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Ultrasonics Sonochemistry 15 (2008) 265–268

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Short Communication

An efficient and practical synthesis of

2-((1H-indol-3-yl)(aryl)methyl)malononitriles under ultrasound
irradiation
Ji-Tai Li *, Zhi-Ping Lin
College of Chemistry and Environmental Science, Hebei University, Key Laboratory of Analytical Science and Technology of Hebei Province,
No. 88, Hezuo Road, Baoding 071002, Hebei Province, PR China

Received 15 May 2007; received in revised form 29 July 2007; accepted 3 August 2007
Available online 1 September 2007

Abstract

Synthesis of 2-((1H-indol-3-yl)(aryl)methyl)malononitrile via the Michael addition of indole with various arylmethylenemalononitriles
was carried out in good yields using anhydrous zinc chloride as the catalyst under ultrasound irradiation.
 2007 Elsevier B.V. All rights reserved.

PACS: 43.35.Vz; 81.20.Ka

Keywords: 2-((1H-Indol-3-yl)(aryl)methyl)malononitrile; Synthesis; Indole; Michael addition; Ultrasound irradiation

1. Introduction indol-3-yl)(aryl)methyl)malononitriles via Michael addition

Indole frameworks have been widely known as promi-
nent agents in compounds of high biological, agrochemical
and pharmacological relevance [1]. Furthermore, 3-substi-
tuted indoles are components of drugs and are commonly
found in molecules of pharmaceutical interest in a variety
of the therapeutic areas [2].
Ultrasound has increasingly been used in organic syn-
thesis in recent years. Compared with traditional methods,
this method is more convenient and reactions can be car-
ried out in higher yield, shorter reaction time and milder
conditions under ultrasound irradiation [3]. Recently, we
reported ultrasound promoted the preparation of b-indo-
lylketones catalyzed by silica sulfuric acid and the synthesis
of bis(indolyl)methanes catalyzed by aminosulfonic acid in
anhydrous ethanol [4]. Continuing our investigations in
this area [5], we herein report the preparation of 2-((1H-
*
Corresponding author. Tel.: +86 312 5079361; fax: +86 312 5079628.
E-mail address: lijitai@mail.hbu.edu.cn (J.-T. Li).
of indole with arylmethylenemalononitriles catalyzed by
zinc chloride in ethyl acetate under ultrasound irradiation
(Scheme 1).
2. Method
2.1. Apparatus and analysis
Melting points were uncorrected. 1H NMR spectra were
measured on a Bruker AVANCE 400 (400 MHz) spec-
trometer using TMS as the internal standard and CDCl3
as a solvent. IR spectra were recorded on a Bio-Rad
FTS-40 spectrometer (KBr). Elemental analyses were mea-
sured on a HERAEUS (CHNO, Rapid) analyzer. Sonica-
tion was performed in Shanghai Branson-CQX ultrasonic
cleaner (with a frequency of 25 kHz and a nominal power
250 W). The reaction flask was located in the ultrasonic
bath, where the surface of reactants is slightly lower than
the level of the water. The reaction temperature was con-
trolled by addition or removal of water from ultrasonic
bath.

1350-4177/$ - see front matter  2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.ultsonch.2007.08.005
266 J.-T. Li, Z.-P. Lin / Ultrasonics Sonochemistry 15 (2008) 265–268

