Name: a microwave-assisted direct heteroarylation of ketones using transition metal catalysis
Uploaded: 2020-02-16T13:00:00
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>
	...

<ol>
	<li>Gedye, R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+use+of+microwave+ovens+for+rapid+organic+synthesis.">The use of microwave ovens for rapid organic synthesis.</a> Tetrahedron Letters. 27 (3), 279-282 (1986).</li><li>Garbacia, S., Desai, B., Lavastre, O., Kappe, C. O. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Microwave-Assisted+Ring-Closing+Metathesis+Revisited.+On+the+Question+of+the+Nonthermal+Microwave+Effect.">Microwave-Assisted Ring-Closing Metathesis Revisited. On the Question of the Nonthermal Microwave Effect.</a> The Journal of Organic Chemistry. 68 (23), 9136-9139 (2003).</li><li>Amato, E., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Investigation+of+fluorinated+and+bifunctionalized+3-phenylchroman-4-one+(isoflavanone)+aromatase+inhibitors.">Investigation of fluorinated and bifunctionalized 3-phenylchroman-4-one (isoflavanone) aromatase inhibitors.</a> Bioorganic &amp; Medicinal Chemistry. 22 (1), 126-134 (2014).</li><li>Bonfield, K., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Development+of+a+new+class+of+aromatase+inhibitors:+Design,+synthesis+and+inhibitory+activity+of+3-phenylchroman-4-one+(isoflavanone)+derivatives.">Development of a new class of aromatase inhibitors: Design, synthesis and inhibitory activity of 3-phenylchroman-4-one (isoflavanone) derivatives.</a> Bioorganic &amp; Medicinal Chemistry. 20 (8), 2603-2613 (2012).</li><li>Y&#305;lmaz, F., Mentese, E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+Rapid+Protocol+for+the+Synthesis+of+N-[2-(alkyl/aryl)-4-phenyl-1Himidazol-1-yl]+benzamides+via+Microwave+Technique.">A Rapid Protocol for the Synthesis of N-[2-(alkyl/aryl)-4-phenyl-1Himidazol-1-yl] benzamides via Microwave Technique.</a> Current Microwave Chemistry. 1 (1), 47-51 (2014).</li><li>Xia, Y., Chen, L. Y., Lv, S., Sun, Z., Wang, B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Microwave-Assisted+or+Cu-NHC-Catalyzed+Cycloaddition+of+Azido-Disubstituted+Alkynes:+Bifurcation+of+Reaction+Pathways.">Microwave-Assisted or Cu-NHC-Catalyzed Cycloaddition of Azido-Disubstituted Alkynes: Bifurcation of Reaction Pathways.</a> The Journal of Organic Chemistry. 79 (20), 9818-9825 (2014).</li><li>Lei, C., Jin, X., Zhou, J. S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Palladium-Catalyzed+Heteroarylation+and+Concomitant+ortho-Alkylation+of+Aryl+Iodides.">Palladium-Catalyzed Heteroarylation and Concomitant ortho-Alkylation of Aryl Iodides.</a> Angewandte Chemie International Edition. 54 (45), 13397-13400 (2015).</li><li>Muratake, H., Hayakawa, A., Nataume, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+Novel+Phenol-Forming+Reaction+for+Preparation+of+Benzene,+Furan,+and+Thiophene+Analogs+of+CC-1065/Duocarmycin+Pharmacophores.">A Novel Phenol-Forming Reaction for Preparation of Benzene, Furan, and Thiophene Analogs of CC-1065/Duocarmycin Pharmacophores.</a> Tetrahedron Letters. 38 (43), 7577 (1997).</li><li>Viciu, M. S., Germaneau, R. F., Nolan, S. P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Well-Defined,+Air-Stable+(NHC)Pd(Allyl)Cl+(NHC=N-Heterocyclic+Carbene)+Catalysts+for+the+Arylation+of+Ketones.">Well-Defined, Air-Stable (NHC)Pd(Allyl)Cl (NHC=N-Heterocyclic Carbene) Catalysts for the Arylation of Ketones.</a> Organic Letters. 23 (4), 4053-4056 (2002).</li><li>Biscoe, M. R., Buchwald, S. L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Selective+Monoarylation+of+Acetate+Esters+and+Aryl+Methyl+Ketones+Using+Aryl+Chlorides.">Selective Monoarylation of Acetate Esters and Aryl Methyl Ketones Using Aryl Chlorides.</a> Organic Letters. 11 (8), 1773-1775 (2009).</li><li>Chobanian, H. R., Liu, P., Chioda, M. D., Guo, Y., Lin, L. S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+facile,+microwave-assisted,+palladium-catalyzed+arylation+of+acetone.">A facile, microwave-assisted, palladium-catalyzed arylation of acetone.</a> Tetrahedron Letters. 48 (7), 1213-1216 (2007).