Chemoselective one-pot conversion of primary alcohols to their bis(indolyl)methanes promoted by Bi(NO3)3·5H 2O

Article abstract of DOI:10.1515/znb-2007-0408

A new, "green" and efficient one-pot protocol for the synthesis of bis(indoyl)methanes from primary alcohols using Bi(NO₃) ₃ · 5H₂O is described. This procedure performs chemoselectively through a solvent-free reaction and

Full text of DOI:10.1515/znb-2007-0408

Chemoselective One-pot Conversion of Primary Alcohols to their
Bis(indolyl)methanes Promoted by Bi(NO3)3·5H2O
Ahmad R. Khosropoura, Iraj Mohammadpoor-Baltorka, Mohammad M. Khodaeib, and
Parvin Ghanbaryb
a Department of Chemistry, Faculty of Science, Isfahan University, Isfahan 81746-7344, Iran
b Department of Chemistry, Faculty of Science, Razi University, Kermanshah 67149, Iran
Reprint requests to Dr. A. R. Khosropour. Fax: +98-311-668-9732. E-mail: khosropour@chem.ui.ac.ir
Z. Naturforsch. 2007, 62b, 537 – 539; received August 29, 2006
A new, “green” and efficient one-pot protocol for the synthesis of bis(indoyl)methanes from
primary alcohols using Bi(NO3)3 · 5H2O is described. This procedure performs chemoselectively
through a solvent-free reaction and the products are obtained in high to excellent yields.
Key words: Bis(indolyl)methane, Primary Alcohol, Bi(NO3)3 ·5H2O, Solvent-free Reaction
Introduction
Indole derivatives are widely distributed in nature
and are known to possess a broad spectrum of bio-
logical and pharmaceutical activities [1, 2]. In partic-
ular, bis(indolyl)methanes have received much atten-
tion in previous years [3]. Such compounds are prone
to develop interesting bioactivity and could be used
as antibacterial [4] and antitumor [5 – 7] agents. Thus
the development of facile and environmentally friendly
synthetic methods towards bis(indolyl)methanes con-
stitutes an active area of investigation in pharmaceu-
tical and organic synthesis. The principal approach
for the synthesis of these compounds is limited to
the direct condensation reaction of indoles with var-
ious aldehydes or ketones in the presence of protic
or Lewis acids [8 – 16]. Then, extension of the access
to new bis(indolyl)methane derivatives starting from
other precursors is highly desirable.
Scheme 1.
a less toxic reaction protocol, avoiding purification
steps, would extend the scope of this transformation.
As part of an ongoing program in our laboratory on
the ability of Bi(III) salts [18 – 20], we observed the
oxidative [21, 22] and catalytic behaviors [23, 24] of
Bi(NO3)3 · 5H2O in organic transformations. Herein,
we would like to report an elegant route for prepar-
ing bis(indolyl)methanes, which involves alcohols as
precursors in the presence of Bi(NO3)3 · 5H2O under
solvent-free conditions (Scheme 1).
As a model system, Bi(NO3)3 · 5H2O was added to
benzyl alcohol in a mortar. The mixture was mixed
and kept at 65 ◦C for a few seconds. When indole was
mixed in at r. t., the corresponding bis(indolyl)methane
resulted quantitatively. In order to establish the reac-
Results and Discussion
For the first time Ireland et. al. reported a one- tion protocol, a series of primary alcohols were ap-
pot scheme in which an aldehyde was generated from plied for this synthesis without affecting other func-
alcohols using Swern oxidation conditions and was tional groups present in the alcohols and the products
trapped in situ by a Wittig reagent [17]. This procedure were also obtained in excellent yields at very short re-
alleviated the necessity of isolating the intermediate action times (Table 1). To the best of our knowledge
aldehyde and vastly improved the yield. These results using primary alcohols in a one-pot manner for this
prompted us to focus our work on the use of primary transformation has not been reported previously. This
alcohols instead of aldehydes in bis(indolyl)methane procedure alleviated the necessity of isolating the inter-
synthesis. On the other hand, the development of mediate aldehyde and vastly improved the yield. The
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538
A. R. Khosropour et al. · Synthesis of Bis(indoyl)methanes from Primary Alcohols
Table 1. One-pot synthesis of bis(indolyl)methanesa from
primary alcohols promoted by Bi(NO3)3·5H2O under
solvent-free conditions.
Encouraged by these results we extended our
method to secondary alcohols and carried out reac-
tions using 1-phenylethanol or cyclohexanol. None
of the secondary alcohols gave bis(indolyl)methanes
even after longer reaction times, showing that the
bis(indolyl)methane synthesis from primary alcohols
in the presence of secondary ones is chemoselective
(Scheme 2).
In conclusion, we have demonstrated a new,
chemoselective, straightforward and efficient protocol
for the one-pot synthesis of bis(indoyl)methanes from
primary alcohols using Bi(NO3)3 ·5H2O as a low toxic,
inexpensive and oxygen and moisture tolerant reagent
under solvent-free conditions. In addition to efficiency
and simplicity, this procedure provides a very fast (2 –
12 min), “green” and low cost procedure for the syn-
thesis of these products from primary alcohols.
R
Time [min]
Yield [%]b
C6H5
4
5
6
2
3
4
4
5
2
4
3
90
95
95
93
91
94
90
93
95
89
91
4-NO2C6H4
2-NO2C6H4
2-ClC6H4
2,4-Cl2C6H3
4-FC6H4
4-CH3C6H4
4-(CH3)3CC6H4
4-CH3OC6H4
2-CH3OC6H4
PhCH2OC6H4
12
80
a
The products were characterized by 1H NMR, 13C NMR and IR
spectroscopy and comparison with reported data. b Isolated yields.
Experimental Section
Typical procedure for the preparation of bis(indolyl)
methanes
A mixture of 4-fluorobenzyl alcohol (126 mg, 1 mmol)
and Bi(NO3)3 · 5H2O (735 mg, 1.5 mmol) was stirred for a
few seconds at 65 – 70 ◦C. When the oxidation reaction was
completed, indole (117 mg, 2.1 mmol) was added and the
mixture was stirred for 4 min at r. t. After completion of the
reaction (monitored by TLC), ethanol (10 mL) was added
and filtered. The filtrate was concentrated and purified on
silica gel (n-heptane/ethyl acetate 4 : 1 as eluent) to afford
the◦pure product in 94 % y◦ield. Pink colored solid; m. p. 70 –
72 C (lit. [5e] = 72 – 74 C). – IR (KBr): v = 3400, 2950,
1600, 1445, 1217, 740 cm−1. – 1H NMR (200 MHz, CDCl3):
δ = 7.91 (br, s, 2H), 7.45 – 6.92 (m, 12H), 6.7 (s, 2H), 5.90 (s,
1H). – 13C NMR (50 MHz, CDCl3): δ = 39.8, 111.5, 115.2,
115.6, 119.8, 120.3, 122.4, 123.9, 127.3, 130.4, 137.1, 140.1,
159.4.
Scheme 2.
reaction proceeded efficiently at ambient pressure and
the corresponding products were obtained in high to
excellent yields. Additionally, our methodology avoids
the use of toxic solvents or reagents.
Acknowledgement
We are thankful to Isfahan University and Razi University
Research Councils for partial support of this work.
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