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.

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

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Although the first reports on aerogels made by Kistler1 in the 1930s dealt with aerogels from both inorganic oxides (silica and others) and biopolymers ...

One-pot Microwave-assisted Conversion of Anomeric Nitrate-esters to Trichloroacetimidates

The goal of the following procedure is to provide a demonstration of the one-pot conversion of a 2-azido-1-nitrate-ester to a trichloroacetimidate glycosyl donor. Following azido-nitration of a glycal, the product 2-azido-1-nitrate ester can be hydrolyzed under microwave-assisted irradiation. This transformation is usually achieved using strongly nucleophilic reagents and extended reaction times. Microwave irradiation induces hydrolysis, in the absence of reagents, with short reaction times. Following denitration, the intermediate anomeric alcohol is converted, in the same pot, to the corresponding 2-azido-1-trichloroacetimidate.

A 2-azido-1-nitrate-ester can be converted to the corresponding 2-azido-1-trichloroacetimidate in a one-pot procedure. The goal of the manuscript is to demonstrate utility of the microwave reactor in carbohydrate synthesis.

The goal of the following procedure is to provide a demonstration of the one-pot conversion of a 2-azido-1-nitrate-ester to a trichloroacetimidate ...

Preparation and Characterization of C60/Graphene Hybrid Nanostructures

Physical thermal deposition in a high vacuum environment is a clean and controllable method for fabricating novel molecular nanostructures on graphene. We present methods for depositing and passively manipulating C60 molecules on rippled graphene that advance the pursuit of realizing applications involving 1D C60/graphene hybrid structures. The techniques applied in this exposition are geared towards high vacuum systems with preparation areas capable of supporting molecular deposition as well as thermal annealing of the samples. We focus on C60 deposition at low pressure using a homemade Knudsen cell connected to a scanning tunneling microscopy (STM) system. The number of molecules deposited is regulated by controlling the temperature of the Knudsen cell and the deposition time. One-dimensional (1D) C60 chain structures with widths of two to three molecules can be prepared via tuning of the experimental conditions. The surface mobility of the C60 molecules increases with annealing temperature allowing them to move within the periodic potential of the rippled graphene. Using this mechanism, it is possible to control the transition of 1D C60 chain structures to a hexagonal close packed quasi-1D stripe structure.

Preparation and Characterization of C60/Graphene Hybrid Nanostructures

Here we present a protocol for the fabrication of C60/graphene hybrid nanostructures by physical thermal evaporation. Particularly, the proper manipulation of deposition and annealing conditions allow the control over the creation of 1D and quasi 1D C60 structures on rippled graphene.

Physical thermal deposition in a high vacuum environment is a clean and controllable method for fabricating novel molecular nanostructures on graphene. We ...

Microfluidic Preparation of Liquid Crystalline Elastomer Actuators

This paper focuses on the microfluidic process (and its parameters) to prepare actuating particles from liquid crystalline elastomers. The preparation usually consists in the formation of droplets containing low molar mass liquid crystals at elevated temperatures. Subsequently, these particle precursors are oriented in the flow field of the capillary and solidified by a crosslinking polymerization, which produces the final actuating particles. The optimization of the process is necessary to obtain the actuating particles and the proper variation of the process parameters (temperature and flow rate) and allows variations of size and shape (from oblate to strongly prolate morphologies) as well as the magnitude of actuation. In addition, it is possible to vary the type of actuation from elongation to contraction depending on the director profile induced to the droplets during the flow in the capillary, which again depends on the microfluidic process and its parameters. Furthermore, particles of more complex shapes, like core-shell structures or Janus particles, can be prepared by adjusting the setup. By the variation of the chemical structure and the mode of crosslinking (solidification) of the liquid crystalline elastomer, it is also possible to prepare actuating particles triggered by heat or UV-vis irradiation.

This article describes the microfluidic process and parameters to prepare actuating particles from liquid crystalline elastomers. This process allows the preparation of actuating particles and the variation of their size and shape (from oblate to strongly prolate, core-shell, and Janus morphologies) as well as the magnitude of actuation.

This paper focuses on the microfluidic process (and its parameters) to prepare actuating particles from liquid crystalline elastomers. The preparation ...

Preparation of Functional Silica Using a Bioinspired Method

The goal of the protocols described herein is to synthesize bioinspired silica materials, perform enzyme encapsulation therein, and partially or totally purify the same by acid elution. By combining sodium silicate with a polyfunctional bioinspired additive, silica is rapidly formed at ambient conditions upon neutralization. 
The effect of neutralization rate and biomolecule addition point on silica yield are investigated, and biomolecule immobilization efficiency is reported for varying addition point. In contrast to other porous silica synthesis methods, it is shown that the mild conditions required for bioinspired silica synthesis are fully compatible with the encapsulation of delicate biomolecules. Additionally, mild conditions are used across all synthesis and modification steps, making bioinspired silica a promising target for the scale-up and commercialization as both a bare material and active support medium.
The synthesis is shown to be highly sensitive to conditions, i.e., the neutralization rate and final synthesis pH, however tight control over these parameters is demonstrated through the use of auto titration methods, leading to high reproducibility in reaction progression pathway and yield. 
Therefore, bioinspired silica is an excellent active material support choice, showing versatility towards many current applications, not limited to those demonstrated here, and potency in future applications.

Here, we present a protocol to synthesize bioinspired silica materials and immobilize enzymes therein. Silica is synthesized by combining sodium silicate and an amine &#39;additive&#39;, which neutralize at a controlled rate. Material properties and function can be altered either by in situ enzyme immobilization or post-synthetic acid elution of encapsulated additives.

The goal of the protocols described herein is to synthesize bioinspired silica materials, perform enzyme encapsulation therein, and partially or totally ...