</li><li>Amat, M., Hadida, S., Pshenichnyi, G., Bosch, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Palladium(0)-Catalyzed+Heteroarylation+of+2-+and+3-Indolylzinc+Derivatives.+An+Efficient+General+Method+for+the+Preparation+of+(2-Pyridyl)indoles+and+Their+Application+to+Indole+Alkaloid+Synthesis.">Palladium(0)-Catalyzed Heteroarylation of 2- and 3-Indolylzinc Derivatives. An Efficient General Method for the Preparation of (2-Pyridyl)indoles and Their Application to Indole Alkaloid Synthesis.</a> The Journal of Organic Chemistry. 62 (10), 3158-3175 (1997).</li><li>Tennant, G. J., Wallis, C. W., Weaver C, G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Synthesis+of+the+first+examples+of+the+imidazo[4,5-c]isoxazole+ring+system.">Synthesis of the first examples of the imidazo[4,5-c]isoxazole ring system.</a> Journal of the Chemical Society, Perkin Transactions. 1, 817-826 (1999).</li><li>Spergel, S. H., Okoro, D. R., Pitts, W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=One-Pot+Synthesis+of+Azaindoles+via+Palladium-Catalyzed+&#945;-Heteroarylation+of+Ketone+Enolates.">One-Pot Synthesis of Azaindoles via Palladium-Catalyzed &#945;-Heteroarylation of Ketone Enolates.</a> The Journal of Organic Chemistry. 75 (15), 5316-5319 (2010).</li><li>Jiang, Y., Liang, G., Zhang, C., Loh, T. P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Palladium-Catalyzed+C-S+Bond+Formation+of+Stable+Enamines+with+Arene/Alkanethiols:+Highly+Regioselective+Synthesis+of+&#946;-Amino+Sulfides.">Palladium-Catalyzed C-S Bond Formation of Stable Enamines with Arene/Alkanethiols: Highly Regioselective Synthesis of &#946;-Amino Sulfides.</a> European Journal of Organic Chemistry. 2016 (20), 3326-3330 (2016).</li><li>King, S. M., Buchwald, S. L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Development+of+a+Method+for+the+N-Arylation+of+Amino+Acid+Esters+with+Aryl+Triflates.">Development of a Method for the N-Arylation of Amino Acid Esters with Aryl Triflates.</a> Organic Letters. 18 (16), 4128-4131 (2016).</li><li>Ge, S., Hartwig, J. F. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Nickel-catalyzed+asymmetric+alpha-arylation+and+heteroarylation+of+ketones+with+chloroarenes:+effect+of+halide+on+selectivity,+oxidation+state,+and+room-temperature+reactions.">Nickel-catalyzed asymmetric alpha-arylation and heteroarylation of ketones with chloroarenes: effect of halide on selectivity, oxidation state, and room-temperature reactions.</a> The Journal of the American Chemical Society. 133 (41), 16330-16333 (2011).</li><li>Quillen, A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Palladium-Catalyzed+Direct+&#945;-C(sp3)+Heteroarylation+of+Ketones+under+Microwave+Irradiation.">Palladium-Catalyzed Direct &#945;-C(sp3) Heteroarylation of Ketones under Microwave Irradiation.</a> The Journal of Organic Chemistry. 84 (12), 7652-7663 (2019).</li><li>Kremsner, J. M., Kappe, C. O. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Silicon+Carbide+Passive+Heating+Elements+in+Microwave-Assisted+Organic+Synthesis+-+SI.">Silicon Carbide Passive Heating Elements in Microwave-Assisted Organic Synthesis - SI.</a> The Journal of Organic Chemistry. 71 (12), 4651-4658 (2006).</li><li>Erythropel, H. C., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+Green+ChemisTREE:+20+years+after+taking+root+with+the+12+principles.">The Green ChemisTREE: 20 years after taking root with the 12 principles.</a> Green Chemistry. 20 (9), 1929-1961 (2018).</li><li>Barge, A., Tagliapietra, S., Tei, L., Cintas, P., Cravotto, G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Pd-catalyzed+reactions+promoted+by+ultrasound+and/or+microwave+irradiation.">Pd-catalyzed reactions promoted by ultrasound and/or microwave irradiation.</a> Current Organic Chemistry. 12 (18), 1588-1612 (2008).</li><li>Kimura, M., Mukai, R., Tanigawa, N., Tanaka, S., Tamaru, Y. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Triethylborane+as+an+efficient+promoter+for+palladium-catalyzed+allylation+of+active+methylene+compounds+with+allyl+alcohols.">Triethylborane as an efficient promoter for palladium-catalyzed allylation of active methylene compounds with allyl alcohols.</a> Tetrahedron. 59 (39), 7767-7777 (2003).</li></ol>

