Name: a two-step protocol for umpolung functionalization of ketones via enolonium species
Uploaded: 2018-08-16T13:30:00
Description: Watch this Scientific Journal Video about A Two-Step Protocol for Umpolung Functionalization of Ketones Via Enolonium Species at JoVE.com

A start-up grant from Ariel University and an ISF Individual Research Grant (1914/15) to AMS is gratefully acknowledged.

1. Preparation of the Enolonium Species
Caution: Before carrying out the protocol, consult the MSDS for all reagents and solvents.
NOTE: All new reagents were used as received from the commercial source. If the boron trifluoride etherate has been stored, distill it before use.
<ol>
	<li>In a dry round bottomed flask equipped with a septum and a magnet for magnetic stirring, add Koser&#39;s reagent (1.5 equiv.) and flush the flask with nitrogen or argon.</li>
	<li>...

<ol>
	<li>Mizar, P., Wirth, T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Flexible+stereoselective+functionalizations+of+ketones+through+umpolung+with+hypervalent+iodine+reagents.">Flexible stereoselective functionalizations of ketones through umpolung with hypervalent iodine reagents.</a> Angewandte Chemie International Edition. 53 (23), 5993-5997 (2014).</li><li>Yoshimura, A., Zhdankin, V. V. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Advances+in+synthetic+applications+of+hypervalent+iodine+compounds.">Advances in synthetic applications of hypervalent iodine compounds.</a> Chemical Reviews. 116 (5), 3328-3435 (2016).</li><li>Zhdankin, V. V. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Hypervalent Iodine Chemistry: Preparation, Structure, and Synthetic Applications of Polyvalent Iodine Compounds. , (2013).</li><li>Wirth, T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Topics in Current Chemistry. 373, (2016).</li><li>Merritt, E. A., Olofsson, B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=&#945;-functionalization+of+carbonyl+compounds+using+hypervalent+iodine+reagents.">&#945;-functionalization of carbonyl compounds using hypervalent iodine reagents.</a> Synthesis. 4 (4), 517-538 (2011).</li><li>Arava, S., 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=Enolonium+Species-Umpoled+Enolates.">Enolonium Species-Umpoled Enolates.</a> Angewandte Chemie International Edition. 56 (10), 2599-2603 (2017).</li><li>Parida, K. N., Maksymenko, S., Pathe, G. K., Szpilman, A. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Cross-Coupling+of+Dissimilar+Ketone+Enolates+via+Enolonium+Species+to+afford+Nonsymmetrical+1,4-Diketones.">Cross-Coupling of Dissimilar Ketone Enolates via Enolonium Species to afford Nonsymmetrical 1,4-Diketones.</a> Beilstein Journal of Organic Chemistry. 14, 992-997 (2018).</li><li>Zhdankin, V. V., 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=Carbon-carbon+bond+formation+in+reactions+of+PhIO&#183;HBF4-silyl+enol+ether+adduct+with+alkenes+or+silyl+enol+ethers.">Carbon-carbon bond formation in reactions of PhIO&#183;HBF4-silyl enol ether adduct with alkenes or silyl enol ethers.</a> Journal of Organic Chemistry. 54 (11), 2605-2608 (1989).</li><li>Maksymenko, S., 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=Transition-metal-free+intermolecular+&#945;-arylation+of+ketones+via+enolonium+species.">Transition-metal-free intermolecular &#945;-arylation of ketones via enolonium species.</a> Organic Letters. 19 (23), 6312-6315 (2017).</li><li>Vita, M. V., Waser, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Azidation+of+&#946;-keto+esters+and+silyl+enol+ethers+with+a+benziodoxole+reagent.">Azidation of &#946;-keto esters and silyl enol ethers with a benziodoxole reagent.</a> Organic Letters. 15 (13), 3246-3249 (2013).</li><li>More, 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=&#945;-N-Heteroarylation+and+&#945;-azidation+of+ketones+via+enolonium+species.">&#945;-N-Heteroarylation and &#945;-azidation of ketones via enolonium species.</a> Journal of Organic Chemistry. 83, 2442-2447 (2018).</li><li>Xie, L., 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=Gold-catalyzed+hydration+of+haloalkynes+to+&#945;-halomethyl+ketones.">Gold-catalyzed hydration of haloalkynes to &#945;-halomethyl ketones.</a> Journal of Organic Chemistry. 78 (18), 9190-9195 (2013).</li><li>Patonay, T., Juh&#225;sz-T&#243;th, &. #. 2. 0. 1. ;., B&#233;nyei, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Base-induced+coupling+of+&#945;-azido+ketones+with+aldehydes+&#8722;+An+easy+and+efficient+route+to+trifunctionalized+synthons+2-azido-3-hydroxy+ketones,+2-acylaziridines,+and+2-acylspiroaziridines.">Base-induced coupling of &#945;-azido ketones with aldehydes &#8722; An easy and efficient route to trifunctionalized synthons 2-azido-3-hydroxy ketones, 2-acylaziridines, and 2-acylspiroaziridines.</a> European Journal of Organic Chemistry. 2002 (2), 285-295 (2002).</li><li>Li, C., Breit, B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Rhodium-catalyzed+chemo-+and+regioselective+decarboxylative+addition+of+&#946;-ketoacids+to+allenes:+Efficient+construction+of+tertiary+and+quaternary+carbon+Centers.">Rhodium-catalyzed chemo- and regioselective decarboxylative addition of &#946;-ketoacids to allenes: Efficient construction of tertiary and quaternary carbon Centers.</a> Journal of the American Chemical Society. 136 (3), 862-865 (2014).</li></ol>

