A new catalytic method for ecofriendly synthesis of bis- and trisindolylmethanes by zirconyldodecylsulfate under mild conditions

Article abstract of DOI:10.1002/jhet.46

(Chemical Equation Presented) Zirconyldodecylsulfate (ZrO(DS)₂) as a versatile Lewis acid-surfactant-combined (LASC) catalyzed ecofriendly synthesis of bis- and tris(indolyl)methanes via electrophilic substitution of indoles with carbonyl compo

Full text of DOI:10.1002/jhet.46

May 2009
A New Catalytic Method for Ecofriendly Synthesis of Bis- and
Trisindolylmethanes by Zirconyldodecylsulfate Under
Mild Conditions
535
Maasoumeh Jafarpour,* Abdolreza Rezaeifard,* and Tayebeh Golshani
Catalysis Research Laboratory, Department of Chemistry, Faculty of Science,
University of Birjand, Birjand, 97179-414, Iran
*E-mail: mjafarpour@birjand.ac.ir or rrezaeifard@birjand.ac.ir
Received April 8, 2008
DOI 10.1002/jhet.46
Published online 5 May 2009 in Wiley InterScience (www.interscience.wiley.com).
Zirconyldodecylsulfate (ZrO(DS)2) as a versatile Lewis acid-surfactant-combined (LASC) catalyzed
ecofriendly synthesis of bis- and tris(indolyl)methanes via electrophilic substitution of indoles with car-
bonyl compounds in high yields at mild conditions.
J. Heterocyclic Chem., 46, 535 (2009).
INTRODUCTION
could be converted into important cage molecules [5]. It
is reported that the cationic form of TIMs could be used
as acceptors of hydride ions.
Replacing current chemical processes with more envi-
ronmentally benign alternatives is an increasingly attrac-
tive subject [1]. The rapid and extensive growth of syn-
thetic procedures using materials with detrimental
effects to the environment has turned the attention of
chemists to the development of environmentally benign
methods in order to avoid or minimize these harmful
effects.
Thus, indole and its derivatives have been a topic of
research interest [6]. Because of their intriguing physio-
logical activities, many synthetic procedures have been
reported so far [7–12], where development of environ-
mentally benign methods are currently of interest in pro-
cess chemistry by using green catalysts.
Green catalysts require high catalytic activity and
atom efficiency, as well as low toxicity, low cost, and
ease of handling. Fortunately, Zr(IV) compounds gener-
ally have low toxicity and are not considered particu-
larly poisonous. Reports on the safety of Zr(IV) salts
show that their LD50 is high [LD50 [ZrOCl2.8H2O, oral
rat] ¼ 3500 mg/Kg] [13]. Although ZrOCl2.8H2O has a
rather high LD50, it should not be very harmful to mam-
malians. Also, this material is commercially available
and is an inexpensive compound.
Bis(indolyl)methanes (BIM) are the most active cru-
ciferous substances for promoting beneficial estrogen
metabolism in woman and men [2]. BIM increases the
body’s natural metabolism of hormones and promotes
good estrogen (2-hydroxyestrogen). This indole antioxi-
dant is patented for alleviating symptoms of fibromyal-
gia. BIM is effective in the prevention of cancer because
of its ability to modulate certain cancer causing estrogen
metabolites [3]. Scientists have demonstrated that BIM
induces apoptosis in human cancer cells and may also
normalize abnormal cell growth associated with cervical
dysplasia.
In continuation of our ongoing interest on develop-
ment of new applications of zirconium salts [8,14–18]
in synthetic methods, we herein report the use of
ZrO(DS)2 as LASC in the electrophilic substitutions of
Also 1,1,1-tris(3,30,300-indolyl)ethane was found in
bacterial metabolites [4], and the triarylmethanes (TIMs)
C
V
2009 HeteroCorporation

