Synthesis of Antiviral Tetrahydrocarbazole Derivatives by Photochemical and Acid-catalyzed C-H Functionalization via Intermediate Peroxides (CHIPS)

The overall goal of the following experiment is to show the usefulness of a new concept called chips, using only visible light oxygen and catalysis to functionalize carbon hydrogen bonds via intermediate high hydro peroxides. This is achieved by irradiating a solution of a tetro hydro Carole, with visible light in the presence of catalytic amounts of a photo initiator to form a hydroperoxide by reaction with singlet oxygen as a second step, the hydroperoxide is treated with catalytic amounts of an acid, which facilitates the substitution of the hydro peroxide group by an added nucleo file. Next chromatography of the reaction mixture is needed, or as is often the case, simply filtration of the precipitate in order to isolate the pure product.

The results show how pharmaceutically active compounds can be synthesized by the concept of chips requiring only catalysts, visible light and oxygen. The main advantage of this technique over existing methods requiring expensive metal catalysts are statue metric. More sub synthetic oxygen is that we use environmentally friendly oxygen and visible light.

Although we never experienced any problems with these compounds, don't forget that peroxides are potentially explosive. Take precautions, for example, never hit the need peroxides or never expose them to pure asset catalysts. Prior to starting this procedure, purify the desired tetra hydro Carole if it is colored using rech crystallization or column chromatography to obtain a colorless starting material, weigh out one gram of the tetra hydro Carole into a 250 milliliter flask.

Then add 100 milliliters of toluene to the flask. Add two milligrams of rose bengal to the reaction mixture. After adding a stir bar, cover the flask with a septum.

Next, insert an oxygen balloon through the septum to keep a positive pressure of oxygen atmosphere on the reaction. Irradiate the reaction mixture with LEDs or a 23 watt lamp for one to three hours. Check the progress of the reaction by proton NMR using derated dimethyl sulfoxide.

Once the reaction is complete, filter the precipitated solid. Wash the solid with pentane in order to remove most of the toluene. After transferring the solid to a round bottom flask, dry it under reduced pressure.

At this point, weigh out 0.49 millimoles of the isolated hydroperoxide and 0.49 millimoles of the desired analy nucleo file into a 12 milliliter vial. Add 10 milliliters of methanol, 3.74 microliters of tri fluoro acidic acid and stir bar to the vial. Then close the container with a cap and stir the reaction mixture at room temperature for four hours.

For products that precipitate over the course of the reaction, filter the precipitated solid to obtain the desired product. Wash the product three times with 0.5 milliliters of methanol to obtain a second fraction of product. Evaporate the methanol from the filtrate when finished.

Dissolved the crude product in five milliliters of ethyl acetate. If necessary, heat gently at 40 degrees Celsius until the solution becomes homogenous. After that, at three to five milliliters of pentane to precipitate the pure product following filtration of the pure product, combine the different fractions of the product and dry them under high vacuum.

For an alternative coupling procedure, weigh out 0.49 millimoles of the synthesized hydro peroxide into a 12 milliliter vial. Add 10 milliliters of acetic acid and stir bar to the vial. Add the alion nucleo vial last if it is a liquid.

After closing the container with a cap, stir the reaction mixture at room temperature for four hours. For products that do not precipitate, evaporate the solvent directly by using a rotary evaporator. Following this, purify the residue by silica gel column chromatography using a 95 to five to five ratio of hexanes ethyl acetate and triethyl amine to obtain the desired product.

This protocol demonstrates how tetra hydro carbazoles can be conveniently functionalized by chips. This method utilizes ly nucleo files to synthesize coupling products including pharmaceutically active compounds. In a two step procedure, the first step is a photo catalyzed oxidation of tetro hydro Carole one, or its derivatives with elemental oxygen giving hydroperoxide two if performed in toluene, the hydroperoxide products precipitate and can be conveniently isolated by filtration in the second step.

Hydroperoxide two is treated with alion three to furnish product four by acid catalyzed substitution. Either a catalytic amount of tri fluoro, acetic acid, and methanol is used, or the reaction is performed in acetic acid without any catalyst products. Four A through C precipitate from the reaction and can be isolated by filtration with no additional purification.

For products such as four D that do not precipitate column chromatography is used for purification and isolation. This technique can be performed in a single day, including two chemical steps work up and Drank. The implications of this technique extend to what the application to other substrate classes.

A goal we are currently pursuing.