Name: microwave-assisted preparation of 1-aryl-1h-pyrazole-5-amines
Uploaded: 2019-06-23T14:00:00
Description: Watch this Scientific Journal Video about Microwave-Assisted Preparation of 1-Aryl-1H-pyrazole-5-amines at JoVE.com

This research was supported by the Bill and Linda Frost Fund.

CAUTION: Please review all relevant material safety data sheets (MSDS) before use. Follow all appropriate safety practices when using the microwave reactor including reviewing the microwave reactor protocols and the use of personal protective equipment (safety glasses, gloves, lab coat, full-length pants, closed-toe shoes). This procedure is designed to work using an aryl hydrazine and either 3-aminocrotononitrile or an &#945;-cyanoketone. The appropriate microwave vial and stir bar should be used according to the scale ...

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A number of 1-aryl-1H-pyrazole-5-amines were prepared by combining an &#945;-cyanoketone or 3-aminocrotonitile with an aryl hydrazine in 1 M HCl and heating the solution to 150 &#176;C in a microwave reactor. Nearly all compounds were synthesized in 10-15 min, with the slowest substrate requiring 35 min of heating14. The use of water as the solvent allows for rapid heating of the solution and minimizes the use of hazardous organic solvents.
Higher temperature a...

The impetus to create a streamlined synthesis of 1-aryl-1H-pyrazole-5-amines is due to the myriad of applications of these small molecules. They appear in kinase inhibitors1, antibiotics2, pesticides3, and among many other biologically active compounds4,5. Synthetic schemes for these compounds are abundant, but most involve complex isolation and purification techniques. A common method involves the reflux of aryl hydrazine and 3-aminocrotononitrile in either alcoholic or aqueous solutions followed by a subsequent purification via chromatography and/or recrystallization6,7,8,9,10. A handful of isolated reports have detailed the synthesis of these compounds using microwave radiation, but all required extensive heating time and offered little advantage when compared to other previously reported methods11,12.
Despite their utility, there are a limited number of 1-aryl-1H-pyrazole-5-amines available from commercial vendors. We recently had success preparing nitrogen heterocycles using a microwave reactor13 and decided to investigate a related methodology for pyrazole-5-amine analogs. In this paper, we detail our procedure to prepare 1-aryl-1H-pyrazole-5-amines by reacting an aryl hydrazine with either 3-aminocrotononitrile or an &#945;-cyanoketone in 1 M HCl under microwave radiation. The advantages of this procedure include a short reaction time and the ability to incorporate a variety of functional groups including halides, nitriles, phenols, sulfones and nitro groups14.

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			<td height="21" style="height:21px;width:284px;">2-5mL Microwave vial set</td>
			<td style="width:121px;">Chemglass</td>
			<td style="width:185px;">CG-4920-01&#160;</td>
			<td style="width:167px;">Set includes appropriate stir bars and 20mm aluminum seals</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:284px;">Biotage Initiator+ microwave</td>
			<td style="width:121px;">Biotage</td>
			<td style="width:185px;">356007</td>
			<td>Includes crimper and decapper tool.</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:284px;">Sonicator</td>
			<td style="width:121px;">Kendal</td>
			<td style="width:185px;">Ultrasonic Cleaner GB-928</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:284px;">Glassware oven</td>
			<td style="width:121px;">Quincy Lab</td>
			<td style="width:185px;">20GC</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:284px;">4-Fluorophenylhydrazine hydrochloride</td>
			<td style="width:121px;">Fisher</td>
			<td style="width:185px;">AC119590100</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:284px;">3-Aminocrotonitrile</td>
			<td style="width:121px;">Fisher</td>
			<td style="width:185px;">AC152451000</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:284px;">CDCl3</td>
			<td style="width:121px;">Cambridge Labs</td>
			<td style="width:185px;">DLM-7-100</td>
			<td>99.8% D</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:284px;">Hydrochloric acid, concentrated</td>
			<td style="width:121px;">Fisher</td>
			<td style="width:185px;">A144SI-212</td>
			<td>Used to prepare 1 M HCl solution</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:284px;">Sodium hydroxide pellets</td>
			<td style="width:121px;">Fisher</td>
			<td style="width:185px;">S318-100</td>
			<td>Used to prepare 10% NaOH solution</td>
		</tr>
	</tbody>
</table>

microwave-assisted preparation of 1-aryl-1h-pyrazole-5-amines

A synthetic process for the preparation of a variety of 1-aryl-1H-pyrazole-5-amines was developed. The microwave-mediated nature of this method makes it efficient in both time and resources and utilizes water as the solvent. 3-Aminocrotononitrile or an appropriate &#945;-cyanoketone is combined with an aryl hydrazine and dissolved in 1 M HCl. The mixture is then heated in a microwave reactor at 150 &#176;C, typically for 10-15 min. The product can be readily obtained by basifying the solution with 10% NaOH and isolating the desired compound with a simple vacuum filtration. The use of water as a solvent in this reaction lends to its ease and utility in production, and this method is easily reproducible with a variety of functional groups. Typical isolated yields range from 70-90%, and reactions can be performed on the milligram to gram scale with little to no change in observed yields. Some of the applications of these molecules and their derivatives include pesticides, anti-malarials, and chemotherapeutics, among many others.

In this demonstration, 3-aminocrotononitrile and 4-fluorophenylhydrazine hydrochloride were reacted to produce 1-(4-fluorophenyl)-3-methyl-1H-pyrazol-5-amine (Figure 1). The mixture of the starting material in the microwave vial seen in Figure 2a shows the heterogeneous suspension created by combining the starting materials in the 1 M HCl solvent. It is recommended to pre-mix the solution for a few seconds over a stir plate to ensure th...

Watch this Scientific Journal Video about Microwave-Assisted Preparation of 1-Aryl-1H-pyrazole-5-amines at JoVE.com

Microwave-Assisted Preparation of 1-Aryl-1H-pyrazole-5-amines

1-Aryl-1H-pyrazole-5-amines are prepared from aryl hydrazines combined with either 3-aminocrotononitrile or an &#945;-cyanoketone in a 1 M HCl solution using a microwave reactor. Most reactions are done in 10-15 minutes and pure product can be obtained via vacuum filtration with typical isolated yields of 70-90%.

Microwave-Assisted Preparation of 1-Aryl-1H-pyrazole-5-amines

A synthetic process for the preparation of a variety of 1-aryl-1H-pyrazole-5-amines was developed. The microwave-mediated nature of this method makes it ...

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.

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