-g,
cases, the reactions proceed efficiently at reflux in water 0.5 mmol) or (2h-k, 1 mmol)], and the catalyst ZrOCl2·SiO2 (20 mol%)
under mild conditions to afford the corresponding prod- in water (8 mL) was heated under reflux until the reaction was com-
pleted, as monitored by TLC. After cooling, the mixture was filtered
ucts in high yields. All products were characterized by IR,
and the filtrate was concentrated. The residue was subjected to col-
1
H-and 13C-NMR spectra, and elemental analysis. umn chromatography eluting with chloroform/n-hexane, 9:1.
Under the optimized conditions, the treatment of
(pyridylmethylene)malononitriles (2h and 2i) and ethyl 2-[Di(1H-indol-3-yl)(phenyl)methyl]malononitrile (3a) Yield
(pyridyl)acrylates (2j and 2k) with indole does not yield 92%; red crystals; mp 89–90°C; IR: 3409, 3050, 2923, 2259, 1619, 1455
cm-1; 1H-NMR: δ 5.94 (s, 1H, CH), 6.67 (s, 2H, CH), 7.07 (t, J  =  6.4 Hz,
bis(indole derivatives. These reactions proceed smoothly,
2H, ArH), 7.23 (t, J  =  6.4 Hz, 2H, ArH), 7.27–7.35 (m, 7H, ArH), 7. 45 (d,
but the products contain only one indole moiety in the J  =  6.9 Hz, 2H, ArH), 7.88 (s, 2H, NH); 13C-NMR: δ 27.7, 40.6, 111.4, 112.6,
molecule. Changes in a molar ratio of the substrates 119.6, 120.1, 120.3, 122.3, 124.0, 126.5, 127.5, 128.6, 129.1, 137.1, 144.4.
(1:2 = 1:0.5 or 1:1) do not affect the final structural outcome. Anal. Calcd for C26H18N 4: C, 80.81; H, 4.69; N, 14.50. Found: C, 80.51;
H, 4.49; N, 14.20.

2-[Di(1H-indol-3-yl)(4-nitrophenyl)methyl]malononitrile
Conclusion (3b) Yield 90%; yellow crystals; mp 243–245°C; IR: 3422, 3047, 2923,
2263, 1592, 1504, 1453, 1339 cm-1; 1H-NMR: δ 5.93 (s, 1H, CH), 6.64 (s,
2H, CH), 6.92 (t, J  =  7.4 Hz, 2H, ArH), 7.09 (t, J  =  7.4 Hz, 2H, ArH), 7.26
Depending on the structure of electron-deficient alkenes,
(d, J  =  7.9 Hz, 2H, ArH), 7.34 (d, J  =  8.1 Hz, 2H, ArH), 7.46 (d, J  =  8.3 Hz,
their addition reactions with indole in the presence of 2H, ArH), 8.15 (d, J  =  8.3 Hz, 2H, ArH), 9.45 (s, 2H, NH); 13C-NMR: δ
ZrOCl2·SiO2 give rise to bis(indole) or mono-indole adducts. 32.0, 45.9, 111.0, 113.0, 113.8, 117.2, 119.8, 120.1, 122.0, 123.8, 124.0, 128.0,
132.4, 148.0, 149.1. Anal. Calcd for C26H17N5O2: C, 72.38; H, 3.97; N, 16.23.
Found: C, 72.15; H, 3.65; N, 16.43.

Experimental 2-[(4-Fluorophenyl)di(1H-indol-3-yl)methyl]malononitrile
(3c) Yield 86%; pink crystals; mp 132–135°C; IR: 3408, 3052, 2923,
Melting points were determined on a Büchi melting point B-540 2252, 1601, 1416, 1217, 743 cm-1; 1H-NMR: δ 5.90 (s, H, CH), 6.33 (s, 2H,
B.V.CHI apparatus in open capillaries and are uncorrected. IR spec- CH), 7.00 (m, 2H, ArH), 7.19–7.27 (m, 4H, ArH), 7.30 (m, 2H, ArH), 7.80
tra were recorded in KBr pellets on a Bruker Eqinox 55 spectrometer. (d, J  =  8.1 Hz, 2H, ArH), 8.00 (d, J  =  7.9 Hz, 2H, ArH), 9.30 (s, 2H, NH);
1
H- and 13C-NMR spectra were obtained in CDCl3 on a BrukerAvance 13
C-NMR: δ 39.9, 48.0, 112.0, 112.8, 113.0, 116.0, 119.0, 120.7, 121.2, 123.8,
500  MHz spectrometer. Elemental analyses were conducted with a 128.4, 131.1, 136.8, 138.0, 159.1. Anal. Calcd for C26H17N4F: C, 77.21; H,
Costech ECS 4010 CHN analyzer. Column chromatography was per- 4.24; N, 13.58. Found: C, 77.00; H, 4.60; N, 13.44.