Ar CN evaporated under reduced pressure to give the crude prod-

Ar CN anhydrous ZnCl2
X
uct, which was separated by column chromatography on
N
+
u.s.
silica (200–300 mesh), eluted with petroleum ether or a
H X N
H H mixture of petroleum ether and diethyl ether. The authen-
X=CN or COOEt
ticity of the products was established by the data of 1H
2
1 NMR, IR and elemental analyses.
Scheme 1.
2.2.1. 2-((3-Chlorophenyl)(1H-indol-3-yl)methyl)
malononitrile (2a)
2.2. General procedure for the Michael additions Solid, m.p.: 179–181 C. 1H NMR (CDCl3): d 4.47 (d,
J = 6.4 Hz, 1H, CH), 4.94 (d, J = 6.4 Hz, 1H, CH), 7.12
The preparation of arylmethylenemalononitriles was (t, J = 7.2 Hz, 1H), 7.25–7.46 (m, 8H, ArH), 8.34 (s, 1H,
referred to Ref. [6]. The preparation of ethyl a-cyanocinna- NH) ppm. IR (KBr) m: 3386, 3059, 2879, 2258,
mates was referred to Ref. [7]. 2220 cm 1. Anal. calcd. for C18H12N3Cl: C 70.82, H 3.93,
Indole (70.2 mg, 0.6 mmol), arylmethylenemalononitr- N 13.77; found C 70.79, H 3.90, N 13.75.
iles or ethyl a-cyanocinnamates (0.5 mmol), anhydrous
ZnCl2 (136 mg, 1.0 mmol), ethyl acetate (3 mL), were 2.2.2. 2-((2-Chlorophenyl)(1H-indol-3-yl)methyl)
mixed in a 50 mL Pyrex flask. The mixture was irradiated malononitrile (2b)
in the water bath of the ultrasonic cleaner for a period as Solid, m.p.: 66–68 C. 1H NMR (CDCl3): d 4.48 (d,
indicated in Table 1 (the reaction was followed by TLC). J = 6.4 Hz, 1H, CH), 4.96 (d, J = 6.4 Hz, 1H, CH), 7.12
After the completion of the reaction, the resulting suspen- (t, J = 7.2 Hz, 1H), 7.26–7.50 (m, 8H, ArH), 8.34 (s, 1H,
sion was quenched with 10 mL water. The reaction mixture NH) ppm. IR (KBr) m: 3384, 3059, 2878, 2258,
was extracted with ethyl acetate (3 · 15 mL). The com- 2220 cm 1. Anal. calcd. for C18H12N3Cl: C 70.82, H 3.93,
bined organic layers were washed with saturated aqueous N 13.77; found C 70.81, H 3.98, N 13.74.
NaHCO3 solution and brine, dried over anhydrous magne-
sium sulfate for 12 h and filtered. Ethyl acetate was 2.2.3. 2-((4-Chlorophenyl)(1H-indol-3-yl)methyl)
malononitrile (2c)
Table 1 Solid, m.p.: 70–72 C. 1H NMR (CDCl3): d 4.47 (d,
Synthesis of 2-((1H-indol-3-yl)(aryl)methyl)malononitriles catalyzed by J = 6.4 Hz, 1H, CH), 4.93 (d, J = 6.4 Hz, 1H, CH), 7.12
anhydrous ZnCl2 at rt under ultrasound irradiation
(t, J = 7.2 Hz, 1H), 7.25–7.47 (m, 8H, ArH), 8.34 (s, 1H,
Entry 1 Time (h) 2 NH) ppm. IR (KBr) mmax: 3385, 3058, 2880, 2259,
Ar X Yield (%) 2220 cm 1. Anal. calcd. for C18H12N3Cl: C 70.82, H 3.93,
a 3-ClC6H4 CN 1.5 95a N 13.77; found C 70.84, H 3.96, N 13.73.
1.5 73b
1.5 78c 2.2.4. Ethyl 3-(4-chlorophenyl)-2-cyano-3-(1H-indol-3-yl)
1.5 64d
1.5 42e
propanoate (2d)
Viscous liquid. 1H NMR (CDCl3): d 1.13 (t, J = 8.0 Hz,
b 2-ClC6H4 CN 1.5 97
3H, CH3), 1.18 (t, J = 8.0 Hz, 3H, CH3), 4.10–4.22 (m, 4H,
1.5 34e
CH2), 4.36 (d, J = 8.0 Hz, 2H, CH), 5.10 (dd, J = 8.0,
c 4-ClC6H4 CN 1.5 96 20.0 Hz, 2H, CH), 7.05–7.51 (m, 18H, ArH), 8.40 (d,
1.5 42e
J = 8.0 Hz, 2H, NH) ppm. IR (KBr) mmax: 3408, 3053,
d 4-ClC6H4 CO2Et 6.0 94 2981, 2933, 2251 cm 1. Anal. calcd. for C20H17N2O2Cl: C
e 2,4-Cl2C6H3 CN 1.5 95
68.18, H 4.83, N 7.95; found C 68.24, H 4.88, N 7.98.
f 3-BrC6H4 CN 1.5 95
g C6H5 CN 1.5 88
