Name: a microwave-assisted direct heteroarylation of ketones using transition metal catalysis
Uploaded: 2020-02-16T13:00:00.000+00:00
Duration: 7 min 6 s
Description: Watch this Scientific Journal Video about A Microwave-Assisted Direct Heteroarylation of Ketones Using Transition Metal Catalysis at JoVE.com

Acknowledgment is made to the donors of the American Chemical Society Petroleum Research Fund for support of this research (PRF# 54968-UR1). This work was also supported by the National Science Foundation (CHE-1760393). We gratefully acknowledge the NKU Center for the Integration of Science and Mathematics, NKU-STEM International Research Program and the Department of Chemistry and Biochemistry for financial and logistical support. We also thank the School of Chemical Sciences Mass Spectrometry Laboratory at the University of Illinois at Urbana-Champaign for obtaining HRMS data.

CAUTION:
<ul>
	<li>Microwave reaction vials should be operated under 20 bar for the microwave reactor equipped with a 4 x 24MG5 rotor. If the reaction uses very volatile solvents, generates gas, or if solvents decompose, it is necessary to calculate the pressure at certain reaction temperatures to make sure the total pressure in the vial is less than 20 bar.</li>
	<li>Standard techniques in organic synthesis for glove box, flash chromatography and nuclear magnetic resonance (NMR) are utilized in this protocol.</li>
	<li>Appropriate Personal Protective Equipment (PPE) should be used during the experiment. These include safety goggles, a lab coat, nitrile gloves, long pants and closed-toe shoes.</li>
	<li>Consult all Safety Data Sheets (SDS) prior to the use of the chemicals in this procedure, as some of the chemicals are hazardous, corrosive, toxic or flammable.</li>
	<li>All chemical waste should be disposed of properly in designated waste containers.</li>
</ul>
1. Reaction set up
<ol>
	<li>Use the following amounts of reagents for the example reaction in Figure 1 - the formation of 1-phenyl-2-(pyridin-3-yl)ethanone (compound 1a) from acetophenone and 3-iodopyridine.</li>
	<li>Oven-dry microwave reaction vials equipped with stirring bars overnight. Purge argon vigorously into toluene for 30 min to degas the solvent prior to use.</li>
	<li>Preparation of reagents and supplies for glove box usage
	<ol>
		<li>Gather two 100 &#181;L syringes, four small spatulas, two glass pipets, two microwave seals, two microwave caps, two microwave stirring bars, at least four pieces of pre-folded weighing paper, four Kimwipes, four rubber bands, and two 100 mL beakers along with all the necessary reactants/solvents.</li>
		<li>Put the microwave vials, seals, and caps in one of the 100 mL beakers, then cover the beaker with a Kimwipe and wrap a rubber band around the beaker to keep the Kimwipe in place.</li>
		<li>Place the beaker and the rest of the items from step 1.3.1 into the transport box and take it into the glove box workstation.</li>
	</ol>
	</li>
	<li>Transport the reagents and supplies in step 1.3 into the glove box.
	<ol>
		<li>Inside the purged glove box, weigh 115 mg of NaOtBu (molecular weight (MW) 96.1, 1.2 mmol, 2.4 eq.) directly into the microwave reaction vial.</li>
		<li>Use a glass pipet to add half of the degassed toluene (1 mL) into microwave reaction vial.</li>
		<li>Weigh 9 mg of precatalyst XPhos Pd G4 (MW 860.5, 0.01 mmol, 2 mol%) and add it into the microwave vial. Dip a spatula into the solution in the vial and swirl to ensure the complete transfer of the catalyst.</li>
		<li>Use a suitable microliter syringe to add 64.4 &#181;L of acetophenone (MW 120.15, 66.1 mg, 0.55 mmol, 1.1 eq.) into the microwave vial.</li>
		<li>Weigh 103 mg of 3-iodopyridine (MW 205.0, 0.5 mmol, 1.0 eq.) and add it into the microwave vial.</li>
		<li>Add the remaining half of degassed toluene so that the total reaction mixture is about 3 mL. 
		NOTE: The reaction solution volume should not exceed &#190; of the total volume capacity of the microwave reaction vial. For the standard glass vials used in this protocol, the vial volume is 4 mL and the recommended reaction volume is 0.3 mL &#8211; 3 mL.</li>
		<li>Line up the seal and the cap carefully and put them on the microwave reaction vial. The cap should be finger tight.</li>
		<li>Take the chemicals, supplies and trash out of the glove box.</li>
	</ol>
	</li>
</ol>
2. Microwave irradiation
<ol>
