Paper
Trityl Chloride as a Novel and Efficient Organic Catalyst For Room Temperature Preparation of Bis(indolyl)methanes under Solvent-Free Conditions in Neutral Media
Published Feb 1, 2008 · A. Khalafi‐Nezhad, A. Parhami, A. Zare
Synthesis
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Abstract
A simple, clean, and highly efficient solvent-free proce- dure for the preparation of bis(1H-indol-3-yl)methanes is described from the reaction of carbonyl compounds (aldehydes and ketones) with 1H-indole in the presence of trityl chloride as a catalyst. The reaction proceeds rapidly in high yields at room temperature in a neutral medium. A proposed mechanism is suggested based upon former reactions and calculated results. Indole and its derivatives are known as an important class of heterocyclic compounds in the pharmaceutical chemis- try. 1 Bis(indol-3-yl)methanes have abundant pharmaco- logical and biological properties, 2 therefore, there is great interest in the synthesis of these compounds. 3-5 Syntheti- cally the reaction of 1H-indole with aldehydes or ketones produces azafulvenium salts that react further with a sec- ond 1H-indole molecule to form bis(indol-3-yl)meth- anes. 6 Previously, the use of various Lewis acids or protic acids has been reported in the literature for the synthesis of bis(indol-3-yl)methanes, 7-27 however, there are only a few reports using neutral organic catalysts for this aim. 4,11,28 The use of organic catalysts instead of inorganic Lewis acids has some advantages including (i) the possibility of using acid-sensitive substrates and (ii) substrates bearing basic functional groups or electron-donating substituents that are prone to capture the acidic catalysts do not affect the reaction results. From another viewpoint, it is always interesting to develop new catalysts with desirable fea- tures such as efficiency, recyclability, and ecofriendliness for organic transformations. In the present investigation, for the first time, we report trityl chloride (triphenylmeth- yl chloride, TrCl) as an efficient organic catalyst for the preparation of bis(indol-3-yl)methanes. The trityl group is a bulky protective group for the selective protection of primary hydroxy functions in the presence of secondary and tertiary hydroxy groups. Trityl chloride can be ob- tained commercially or easily prepared by a known proce- dure. 29 The application of solvent-free reaction conditions in or- ganic chemistry has been explored extensively within the last decade. Solvent-free reactions have been demonstrat- ed to be an efficient technique for various organic reac- tions instead of using harmful organic solvents. Solvent- free conditions often lead to a remarkable decrease in re- action time, increased yields, easier workup, matching with green chemistry protocols and they may enhance the regio- and stereoselectivity of reactions. 30 Following from our previous work on the application of solvent-free tech- niques in organic transformations, 31 we report here the use of trityl chloride as an excellent organic catalyst in the re- action of 1H-indole with aromatic/aliphatic aldehydes and ketones at room temperature or 35 °C under solvent-free conditions (Scheme 1). We first examined the synthesis of bis(indol-3-yl)meth- anes using trityl chloride (2 mmol), 1H-indole (1, 20 mmol), and benzaldehyde (10 mmol) in the absence of solvent as a model reaction. The reaction was achieved at room temperature and the corresponding product 3a was obtained in 90% yield in approximately 20 minutes.
Trityl chloride is an efficient, eco-friendly catalyst for the rapid, room temperature preparation of bis(indolyl)methanes in neutral media, offering advantages over inorganic Lewis acids.
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