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

Summary

1-Aryl-1H-pyrazole-5-amines are prepared from aryl hydrazines combined with either 3-aminocrotononitrile or an α-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%.

Abstract

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 α-cyanoketone is combined with an aryl hydrazine and dissolved in 1 M HCl. The mixture is then heated in a microwave reactor at 150 °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.

Introduction

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 compounds^4,5. 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 recrystallization^6,7,8,9,10. 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 methods^11,12.

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 α-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.

Protocol

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 α-cyanoketone. The appropriate microwave vial and stir bar should be used according to the scale of the reaction as specified by the manufacturer.

1. Preparation of reaction mixture

NOTE: The following reaction between 4-fluorophenylhydrazine hydrochloride and 3-aminocrotononitrile on a 2 mmol scale is representative. The procedure is identical when substituting α-cyanoketones in place of 3-aminocrotononitrile¹⁴.

1. Obtain a microwave vial designed for reaction volumes of 2-5 mL that has been dried overnight in a glassware oven and add an appropriate stir bar.
2. Add 0.325 g of 4-fluorophenylhydrazine hydrochloride (1 equiv., 2 mmol) and 0.164 g of 3-aminocrotononitrile (1 equiv., 2 mmol) to the microwave vial.
3. Add 5 mL of 1 M HCl to make the concentration of starting reagents as 0.4 M. Using a stir plate, ensure that the heterogeneous suspension is stirred. Add additional solvent if reactants have poor solubility and the reaction mixture cannot be stirred properly. Transfer the solution to a larger vial if necessary, to avoid exceeding the recommend solvent volume as specified by the microwave reactor operating manual.

2. Heating the reaction in the microwave reactor

1. Seal the microwave vial with a microwave vial cap using the appropriate crimper tool.
2. Place the vial in the microwave reactor. Program the microwave settings for time (10 min), temperature (150 °C), and absorption (Very High).
   CAUTION: Pay attention to the reactor pressure during the heating phase. A sudden drop in pressure may indicate a leak and/or vessel failure.
3. Once the reaction has cooled (< 40 °C), remove the vial from the microwave reactor.
4. Remove the cap using an appropriate decapper tool.

3. Isolation of the product by vacuum filtration

1. In a well ventilated fume hood, clamp the microwave vial over a stir plate.
2. Add 2 mL of 10% NaOH with stirring to make the solution alkaline and cause immediate precipitation of product. The pH of the solution should be >10 as indicated by pH paper. Sonication and scraping the vial with a spatula can aid with mixing and dislodging product from the vessel walls.
   NOTE: Some products oil out of the alkaline solution. If this occurs, transfer the solution with the aid of ~20 mL of deionized water to a separatory funnel and extract 3x with dichloromethane or ethyl acetate. Dry the combined organic layers and evaporate to obtain the product.
3. Set up a vacuum filtration apparatus to isolate solid product precipitate. Use deionized water to rinse any remaining product from the microwave vial and wash the isolated product.
4. Allow the product to dry overnight on the bench top or in a desiccator. Isolated yields are typically in the 70-90% range¹⁴.
5. Obtain a ¹H NMR spectrum in CDCl₃ to confirm product identity and purity.

Results

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...

Discussion

A number of 1-aryl-1H-pyrazole-5-amines were prepared by combining an α-cyanoketone or 3-aminocrotonitile with an aryl hydrazine in 1 M HCl and heating the solution to 150 °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...

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
2-5mL Microwave vial set	Chemglass	CG-4920-01	Set includes appropriate stir bars and 20mm aluminum seals
Biotage Initiator+ microwave	Biotage	356007	Includes crimper and decapper tool.
Sonicator	Kendal	Ultrasonic Cleaner GB-928
Glassware oven	Quincy Lab	20GC
4-Fluorophenylhydrazine hydrochloride	Fisher	AC119590100
3-Aminocrotonitrile	Fisher	AC152451000
CDCl3	Cambridge Labs	DLM-7-100	99.8% D
Hydrochloric acid, concentrated	Fisher	A144SI-212	Used to prepare 1 M HCl solution
Sodium hydroxide pellets	Fisher	S318-100	Used to prepare 10% NaOH solution