The successful preparation of enolonium species from TMS-enolates is dependent on a number of factors. The major side reaction in the preparation step is the homo coupling of the starting material by reaction of a molecule of formed enolonium species with a molecule of TMS-enolate. Thus, the requirement of the reaction conditions is to avoid this dimerization by ensuring fast reaction of the Lewis acid activated hypervalent iodine reagent with added TMS-enolate relative to the rate of dimerization. This is achieved in th...

Enolates are classical carbon nucleophiles in organic chemistry and among the most widely used. Umpolung of enolates to create electrophilic enolonium species allows valuable alternative ways to produce &#945;-functionalized ketones as well as to enable novel reactions not possible via classical enolate chemistry. Enolonium species have been proposed as intermediates in numerous reactions, in particular reactions involving hypervalent iodine reagents. These reactions include &#945;-halogenation, oxygenation, and amination1 as well as other reactions2,3,4,5.
However, the scopes of these reactions were always limited by the transient nature of the reactive enolonium species. This transiency required any nucleophile to be present in the reaction mixture during the reaction of the carbonyl enolates with the strongly oxidizing hypervalent iodine reagent. Thus, any nucleophile prone to oxidation, such as electron rich aromatic compounds (heterocycles) and alkenes, could not be used.
In the last year, we have overcome these limitations by developing conditions in which the enolonium species is formed as a discrete intermediate in one step followed by addition of the nucleophile in a second step. This protocol allows not only the classical type of functionalization such as chlorination6, but also the use of oxidizable carbon nucleophiles, such as allylsilanes6,8, enolates1,6,7, and electron rich aromatic compounds9, resulting in C-C bond formation. The allylation method is amenable to the formation of quaternary and tertiary centers. The ketone arylation method constitutes formal C-H functionalization of the aromatic compound without the need for a directing group9. Recently, we have reported the addition of azoles and azides10 as well11. The detailed presentation of the protocol is expected to assist in the introduction of these methods into the day to day tool box of the synthetic organic chemist.

<table>
	<tbody>
		<tr>
			<td>Chlorotrimethylsilane, 98+%</td>
			<td>Alfa Aesar</td>
			<td>A13651</td>
			<td>TMS-Cl</td>
		</tr>
		<tr>
			<td>Boron trifluoride diethyl etherate, 98+%</td>
			<td>Alfa Aesar</td>
			<td>A15275</td>
			<td>BF3*Et2O</td>
		</tr>
		<tr>
			<td>2-Methylindole, 98+%</td>
			<td>Alfa Aesar</td>
			<td>A10764</td>
			<td>2-Me-indole</td>
		</tr>
		<tr>
			<td>Hydroxy(tosyloxy) iodobenzene, 97%</td>
			<td>Alfa Aesar</td>
			<td>L15701</td>
			<td>Koser&#39;s reagent</td>
		</tr>
		<tr>
			<td>Acetophenone, &#62;98%</td>
			<td>Merck</td>
			<td>800028</td>
			<td></td>
		</tr>
		<tr>
			<td>n-Butyllithium solution 1.6M in hexanes</td>
			<td>Aldrich</td>
			<td>186171</td>
			<td>nBuLi</td>
		</tr>
		<tr>
			<td>BIS(ISOPROPYL)AMINE</td>
			<td>Apollo</td>
			<td>OR1090</td>
			<td>DIPA</td>
		</tr>
		<tr>
			<td>Trimethylsilyl azide, 94%</td>
			<td>Alfa Aesar</td>
			<td>L00173</td>
			<td>TMS-N3</td>
		</tr>
	</tbody>
</table>

