This procedure describes a method to isolate 1-Aryl-1H-pyrazole-5-amines using aryl hydrazines with either 3-Aminocrotononitrile or alpha cyanoketones under microwave radiation. The main advantage of this procedure I the rapid reaction time, as most reactions are complete within a matter of minutes. Our procedure also tolerates a wide range of functional groups, such as halides, nitriles, phenols, sulfones, and heterocycycles.
In order for the reaction to be successful it is critical that the reaction is storing properly and that the microwave vile is sealed completely before heating. To begin, obtain a microwave vile designed for reaction volumes of two to five milliliters that has been dried overnight in the glassware oven and add an appropriate stir bar. In a fume hood, add two millimoles of four-fluorophenylhydrazine hydrochloride and two millimoles of 3-aminocrotononitrile to the microwave vile.
Then, add five milliliters of one molar hydrochloric acid to make the concentration of starting reagents 0.4 molar. Place the vile on a stir plate to stir the heterogeneous suspension. If the reactants have poor solubility and the reaction mixture cannot be stirred properly, transfer the solution to a larger vile and add additional one molar hydrochloric acid.
Avoid exceeding the recommended solvent volume as specified by the microwave reactor operating manual. Now, use an appropriate crimper tool to seal the microwave vile with the microwave vile cap. Transfer the vile from the fume hood into the microwave reactor and adjust the reaction time of the microwave program to 10 minutes, temperature at 150 degrees Celsius and absorption to very high.
During the heating phase, pay attention to the reactor pressure. A sudden drop in pressure may indicate a leak or vessel failure. Once the reaction has cooled to less than 40 degrees Celsius, transfer the vile from the microwave reactor to a fume hood.
With an appropriate decapper tool, remove the cap. In the fume bood, clamp the microwave vile on a support stand over a stir plate. Add two milliliters of 10%sodium hydroxide with stirring to cause immediate precipitation of the product.
Place a drop of the solution in indicator paper to show the pH is greater than 10. Then, place the vile in a sonicator for five to 10 minutes to aid mixing as needed. Set up a vacuum filtration apparatus and pour the solution into the funnel.
Scrape the vile with a spatula to dislodge the product from the vessel walls. Then, use deionized water to rinse any remaining product from the microwave vile and wash the isolated solid product. In some cases, the product oils out of the alkaline solution.
Obtain the product with a liquid liquid extraction using dichloromethane or ethyl acetate. After that, transfer the crude product to a desiccator to dry overnight. Obtain a proton NMR spectrum in deuterochloroform to confirm product identity and purity.
In this demonstration, 3-aminocrotononitrile and 4-fluorophenylhydrazine hydrochloride were reacted to produce 1, 4-flurophenyl-3-methyl-1H-pyrazole-5-amine. The NMR confirms the synthesis of the target 5-aminopyrazole with the characteristic singlet peak in the region of chemical shift between 5.4 to 6.0 ppm, corresponding to the aromatic proton at the four position of the pyrazole. By varying the scale of the reaction, users can rapidly produce milligrams to grams of product.
Additional functionality can also be added by varying the reactants. The key advantage of our method is that it allows for the rapid synthesis of 1-Aryl-1H-pyrazole-5-amines. These are useful scaffolds that have been incorporated into a number of bioactive molecules.
Remember to follow standard operating procedures while working with caustic solutions. Observe the safety guidelines when using the microwave reactor.
