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>Add dry dichloromethane&#160;to give a suspension of 0.234 mol/L formal concentration.</li>
	<li>Cool the suspension to -78 &#176;C using a dry ice/acetone bath or a cold finger instrument/acetone bath.</li>
	<li>Add neat BF3OEt2 (1.5 equiv.) slowly.</li>
	<li>Warm the heterogeneous mixture to room temperature until the formation of yellow solution. Typically, this happens within 5 min.</li>
	<li>Cool the solution to -78 &#176;C.</li>
	<li>To the cooled solution, add the trimethylsilyl-enolether (1 equiv., 0.313 mol/L) in dry dichloromethane dropwise over 2-10 min (depending on the scale). After the addition of silyl enol ether is complete, the formation of the enolonium species is complete. 
	NOTE: The solution of enolonium species can be left at -78 &#176;C for at least 30 min with no deterioration in yield. The enolonium species is stable during this time as indicated by reported NMR studies6.</li>
</ol>
2. Functionalization of the Enolonium Species
<ol>
	<li>Chlorination with the chloride anion
	<ol>
		<li>To the prepared solution of enolonium species, add benzyl-dimethyl-decylammonium chloride (2.0 equiv., 1.25 mol/L) in dry dichloromethane in a drop wise manner. Add this solution at a rate such that the temperature remains below -55 &#176;C. At the 0.5-2 mmol scale, addition over 5 min is satisfactory.</li>
		<li>Leave the reaction mixture at -78 &#176;C for 5 min.</li>
		<li>Remove the cooling bath and allow the reaction mixture to reach room temperature.</li>
		<li>Leave the reaction at room temperature for 20 min.</li>
		<li>Add water to the reaction mixture (half the volume of dichloromethane used in the preparation of the enolonium species).</li>
		<li>Extract thrice with dichloromethane. Typically, use 2-3 times the reaction volume in each extraction at the 0.5-2 mmol small scale.</li>
		<li>Wash the combined organic layers twice with brine. Typically, use the same volume of brine as the combined reaction volume.</li>
		<li>Dry with anhydrous sodium sulfate for 30 min.</li>
		<li>Filter off the sodium sulfate (e.g., through a Celite plug).</li>
		<li>Remove the solvent on a rotary evaporator at reduced pressure and at 40 &#176;C.</li>
		<li>Purify the crude product by column chromatography on silica gel using hexane and ethyl acetate eluents to afford, after removal of the solvents, the pure corresponding &#945;-azido ketone. 
		Note: At scales of 0.5 mmol to 2 mmol of trimethylsilyl enolate, carry out column chromatography on a glass column of 2 cm diameter using standard silica gel 60 at a height (length) of 15 cm. The volume will need to be varied for other scales.</li>
	</ol>
	</li>
	<li>Azidation with TMS-Azide 
	Caution: Organic-azides in general are explosive and care should be taken in handling and preparing the products. TMS-azide is toxic. Consult MSDS before use.
	<ol>
		<li>To the prepared solution of enolonium species at -78 &#176;C, add neat azidotrimethylsilane (2.5 equiv.) in a dropwise fashion. Add this solution at a rate so that the temperature remains below -55 &#176;C. At the 0.5-2 mmol scale, addition over 2-3 min is satisfactory.</li>
		<li>Stir the reaction mixture for 15 min at -78 &#176;C.</li>
		<li>Heat the reaction mixture to -55 &#176;C and leave at this temperature for 2 to 3 h.</li>
		<li>Add water to the reaction mixture (half the volume of dichloromethane used in the preparation of the enolonium species).</li>
		<li>Extract thrice with dichloromethane. Typically, use 2-3 times the reaction volume in each extraction at the 0.5-2 mmol small scale.</li>
		<li>Wash the combined organic layers twice with brine. Typically, use the same volume of brine as the combined reaction volume.</li>
		<li>Dry the extracts with anhydrous sodium sulfate for 30 min.</li>
		<li>Filter off the sodium sulfate.</li>
		<li>Remove the solvent on a rotary evaporator at reduced pressure and at 40 &#176;C.</li>
		<li>Purify the crude product by column chromatography on silica gel using hexane and ethyl acetate eluents to afford, after removal of the solvents, the pure corresponding &#945;-azido ketone.</li>
	</ol>
	</li>
	<li>Reaction with azoles
	<ol>
		<li>To the prepared solution of enolonium species at -78 &#176;C, add azole (4 to 5 equiv., 1 mol/L) dissolved in 5 mL of dichloromethane in a dropwise fashion. At the 0.5-2 mmol scale, addition over 5 min is satisfactory. 
