Scientific paper
Titania (TiO2)-Catalyzed Expedient, Solventless and Mild Synthesis of Bis(Indolyl)Methanes
Mona Hosseini-Sarvari*
Department of Chemistry, Shiraz University, Shiraz 71454, I.R. Iran Fax: +98(711)2280926; E-mail: hossaini@susc.ac.ir
Received: 13-03-2007
Abstract
Titania (TiO2) is found to be an efficient catalyst for the electrophilic substitution reaction of indoles with aldehydes to afford the corresponding bis(indolyl)methanes in high yields under solvent free conditions.
Keywords: Titania, aldehydes, bis(indolyl)methane, indole
1. Introduction
Bis(indolyl)alkanes and their derivatives constitute an important group of bioactive metabolites of terrestrial and marine origin.1 During the last few years a large number of natural products containing bis(indolyl)methanes2 and bis(indolyl)ethanes3 have been isolated from marine sources. Indoles and their derivatives are used as antibiotics.4 The acid catalyzed reaction of electron rich heterocyclic compounds with p-dimethylaminobenzaldehyde is known as the Ehrlich test5 for electron rich heterocycles, such as pyrroles and indoles. The analogous reaction of indoles with other aromatic or aliphatic aldehydes and ke-tones produces azafulvenium salts. The azafulvenium salts can undergo further addition with a second indole molecule to afford bis(indolyl)methanes.6 Protic acids7 as well as Lewis acids8'9 are known to promote these reactions. Recently montmorillonite clay K-1010 and lanthanide triflates11 have been also found to catalyze these transformations. However, many Lewis acids become deactivated or sometimes decomposed by nitrogen containing reactants. Even when the desired reactions proceed, more than stoichiometric amounts of the Lewis acids are required because the acids are trapped by nitrogen.12 These problems can be somewhat circumvented by using expensive lithium perchlorate.13 However, longer reaction
times and moderate to poor yields for nitro-substituted aromatic aldehydes are the limitations.
The use of metal oxides as catalysts has received considerable attention in organic synthesis due to their environmental compatibility, ease of handling, non-toxic nature and above all their reusability and the development of solvent-less protocol has an added advantage in green context. Recently, titania (TiO2) has been used as a solid catalyst in many organic transformations.14 To my knowledge all the catalysts and reagent which are useful for the synthesis of bis(indolyl)methanes are acids (Lewis or pro-tic acids) and there are not any reports for such reaction in the presence of a neutral catalyst.
2. Results and Discussion
Herein and according to our previous works aimed at solvent-less procedures,151 wish to report the use of a catalytic amount of TiO2 as a reusable and neutral solid catalyst for the synthesis of bis(indolyl)methanes (Scheme 1).
Firstly, benzaldehyde was chosen as a model for the reaction with indole. Benzaldehyde (1a) was treated with 2 mmol of indole (2) with various amounts of TiO2 and under various conditions (Table 1). The best result was
O
A.
Ar H
%
N H
20 mol% Ti02 solvent free, 80°C
Scheme 1
3
obtained when 20 mol% of TiO2 has been used in solvent free conditions (entry 1).
Table 1: Effect of reaction conditions on the TiO2 catalyzed reaction of benzaldehyde (1 mmol) with indole (2 mmol)
Entry	Catalyst	Solvent	Time (h)	Yield (%)a)
1	20% TiO2	None	3	95
2	10% TiO2	None	5	90
3	5% TiO22	None	7.5	90
4	20% TiO22	ch3cn	12	10
5	20% TiO22	ch2cl2	12	trace
6	20% TiO22	EtOAc	12	trace
1 Isolated yields.
To prove the generality of the protocol, the reaction was then extended towards a variety of aldehydes 1b-q with indole and the results are summarized in Table 2.
The methodology is found to be general as the reactions of a variety of substituted aromatic aldehydes (1a-j) as well as heterocyclic (1k-n), with indoles have furnished the corresponding bis(indolyl)methanes in excellent yields. In this context, the present protocol is noteworthy because even nitro substituted aromatic aldehydes (1i,j) underwent smooth reactions with indole giving excellent yields of products under mild conditions. It is also interesting to note that even the reaction of indole with terephthalaldehyde (1o) under this reaction condi-
Table 2: TiO2-catalyzed synthesis of bis(indolyl)methanes 3a by condensation reaction of indole with aldehydes 1
Entry	Adehyde 1
Product 3
Time (h) Yield (%)b
98
wie'
90
5.5
95
95
7.5
90
c
e
a) All products, except 3q are known and were characterized by 'H NMR, IR and mass spectral data which were found to be identical with those described in ref. 16: for compounds 3a-c, 3e, 3g, 3i, 3k, 3m and 3o see 16a, for 3d, 3f, 3j, and 3p see 16b, for 31 see 16c and for 3h, and 3n see 16d. b) Isolated yields. c) The reaction was done at room temperature.
tion furnished the corresponding tetra(indolyl)methane derivative 3o in excellent yield. It is important to note that heterocyclic aldehydes 1k-n underwent smooth reactions with indole giving excellent yields of the corresponding bis(indolyl)methanes under mild conditions, especially in the case of acid sensitive compound 1m, a
reaction otherwise problematic under highly acidic conditions.