	<li>Take the assembled reaction vial to the microwave reactor and place it on the silicon carbide (SiC) plate on the rotor. For multiple reaction vials, space them evenly across the four silicon carbide (SiC) plates on the rotor.</li>
	<li>Parameter set-up 
	NOTE: The most important parameters are the IR sensor temperature limit, microwave power and time.
	<ol>
		<li>Set the Infrared (IR) sensor temperature limit to 113 &#176;C. 
		NOTE: IR sensor-measured temperatures tend to be lower than reaction solution temperatures due to a non-preventable temperature gradient between the sample and the outside of the vessel. There is a linear relationship between these two temperatures: IR T (&#176;C) = Reaction T (&#176;C)/1.152. When the IR sensor temperature is 113 &#176;C, the actual reaction temperature will be 130 &#176;C using the equation given above.</li>
		<li>Program the microwave power and time for each step: 
		Step 1: Power ramp = 1300 W, 10 min, Fan Level = 1, Stirrer = High 
		Step 2: Power hold = 1300 W, 10 min, Fan Level = 1, Stirrer = High 
		Step 3: Cooling = 60 &#176;C, Fan Level = 3 
		NOTE: The microwave power will adjust automatically when the actual reaction temperature reaches the target temperature.</li>
	</ol>
	</li>
	<li>Run the reaction under microwave irradiation. Record the actual reaction time and temperature.</li>
</ol>
3. Product isolation
<ol>
	<li>After the microwave reaction vial cools to ambient temperature, transfer the reaction mixture into a separatory funnel using a minimal amount of ethyl acetate (EtOAc).</li>
	<li>Use acid-base extraction to isolate the crude product.
	<ol>
		<li>Add 2 mL of saturated NH4Cl to the separatory funnel.</li>
		<li>Add 10 mL of EtOAc to the separatory funnel and extract the product. Separate the organic layer and save it in a clean, dry beaker. Repeat the extraction two more times, and combine the organic layers.</li>
		<li>Dry the combined organic layer with anhydrous Na2SO4 for 20 min.</li>
		<li>Decant the clear solution into a round bottom flask and evaporate the solvent by rotatory evaporation under reduced pressure to yield the crude product.</li>
		<li>Record the shape, color and mass of the crude product.</li>
	</ol>
	</li>
	<li>Take 1H and 13C NMR spectra for the crude product to confirm the presence of the characteristic peaks for the expected product.</li>
	<li>Combine the crude product from the NMR sample with the rest of the crude product for flash chromatography purification below.</li>
	<li>Use automated flash chromatography to purify the final product.
	<ol>
		<li>Sample loading: Dissolve the crude product in 1-2 mL of acetone, followed by the addition of 1.5 g of silica gel to make a slurry. Use rotatory evaporation to remove 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.</li>
		<li>Assemble the loading cartridge, prepacked column, test tube rack and solvent lines for the automated medium pressure liquid chromatography (MPLC) system.</li>
		<li>Set up the solvent gradient and other parameters for the MPLC system and run the flash chromatography. 
		NOTE: The automated flash chromatography solvent gradients are suggested based on the heteroaryl product structural features: 
		1) If the product has one or zero nitrogen atoms (N) or hydroxyl groups (OH), use EtOAc/hexanes (0% to 100% over 12 min) with an extension at 100% EtOAc gradient for 2-6 min. 
		2) If the product has two or more nitrogen atoms (N) or hydroxyl groups (OH), use CH3OH/CH2Cl2 (0% to 30% over 12 min) with an extension at 30% CH3OH gradient for 1-3 min.</li>
		<li>Combine the desired MPLC fractions and evaporate the solvent to collect the pure product. Dry the purified product under high vacuum for at least 1 h to remove residual solvent.</li>
	</ol>
	</li>
</ol>
4. Product characterization
<ol>
	<li>Weigh 5 - 10 mg of the final purified product, dissolve it in deuterated chloroform (CDCl3) (or other appropriate deuterated solvent), and take a 1H NMR spectrum.</li>
	<li>Weigh 10 - 30 mg of the final purified product, dissolve it in CDCl3 (or other appropriate deuterated solvent), and take a 13C NMR spectrum.</li>
	<li>Analyze the NMR spectra to confirm the product structure.</li>
	<li>Recover the NMR sample in a 1 dram vial by evaporating the solvent.</li>
	<li>Once the NMR spectra support the correct structure, submit a 1 mg sample for HRMS testing to confirm the molecular formula.</li>
</ol>

