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Formic Acid as Carbon Monoxide Source in the Palladium-Catalyzed N-Heterocyclization of o-Nitrostyrenes to Indoles

Manar Ahmed Fouad, Francesco Ferretti* and Fabio Ragaini

*Dipartimento di Chimica, Universitą degli Studi di Milano, Via C. Golgi 19, 20133 Milano, Italy, Email: francesco.ferrettiunimi.it

M. A. Fouad, F. Ferretti, F. Ragaini, J. Org. Chem., 2023, 88, 5108-5117.

DOI: 10.1021/acs.joc.2c02613


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Abstract

Cheap and readily available formic acid is an effective reductant for the reductive cyclization of o-nitrostyrenes. The reaction is air and water tolerant and provides the desired indoles in very good yields, at a low catalyst loading and without generating toxic or difficult to separate byproducts. A cheap glass thick-walled "pressure tube" can be used instead of less available autoclaves.


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General Procedure for the Preparation of Indoles

Stock solutions of the Pd-catalyst and Phen were prepared separately under dinitrogen in acetone to avoid weighing errors. In a typical catalytic reaction, the substrate o-nitrostyrene (0.5 mmol) was weighed in air and placed in a 23 mL thick-walled glass pressure tube with screw thread (Duran) containing a magnetic stirring bar. The tube was placed inside a Schlenk tube with a wide mouth, evacuated, and filled three times with dinitrogen. The proper volume of stock solutions of the catalysts and Phen was added, and the mixture was stirred (10 min) to enable the formation of the Pd/Phen complex. Subsequently, triethylamine (1.25 mmol) and acetic anhydride (1.25 mmol) were added without stirring, and then the acetone (10 mL total volume) was layered. Finally, formic acid (1.25 mmol) was added, and the pressure tube sealed under dinitrogen. The order of addition of the reagents and solvent layering is crucial to avoid loss of CO that starts to evolve, even at room temperature, as soon as HCOOH, Ac2O, and the base are mixed. The pressure tube was then placed and heated while stirring in a custom-made aluminum block preheated to 110 °C. At the end of the reaction, the pressure tube was removed from the aluminum block, allowed to cool to room temperature, and slowly opened under a fume hood. Acetone was evaporated, and the crude was subjected to silica-gel column chromatography using hexane/ethyl acetate as the eluent with the addition of 1 or 2% of Et3N to partly deactivate acidic sites of silica gel.

Procedure for Gram-Scale Reaction

A large-scale reaction was carried out in a 250 mL heavy-walled glass pressure bottle to prepare 2-phenylindole under the optimal conditions. The reaction was scaled up by increasing the substrate amount 17.6-fold with respect to the standard conditions. The pressure bottle was charged with the solid reagents, substrate 1e (2.00 g, 8.8 mmol), Pd(acac)2 (0.5 mol %), and phenanthroline (5 mol %) and then placed in a Schlenk tube with a large mouth. The tube was evacuated and filled three times with dinitrogen. Acetone (30 mL), triethylamine (3.1 mL, 22 mmol), and acetic anhydride (2.1 mL, 22 mmol) were added, and the mixture stirred for 10 min. The stirring was stopped, and the remaining solvent amount (acetone, 68 mL) was layered. At last, formic acid (0.84 mL, 22 mmol) was added, and the bottle sealed with the screwcap. The total amount of solvent was only 8.8 times increased instead of 17.6 to facilitate the subsequent workup. The pressure bottle was placed in a preheated (110 °C) oil bath. Despite the possibility that the reaction had already reached full conversion of the substrate, the reaction time was extended from 10 to 12 h to ensure completion. Metallic palladium precipitated on the bottle walls at the end of the reaction. At the end of the reaction, the pressure bottle was raised from the oil bath, allowed to cool to room temperature, and slowly opened under a fume hood.

Attention: scale-up of the reaction should be performed carefully considering the maximum CO pressure developed by HCOOH decomposition and scaling-up the reactor volume accordingly. Subsequently, the solution was filtered on a short pad of Celite in a Pasteur pipet using cannula technique to get rid of any potential colloidal palladium particles. The product was precipitated with water, collected by filtration on a Buchner funnel, dissolved in ethyl acetate (50 mL), and washed with saturated NaHCO3 aqueous solution (3 × 30 mL), brine (50 mL), and water (50 mL). The organic layer was then dried over Na2SO4 and filtered, and the solvent was evaporated under vacuum to yield the final product as a white, analytically and spectroscopically pure crystalline solid (1.54 g, 90% yield), without the need for any chromatographic purification. Phenanthroline and any other byproducts present in small amounts remained in solution.


Key Words

indoles, formic acid


ID: J42-Y2023