		Note: In the case of poorly soluble azoles such as tetrazoles, use acetonitrile at a concentration of 0.5 mol/L instead of dichloromethane. Add this solution at a rate so that the temperature remains below -55 &#176;C.</li>
		<li>Stir the reaction mixture for 15 min at -78 &#176;C.</li>
		<li>Heat the reaction mixture to -55 &#176;C and leave at this temperature for 4 to 8 h.</li>
		<li>Add water to the reaction mixture (half the volume of organic solvents used in the preparation of the enolonium species).</li>
		<li>Extract thrice with dichloromethane. Typically, use 2-3 times the reaction volume in each extraction at the 0.5-2 mmol small scale.</li>
		<li>Wash the combined organic layers twice with brine. Typically, use the same volume of brine as the combined reaction volume.</li>
		<li>Dry the extracts with anhydrous sodium sulfate for 30 min.</li>
		<li>Filter off the sodium sulfate.</li>
		<li>Remove the solvent on a rotary evaporator at reduced pressure and at 40 &#176;C.</li>
		<li>Purify the crude product by column chromatography on silica gel using hexane and ethyl acetate eluents to afford, after removal of the solvents, the pure corresponding &#945;-azole ketone.</li>
	</ol>
	</li>
	<li>Allylation, crotylation, cinnamylation, and prenylation using allyl-silanes
	<ol>
		<li>Add neat allyl,-, crotyl-, cinnamyl-, or prenyl-trimethylsilane (2 equiv.) slowly at -78 &#176;C. Add this solution at a rate so that the temperature remains below -55 &#176;C. At a 0.5-2 mmol scale, addition over 2-3 min is satisfactory.</li>
		<li>Stir the reaction mixture for 10 min at -78 &#176;C.</li>
		<li>Allow the reaction mixture to warm slowly to room temperature by removing the cooling bath. Leave the reaction at room temperature for 20 min.</li>
		<li>Add water to the reaction mixture (half the volume of dichloromethane used in the preparation of the enolonium species).</li>
		<li>Extract thrice with dichloromethane. Typically, use 2-3 times the reaction volume in each extraction at the 0.5-2 mmol small scale.</li>
		<li>Wash the combined organic layers twice with brine. Typically, use the same volume of brine as the combined reaction volume.</li>
		<li>Dry the extracts with anhydrous sodium sulfate for 30 min.</li>
		<li>Filter off the sodium sulfate.</li>
		<li>Remove the solvent on a rotary evaporator at reduced pressure and at 40 &#176;C.</li>
		<li>Purify the crude product by column chromatography on silica gel using hexane and ethyl acetate eluents to afford, after removal of the solvents, the pure corresponding &#945;-allyl product.</li>
	</ol>
	</li>
	<li>Arylation 
	Note: For arylation, use 3 equivalents of BF3OEt2 during the preparation of the enolonium species in order to avoid tosylation of the enolonium species as a major side reaction. In general, only 1.6 equivalent of the aromatic substrate is needed. However, if the aromatic substrate is a pyrane, thiophene, or pyrrole, the best results are achieved using 5 equivalents of the aromatic substrate.
	<ol>
		<li>To the solution of prepared enolonium species add a solution of aromatic substrate in dry dichloromethane (1.6 equiv., 0.5 mol/L) in a dropwise manner. Add this solution at a rate so that the temperature remains below -55 &#176;C. At the 0.5-2 mmol scale, addition over 5-10 min is satisfactory.</li>
		<li>After the addition of the aromatic substrate is complete, increase the temperature of the mixture to -55 &#176;C and leave the mixture at this temperature for 20 min.</li>
		<li>Add water to the reaction mixture (half the volume of dichloromethane used in the preparation of the enolonium species).</li>
		<li>Extract thrice with dichloromethane. Typically, use 2-3 times the reaction volume in each extraction at the 0.5-2 mmol small scale.</li>
		<li>Wash the combined organic layers twice with brine. Typically, use the same volume of brine as the combined reaction volume.</li>
		<li>Dry the extracts with anhydrous sodium sulfate for 30 min.</li>
		<li>Filter off the sodium sulfate.</li>
		<li>Remove the solvent on a rotary evaporator at reduced pressure and at 40 &#176;C.</li>
		<li>Purify the crude product by column chromatography on silica gel using hexane and ethyl acetate eluents to afford, after removal of the solvents, the pure corresponding &#945;-arylated ketone.</li>
	</ol>
	</li>
</ol>