1.5 28e 2.2.5. 2-((2,4-Dichlorophenyl)(1H-indol-3-yl)methyl)
malononitrile (2e)
h 2-NO2C6H4 CN 1.5 76
2.0 0e Solid, m.p.: 162–164 C. 1H NMR (CDCl3): d 4.53 (d,
J = 6.0 Hz, 1H, CH), 5.51 (d, J = 5.6 Hz, 1H, CH), 7.10
i 3-NO2C6H4 CN 1.5 60
2.0 0e
(t, J = 7.2 Hz, 1H), 7.20–7.62 (m, 7H, ArH), 8.38 (s, 1H,
NH) ppm. IR (KBr) mmax: 3411, 3059, 2899, 2256,
j 4-NO2C6H4 CN 1.5 57
2219 cm 1. Anal. calcd. for C18H11N3Cl2: C 63.72, H
k 2,4-(NO2)2C6H3 CN 3.0 34
l 4-CH3OC6H4 CN 3.0 0 3.24, N 12.39; found C 63.74, H 3.25, N 12.39.
m 4-CH3OC6H4 CO2Et 3.0 51
n 4-CH3C6H4 CN 3.0 trace 2.2.6. 2-((3-Bromophenyl)(1H-indol-3-yl)methyl)
o 4-CH3C6H4 CO2Et 3.0 19 malononitrile (2f)
The amount of ZnCl2: a1.0 mmol; b0.5 mmol; c0.75 mmol; d2.0 mmol; Solid, m.p.: 82–84 C. 1H NMR (CDCl3): d 4.46 (d,
e
1.0 mmol and stirred without ultrasound. J = 6.4 Hz, 1H, CH), 4.93 (d, J = 6.4 Hz, 1H, CH), 7.12
 J.-T. Li, Z.-P. Lin / Ultrasonics Sonochemistry 15 (2008) 265–268
(t, J = 7.2 Hz, 1H), 7.25–7.59 (m, 8H, ArH), 8.34 (s, 1H,
NH) ppm. IR (KBr) mmax: 3385, 3059, 2880, 2258,
2220 cm 1. Anal. calcd. for C18H12N3Br: C 61.72, H
3.43, N 12.00; found C 61.70, H 3.40, N 11.97.
2.2.7. 2-((1H-Indol-3-yl)(phenyl)methyl)malononitrile
(2g)
Solid, m.p.: 76–78 C. 1H NMR (CDCl3): d 4.48 (d,
J = 6.4 Hz, 1H, CH), 4.96 (d, J = 6.4 Hz, 1H, CH), 7.10
(t, J = 7.2 Hz, 1H), 7.23–7.49 (m, 9H, ArH), 8.30 (s, 1H,
NH) ppm. IR (KBr) mmax: 3345, 3058, 3030, 2881, 2360,
2262 cm 1. Anal. calcd. for C18H13N3: C 79.70, H 4.80,
N 15.50; found C 79.71, H 4.83, N 15.52.
2.2.8. 2-((1H-Indol-3-yl)
(2-nitrophenyl)methyl)malononitrile (2h)
Viscous liquid. 1H NMR (CDCl3): d 4.54 (d, J = 6.0 Hz,
1H, CH), 5.09 (d, J = 6.0 Hz, 1H, CH), 7.12 (t, J = 7.6 Hz,
1H), 7.22–7.71 (m, 7H, ArH), 8.29 (s, 1H, ArH), 8.41 (s,
1H, NH) ppm. IR (KBr) mmax: 3414, 3126, 3067, 2900,
2263 cm 1. Anal. calcd. for C18H12N4O2: C 68.35, H
3.80, N 17.72; found C 68.41, H 3.85, N 17.75.
2.2.9. 2-((1H-Indol-3-yl)
(3-nitrophenyl)methyl)malononitrile (2i)
Solid, m.p.: 81–83 C. 1H NMR (CDCl3): d 4.53 (d,
J = 6.0 Hz, 1H, CH), 5.09 (d, J = 6.0 Hz, 1H, CH), 7.11
(t, J = 7.6 Hz, 1H), 7.21–7.70 (m, 6H, ArH), 8.24 (s, 1H,
ArH), 8.28 (s, 1H, ArH), 8.40 (s, 1H, NH) ppm. IR
(KBr) mmax: 3413, 3124, 3067, 2899, 2263 cm 1. Anal. calcd.
for C18H12N4O2: C 68.35, H 3.80, N 17.72; found C 68.37,
H 3.83, N 17.74.
2.2.10. 2-((1H-Indol-3-yl)
(4-nitrophenyl)methyl)malononitrile (2j)
Solid, m.p.: 198–200 C. 1H NMR (CDCl3): d 4.54 (d,
J = 6.0 Hz, 1H, CH), 5.08 (d, J = 6.0 Hz, 1H, CH), 7.11
(t, J = 7.6 Hz, 1H), 7.22–7.69 (m, 6H, ArH), 8.28 (s, 1H,
ArH), 8.30 (s, 1H, ArH), 8.40 (s, 1H, NH) ppm. IR
(KBr) mmax: 3414, 3125, 3069, 2899, 2263 cm 1. Anal. calcd.
for C18H12N4O2: C 68.35, H 3.80, N 17.72; found C 68.36,
H 3.84, N 17.73.
2.2.11. 2-((1H-Indol-3-yl)
(2,4-dinitrophenyl)methyl)malononitrile (2k)
Viscous liquid. 1H NMR (CDCl3): d 4.61 (d, J = 6.0 Hz,
1H, CH), 5.16 (d, J = 6.0 Hz, 1H, CH), 7.13 (t, J = 7.6 Hz,
1H), 7.25–7.76 (m, 5H, ArH), 8.31 (s, 1H, ArH), 8.41 (s,
1H, ArH), 8.43 (s, 1H, NH) ppm. IR (KBr) mmax: 3418,
3127, 3070, 2901, 2265 cm 1. Anal. calcd. for
C18H11N5O4: C 59.83, H 3.05, N 19.39; found C 59.89, H
3.10, N 19.43.
3. Results and discussion
The Michael addition of indole to arylmethylenemalon-