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The authors have nothing to disclose.

The methodology described herein was developed to access valuable synthesis building blocks &#8211; heteroaryl compounds. Compared to precedent literature reports on heteroarylation, the choice of this current catalytic system showed several significant advantages. First, it avoids the use of protecting groups, the isolation of reactive intermediates, the stoichiometry requirement of catalysts, and the extended reaction times11,17. Second, the SiC plates offer a ...

Microwaves interact with materials through ionic conduction or dipolar polarization to provide rapid and homogeneous heating. Microwave-assisted organic reactions have gained increasing popularity in research laboratories after the first report for rapid organic synthesis in 19861. Though the exact nature of microwave heating is not clear and the existence of a &#34;nonthermal&#34; microwave effect is still under debate, significant rate enhancements for microwave-assisted organic reactions have been observed and reported2. Sluggish reactions that normally take hours or days to finish have been reported to be completed within minutes under microwave irradiation3,4,5,6. Difficult organic reactions that require high activation energy such as cyclizations and construction of sterically hindered sites were reported to be successful under microwave irradiation with improved reaction yields and purity7. Combined with other features such as solvent-free reactions and domino reactions, microwave-assisted organic synthesis offers unparalleled advantages in the design of eco-friendly reactions.
Unlike its arylation equivalent, which has been widely studied, heteroarylation, especially on the &#945;-C(sp3) of carbonyl compounds, has been rarely reported in the literature8,9,10. The few literature reports of &#945;-heteroarylation of carbonyl compounds had great limitations such as a stoichiometric amount of catalysts, narrow substrate scope, and isolation of reaction intermediates11,12,13. There are several challenges for the direct &#945;-heteroarylation of ketones that remain to be solved in order to make it a general approach. First, heteroatoms tend to coordinate to the transition metal catalyst and cause catalyst poisoning14,15. Second, the &#945;-H in the mono(hetero)arylation product is more acidic than those in the starting material. Thus, it tends to react further to make the undesired (bishetero)arylation or (multihetero)arylation products. Third, carbonyl compounds often have a lower cost than heteroaryl compounds, so it is practical to use excess carbonyl compounds to drive the reaction to completion. However, excess carbonyl compounds would often cause self-condensation, a frequently encountered problem in the transition metal-catalyzed &#945;-heteroarylation of carbonyl compounds.
In this report, we describe our recent study on the direct &#945;-C(sp3) heteroarylation of ketones using a microwave-assisted reaction protocol. To address the first challenge, catalyst poisoning discussed above, strongly coordinating and sterically hindered ligands were utilized to minimize the catalyst poisoning by heteroatoms. Bulky ligands were also expected to slow down the side reactions such as (bishetero)arylation or (multihetero)arylation16,17, the second challenge mentioned above. To minimize the effect of the third challenge, the formation of the ketone self-condensation side products, more than 2 equivalents of base was employed to convert ketones to their corresponding enolates. The long reaction time and high reaction temperature, together with the challenges specifically associated with the direct &#945;-C(sp3) heteroarylation of ketones, render it a suitable candidate for microwave-assisted organic synthesis research.