<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>

We have nothing to disclose.

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 the protocol by activating and solubilizing the Koser reagent using stoichiometric BF3. Many hypervalent iodine reagents including the Koser reagent have poor solubility in standard organic solvents. The role of the boron trifluoride is thus double. First of all, it augments the reactivity of the Koser reagent by increasing the leaving group ability of one of its ligands, presumably the tosyl group. This ensures fast reaction with the TMS-enolether. Secondly, the activated Koser reagent is highly soluble especially relative to the unactivated Koser reagent. It is essential to check that all of the reagents have dissolved before adding the TMS-enolether. In order to ensure successful reaction, a small excess of reagent is required. The noted protocol uses 1.5 equivalents each of Koser&#39;s reagent and of boron trifluoride. This amount is preferable for first time users. However, the reaction may be carried out equally successfully with as little as 1.2 equivalents of Lewis acid and the hypervalent iodine. We typically carried out the described protocols at 0.5 to 2 mmol scales of trimethylsilyl enolate with no significant variation in the yield, as long as care was taken to follow the procedure accurately.
Another crucial parameter is the slow addition of TMS-enolether to the reaction in order to ensure both a low concentration of TMS-enolether as well as to avoid local warming of the reaction mixture. At the noted scale, addition over 2-10 minutes is usually sufficient; five minutes of addition time is used at the 1 mmol scale. However, if homo-coupling of the ketone enolate is observed, this likely stems from too rapid addition of the TMS-enolether to the activated Koser reagent and longer addition times should be used. For a large-scale reaction, it is preferable to use a pre-cooled solution of TMS-enolether. For &#946;-keto esters, it is not necessary to use a TMS-enolether, and it is not necessary to take any of the addition time and temperature precautions as these enolonium species do not homo couple. In addition, the reaction of &#946;-keto ester is much slower and can therefore be carried out at room temperature. Lithium enolates of &#946;-keto ester may be used to increase the reaction rate. The TMS-enolether of acetone is not a good substrate as homo-coupling for this unhindered compound is very rapid.
The protocol is successful for a wide variety of substituted aryl-alkyl ketones with electron withdrawing, and electron donating substituents alike. The reaction also works for dialkyl ketones. Notably, enolates containing conjugated double bonds are successful substrates in the reaction. However, &#945;,&#945;-disubstituted ketones often fail in the subsequent nucleophilic addition step if the nucleophile is sterically hindered due to competing reaction by the relatively unhindered tosyl anion. &#945;-Tosyloxy ketones are observed as minor byproducts in many reactions.
The prepared solution of enolonium species is stable for at least 30 minutes at &#8722;78 &#176;C. In the second step of the protocol a reactive nucleophile is added. A wide range of nucleophiles are compatible with the enolonium species including nucleophiles that would have reacted with the Koser reagent or the Lewis acid Koser reagent. Thus, both traditional nucleophiles like chloride or azide anion may be used as may easily oxidizable substrates. Notably, allyl-silanes work successfully in the reaction. A second remarkable feature of the reaction with substituted allyl-silanes is the complete regioselectivity with bond formation at the terminal position of the allyl silane. Thus, when prenyl silane is used, as in the described protocol, quaternary centers are formed. Aromatic and heteroaromatic substrates may also be used. Remarkably, nitrogen containing heteroaromatics with more than one nitrogen and with no substituents on the nitrogen react at nitrogen. In contrast, indoles, and pyrroles react exclusively at carbon. The position of attack is as predicted by the reactivity of these substrates in Friedel-Crafts type reactions. These reactions constitute the C-H functionalization reaction and obviate the need for halogenated aromatic substrates as in classical transition metal catalyzed coupling reactions. The scope is limited to electron-rich aromatic compounds: indoles, pyrroles, furans, thiophene, and electron rich benzenes. It is notable that electron-rich aromatic compounds tend to undergo oxidation by the hypervalent iodine, leading to homo-coupling, and other reactions, but not by enolonium species. In most cases, only 1.6 equivalent of the substrate is needed so that more precious materials may be used in the reaction. The excess aromatic substrate may be isolated. Only in the case of unsubstituted pyrroles, thiophenes, and furanes is the use of 5 equivalents recommended.
Thus, this protocol reported here in allows the use of both traditional, inert nucleophiles as well as nucleophiles incompatible with traditional reaction protocols. The list of suitable nucleophiles will certainly continue to expand in the future.