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 border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<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&#174; 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...

Watch this Scientific Journal Video about A Microwave-Assisted Direct Heteroarylation of Ketones Using Transition Metal Catalysis at JoVE.com

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 ...

This protocol utilizes microwave irradiation and a palladium catalyst to attach a heteroaryl fragment directly on the alpha carbon of a ketone. The main advantage of this technique is the rapid construction of a heteroaryl compound for medicinal chemistry screening, for catalyst-assisting development, and for tandem organic reaction discovery. The long term implication of our research is the synthesis of an effective aromatase inhibitor to be used as a potential treatment for hormone receptor-positive breast cancer.Mistakes would most likely come from spills while using the glove box, so our advice is to take your time, as the reaction doesn't require a fast pace to be successful. Transport the needed reagents and supplies into the glove box. Inside the perched glove box, weigh 115 milligrams of sodium tert-butoxide directly into the four-milliliter microwave reaction vial.Use a glass pipette to add one milliliter of degassed toluene into the microwave reaction vial. Weigh nine milligrams of XPhos Palladacycle Generation 4 Catalyst and add it into the microwave vial. Dip the spatula into the solution in the vial and swirl to ensure the complete transfer of the catalyst.Then, use a suitable microliter syringe to add 64.4 microliters of acetophenone into the microwave vial. Weigh 103 milligrams of 3-iodopyridine and add it into the microwave vial. Next, add another one milliliter of degassed toluene so that the total reaction mixture is about three milliliters.Line up the seal and the cap carefully and put them on the microwave reaction vial. Screw tight. Take the chemicals, supplies, and trash out of the glove box.Take the assembled reaction vial to the microwave reactor, and place it on the silicon carbide plate on the rotor. For multiple reaction vials, space them evenly across the four silicon carbide plates on the rotor. Set the infrared sensor temperature limit to 113 degrees Celsius, corresponding to the actual reaction temperature at 130 degrees Celsius.Program the microwave power and time for each step according to the manuscript. Run the reaction under microwave irradiation. Record the actual reaction time and temperature.After the microwave reaction vial cools to ambient temperature, transfer the reaction mixture into a separatory funnel and rinse with a minimal amount of ethyl acetate into the funnel. Add two milliliters of saturated ammonium chloride and ten milliliters of ethyl acetate to the separatory funnel, and shake to mix. Place the separatory funnel on a rack to settle for five minutes.Open the valve to drain the aqueous layer, then separate the top organic layer, and save it in a clean, dry beaker. Repeat the extraction by adding ten milliliters of ethyl acetate two more times, and combine the organic layers. After drying and rotary evaporation, record the shape, color, and mass of the crude product.Verify the final product using automated flash chromatography. First, dissolve the crude product in one to two milliliters of acetone in a round-bottom flask, followed by addition of 1.5 grams of silica gel to make a slurry. Perform rotary evaporation for about five minutes, removing 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. Assemble the loading cartridge, prepacked column, test tube rack, and solvent lines for the automated MPLC system. Set up the solvent gradient and other parameters for the MPLC system and run the flash chromatography.Combine the desired MPLC fractions in a round-bottom flask, and evaporate the solvent on a rotary evaporation apparatus to collect the pure product. Dry the purified product under high vacuum for at least one hour to remove residual solvent. Then, weigh five to 10 milligrams of the final purified product.Dissolve it 0.75 milliliters of deuterated chloroform or other appropriate deuterated solvent. And take a proton NMR spectrum. Using this efficient microwave-assisted protocol, the direct alpha-carbon heteroarylation of ketones was performed.For example, compound 1A was synthesized and isolated as a pale-yellow compound. Its proton and carbon-13 NMR spectra are shown here. The presence of a two-proton singlet signal at delta 4.26 ppm in the proton spectrum confirmed the successful carbon-carbon coupling between the ketone and the heteroaryl halide.The purification based on ethyl acetate and hexanes solvent system allowed the isolation of the compounds with one nitrogen very well. When this method was utilized for compounds with two or more nitrogen atoms, the methanol and methylene chloride solvent system should be employed to get faster elution. The most important thing to remember is to ensure the accurate and complete transfer of all of the reagents, especially the catalyst.This technique allows the researchers to perform parallel synthesis for the discovery of pharmaceutical reagents and to develop domino approach for natural product synthesis.

