Convenient synthesis of bis(indol)alkanes by niobium(V) chloride

Article abstract of DOI:10.1080/00397910902752246

Bis(indolyl)alkanes have been synthesized in excellent yields in the presence of a catalytic amount of niobium(V) chloride under solvent-free conditions. Copyright Taylor & Francis Group, LLC.

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Convenient Synthesis of
Bis(indol)alkanes by Niobium(V)
Chloride
Majid M. Heravi a , Fatemeh Nahavandi a , Samaheh
Sadjadi a , Hosien A. Oskooie a & Mahmood
Tajbakhsh b
a Department of Chemistry, School of Sciences,
Azzahra University, Vanak, Tehran, Iran
b Department of Chemistry, University of
Mazandaran, Babolsar, Iran
Version of record first published: 12 Aug 2009.
To cite this article: Majid M. Heravi , Fatemeh Nahavandi , Samaheh Sadjadi , Hosien
A. Oskooie & Mahmood Tajbakhsh (2009): Convenient Synthesis of Bis(indol)alkanes by
Niobium(V) Chloride, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 39:18, 3285-3292
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Synthetic Communications1, 39: 3285–3292, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902752246
Convenient Synthesis of Bis(indol)
alkanes by Niobium(V) Chloride
Majid M. Heravi,1 Fatemeh Nahavandi,1 Samaheh Sadjadi,1
Hosien A. Oskooie,1 and Mahmood Tajbakhsh2
1Department of Chemistry, School of Sciences, Azzahra University,
Vanak, Tehran, Iran
2Department of Chemistry, University of Mazandaran, Babolsar, Iran
Abstract: Bis(indolyl)alkanes have been synthesized in excellent yields in the
presence of a catalytic amount of niobium(V) chloride under solvent-free
conditions.
Keywords: Bis(indolyl)alkanes, niobium(V) chloride, solvent-free conditions
INTRODUCTION
The synthesis of bis(indolyl)alkane has been of considerable interest in
organic synthesis because of its wide occurrence in various natural pro-
ducts possessing biological activity and its usefulness for drug design.[1]
Bis(indolyl)alkane is known to promote estrogen metabolism in both
women and men and is expected to have an application in the prevention
of breast cancer.[2] Several catalysts have been used for the preparation
of these compounds, such as lanthanide triflate,[3] FeCl3,[4] HOAc,[5]
molecular iodine,[6] indium trichloride,[7] trifluoroacetic acid,[8] triphenyl
phosphonium perchlorate,[9] copper(II) bromide,[10] molibdatophosphoric-
acid,[11] and trichloro-1,3,5-triazine.[12]
Received October 26, 2008.
Address correspondence to Majid M. Heravi, Department of Chemistry,
School of Sciences, Azzahra University, Vanak, Tehran, Iran. E-mail: mmh1331@
yahoo.com
3285

3286
M. M. Heravi et al.
Niobium(V) chloride, known as niobium pentachloride, is a yellow
crystalline solid often used as a starting material in niobium chemistry.[13]
Recently, it has been shown that niobium chloride is an efficient
Lewis acid catalyst in various organic transformations.[14,15] For exam-
ple, the Diels–Alder reaction,[16] ring opening of epoxides,[17] allylation
of aldehydes,[18] and N-acyliminium ions[19] have been catalyzed in the
presence of this catalyst. Some of the advantages of application of this
catalyst are ease of handling and low catalyst loading.[20]
Herein, we describe the electrophilic substitution reaction of indoles
with aldehydes in the presence of a catalytic amount of niobium(V)
chloride under solvent-free conditions (Scheme 1).
According to previous work using NbCl5 as catalyst in organic
reactions,[20] the proposed mechanism may involve the activation of the
carbonyl group through coordination with Nb(V) and subsequent
reaction of indoles with this activated aldehydes (Scheme 2).
To optimize the reaction conditions, the reaction of indole and
benzaldehyde was selected as the model reaction.
To find the optimum amount of catalyst, the yields of the model
reaction using various amounts of catalysts (0.5, 1, and 1.5 mol%) were
obtained and compared. The results are summarized in Table 1. From
these results, it can be concluded that the yields of reaction with very
small amounts of catalyst are very high and the optimum amount of
catalyst is 0.5 mol%.
To investigate the effect of solvent on the yields of reactions, the
model reaction was performed in various solvents including methanol
(MeOH), H2O, CH2Cl2, and ethanol (EtOH) and without solvent. The
results are shown in Table 2. Considering these results, the solvent-free
condition was selected as the best condition for all reactions.
It is known that NbCl5 is very hygroscopic and readily hydrolyzes
to niobic acid. To check the active catalyst in the case of using water
as solvent, the infrared (IR) spectrum of the recovered catalyst was com-
pared with that of NbCl5. The results show that NbCl5 in water will be
hydrolyzed to niobic acid. From this observation, it can be concluded
Scheme 1. Synthesis of bis(indolyl)alkanes.

Synthesis of Bis(indol)alkanes
3287
Scheme 2. The proposed mechanism for the synthesis of bis(indolyl)alkanes.
Table 1. Effect of amount of catalyst on the yield of the reaction
Entry
Time (min)
Catalyst amount (mol %)
Yield (%)a
1
2
3
10
15
10
1.5
1
0.5
96
94
93
aYields refer to isolated products.
Table 2. Effect of kind of solvent on the reaction of
indole with benzaldehyde
Entry
Solvent
Time (min)
Yield (%)a
1
2
3
4
5
MeOH
EtOH
CH2Cl2
H2O
Solvent-free
10
15
10
30
5
96
94
93
97
98
aYields refer to isolated products.