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 containing heterocycles. The scope of the allylation procedure includes both allyl-, crotyl- and prenyl-trimethylsilane6. Only cinnamylation requires slightly different conditions. The use of 3 equivalents of BF3, similarly to the conditions needed for C-arylation, gives optimal results in this case. The C-arylation procedure works for both indoles and electron-rich benzene derivatives. Thiophene, furane and pyrroles are also good substrates, but the products are isolated in slightly lower yields9. We have tested the procedure in a scale from 0.5 mmol to 2 mmol of trimethylsilyl enolate with no significant variation in the yield, as long as care was taken to follow the procedure accurately. At this scale, column chromatography is carried out on a glass column of 2 cm diameter using standard silica gel 60 from different commercial sources at a height (length) of 15 cm. The solvent indicated for TLC is also the solvent used for chromatography.
Examples:
Chlorination (synthesis of 2-chloro-1-phenylethan-1-one). 
The chlorination of 1-phenyl-1-trimethylsiloxyethylene (239 mg, 1.24 mmol) according to the described protocol afforded 2-chloroacetophenone12&#160;(146 mg, 76%) as a colorless solid. The characterization data for the compound were as follows: Rf = 0.4 (1:9 v/v EtOAc/hexane); 1H NMR (400 MHz, CDCl3) &#948; 7.97 (d, J = 7.2 Hz, 2H), 7.61 (t, J = 7.2 Hz, 1H), 7.51 (t, J = 7.2 Hz, 2H), 4.72 (s, 2H); 13C NMR (101 MHz, CDCl3) &#948; 191.2, 134.3, 134.1, 129.0, 128.6, 46.2.
Azidation (synthesis of 2-Azido-1-(4-fluorophenyl)ethan-1-one). 
Azidation of 1-(4-fluorophenyl)vinyl)oxy)trimethylsilane (150 mg, 0.71 mmol) was carried out according to the protocol for azidation to give the product13&#160;(98 mg, 77%) as a white solid. The characterization data for the compound were as follows: Rf = 0.5 (1:20 v/v EtOAc/hexane); 1H NMR (400 MHz, CDCl3) &#948; 8.01 - 7.88 (m, 2H), 7.23 - 7.12 (m, 2H), 4.53 (s, 2H); 13C NMR (101 MHz, CDCl3) &#948; 192.9, 167.5 (d, J = 256.7 Hz), 132.1 (d, J = 3.1 Hz), 131.95 (d, J = 9.5 Hz), 129.7 (d, J = 106.6 Hz), 117.5 (d, J = 22.1 Hz), 56.0.
Addition of azoles (Synthesis of 1-Phenyl-2-(1H-tetrazol-1-yl)ethan-1-one). 
Trimethyl((1-phenylvinyl)oxy)silane (300 mg, 1.56 mmol) was coupled with 1H-tetrazole (4.9 equiv., 17 mL, 0.45 M, 7.65 mmol) as described for addition of tetrazoles to give the product (229 mg,78%) as a white solid. The characterization data for the compound were as follows: Rf = 0.3 (1:1 v/v EtOAc/hexane); mp 122-124 &#176;C; FT-IR: &#1140;max 3141, 2936, 2869, 2115, 1695, 1596, 1449, 1351, 1228, 1173 cm-1; 1H NMR (400 MHz, CDCl3): &#948; 8.86 (s, 1H), 7.99 (dd, J = 8.5, 1.2 Hz, 2H), 7.70 (tt, J = 7.5, 2.9 Hz, 1H), 7.56 (t, J = 7.8 Hz, 2H), 5.98 (s, 2H); 13C NMR (101 MHz, CDCl3): &#948; 189.0, 144.2, 135.2, 133.5, 129.5, 128.3, 53.5; HRMS (ESI+): m/z calcd for C9H9N4O 189.0776 [M+H]+; found 189.0745.
Allylation (synthesis of 3,3-dimethyl-1-phenylpent-4-en-1-one). 
The prenylation of 1-phenyl-1-trimethylsiloxyethylene (99 mg , 0.517 mmol)was carried out according to the protocol to afford the product14&#160;(73 mg, 75% yield) as a colorless oil. The characterization data for the compound were as follows: Rf = 0.3 (1:20 v/v EtOAc/hexane); 1H NMR (400 MHz, CDCl3) 7.84 (d, J = 7.2, 2H), 7.45 (t, J = 7.3, 1H), 7.36 (t, J = 7.6, 2H), 5.94 - 5.84 (m, J = 17.4, 10.7, 1H), 4.92 - 4.81 (m, J = 14.1, 11.6, 0.8, 2H), 2.89 (s, 2H), 1.10 (s, 6H); 13C NMR (101 MHz, CDCl3) 13C NMR (101 MHz, CDCl3) &#948; 199.48, 147.43, 138.37, 132.76, 128.47, 128.25, 110.57, 49.17, 36.73, 27.30.
Arylation (Synthesis of 4-Methoxyphenyl)-2-(2-methyl-1H-indol-3-yl)propan-1-one) 
The synthesis was carried out as described for arylation of 1-(4-methoxyphenyl)prop-1-en-1-yl)oxy)trimethylsilane (200 mg, 0.846 mmol) using 2-methyl-1H-indole (1.5 equivalent) to give the product (205 mg, 83%) as a colorless solid. The characterization data for the compound were as follows: Rf: 0.2 (1:5 v/v, EtOAc/pet. ether); IR (cm-1): 3377, 2967, 1739, 1595, 1458, 1362, 1208, 837; 1H NMR: (400 MHz, CDCl3) &#948; 7.91 (dt, J = 9.1, 2.8 Hz, 2H), 7.80 (br. s., 1H), 7.64 (m, 1H), 7.20 (m, 1H), 7.09 (dt, J = 9.1, 4.1 Hz, 2H), 6.74 (dt, J = 9.1, 2.8 Hz, 2H), 4.76 (q, J = 6.9 Hz, 1H), 3.73 (s, 3H), 2.33 (s, 3H), 1.54 (d, J = 6.9 Hz, 3H). 13C NMR: (101 MHz, CDCl3) &#948; 199.3, 162.9, 135.1, 131.0, 130.5, 129.7, 127.3, 121.1, 119.6, 118.1, 111.6, 111.4, 110.3, 55.2, 38.7, 16.9, 12.0; HRMS (ESI+): m/z calcd for C19H20NO2 294.1494 [M+H]+; found 294.1490.
<img alt="Figure 1" class="xfigimg" src="/files/ftp_upload/57916/57916fig1.jpg" /> 
Figure 1: Representative results showing the yields achievable using the chlorination, azidation, amination with azoles, allylation, and arylation protocols. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/57916/57916fig1large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>

