A Direct, Regioselective and Atom-Economical Synthesis of 3-Aroyl-N-hydroxy-5-nitroindoles by Cycloaddition of 4-Nitronitrosobenzene with Alkynones

This novel technique can be used to prepare n-hydroxy 3-aroyl indole compounds. These products are particularly interesting for their use as antibiotics, antinociceptics, antidiabetes and anticancer drugs. Although n-hydroxyindoles are frequently considered unstable and elusive products, we have acquired a very stable library of n-hydroxyindole derivatives.

The reaction of the cycloaddition of nitrosamines with alkynes can be used to selectively prepare a wide library of free substituted indole products. This method provides a simple and to potentially bioactive products. We consider this protocol to be an interesting improvement and advancement in the field of synthetic organic chemistry.

For 1-phenyl-2-propyne-1-one synthesis, first add 75 milliliters of acetone and two grams of 1-phenyl-2-propyne-1-ol into an open air round bottom flask containing a magnetic stirring bar. Place the reaction mixture at zero degrees Celsius with stirring and add a solution of Jones reagent drop wise until a persistent orange color is observed. Add 2-propanol drop wise until the excess of hexavalent chromium reactant is consumed and the solution exhibits a green color and filter the solution through a pad of diatomaceous Earth.

Concentrate the washings by rotary evaporation until an oil is obtained and dissolve the oil in 100 milliliters of dichloromethane. Add the solution to a separatory funnel and wash the organic phase two times with 125 milliliters of a saturated solution of sodium bicarbonate per wash. After the second wash, wash the organic layer with 125 milliliters of brine before drying the organic solution over n-hydro sodium sulfate.

After filtering, evaporate the solution to yield a yellow 1-phenyl-2-propyne-1-one solid and dry the solid under vacuum. For 4-nitronitrosobenzene preparation, first add 16 grams of potassium peroxy monosulfate and 150 milliliters of water to a beaker and stir the solution at zero degrees Celsius. When the potassium peroxy monosulfate has completely dissolved, add 3.6 grams of 4-nitroaniline to the beaker with a spatula and stir the suspension at room temperature.

To check the reaction by thin layer chromatography, after 48 hours, filter the crude reaction mixture on a Buchner funnel into a one neck round bottom flask and recrystallize the solid in 50 milliliters of methanol. Use a heat gun to warm the suspension until it reaches the boiling point of methanol and immediately filter the hot suspension into an Erlenmeyer flask. When the solution reaches room temperature, filter the second precipitate onto a Buchner funnel and dry the solid in a vacuum.

For a 3-benzoyl-1-hydroxy-5-nitroindole synthesis, first place a 250 milliliter two neck round bottom flask under vacuum before flushing the flask with nitrogen. Leave the flask inert under atmosphere and add 1.52 grams of 4-nitronitrosobenzene and 1.3 grams of 1-phenyl-2-propyne-1-one to the flask. Use a syringe to add 80 milliliters of toluene and keep the reaction mixture under magnetic stirring at 80 degrees Celsius.

After a few minutes, check the complete solubilization of the reactants. After 30 to 40 minutes, verify the formation of an orange precipitate. After the complete precipitation of the orange solid, turn off the heat to allow the reaction to reach room temperature.

Then filter the mixture to collect the 3-benzoyl-1-hydroxy-5-nitroindole on a Buchner funnel and dry the orange solid under vacuum. Here the preparation of 4-nitronitrosobenzene two as achieved by oxidation of 4-nitroaniline one by reaction with potassium peroxy monosulfate is shown. The product two can be obtained in a 64%yield after recrystallization in methanol two times with a 3-5%contamination of four 4’bis-nitroazoxybenzene-6 and the structure of the product can be confirmed by proton NMR.

Here preparation of 1-phenyl-2-propyne-1-one four as afforded by oxidation of 1-phenyl-2-propyne-1-ol three with Jones reagent is shown. The product four can be isolated as a yellow solid in 90%yield and the structure can be confirmed by proton NMR. The synthesis of 3-benzoyl-1-hydroxy-5-nitroindole is accomplished by thermal reaction of 4-nitronitrosobenzene two and 1-phenyl-2-propyne-1-one four in toluene at 80 degrees Celsius.

After isolation of the azoxy derivative six in 22%yield as the major product of the mother liquor after chromatography, the structure of product six can be confirmed by proton NMR. The structure of compound five can then be determined by proton NMR, carbon-13 NMR, and high resolution mass spectrometry. The two most delicate aspects of this procedure are the purification of the 4-nitronitrosobenzene by recrystallization and the synthesis of the indole product under an inert atmosphere.

Following this procedure, many different indole products can be achieved. Working with electron-rich nitroaromatic derivatives, the target compounds are generally isolated by chromatographic purification techniques. An interesting mechanistic study will be developed in the near future to study any of the redox steps which are not clearly understood.

The Jones reagent is very stable, but it is necessary to handle all of the chromium reagents with care.