<table><tbody><tr><td>Chloroform-d (99.8+% atome D)</td><td>Acros Organics</td><td>AC209561000</td><td>contains 0.03 v/v% TMS</td></tr><tr><td>CombiFlash Rf Flash Chromatography system</td><td>Teledyne Isco</td><td></td><td>automated flash chromatography system</td></tr><tr><td>CombiFlash Solid load catridges (5 gram)</td><td>Teledyne Isco</td><td>69-3873-235</td><td>disposable</td></tr><tr><td>CombiFlash prepacked column (4g)</td><td>Teledyne Isco</td><td>69-2203-304</td><td>RediSep Rf silica 40-60 um, disposable</td></tr><tr><td>Microwave Reactor - Multiwave Pro</td><td>Anton Paar</td><td>108041</td><td>Microwave Reactor</td></tr><tr><td>Microwave Reactor Rotor 4X24 MG5</td><td>Anton Paar</td><td>79114</td><td>for parallel organic synthesis with with 4 SiC Well Plate 24</td></tr><tr><td>Microwave reaction vials</td><td>Wheaton&amp;reg; glass</td><td>224882</td><td>disposible, 13-425, 15x46 mm, reaction solution 0.3 - 3.0 mL, working pressure 20 bar</td></tr><tr><td>Microwave reaction vial seals, set</td><td>Anton Paar</td><td>41186</td><td>made of Teflon; disposable</td></tr><tr><td>Microwave reaction vial screw cap</td><td>Anton Paar</td><td>41188</td><td>made of PEEK; forever reusable</td></tr><tr><td>Microwave reaction vial stirring bar</td><td>CTechGlass</td><td>S00001-0000</td><td>Magnetic, PTFE, Length 9mm. Diameter: 3mm. (Package of 5)</td></tr><tr><td>NaOtBu</td><td>Sigma-Aldrich</td><td>703788</td><td>stored in a glovebox under nitrogen atmosphere</td></tr><tr><td>Nuclear Magnetic Resonance Spectrometer</td><td>Joel</td><td></td><td>500 MHz spectrometer</td></tr><tr><td>Silica gel</td><td>Teledyne Isco</td><td>605394478</td><td>40-60 microns, 60 angstroms</td></tr><tr><td>Toluene</td><td>Sigma-Aldrich</td><td>244511</td><td>vigorously purged with argon for 2 h before use</td></tr><tr><td>XPhos Palladacycle Gen. 4 Catalyst</td><td>STREM</td><td>46-0327</td><td>stored in a glovebox under nitrogen atmosphere</td></tr><tr><td>various ketones</td><td>Sigma-Aldrich or Fisher or Ark Pharm.</td><td></td><td>substrates for heteroarylation</td></tr><tr><td>various heteroaryl halides</td><td>Sigma-Aldrich or Fisher or Ark Pharm.</td><td></td><td>substrates for heteroarylation</td></tr></tbody></table>

a microwave-assisted direct heteroarylation of ketones using transition metal catalysis

Heteroarylation introduces heteroaryl fragments to organic molecules. Despite the numerous available reactions reported for arylation via transition metal catalysis, the literature on direct heteroarylation is scarce. The presence of heteroatoms such as nitrogen, sulfur and oxygen often make heteroarylation a challenging research field due to catalyst poisoning, product decomposition and the rest. This protocol details a highly efficient direct &#945;-C(sp3) heteroarylation of ketones under microwave irradiation. Key factors for successful heteroarylation include the use of XPhos Palladacycle Gen. 4 Catalyst, excess base to suppress side reactions and the high temperature and pressure achieved in a sealed reaction vial under microwave irradiation. The heteroarylation compounds prepared by this method were fully characterized by proton nuclear magnetic resonance spectroscopy (1H NMR), carbon nuclear magnetic resonance spectroscopy (13C NMR) and high-resolution mass spectrometry (HRMS). This methodology has several advantages over literature precedents including broad substrate scope, rapid reaction time, greener procedure and operational simplicity by eliminating the preparation of intermediates such as silyl enol ether. Possible applications for this protocol include, but are not limited to, diversity-oriented synthesis for the discovery of biologically active small molecules, domino synthesis for the preparation of natural products and ligand development for new transition metal catalytic systems.

The direct &#945;-C(sp3) heteroarylation of ketones can be performed using this efficient microwave-assisted protocol. Selected examples of heteroaryl ketones synthesized in this study are shown in Figure 1. Specifically, compound 1a was synthesized and isolated as a pale-yellow oil (0.49 mmol, 192 mg, 98 %). Its 1H and 13C NMR spectra are shown in Figure 2 to confirm the structure and purity. The presence of a two-proton s...