onitriles or ethyl a-cyanocinnamates was performed at
267
room temperature catalyzed by anhydrous ZnCl2 in ethyl
acetate under ultrasound irradiation. The results are sum-
marized in Table 1.
As shown in Table 1, synthesis of 2-((1H-indol-3-
yl)(aryl)methyl)malononitriles via addition of indole to
arylmethylenemalononitriles was carried out in moderate
to good yield catalyzed by ZnCl2 under ultrasound irradi-
ation. In the absence of ultrasound, the addition of indole
with 2-(3-chlorobenzylidene)malononitrile was proceeded
in 42% yield within 1.5 h by stirring alone (Table 1, Entry
ae). While under the ultrasonication, the reaction was com-
pleted in the same time to give 2-((3-chlorophenyl)(1H-
indol-3-yl)methyl)malononitrile (2a) in 95% yield (Table
1, Entry aa). It is apparent that the ultrasound can acceler-
ate the reaction significantly. We also observed the influ-
ence of the amount of catalyst on the reaction yields. It
was found that 1.0 mmol of anhydrous ZnCl2 gave the best
yield (95%) of 2a (Entry a).
From the data in Table 1, we can see the effect of differ-
ent substrate on the reaction yield. When 2-(4-chlorobenzy-
lidene)malononitrile (1c) as substrate, 2-((4-chlorophenyl)
(1H-indol-3-yl)methyl)malononitrile (2c) was obtained in
96% yield within 1.5 h under ultrasound irradiation (Table
1, Entry c). While the reaction of (E)-ethyl 3-(4-chlor-
ophenyl)-2-cyanoacrylate (1d) and indole took 6 h under
ultrasound to obtain the ethyl 3-(4-chlorophenyl)-2-
cyano-3-(1H-indol-3-yl)-propanoate (2d) in 93% yield. This
fact further verified that these active methylene species’
reactivity order was malononitrile > ethyl cyanoacetate.
We also carried out the reaction of indole with 2-(3-
chlorobenzylidene)malononitrile using different catalyst
such as AlCl3 and I2 under ultrasound, but no reaction
took place at all.
4. Conclusion
In conclusion, we have found an efficient and practical
procedure for the preparation of 2-((1H-indol-3-yl)
(aryl)methyl)malononitriles from some arylmethylenemal-
ononitriles and indole under ultrasound irradiation.
Acknowledgement
We thank the Natural Science Foundation of Hebei
Province (B2006000969), China, for financial support.
References
[1] (a) R.J. Sundberg, The Chemistry of Indoles, Academic Press, NY,
1970;
(b) T. Fukuyama, X. Chen, J. Am. Chem. Soc. 116 (1994) 3125;
(c) V. Vaillancouirt, K.F. Albizati, J. Am. Chem. Soc. 115 (1993) 3499;
(d) H. Murakatake, H. Kumagami, M. Natsume, Tetrahedron 46
(1990) 6351.
[2] (a) G.W. Gribble, J. Chem. Soc., Perkin Trans. 1 (2000) 1045;
(b) R.L. Garnick, S.B. Levery, P.W. Lequesne, J. Org. Chem. 43
(1978) 1226.
268 J.-T. Li, Z.-P. Lin / Ultrasonics Sonochemistry 15 (2008) 265–268

[3] T.J. Mason, D. Peters, Practical Sonochemistry, Power Ultrasound
Uses and Applications, second ed., Ellis Horwood Publishers, 2002.
[4] (a) J.T. Li, H.G. Dai, W.Z. Xu, T.S. Li, J. Chem. Res. (S) (2006) 41;
(b) J.T. Li, H.G. Dai, W.Z. Xu, T.S. Li, Ultrason. Sonochem. 13
(2006) 24.
[5] J.T. Li, H.G. Dai, Z.P. Lin, Prog. Chem. 19 (2007) 751.
[6] W.Z. Xu, G.F. Chen, J.F. Han, T.S. Li, Chem.: Indian J. 1 (2003) 109.
[7] S.X. Wang, J.T. Li, W.Z. Yang, T.S. Li, Ultrason. Sonochem. 9 (2002)
159.