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.

Representative results, achieved following the protocol, are given in Figure 1 and are discussed in the discussion section. Notably, a very large range of different ketones may be used successfully in the reaction to give the products in good yields as may be seen for the azidation11. The scope of the reaction for introducing azoles in the &#945;-position of ketones includes most of the common mono-cyclic and bicyclic nitrogen containi...

Watch this Scientific Journal Video about A Two-Step Protocol for Umpolung Functionalization of Ketones Via Enolonium Species at JoVE.com

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

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. ...

Umpolung of ketone enolates by virtue of reversing natural activity, enables the development of unprecedented reactions to functionalized carbon neo-compounds. The key is the formation of electrophilic enolonium species as a discreet species. A main advantage of methods based on electrophilic enolonium species is that it obviates the need for older multiple step methods, allows the use of commercial starting materials and is simple to use.We recently had the idea for this method when we were able to characterize the electrophilic enolonium species for the first time. Over the last year, we have developed a series of new reactions based on the two-step protocol presented here. Today, we will describe how enolonium species made in the first step can be used in in situ coupling with allyl-silanes, aromatic compounds, chloride, azide and azoles.Keep in mind that the implications of this technique extend toward other reactions, because the type of nucleophile that may be used is much less restricted than earlier hypervalent iodine-based methods. Demonstrating the procedure will be Shlomy Arava, a graduate student in our group. In a dry round-bottomed flask equipped with a septum and a magnetic stir bar, add 1.5 equivalents of Koser's reagent and flush the flask with nitrogen or argon.Add dry dichloromethane to give a formal concentration of 0.234 millimolars per liter. Cool the resulting suspension to minus 78 degrees Celsius using a dry ice acetone bath. Then, add 1.5 equivalents of neat boron trifluoride etherate slowly.Warm the heterogeneous mixture to room temperature until it becomes a yellow solution, which typically occurs within five minutes. Following this, cool the solution to minus 78 degrees Celsius. To the cooled solution, add one equivalent of previously prepared trimethylsilyl ether solution drop-wise over two to 10 minutes to afford the enolonium species.This is the most critical step of the protocol. If the TMS-enolate ether is added too fast, dimerization products form. Add two equivalents of a previously prepared allyl trimethylsilane solution slowly to the prepared solution of enolonium species at minus 78 degrees Celsius with stirring.After five minutes, remove the cooling bath and allow the reaction mixture to reach room temperature. Once the reaction is complete, add water to the reaction mixture and transfer to a separatory funnel. Then, extract three times with dichloromethane, using two to three times the reaction volume for each extraction.Next, wash the combined organic layers twice with brine using the same volume of brine as the combined reaction volume. After transferring the combined organic layers to a flask, dry with anhydrous sodium sulfate for 30 minutes. Following this, remove the sodium sulfate by filtration.Then, remove the solvent on a rotary evaporator under reduced pressure at 40 degrees Celsius. Purify the crude product by column chromatography on silica gel using hexane and ethyl acetate as the eluant to afford the pure corresponding alpha allyl ketone. For the benzyldimethyldecylammonium chloride reaction, add two equivalents of a previously prepared chloride solution drop-wise to the prepared solution of enolonium species at minus 78 degrees Celsius with stirring.After five minutes, remove the cooling bath and allow the reaction mixture to reach room temperature. For azedation, add 2.5 equivalents of neat azedo trimethylsilane drop-wise to the prepared solution of enolonium species at minus 78 degrees Celsius with stirring. After 15 minutes, heat the reaction mixture to minus 55 degrees Celsius and stir for two to three hours until the reaction is complete by TLC.For the azole reaction, add four to five equivalents of a previously prepared azole solution drop-wise to the prepared solution of enolonium species at minus 78 degrees Celsius with stirring. After 15 minutes, heat the reaction mixture to minus 55 degrees Celsius and stir for four to eight hours until the reaction is complete by TLC. For arylation, add 1.6 equivalents of a previously prepared aromatic substrate solution drop-wise to the solution of prepared enolonium species at minus 78 degrees Celsius with stirring.After the addition of the aromatic substrate is complete, increase the temperature of the mixture to minus 55 degrees Celsius and stir for 20 minutes until the reaction is complete by TLC. A very large range of different ketones may be used successfully in the alpha functionalization reaction to give the products in good yields, as observed for the azidation. The scope of the reaction for introducing azoles in the alpha position of ketones includes most of the common monocyclic and bicyclic nitrogen-containing heterocycles.The scope of the allylation procedure includes allyl-crotyl-and prenyl-trimethylsilane. The C-aryllation procedure works for both indoles and electron-rich benzene derivatives using only 1.5 to 1.6 equivalents of the aromatic substrate. Thiophene, furane and pyrroles are also good substrates but the products are isolated in slightly lower yields and five equivalents of aromatic substrate are required.Once mastered, both steps of the protocol can be done in less than five hours for most of the reactions and overnight for the azole coupling. While attempting this procedure, it's important to remember to add the TMS-enolate slowly when making enolorium species to avoid dimerization of the enolate as a side reaction. Don't forget that working with azides can be hazardous and appropriate precautions such as limiting the scale should always be taken.Following the allylation procedure, you can add the prenyl group to make a quaternary center which is something that cannot be done using other methods. Using the arylation procedure means that you don't need to worry about using a transition metal catalyst or a halogenated aromatic starting material. Just use a aromatic substrate.After watching this video, we hope that the enolate umpolung will be a familiar concept to you and that you'll be tempted to develop new reactions of your own.