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A Microwave-Assisted Direct Heteroarylation of Ketones Using Transition Metal Catalysis

Heteroaryl compounds are important molecules utilized in organic synthesis, medicinal and biological chemistry. A microwave-assisted heteroarylation using palladium catalysis provides a rapid and efficient method to attach heteroaryl moieties directly to ketone substrates.

Heteroarylation introduces heteroaryl fragments to organic molecules. Despite the numerous available reactions reported for arylation via transition metal ...

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8.1K Views.  Northern Kentucky University. Heteroaryl compounds are important molecules utilized in organic synthesis, medicinal and biological chemistry. A microwave-assisted heteroarylation using palladium catalysis provides a rapid and efficient method to attach heteroaryl moieties directly to ketone substrates.

Video: A Microwave-Assisted Direct Heteroarylation of Ketones Using Transition Metal Catalysis

Facile Preparation of (2Z,4E)-Dienamides by the Olefination of Electron-deficient Alkenes with Allyl Acetate

Direct cross-coupling between two alkenes via vinylic C-H bond activation represents an efficient strategy for the synthesis of butadienes with high atomic and step economy. However, this functionality-directed cross-coupling reaction has not been developed, as there are still limited directing groups in practical use. In particular, a stoichiometric amount of oxidant is usually required, producing a large amount of waste. Due to our interest in novel 1,3-butadiene synthesis, we describe the ruthenium-catalyzed olefination of electron-deficient alkenes using allyl acetate and without external oxidant. The reaction of 2-phenyl acrylamide and allyl acetate was chosen as a model reaction, and the desired diene product was obtained in 80% isolated yield with good stereoselectivity (Z,E/Z,Z = 88:12) under optimal conditions: [Ru(p-cymene) Cl2]2 (3 mol %) and AgSbF6 (20 mol %) in DCE at 110 &#186;C for 16 h. With the optimized catalytic conditions in hand, representative &#945;- and/or &#946;-substituted acrylamides were investigated, and all reacted smoothly, regardless of aliphatic or aromatic groups. Also, differently N-substituted acrylamides have proven to be good substrates. Moreover, we examined the reactivity of different allyl derivatives, suggesting that the chelation of acetate oxygen to the metal is crucial for the catalytic process. Deuterium-labeled experiments were also conducted to investigate the reaction mechanism. Only Z-selective H/D exchanges on acrylamide were observed, indicating a reversible cyclometalation event. In addition, a kinetic isotope effect (KIE) of 3.2 was observed in the intermolecular isotopic study, suggesting that the olefinic C-H metalation step is probably involved in the rate-determining step.

Facile Preparation of 2Z,4E-Dienamides by the Olefination of Electron-deficient Alkenes with Allyl Acetate

The ruthenium-catalyzed olefination of electron-deficient alkenes with allyl acetate is described here. By using aminocarbonyl as a directing group, this external oxidant-free protocol has high efficiency and good stereo- and regioselectivity, opening a novel synthetic route to (Z,E)-butadiene skeletons.

Direct cross-coupling between two alkenes via vinylic C-H bond activation represents an efficient strategy for the synthesis of butadienes with high ...

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 ...

Utilization of Stop-flow Micro-tubing Reactors for the Development of Organic Transformations

A new reaction screening technology for organic synthesis was recently demonstrated by combining elements from both continuous micro-flow and conventional batch reactors, coined stop-flow micro-tubing (SFMT) reactors. In SFMT, chemical reactions that require high pressure can be screened in parallel through a safer and convenient way. Cross-contamination, which is a common problem in reaction screening for continuous flow reactors, is avoided in SFMT. Moreover, the commercially available light-permeable micro-tubing can be incorporated into SFMT, serving as an excellent choice for light-mediated reactions due to a more effective uniform light exposure, compared to batch reactors. Overall, the SFMT reactor system is similar to continuous flow reactors and more superior than batch reactors for reactions that incorporate gas reagents and/or require light-illumination, which enables a simple but highly efficient reaction screening system. Furthermore, any successfully developed reaction in the SFMT reactor system can be conveniently translated to continuous-flow synthesis for large scale production.