3288
M. M. Heravi et al.
Table 3. Solvent-free synthesis of bis(indolyl)alkanes derivatives catalyzed by
niobium(V) chloride
Mp(ꢀC)
Entry
R
R0
R00
Time (min) Yield (%)a Found
Reported
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
4-OH
4-Cl
3-NO2
OMe
3-NO2
5
10
12
12
10
3
96
98
97
98
96
95
94
92
125
123
77
263
112
254
72
125–127[21]
122–124[22]
77–81[21]
265–266[21]
112–114[23]
257–259[23]
—
H
Me
Me
H
Br OH
Br OMe
16
12
H
208
—
aYields refer to isolated products.
that in water NbCl5 is not an active catalyst and should not be selected as
a suitable and appropriate solvent for this reaction.
The results of synthesis of bis(indolyl)alkanes in the presence of
catalytic amounts of NbCl5 are shown in Table 3.
To show the merits of this method, the yield of the model reaction in
the presence of NbCl5 was compared with various catalysts as reported in
previous works. This comparison is shown in Table 4. As is shown in this
table, NbCl5 can catalyze the synthesis of bis(indol)alkanes in good yields
and short reaction times with no solvent.
In conclusion, we have found a simple, efficient, and convenient proce-
dure for the synthesis of bis(indolyl)alkanes under solvent-free conditions.
Some advantages of this procedure are good yields, absence of volatile and
hazardous solvents, short reaction times, and good conversions.
EXPERIMENTAL
Chemicals and Apparatus
Melting points were measured using the capillary tube method with an
1
electrothermal 9200 apparatus. H NMR spectra were recorded on a
Bruker AQC Avance 300-MHz spectrometer using tetramethylsilane
(TMS) as an internal standard (CDCl3 and dimethyl sulfoxide [DMSO]
solution). IR spectra were recorded from KBr disk on the Fourier
transform (FT)–IR Bruker Tensor 27. Mass spectra (MS) were recorded
on a 5973 network mass selective detector. Known products were

Synthesis of Bis(indol)alkanes
3289
Table 4. Comparison between NbCl5 and various catalysts used in synthesis of
bis(indolyl)alkanes
Time
(min)
Entry
Condition
Catalyst
NbCl5
Yield (%)
1
2
Solvent-free condition
Solvent-free condition at
room temperature
30–38ꢀC in EtOH aqueous
solution under ultrasound
irradiation
5
10
96
72[6]
I2
3
30
H2NSO3H
93–95[23]
4
5
Stirring at 60ꢀC
30
720
TPA-ZrO2
—
90[24]
70[25]
Stirring at room
temperature
Stirring at 90ꢀC,
6
7
120
15
NH4Cl
96[26]
92[12]
Solvent-free condition
Stirring at room
temperature
Trichloro-1,
3,5-triazine
ZrOCl2 ꢁ 8H2O
H6P2W18O62
Zn(HSO4)2
8
9
10
Stirring at 50ꢀC
40
40
180
84[27]
96[21]
91[22]
Solvent-free condition
Stirring in ethanol at
room temperature
Stirring in ethanol at room
temperature
Stirring in ethanol at room
temperature
Stirring in ethanol at room
temperature
11
12
13
14
360
210
150
120
Mg(HSO4)2
Ca(HSO4)2
Al(HSO4)3
89[22]
91[22]
92[22]
Stirring in ethanol at room
temperature
Silica sulfuric
acid
No reaction[22]
characterized by 1H NMR, FT-IR, and comparison of their melting
points with authentic samples.
General Procedure
A mixture of benzaldehyde (1 mmol), indole (2 mmol), and niobium(V)
chloride (0.5 mol%) was magnetically stirred in a round-bottomed flask
at 90ꢀC. The progress of the reaction was monitored by thin-layer
chromatography (TLC) using n-hexane–ethylacetate (4:1) as eluents.
After completion of the reaction, the product was solved in the dichloro-
methane (DCM), and the catalyst was separated from the reaction
mixture by simple filtration. After evaporating the solvent, the crude

3290
M. M. Heravi et al.
product was obtained. For further purification, the product was
recrystallized from n-hexane–dichloromethane 4:96.
Spectral Data for New Compounds
Entry 7
Mp: 72ꢀC, IR (KBr): 3480, 3385, 3128, 2917, 2855, 1457, 1196, 782,
1
470 cmꢂ1; H NMR (300 MHz, DMSO): d 10.90 (s, 2H, NH), 9.11 (s,
1H), 7.30–7.42 (m, 2H), 7.20–7.32 (m, 2H), 6.80 (d, 2H), 6.61–6.70 (d,
2H), 5.70 (s, 1H); 13C NMR (300 MHz, DMSO, d, d): 156.35, 136.14,
135.37, 129.93, 129.26, 125.96, 124.21, 122.12, 119.10, 115.81, 115.60,
114.40, 111.67, 38.98; MS (m=z): 496, 479, 323, 89.
Entry 8
Mp: 208ꢀC, IR (KBr): 3455, 3429, 3128, 2956, 2928, 1508, 1456, 1247, 1096,
792 cmꢂ1; 1H NMR (300MHz, DMSO): d 11.22 (s, 2H, NH), 7.10–7.30 (m,
8H), 6.80–6.91 (m, 4H), 5.83 (s, 1H), 3.80 (s, 1H); 13CNMR (300MHz,
DMSO, d, d): 158.35, 137.12, 136.14, 129.97, 129.22, 125.99, 124.26, 122.08,
118.88, 114.44, 111.70, 55.81, 38.90; MS (m=z): 510, 479, 429, 403, 107.
ACKNOWLEDGMENT
The authors are thankful to Azzahra Research Council for partial
financial support.
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