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Solid-phase synthesis has been used to obtain canonical and modified polymers of nucleic acids, specifically of DNA or RNA, which has made it a popular methodology for applications in various fields and for different research purposes. The procedure described herein focuses on the synthesis, purification, and characterization of dodecamers of RNA 5&#39;-[CUA CGG AAU CAU]-3&#39; containing zero, one, or two modifications located at the C2&#39;-O-position. The probes are based on 2-thiophenylmethyl groups, incorporated into RNA nucleotides via standard organic synthesis and introduced into the corresponding oligonucleotides via their respective phosphoramidites. This report makes use of phosphoramidite chemistry via the four canonical nucleobases (Uridine (U), Cytosine (C), Guanosine (G), Adenosine (A)), as well as 2-thiophenylmethyl functionalized nucleotides modified at the 2&#39;-O-position; however, the methodology is amenable for a large variety of modifications that have been developed over the years. The oligonucleotides were synthesized on a controlled-pore glass (CPG) support followed by cleavage from the resin and deprotection under standard conditions, i.e., a mixture of ammonia and methylamine (AMA) followed by hydrogen fluoride/triethylamine/N-methylpyrrolidinone. The corresponding oligonucleotides were purified via polyacrylamide electrophoresis (20% denaturing) followed by elution, desalting, and isolation via reversed-phase chromatography (Sep-pak, C18-column). Quantification and structural parameters were assessed via ultraviolet-visible (UV-vis) and circular dichroism (CD) photometric analysis, respectively. This report aims to serve as a resource and guide for beginner and expert researchers interested in embarking in this field. It is expected to serve as a work-in-progress as new technologies and methodologies are developed. The description of the methodologies and techniques within this document correspond to a DNA/RNA synthesizer (refurbished and purchased in 2013) that uses phosphoramidite chemistry.

Protocol for the Solid-phase Synthesis of Oligomers of RNA Containing a 2&#039;-O-thiophenylmethyl Modification and Characterization via Circular Dichroism

This article provides a detailed procedure on the solid-phase synthesis, purification, and characterization of dodecamers of RNA modified at the C2&#39;-O-position. UV-vis and circular dichroism photometric analyses are used to quantify and characterize structural aspects, i.e., single-strands or double-strands.