A protocol for organic reaction screening using stop-flow micro-tubing (SFMT) reactors employing gaseous reactants and/or visible-light mediated reactions is presented.

A new reaction screening technology for organic synthesis was recently demonstrated by combining elements from both continuous micro-flow and conventional ...

A Two-Step Protocol for Umpolung Functionalization of Ketones Via Enolonium Species

&#945;-Functionalization of ketones via umpolung of enolates by hypervalent iodine reagents is an important concept in synthetic organic chemistry. Recently, we have developed a two-step strategy for ketone enolate umpolung that has enabled the development of methods for chlorination, azidation, and amination using azoles. In addition, we have developed C-C bond&#8211;forming arylation and allylation reactions. At the heart of these methods is the preparation of the intermediate and highly reactive enolonium species prior to addition of a reactive nucleophile. This strategy is thus reminiscent of the preparation and use of metal enolates in classical synthetic chemistry. This strategy allows the use of nucleophiles that would otherwise be incompatible with the strongly oxidizing hypervalent iodine reagents. In this paper we present a detailed protocol for chlorination, azidation, N-heteroarylation, arylation, and allylation. The products include motifs prevalent in medicinally active products. This article will greatly assist others in using these methods.

A two step one-pot protocol for the umpolung of ketone enolates to enolonium species and addition of a nucleophile to the &#945;-position is described. Nucleophiles include chloride, azide, azoles, allyl-silanes, and aromatic compounds.

&#945;-Functionalization of ketones via umpolung of enolates by hypervalent iodine reagents is an important concept in synthetic organic chemistry. ...

Efficient Synthesis of All-Carbon Quaternary Centers via the Conjugate Addition of Functionalized Monoorganozinc Bromides

The conjugate addition of organometallic reagents to &#945;,&#946;-unsaturated carbonyls represents an important method to generate C&#8211;C bonds in the preparation of all-carbon quaternary centers. Though conjugate additions of organometallic reagents are typically performed utilizing highly reactive organolithium or Grignard reagents, organozinc reagents have garnered attention for their enhanced chemoselectivity and mild reactivity. Despite numerous recent advances with more reactive diorganozinc and mixed diorganozinc reagents, the generation of all-carbon quaternary centers via the conjugate addition of functionalized monoorganozinc reagents remains a challenge. This protocol details a convenient and mild &#8220;one-pot&#8221; preparation and copper mediated conjugate addition of functionalized monoorganozinc bromides to cyclic &#945;,&#946;-unsaturated carbonyls to afford a broad scope of all-carbon quaternary centers in generally excellent yield and diastereoselectivity. Key to the development of this technology is the utilization of DMA as a reaction solvent with TMSCl as a Lewis acid. Notable advantages to this methodology include the operational simplicity of the organozinc reagent preparation afforded by the utilization of DMA as a solvent, as well as an efficient conjugate addition mediated by various Cu(I) and Cu(II) salts. Moreover, an intermediate silyl enol ether can be isolated utilizing a modified workup procedure. The substrate scope is limited to cyclic unsaturated ketones, and the conjugate addition is impeded by stabilized (e.g., allyl, enolate, homoenolate) and sterically encumbered (e.g., neopentyl, o-aryl) monoorganozinc reagents. Conjugate additions to five- and seven-membered rings were effective, albeit in lower yields compared with six-membered ring substrates.

A simple and practical protocol for the efficient conjugate addition of functionalized monoorganozinc bromides to cyclic &#945;,&#946;-unsaturated carbonyls to furnish all-carbon quaternary centers was developed.

The conjugate addition of organometallic reagents to &#945;,&#946;-unsaturated carbonyls represents an important method to generate C&#8211;C bonds in the ...

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.

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%.

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 ...