formed on silica gel (230–400) mesh. Analytical thin-layer chroma-
tography (TLC) was performed on precoated plastic sheets of silica 2-[(4-Chlorophenyl)di(1H-indol-3-yl)methyl]malononitrile
gel G/UV-254 of 0.2 mm thickness. The catalyst ZrOCl2·SiO2 was pre- (3d) Yield 85%; viscous oil; IR: 3411, 3070, 2923, 2257, 1616, 1470, 744
pared as previously reported [32]. cm-1; 1H-NMR: δ 5.89 (s, 1H, CH), 6.66 (s, 2H, CH), 6.93–7.04 (m, 4H,
 T. Jari et al.: ZrOCl2·SiO2-catalyzed synthesis of bis(indoles)      91

ArH), 7.21 (d, 2H, J  =  8.0 Hz, ArH,), 7.44 (d, 2H, J  =  7.3 Hz, ArH), 7.80 112.9, 116.1, 118.6, 119.9, 122.1, 122.6, 123.0, 124.0, 133.2, 135.29, 136.9,
(d, 2H, J  =  8.0 Hz, ArH), 8.00 (d, J  =  7.3 Hz, 2H, ArH), 8.60 (s, 2H, NH); 148.2, 149.9, 165.2. Anal. Calcd for C19H17N3O2: C, 71.46; H, 5.37; N, 13.16.
13
C-NMR: δ 37.6, 50.0, 112.1, 113.2, 113.8, 118.5, 120.1, 121.5, 121.7, 125.5, Found: C, 71.16; H, 5.67; N, 13.36.
128.3, 130.1, 131.9, 138.1, 140.0. Anal. Calcd for C26H17N4Cl: C, 74.19; H,
4.07; N, 13.31. Found: C, 74.42; H, 4.28; N, 13.55. Ethyl 2-cyano-3-(1H-indol-3-yl)-3-(pyridine-4-yl)propanoate (3k) 
Yield 85%; viscous oil; IR: 3402, 3060, 2981, 2250, 1741, 1599, 1458 cm-1;
2[(3,4-Dimethoxyphenyl)di(1H-indol-3-yl)methyl]malononitrile 1
H-NMR: δ 1.06 (t, J  =  7.1 Hz, 3H, CH3), 4.08 (q, J  =  7.1 Hz, 2H, CH2),
(3e) Yield 81%; light yellow crystals; mp 168–169°C; IR: 3309, 3055, 4.34 (d, J  =  6.2 Hz, 1H, CH), 5.01 (d, J  =  6.1 Hz, 1H, CH), 7.18 (m, 4H,
2926, 2250, 1593, 1580, 1455 cm-1; 1H-NMR: δ 3.80 (s, 3 H, CH3), 3.89 (s, ArH), 7.28 (d, J  =  8.0 Hz, 2H), 8.46 (d, J  =  8.0 Hz, 2H, ArH), 8.63 (s, 1H,
3H, CH3), 5.88 (s, 1H, CH), 6.67 (d, J  =  1.8 Hz, 1H, ArH), 6.71 ( s, 2H, CH), 10.04 (s, 1H, NH); 13C-NMR: δ 14.1, 38.1, 40.1, 63.4, 112.0, 117.4,
CH), 6.81 (d, J  =  8.2 Hz, 1H, ArH), 6.88 (dd, J1  =  8.2 Hz, J2  =  1.8 Hz, 1H, 120.9, 121.7, 122.6, 123.2, 124.5, 124.7, 137.1, 141.0, 150.0, 153.4, 164.7.
ArH), 7.05 (t, J  =  7.5 Hz, 2H, ArH), 7.21 (t, J  =  7.5 Hz, 2H, ArH), 7.4 (d, Anal. Calcd for C19H17N3O2: C, 71.46; H, 5.37; N, 13.16. Found: C, 71.23;
J  =  8.0 Hz, 2H, ArH), 7.45 (d, J  =  8.0 Hz, 2H, ArH), 7.96 (s, 2H, NH); 13C- H, 5.14; N, 13.54.
NMR: δ 38.0, 50.0, 57.3, 57.4, 110.0, 112.0, 112.8, 115.0, 117.7, 119.7, 120.0,
122.0, 123.01, 123.7, 128.7, 133.0, 136.5, 148.0, 150.0. Anal. Calcd for
C28H22N4O2: C, 75.32; H, 4.97; N, 12.55. Found: C, 75.52; H, 4.63; N, 12.22. Acknowledgments: The authors thank the Research Coun-
cil of Yazd University for financial support.
