This protocol utilizes microwave irradiation and a palladium catalyst to attach a heteroaryl fragment directly on the alpha carbon of a ketone. The main advantage of this technique is the rapid construction of a heteroaryl compound for medicinal chemistry screening, for catalyst-assisting development, and for tandem organic reaction discovery. The long term implication of our research is the synthesis of an effective aromatase inhibitor to be used as a potential treatment for hormone receptor-positive breast cancer.
Mistakes would most likely come from spills while using the glove box, so our advice is to take your time, as the reaction doesn't require a fast pace to be successful. Transport the needed reagents and supplies into the glove box. Inside the perched glove box, weigh 115 milligrams of sodium tert-butoxide directly into the four-milliliter microwave reaction vial.
Use a glass pipette to add one milliliter of degassed toluene into the microwave reaction vial. Weigh nine milligrams of XPhos Palladacycle Generation 4 Catalyst and add it into the microwave vial. Dip the spatula into the solution in the vial and swirl to ensure the complete transfer of the catalyst.
Then, use a suitable microliter syringe to add 64.4 microliters of acetophenone into the microwave vial. Weigh 103 milligrams of 3-iodopyridine and add it into the microwave vial. Next, add another one milliliter of degassed toluene so that the total reaction mixture is about three milliliters.
Line up the seal and the cap carefully and put them on the microwave reaction vial. Screw tight. Take the chemicals, supplies, and trash out of the glove box.
Take the assembled reaction vial to the microwave reactor, and place it on the silicon carbide plate on the rotor. For multiple reaction vials, space them evenly across the four silicon carbide plates on the rotor. Set the infrared sensor temperature limit to 113 degrees Celsius, corresponding to the actual reaction temperature at 130 degrees Celsius.
Program the microwave power and time for each step according to the manuscript. Run the reaction under microwave irradiation. Record the actual reaction time and temperature.
After the microwave reaction vial cools to ambient temperature, transfer the reaction mixture into a separatory funnel and rinse with a minimal amount of ethyl acetate into the funnel. Add two milliliters of saturated ammonium chloride and ten milliliters of ethyl acetate to the separatory funnel, and shake to mix. Place the separatory funnel on a rack to settle for five minutes.
Open the valve to drain the aqueous layer, then separate the top organic layer, and save it in a clean, dry beaker. Repeat the extraction by adding ten milliliters of ethyl acetate two more times, and combine the organic layers. After drying and rotary evaporation, record the shape, color, and mass of the crude product.
Verify the final product using automated flash chromatography. First, dissolve the crude product in one to two milliliters of acetone in a round-bottom flask, followed by addition of 1.5 grams of silica gel to make a slurry. Perform rotary evaporation for about five minutes, removing acetone very carefully, so that the product is loaded on the silica gel.
Transfer the resulting silica gel to an empty flash chromatography loading cartridge. Assemble the loading cartridge, prepacked column, test tube rack, and solvent lines for the automated MPLC system. Set up the solvent gradient and other parameters for the MPLC system and run the flash chromatography.
Combine the desired MPLC fractions in a round-bottom flask, and evaporate the solvent on a rotary evaporation apparatus to collect the pure product. Dry the purified product under high vacuum for at least one hour to remove residual solvent. Then, weigh five to 10 milligrams of the final purified product.
Dissolve it 0.75 milliliters of deuterated chloroform or other appropriate deuterated solvent. And take a proton NMR spectrum. Using this efficient microwave-assisted protocol, the direct alpha-carbon heteroarylation of ketones was performed.
For example, compound 1A was synthesized and isolated as a pale-yellow compound. Its proton and carbon-13 NMR spectra are shown here. The presence of a two-proton singlet signal at delta 4.26 ppm in the proton spectrum confirmed the successful carbon-carbon coupling between the ketone and the heteroaryl halide.
The purification based on ethyl acetate and hexanes solvent system allowed the isolation of the compounds with one nitrogen very well. When this method was utilized for compounds with two or more nitrogen atoms, the methanol and methylene chloride solvent system should be employed to get faster elution. The most important thing to remember is to ensure the accurate and complete transfer of all of the reagents, especially the catalyst.
This technique allows the researchers to perform parallel synthesis for the discovery of pharmaceutical reagents and to develop domino approach for natural product synthesis.