Organocatalysis

Source: Vy M. Dong and Faben Cruz, Department of Chemistry, University of California, Irvine, CA
This experiment will demonstrate the concept of organocatalysis by illustrating the proper setup of a reaction that utilizes enamine catalysis. Organocatalysis is a form of catalysis that uses substoichiometric amounts of small organic molecules to accelerate reactions. This type of catalysis is complementary to other forms of catalysis such as transition metal or biocatalysis. Transition metal catalysis involves transition metals as catalysts and biocatalysis uses enzymes as catalysts. Some advantages of organocatalysis include the low toxicity and cost of the organocatalysts in comparison to many metal catalysts. In addition, most organocatalysts are not sensitive to air and moisture, unlike metal catalysts. In contrast to enzymes found in living organisms, the small molecules that act as organocatalysts are typically easy to access. Furthermore, organocatalysis offers complementary and new reactivity not observed with other forms of catalysis.

Organocatalysis: Principles and Applications

Source: Vy M. Dong and Faben Cruz, Department of Chemistry, University of California, Irvine, CA
This experiment will demonstrate the concept of ...

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Organic Chemistry II

Acid-Catalyzed &alpha;-Halogenation of Aldehydes and Ketones

By replacing an &#945;-hydrogen with a halogen, acid-catalyzed &#945;-halogenation of aldehydes or ketones yields a monohalogenated product
In the first step of the mechanism, the acid protonates the carbonyl oxygen resulting in a resonance-stabilized cation, which subsequently loses an &#945;-hydrogen to form an enol tautomer. The C=C bond in an enol is highly nucleophilic because of the electron-donating nature of the &#8211;OH group. Consequently, the double bond attacks an electrophilic halogen to form a monohalogenated carbocation. In the final step, deprotonation of the carbocation yields the &#945;-halo aldehydes or ketones.
Note that the enol formation is the rate-determining step of the reaction, and the halogen is not involved in the rate-limiting step. Therefore, the initial rates of the &#945;-halogenation are independent of the type and concentration of halogen. Overall, the reaction follows second-order kinetics, wherein the rates depend on the concentration of the carbonyl and the acid.
The addition of a second halogen is unfavorable as the carbocation intermediate formed by the reaction of a monohalogenated enol with halogens is highly destabilized by the electron-withdrawing polar effect of two halogen atoms. Interestingly, the acid formed as a by-product of this reaction can ultimately catalyze the first step of enolization, thus turning the reaction autocatalytic. The unsymmetrical ketones undergo &#945;-halogenation at the more substituted carbon by the preferential formation of a thermodynamic enol. As shown below, the acid-catalyzed &#945;-halogenation reaction also works well to convert ketones to &#945;,&beta;&#8210;unsaturated ketones via E2 elimination reactions forming a new &#960; bond.
<img alt="Figure1" src="/files/ftp_upload/12382/12382_PT_Figure_1.svg" style="text-align: center; height: 110px;" />

Acid-Catalyzed &amp;#945;-Halogenation of Aldehydes and Ketones

By replacing an &#945;-hydrogen with a halogen, acid-catalyzed &#945;-halogenation of aldehydes or ketones yields a monohalogenated product
In the first ...