2-[(4-Hydroxyphenyl)di(1H-indol-3-yl)methelyl]malononitrile
(3f) Yield 80%; red crystals; mp 87–88°C; IR: 3407, 3055, 2922, 2273,
1611, 1509, 1455 cm-1; 1H-NMR: δ 5.30 (s, 1H, OH), 5.40 (s, 1H, CH), 6.67
(s, 2H, NH), 6.80 (d, J  =  8.2 Hz, 2H, ArH), 7.00 (m, 2H, ArH), 7.14 (d, J  =  References
7.9 Hz, 2H, ArH), 7.60 (m, 2H, ArH), 7.90 (d, J  =  8.2 Hz, 2H, ArH), 7.97
(d, J  =  8.2 Hz, 2H, ArH), 8.30 (s, 2H, NH); 13C-NMR: δ 39.0, 49.1, 111.2, [1] Yadav, J. S.; Abraham, S.; Reddy, B. V. S.; Sabitha, G. InCl3-
113.0, 116.1, 119.6, 121.1, 123.0, 128.2, 129.0, 129.3, 132.7, 136.5, 138.1, catalysed conjugate addition of indoles with electron-deficient
155.5. Anal. Calcd for C26H18N4O: C, 77.59; H, 4.51; N, 13.92. Found: C, olefins. Synthesis 2001, 14, 2165–2169.
77.65; H, 4.71; N, 13.62. [2] Mariappan, J.; Kuppusamy, K.; Amarajothi, D.; Kasi, P. Michael
addition of indoles to b-nitrostyrenes catalyzed by HY zeolite
2-[Di(1H-indol-3-yl)(p-tolyl)methyl]malononitrile (3g) Yield under solvent-free conditions. Tetrahedron Lett. 2014, 55,
82%; red crystals; mp 174–176°C; IR: 3380, 3030, 2923, 2267, 1610, 1475 2061–2064.
cm-1; 1H-NMR: δ 2.54 (s, 3H, CH3), 5.32 (s, 1H, CH), 6.80 (s, 2H, CH), [3] Osawa, T.; Namiki, M. Structure elucidation of streptindole, a
7.00–7.25 (m, 4H, ArH), 7.35 (d, J  =  7.3 Hz, 2H, ArH), 7. 49 (d, J  =  8.1 novel genotoxic metabolite isolated from intestinal bacteria.
Hz, 2H, ArH), 7.65 (d, J  =  7.3, 2H, ArH), 7. 95 (d, J  =  8.1 Hz, 2H, ArH), Tetrahedron Lett. 1983, 24, 4719–4722.
8.93 (s, 2H, NH); 13C-NMR: δ 21.4, 37.8, 55.7, 112.6, 113.4, 119.6, 120.1, [4] Sadaphal, S. A.; Kategaonkar, A. H.; Labade, V. B.; Shingare
120.9, 122.3, 124.0, 126.5, 127.5, 128.6, 129.1, 137.1, 144.4. Anal. Calcd for Murlidhar, S. Synthesis of bis(indolyl) methanes using alu-
C27H20N 4: C, 80.98; H, 5.03; N, 13.99. Found: C, 80.71; H, 4.69; N, 14.20. minium oxide (acidic) in dry media. Chinese Chem. Lett. 2010,
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2-[(1H-Indol-3-yl)( pyridine-3-yl)methyl]malononitrile [5] Ganguly, N. C.; Mondal, P.; Barik, S. K. Iodine in aqueous micel-
(3h) Yield 92%; white crystals; mp 159–161°C; IR: 3407, 3075, 2902, lar environment: a mild effective eco-friendly catalytic system
2258, 1618, 1494; 1H-NMR: δ 4.80 (d, J  =  6.9 Hz, 1H, CH), 5.00 (d, J  =  for expedient synthesis of bis(indolyl)methanes and 3-substi-
6.9 Hz, 1H, CH), 7.50–7.90 (m, 7H, ArH), 8.42 (s, 1H, CH), 8.61 (s, 1H, tuted indolyl ketones. Green Chem. Lett. Rev. 2012, 5, 73–81.
CH), 10.37 (s, 1H, NH); 13C-NMR: δ 29.5, 42.1, 110.9, 112.2, 112.9, 116.1, [6] Ji, S. J.; Wang, S.; Zhang, Y.; Loh, T. P. Facile synthesis of
118.6, 120.0, 122.8, 124.0, 127.9, 134.1, 136.1, 136.9, 141.4, 156.1, 165.7. bis(indolyl)methanes using catalytic amount of iodine at room
Anal. Calcd for C17H12N4: C, 74.98; H, 4.44; N, 20.58. Found: C, 74.55; temperature under solvent-free conditions. Tetrahedron 2004,
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1472 cm-1; 1H-NMR: δ 4.80 (d, J  =  6.9 Hz, 1H, CH), 4.50 (d, J  =  6.9 Hz, [8] Nagawade, R. R.; Shinde, D. B. Zirconyl(IV) chloride—catalysed
1H, CH), 7.10 (s, 1H, ArH), 7.10–7.30 (m, 4H, ArH), 7.28 (d, J  =  7.7 Hz, reaction of indoles: an expeditious synthesis of bis(indolyl)
2H, ArH), 8.61 (d, J  =  7.7 Hz, 2H, ArH), 9.37 (s, 1H, NH); 13C-NMR: δ 49.5, methanes. Acta Chim. Slov. 2006, 53, 210–213.
62.1, 110.9, 112.9, 116.1, 118.6, 119.8, 120.7, 123.3, 124.0, 127.3, 134.1, 136.9, [9] Pashas, M. A.; Jayashankara,V. P. p-Toluenesulfonic acid (p-TSA)
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