Research

Education

JoVE Journal

JoVE Core

Chemistry

Cell Biology

Organic Chemistry

Unit 1

Aldehydes and Ketones

Biochemistry of the Cell

SCIENTISTS IN ACTION

Microwave-assisted Intramolecular Dehydrogenative Diels-Alder Reactions for the Synthesis of Functionalized Naphthalenes/Solvatochromic Dyes

Functionalized naphthalenes have applications in a variety of research fields ranging from the synthesis of natural or biologically active molecules to ...

Microwave-assisted Functionalization of Poly(ethylene glycol) and On-resin Peptides for Use in Chain Polymerizations and Hydrogel Formation

Microwave-assisted Functionalization of Polyethylene glycol and On-resin Peptides for Use in Chain Polymerizations and Hydrogel Formation

One of the main benefits to using poly(ethylene glycol) (PEG) macromers in hydrogel formation is synthetic versatility. The ability to draw from a large ...

Preparation of Silica Nanoparticles Through Microwave-assisted Acid-catalysis

Microwave-assisted synthetic techniques were used to quickly and reproducibly produce silica nanoparticle sols using an acid catalyst with nanoparticle ...

Reverse Microemulsion-mediated Synthesis of Monometallic and Bimetallic Early Transition Metal Carbide and Nitride Nanoparticles

A reverse microemulsion is used to encapsulate monometallic or bimetallic early transition metal oxide nanoparticles in microporous silica shells. The ...

Rapid High-throughput Species Identification of Botanical Material Using Direct Analysis in Real Time High Resolution Mass Spectrometry

We demonstrate that direct analysis in real time-high resolution mass spectrometry can be used to produce mass spectral profiles of botanical material, ...

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 ...

Synthesis and Performance Characterizations of Transition Metal Single Atom Catalyst for Electrochemical CO2 Reduction

Synthesis and Performance Characterizations of Transition Metal Single Atom Catalyst for Electrochemical CO2 Reduction

This protocol presents both the synthesis method of the Ni single atom catalyst, and the electrochemical testing of its catalytic activity and selectivity ...

Separation of Aldehydes and Reactive Ketones from Mixtures Using a Bisulfite Extraction Protocol

The purification of organic compounds is an essential component of routine synthetic operations. The ability to remove contaminants into an aqueous layer ...

Reducing Willow Wood Fuel Emission by Low Temperature Microwave Assisted Hydrothermal Carbonization

Biomass is a sustainable fuel, as its CO2 emissions are reintegrated in biomass growth. However, the inorganic precursors in the biomass cause a negative ...

Imine Metathesis by Silica-Supported Catalysts Using the Methodology of Surface Organometallic Chemistry

With this protocol, a well-defined singlesite silica-supported heterogeneous catalyst [(&#8801;Si-O-)Hf(=NMe)(&#951;1-NMe2)] is designed and prepared ...