536
M. Jafarpour, A. Rezaeifard, and T. Golshani
Vol 46
Scheme 1
ically important bis- and trisindolylmethanes in high
yields through the electrophilic substitution reaction of
indoles with carbonyl compounds using ZrO(DS)2 as
new LASC. This protocol will contribute to reducing
the use of harmful organic solvents.
EXPERIMENTAL
General. ZrOCl2.8H2O, SDS, carbonyl compounds, and
indoles were purchased from Merck or Fluka Chemical Com-
panies. Progress of the reactions was monitored by TLC using
silica-gel SIL G/UV 254 plates. NMR spectra were recorded
on a Brucker Avance DPX 300 MHz and 500 MHz instru-
ments. Mass spectra were recorded on a Shimadzu GC-MS-QP
5050A.
indoles with a variety of aldehydes and ketones in H2O
and EtOH, both of which are green solvents, affording
excellent yields of bis- and tris(indolyl)methanes under
mild condition (Scheme 1).
Preparation of ZrO(DS)2 from ZrOCl2.8H2O and sodium
dodecyl sulfate (SDS). A solution of ZrOCl2.8H2O (5 mmol,
1.61 g in 50 mL of water) was added to a solution of sodium
dodecyl sulfate (SDS) (10 mmol, 2.88 g in 50 mL of distilled
water) while stirring at room temperature. A white precipitate
was appeared immediately and the mixture was stirred for
another 30 min. The white solid was collected by filtration and
washed with water (2 ꢁ 100 mL). The isolated solid was dried
under reduced pressure and ZrO(DS)2 was obtained as a white
RESULTS AND DISCUSSION
Optimized reaction conditions were investigated using
a reaction of benzaldehyde and indole (1:2.2), with
respect to temperature, time, and the molar ratio of
ZrO(DS)2 to the substrate in water. We found that
10 mol % of ZrO(DS)2 was sufficient to obtain the desired
bisindolylmethane in 96% yield within 20 min at 60ꢀC.
Based on the optimized reaction conditions, the pres-
ent protocol was applied to a variety of carbonyl com-
pounds (Table 1). As shown in Table 1 aryl aldehydes
with both electron-donating and electron-withdrawing
characteristics afforded bis(indolyl)methane in excellent
yields. Not only aryl aldehydes but also aliphatic alde-
hydes provided the desired bis(indolyl)methane (Table 1,
entry 9).
1
powder in 90% yield (2.87 g). M.p: 125ꢀC; H NMR (DMSO,
500 MHz): d 0.82 (t, 6H, J ¼ 6.8 Hz), 1.1–1.35 (m, 36H),
1.45 (m, 4H), 3.69 (t, 4H, J ¼ 6.6 Hz) ppm; 13C NMR
(DMSO, 125.77 MHz): 13.90, 22.14, 25.58, 28.78, 28.90,
29.04, 29.11, 29.13, 31.37, 32.63, 60.83, 65.99 ppm.
General procedure for condensation of indoles with car-
bonyl compounds catalyzed by ZrO(DS)2. Indole (2.2 mmol)
and carbonyl compound (1 mmol) was added to a suspension
of ZrO(DS)2 (10 mol %, 0.0638 g in 2 mL of water or EtOH)
(see Table 1). The reaction mixture was stirred at 60ꢀC for
appropriate time which was monitored by TLC (Table 1).
After completion of the reaction, EtOAc (5 mL) was added to
the reaction mixture; organic phase was separated and dried
over CaCl2 followed by filtration and evaporation of the sol-
vent. The desired product was secured in high purity (Table
1). Further purification was performed by plate chromatogra-
phy eluted with n-hexan/EtOAc (3/1). Structural assignments
of the products are based on their 1H NMR, 13C NMR, MS
spectra and elemental analysis.
We have found that the reaction of both activated and
deactivated aromatic aldehydes with 2-methyl indole is
faster than indole (Table 1, entries 10,11).
When 3-formylindole was used as a carbonyl com-
pound, the corresponding trisindolylmethanes are
formed. The reaction proceeded at room temperature in
EtOH and the time required for the conversion was short
(Table 1, entreis 12,13).
Selected spectral data. Table 1, entry 2: Solid; mp: 97–
1
98ꢀC; H NMR (CDCl3, TMS, 300 MHz): d 2.37 (s, 3H), 5.83
(s, 1H), 6.70(d, 2H, J ¼ 2.45 Hz), 7.02(t, 2H, J ¼ 8.2 Hz),
7.12(d, 2H, J ¼ 8.2 Hz), 7.21–7.3(m, 6H), 7.45(d, 2H, J ¼ 8.2
Hz), 7.9(br, s, 2H) ppm; 13C NMR (CDCl3, TMS, 62.9 MHz):
21, 40.25, 110.9, 112, 119.5, 120.2, 121.6, 122.6, 129.5, 131.5,
134.3, 136.8 ppm; MS (70 ev), m/e: 336 [Mþ]. Anal. Calcd
for (C24H20N2): C, 85.68; H, 5.99; N, 8.33. Found: C, 85.70;
H, 5.96; N, 8.35.
Table 1, entry 12: Solid; mp: 161ꢀC(dec.); 1H NMR
(DMSO, 300 MHz): d 6.08 (s, 1H), 6.89 (s, 3H), 6.87(t, 3H, J
¼ 7.45 Hz), 7.02 (t, 3H, J ¼ 7.25 Hz), 7.44 (d, 3H, J ¼ 7.83
Hz), 7.56 (d, 3H, J ¼ 7.83 Hz), 10.72 (s, 3H) ppm; 13C NMR
(DMSO, 62.9 MHz): 30.8 ,111.4, 117.5, 118, 119,120.6, 124,
126.8, 136.5 ppm; MS (70 eV), m/e: 361 [Mþ]. Anal. Calcd.
for (C25H19N3): C, 83.08; H, 5.30; N, 11.63. Found: C, 83.10;
H, 5.32; N, 11.65.
The reaction of acetophenone with indole is slower
than with aldehydes, and unreacted ketone and indole
remains (Table 1, entry 14).
To show the merit of ZrO(DS)2 in comparison with
other catalysts used for the similar reactions in
green solvents, we have tabulated some of the results in
Table 2.
CONCLUSION
We have developed a highly convenient, efficient,
and green catalytic system for the preparation of biolog-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2009
A New Catalytic Method for Ecofriendly Synthesis of Bis- and Trisindolylmethanes
by Zirconyldodecylsulfate Under Mild Conditions
537
Table 1
Condensation of indoles with carbonyl compounds catalyzed by ZrO(DS)2.
Entry
Indole
Substrate
Product
Time (min)
Isolated Yield%
1a
X ¼ H
X ¼ H
20
30
95
95
2a
X ¼ 4-Me
X ¼ 4-Me
3a
4a
5a
6a
7a
8b
X ¼ 4-OMe
X ¼ 4-OH
X ¼ 2-Me
X ¼ 4-Br
X ¼ 4-OMe
X ¼ 4-OH
X ¼ 2-Me
X ¼ 4-Br
45
25
45
15
15
20
96
94
96
95
97
96
X ¼ 4-NO2
X ¼ 4-NO2
(continued)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