&alpha;-Carbon Chemistry: Enols, Enolates, and Enamines

KEY TERMS AND CONCEPTS

Alkynes to Aldehydes and Ketones: Hydroboration-Oxidation

<h4>Introduction</h4>
One of the convenient methods for the preparation of aldehydes and ketones is via hydration of alkynes. Hydroboration-oxidation of alkynes is an indirect hydration reaction in which an alkyne is treated with borane followed by oxidation with alkaline peroxide to form an enol that rapidly converts into an aldehyde or a ketone. Terminal alkynes form aldehydes, whereas internal alkynes give ketones as the final product.
<img alt="Figure1" src="/files/ftp_upload/11839/11839_PT_Figure_1.svg" style="text-align: center; height: 200px;" />
<h4>Mechanism</h4>
The hydroboration-oxidation reaction is a two-step process. It begins with the hydroboration step, which involves a concerted syn addition of BH3 across the carbon&#8211;carbon triple bond to form an alkenylborane. The concerted nature of the reaction also accounts for the anti-Markovnikov regiochemistry, where the BH2 group adds to the less substituted carbon and H to the more substituted carbon of the triple bond.
<img alt="Figure2" src="/files/ftp_upload/11839/11839_PT_Figure_2.svg" style="text-align: center; height: 120px;" />
&#160;Three successive hydroboration reactions convert an alkene into a trialkenylborane intermediate. The second part of the sequence is oxidation, where the trialkenylborane is treated with alkaline hydrogen peroxide to form an enol. The enol eventually converts into a stable carbonyl product via keto-enol tautomerism.
<img alt="Figure3" src="/files/ftp_upload/11839/11839_PT_Figure_3.svg" style="text-align: center; height: 250px;" />
<h4>Hydroboration of Alkynes with Disubstituted Boranes</h4>
Unlike alkenes, hydroboration of alkynes does not stop at the first addition of BH3. This is because alkynes have two &#960; bonds, each capable of reacting with BH3. The first addition forms an organoborane, which is an alkene derivative that can react further with another equivalent of BH3.
Terminal alkynes being less hindered than internal alkynes are more susceptible to a second BH3 addition. With internal alkynes, the addition of BH3 stops after the first stage and proceeds in a direction to give the trialkenylborane.
<img alt="Figure4" src="/files/ftp_upload/11839/11839_PT_Figure_4.svg" style="text-align: center; height: 250px;" />
&#160;Nevertheless, hydroboration of terminal alkynes can be stopped at the first step by using bulky disubstituted boranes (R2BH) such as disiamylborane and 9-BBN instead of BH3.
<img alt="Figure5" src="/files/ftp_upload/11839/11839_PT_Figure_5.svg" style="text-align: center; height: 130px;" />
The first addition of the bulky reagent forms a sterically hindered alkenylborane that resists any further additions and helps in the efficient conversion of alkynes to stable carbonyl compounds.
<img alt="Figure6" src="/files/ftp_upload/11839/11839_PT_Figure_6.svg" style="text-align: center; height: 100px;" />

Hydroboration-Oxidation of Alkynes to Aldehydes and Ketones

Introduction
One of the convenient methods for the preparation of aldehydes and ketones is via hydration of alkynes. Hydroboration-oxidation of alkynes is ...

Alkynes

Reduction of Alkenes: Asymmetric Catalytic Hydrogenation

Catalytic hydrogenation of alkenes is a transition-metal catalyzed reduction of the double bond using molecular hydrogen to give alkanes. The mode of hydrogen addition follows syn stereochemistry.
The metal catalyst used can be either heterogeneous or homogeneous. When hydrogenation of an alkene generates a chiral center, a pair of enantiomeric products is expected to form. However, an enantiomeric excess of one of the products can be facilitated using an enantioselective reaction or an asymmetric hydrogenation process using chiral homogeneous catalysts. The chiral catalysts are designed such that the metal coordinates to a chiral ligand. The most frequently used chiral ligand is BINAP [(2,2&#39;-bis(diphenylphosphino)-1,1&#39;-binaphthyl] &#8212; a chelating diphosphine. The metal coordinates to the two phosphorus atoms of BINAP, creating a chiral environment for itself. Such chiral catalysts have tremendous applications in pharmaceutical industries, such as the asymmetric synthesis of (S)-naproxen, an anti-inflammatory drug molecule, and the synthesis of L-dopa, a drug used to treat patients with Parkinson&#39;s disease.
Asymmetric hydrogenation is specific to the type of double bond undergoing reduction. The presence of a functional group directly adjacent to the target double bond is essential for the hydrogenation process as it aids with effective coordination of the metal.

Catalytic hydrogenation of alkenes is a transition-metal catalyzed reduction of the double bond using molecular hydrogen to give alkanes. The mode of ...

A Microwave-Assisted Direct Heteroarylation of Ketones Using Transition Metal Catalysis

Summary

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Chapters in this video

Facile Preparation of (2Z,4E)-Dienamides by the Olefination of Electron-deficient Alkenes with Allyl Acetate

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

Utilization of Stop-flow Micro-tubing Reactors for the Development of Organic Transformations

A Two-Step Protocol for Umpolung Functionalization of Ketones Via Enolonium Species

Efficient Synthesis of All-Carbon Quaternary Centers via the Conjugate Addition of Functionalized Monoorganozinc Bromides

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

Organocatalysis

Acid-Catalyzed α-Halogenation of Aldehydes and Ketones

Alkynes to Aldehydes and Ketones: Hydroboration-Oxidation

Reduction of Alkenes: Asymmetric Catalytic Hydrogenation