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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. ...

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9.9K Views.  Ariel University. A two step one-pot protocol for the umpolung of ketone enolates to enolonium species and addition of a nucleophile to the α-position is described. Nucleophiles include chloride, azide, azoles, allyl-silanes, and aromatic compounds.

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

Synthesis of Antiviral Tetrahydrocarbazole Derivatives by Photochemical and Acid-catalyzed C-H Functionalization via Intermediate Peroxides (CHIPS)

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Synthesis of Antiviral Tetrahydrocarbazole Derivatives by Photochemical and Acid-catalyzed C-H Functionalization via Intermediate Peroxides CHIPS

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A Protocol for the Production of Gliadin-cyanoacrylate Nanoparticles for Hydrophilic Coating

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

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

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'-O-thiophenylmethyl Modification and Characterization via Circular Dichroism

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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.

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Surface Functionalization of Metal-Organic Frameworks for Improved Moisture Resistance

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Automation of a Positron-emission Tomography PET Radiotracer Synthesis Protocol for Clinical Production

Positron-emission tomography (PET) imaging sites that are involved in multiple early clinical research trials need robust and versatile radiotracer manufacturing capabilities. Using the radiotracer [18F]Clofarabine as an example, we illustrate how to automate the synthesis of a radiotracer using a flexible, cassette-based radiosynthesizer and validate the synthesis for clinical use.

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

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