538
M. Jafarpour, A. Rezaeifard, and T. Golshani
Vol 46
Table 1
(Continued)
Entry
Indole
Substrate
Product
Time (min)
60
Isolated Yield%
9a
94
10b
11a
12b
X ¼ 4-OMe
X ¼ 4-OMe
15
97
96
96
X ¼ 4-NO2
X ¼ 4-NO2
5
30
13b
20
97
14b
75
50
a Reactions were carried out in water at 60ꢀC.
b Reactions were carried out in EtOH at room temperature.
All products were identified by their spectroscopic data and their comparison with known samples [7–12].
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2009
A New Catalytic Method for Ecofriendly Synthesis of Bis- and Trisindolylmethanes
by Zirconyldodecylsulfate Under Mild Conditions
539
Table 2
Reaction of indole with benzaldehyde in the presence of different catalysts.
Entry
Catalyst/solvent
ZrO(DS)2/H2O
Dy(OTf)3/ EtOH.H2O
HMTABa/H2O
FeCl3.6H2O/[omim]PF6
Catalyst (mol %)
Time (h)
Yield (%)
Reference
1
2
3
4
10
10
20 min
12
2.5
97
95
86
98
[19]
[20]
[21]
0.1 g
5
1.5
a Hexamethylenetetraamine-bromine.
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