Camphorsulfonic acid-catalyzed Michael reaction of indoles with enones

November 28, 2018

Application of the Michael reaction in organic synthesis is well established. A conjugate addition of nucleophilic substrates to unsaturated carbonyl compounds in the presence of basic or acidic reagents takes place by this method. Due to the sensitivity of the substrates, undesirable pathways lower the yields of the desired products in some examples. Catalytic methods have proven to be significant to overcome the limitations. In this connection, indium and bismuth salts are effective as catalysts. Our research indicates that camphorsulfonic acid can be an effective promoter for the Michael reaction of indoles.

Numerous indole derivatives are extremely important medicinally active compounds. The -NH and C-3 positions of the ring are the two reactive sites present in indoles and these can react with unsaturated carbonyl compounds. Numerous indoles react efficiently with a number of ketones through a camphorsulfonic acid-catalyzed procedure. Various sensitive substituents at the indoles and carbonyl compounds tolerate the reaction conditions and produces exclusively 3-indole-substituted compounds in excellent yield. The success of the reaction, however, depends on the choice of solvents. Acetonitrile, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, ethanol, ethanol-water, ethyl acetate and methanol are used as solvents. Ethanol-water mixtures are the best combinations found for this method.

The mechanism of this reaction can be explained through an initial protonation of the carbonyl compound by camphorsulfonic acid. Indole then reacts with the protonated carbonyl compound at the C-3-center through donation of electron by the nitrogen and this process makes the C-3 position electron rich. The positive charge at the nitrogen stabilizes the system by the removal of the proton by camphorsufonate anion.

In conclusion, Michael reactions of diverse indoles with enones are successfully investigated in the presence of a catalytic amount of camphorsulfonic acid in aqueous ethanol. This procedure is simple, effective and environmentally friendly. This mechanistic route suggests that camphorsulfonic acid can be used extensively in diverse research programs. Considering the overall process, chiral C-3-substituted indoles can be prepared using functionalized enones.
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Ram Naresh Yadav1, Lohany Garcia1 and Bimal Krishna Banik*§1, 2

1Department of Chemistry, The University of Texas-Pan American, 1201 West University Drive, Edinburg, TX 78539, USA;

2The University of Texas, M. D. Anderson Cancer Center, Department of Molecular Pathology Box-89, 1515 Holcombe Blvd., Houston, Texas 77030, USA; §Current Address: Community Health System of South Texas, 3135 S. Sugar Road, Edinburg, TX 78539

Contact for authors: and

Bentham Science Publishers

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