To check the reusability of the catalyst, when the reaction of indole with benzaldehyde 1a was finished, the product formed was extracted with EtOAc and the catalyst was filtered. It was washed with water repeatedly,
dried and reused for the reaction of indole with the same or different aldehydes. It was found that catalyst can be recycled for at least eight cycles without any change in activity.
According to the literature data,17 I think that TiO2 catalyzes the reaction as a mild Lewis acid even under solvent-free conditions. TiO2 has (i) Ti4+ site, which is of Lewis-acid type, (ii) O2- site, which is of Lewis-base type, and (iii) surface -OH groups.18 The activation of car-bonyls through hydrogen bonding by Lewis acids is also known.19 So, I propose a mechanism for this reaction using TiO2 as shown in Scheme 2. The Lewis acid moiety (Ti4+) activates the carbonyl groups to give intermediate I and is followed by indole attack to I to give II and loss of H2O from II to afford III which is activated by TiO2. The other indole is added to III in the following step to give the final product 3.
ed on Bruker DPX 250 MHz instrument and mass spectra on Shimadzu QP 1100 EX spectrometer using EI 70 eV modes.
3.1. General Procedure
A mixture of TiO2 (0.016 g, 0.2 mmol), benzaldehyde (1 mmol) and indole (0.2 g, 2 mmol) was added to a test tube and heated in an oil bath at 80 °C with stirring. The progress of the reaction was monitored by TLC (hexane : EtOAc = 80 : 20). After the reaction was completed, the catalyst was filtered, following by washing with ethyl acetate (3 x 30 ml). The volume was concentrated under reduced pressure and the product was purified by column chromatography (hexane : EtOAc = 80 : 20).
2-[Di(1tf-indol-3-yl)methyl]phenol (3p): Yield 93%, oil,1H NMR (250 MHz, CDCl3) 5.82 (s, 1H, CH), 6.50 (brs, 1H, -OH), 6.59 (s, 2H, 2 x NH), 6.89 (t, 2H, J = 6.5 Hz, Ar-H), 7.03-7.09 (m, 2H, Ar-H), 7.11-7.23 (m,
6H, Ar-H), 7.45 (d, 2H, J = 7.8 Hz, Ar-H), 7.64 (s, 2H, Ar-H).13C NMR (125 MHz, CDCl3) 29.8, 111.3, 117.6, 119.5, 120.0, 120.8, 122.3, 124.5, 126.8, 127.9, 129.5, 130.1, 136.8, 137.2, 154.4. Mass (ES/MS): m/z 338 (M+, 100%). Anal. Calcd. for C23H18N2O: C 81.63, H 5.36, N 8.28. Found: C 81.78, H 5.42, N 8.32.
2-[Di(1#-indol-3-yl)methyl]-4-(4-morphoHnyl-methyl)phenol (3q): Yield 61%, yellow oil, 1H NMR (250 MHz, DMSO-d6) 1.94 (s, 4H, 2 x N-CH2), 2.98 (s, 2H, CH2), 3.28 (s, 4H, 2 x O-CH2), 5.99 (s, 1H, CH), 6.53 (s, 2H, 2 x NH), 6.60-7.33 (m, 13H, Ar-H), 10.42 (br s, 1H, OH). 13C NMR (125 MHz, DMSO-d6) 31.8, 52.3, 59.7, 66.1, 11.2, 118.7, 119.2, 120.6, 120.8, 123.5, 124.8, 126.8, 127.3, 130.1, 130.4, 136.6, 152.2, 153.3. Mass (ES/MS): m/z 437 (M+, 100%). Anal. Calcd. for C28H27N3O2: C 76.86, H 6.22, N 9.60. Found: C 76.95, H 6.30, IN 9.72.
4. Conclusions
In summary, a simple, convenient, environmentally friendly and efficient synthetic protocol for the synthesis of 3, using a catalytic amount of TiO2 under solvent free conditions has been developed. High yields, use of very safe and cheap catalyst and the simplicity of the reaction procedure make this method one of the most efficient methods for the synthesis of this class of compounds.
5. Acknowledgment
I gratefully acknowledge the support of this work by the Shiraz University. I am also grateful to Prof. H. Sharghi for synthesis of aldehyde 1q and his helpful cooperation.
1.
Ar H
Scheme 2
TiO;
X.
Ar H I
3. Experimental
Progress of the reactions was monitored by the use of silica gel polygrams SIL G/UV 254 plates. IR spectra were recorded on Perkin Elmer 781 and on Impact 400 D Nickolet FTIR spectrometers. NMR spectra were record-
Ill
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Povzetek
Titanov dioksid (TiO2) učinkovito katalizira elektrofilne substitucije indolov z aldehidi. Pri teh reakcijah, ki potekajo brez dodanih topil, z visokimi izkoristki nastanejo ustrezni bis(indolil)metani.