Solid-phase synthesis has been used to obtain canonical and modified polymers of nucleic acids, specifically of DNA or RNA, which has made it a popular ...

Fabrication and Testing of Catalytic Aerogels Prepared Via Rapid Supercritical Extraction

Protocols for preparing and testing catalytic aerogels by incorporating metal species into silica and alumina aerogel platforms are presented. Three preparation methods are described: (a) the incorporation of metal salts into silica or alumina wet gels using an impregnation method; (b) the incorporation of metal salts into alumina wet gels using a co-precursor method; and (c) the addition of metal nanoparticles directly into a silica aerogel precursor mixture. The methods utilize a hydraulic hot press, which allows for rapid (&#60;6 h) supercritical extraction and results in aerogels of low density (0.10 g/mL) and high surface area (200-800 m2/g). While the work presented here focuses on the use of copper salts and copper nanoparticles, the approach can be implemented using other metal salts and nanoparticles. A protocol for testing the three-way catalytic ability of these aerogels for automotive pollution mitigation is also presented. This technique uses custom-built equipment, the Union Catalytic Testbed (UCAT), in which a simulated exhaust mixture is passed over an aerogel sample at a controlled temperature and flow rate. The system is capable of measuring the ability of the catalytic aerogels, under both oxidizing and reducing conditions, to convert CO, NO and unburned hydrocarbons (HCs) to less harmful species (CO2, H2O and N2). Example catalytic results are presented for the aerogels described.

Here we present protocols for preparing and testing catalytic aerogels by incorporating metal species into silica and alumina aerogel platforms. Methods for preparing materials using copper salts and copper-containing nanoparticles are featured. Catalytic testing protocols demonstrate the effectiveness of these aerogels for three-way catalysis applications.

Protocols for preparing and testing catalytic aerogels by incorporating metal species into silica and alumina aerogel platforms are presented. Three ...

The MPLEx Protocol for Multi-omic Analyses of Soil Samples

Mass spectrometry (MS)-based integrated metaproteomic, metabolomic, and lipidomic (multi-omic) studies are transforming our ability to understand and characterize microbial communities in environmental and biological systems. These measurements are even enabling enhanced analyses of complex soil microbial communities, which are the most complex microbial systems known to date. Multi-omic analyses, however, do have sample preparation challenges, since separate extractions are typically needed for each omic study, thereby greatly amplifying the preparation time and amount of sample required. To address this limitation, a 3-in-1 method for the simultaneous extraction of metabolites, proteins, and lipids (MPLEx) from the same soil sample was created by adapting a solvent-based approach. This MPLEx protocol has proven to be both simple and robust for many sample types, even when utilized for limited quantities of complex soil samples. The MPLEx method also greatly enabled the rapid multi-omic measurements needed to gain a better understanding of the members of each microbial community, while evaluating the changes taking place upon biological and environmental perturbations.

A protocol is presented for simultaneously extracting metabolites, proteins, and lipids from a single soil sample, allowing reduced sample preparation times and enabling multi-omic mass spectrometry analyses of samples with limited quantities.

Mass spectrometry (MS)-based integrated metaproteomic, metabolomic, and lipidomic (multi-omic) studies are transforming our ability to understand and ...

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 by generating a charged structure provides an opportunity to use extraction as a simple purification technique. By combining the use of a miscible organic solvent with saturated sodium bisulfite, aldehydes and reactive ketones can be successfully transformed into charged bisulfite adducts that can then be separated from other organic components of a mixture by the introduction of an immiscible organic layer. Here, we describe a simple protocol for the removal of aldehydes, including sterically-hindered neopentyl aldehydes and some ketones, from chemical mixtures. Ketones can be separated if they are sterically unhindered cyclic or methyl ketones. For aliphatic aldehydes and ketones, dimethylformamide is used as the miscible solvent to improve removal rates. The bisulfite addition reaction can be reversed by basification of the aqueous layer, allowing for the re-isolation of the reactive carbonyl component of a mixture.

Here, we present a protocol to remove aldehydes and reactive ketones from mixtures by a liquid-liquid extraction protocol directly with saturated sodium bisulfite in a miscible solvent. This combined protocol is rapid and facile to perform. The aldehyde or ketone can be re-isolated by the basification of the aqueous layer.

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