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/pubmed?term=((Flexible+stereoselective+functionalizations+of+ketones+through+umpolung+with+hypervalent+iodine+reagents%5BTitle%5D)+AND+%22Angewandte+Chemie+International+Edition%22%5BJournal%5D)">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/pubmed?term=((Advances+in+synthetic+applications+of+hypervalent+iodine+compounds%5BTitle%5D)+AND+%22Chemical+Reviews%22%5BJournal%5D)">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://scholar.google.com/scholar?hl=en&safe=off&q=author%3aZhdankin%2C+VV+%22Hypervalent+Iodine+Chemistry%3A+Preparation%2C+Structure%2C+and+Synthetic+Applications+of+Polyvalent+Iodine+Compounds%22">Hypervalent Iodine Chemistry: Preparation, Structure, and Synthetic Applications of Polyvalent Iodine Compounds</a>. , Wiley. (2013).</li>
<li>Wirth, T. <a target="_blank" href="http://scholar.google.com/scholar?hl=en&safe=off&q=author%3aWirth%2C+T+%22Topics+in+Current+Chemistry%22">Topics in Current Chemistry</a>. 373, Springer International Publishing. (2016).</li>
<li>Merritt, E. A., Olofsson, B. <a target="_blank" href="https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0030-1258328">α-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="https://onlinelibrary.wiley.com/doi/full/10.1002/anie.201610274">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/pubmed?term=((Cross-Coupling+of+Dissimilar+Ketone+Enolates+via+Enolonium+Species+to+afford+Nonsymmetrical+1%2C4-Diketones%5BTitle%5D)+AND+%22Beilstein+Journal+of+Organic+Chemistry%22%5BJournal%5D)">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="https://pubs.acs.org/doi/abs/10.1021/jo00272a028">Carbon-carbon bond formation in reactions of PhIO·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/pubmed?term=((Transition-metal-free+intermolecular+%CE%B1-arylation+of+ketones+via+enolonium+species%5BTitle%5D)+AND+%22Organic+Letters%22%5BJournal%5D)">Transition-metal-free intermolecular α-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/pubmed?term=((Azidation+of+%CE%B2-keto+esters+and+silyl+enol+ethers+with+a+benziodoxole+reagent%5BTitle%5D)+AND+%22Organic+Letters%22%5BJournal%5D)">Azidation of β-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/pubmed?term=((%CE%B1-N-Heteroarylation+and+%CE%B1-azidation+of+ketones+via+enolonium+species%5BTitle%5D)+AND+%22Journal+of+Organic+Chemistry%22%5BJournal%5D)">α-N-Heteroarylation and α-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/pubmed?term=((Gold-catalyzed+hydration+of+haloalkynes+to+%CE%B1-halomethyl+ketones%5BTitle%5D)+AND+%22Journal+of+Organic+Chemistry%22%5BJournal%5D)">Gold-catalyzed hydration of haloalkynes to α-halomethyl ketones.</a> Journal of Organic Chemistry. 78 (18), 9190-9195 (2013).</li>
<li>Patonay, T., Juhász-Tóth, É, Bényei, A. <a target="_blank" href="https://onlinelibrary.wiley.com/doi/abs/10.1002/1099-0690%2820021%292002%3A2%3C285%3A%3AAID-EJOC285%3E3.0.CO%3B2-J">Base-induced coupling of α-azido ketones with aldehydes − 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/pubmed?term=((Rhodium-catalyzed+chemo-+and+regioselective+decarboxylative+addition+of+%CE%B2-ketoacids+to+allenes%3A+Efficient+construction+of+tertiary+and+quaternary+carbon+Centers%5BTitle%5D)+AND+%22Journal+of+the+American+Chemical+Society%22%5BJournal%5D)">Rhodium-catalyzed chemo- and regioselective decarboxylative addition of β-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 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&#039;s reagent</td></tr><tr><td>Acetophenone, &gt;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. ...

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9.9K Views.  Ariel University. Een twee stap één-pot-protocol voor de umpolung van keton enolaten enolonium soorten en toevoeging van een nucleofiel naar de α-positie wordt beschreven. Nucleofiel omvatten chloride, azide azoles, allyl-silanes en aromatische verbindingen.

Video: 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

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 ...

Versatile CO2 Transformations into Complex Products: A One-pot Two-step Strategy

CO2 transformations using a one-pot two-step method are presented herein. The purpose of the method is to give access to a variety of value-added products and notably to generate chiral carbon centers. The crucial first step consists in the selective double hydroboration of CO2 catalyzed by an iron hydride complex. The product obtained with this 4 e- reduction is a rare bis(boryl)acetal, compound 1, which is subjected in situ to three different reactions in a second step. The first reaction concerns a condensation reaction with (diisopropyl)phenylamine affording the corresponding imine 2. In the second and third reaction, intermediate 1 reacts with triazol-5-ylidene (Enders&#39; carbene) to afford compounds 3 or 4, depending on the reaction conditions. In both compounds, C-C bonds are formed, and chiral centers are generated from CO2 as the only source of carbon. Compound 4 exhibits two chiral centers obtained in a diastereoselective manner in a formose-type mechanism. We proved that the remaining boryl fragment plays a key role in this unprecedented stereocontrol. The interest of the method stands on the reactive and versatile nature of 1, giving rise to various complex molecules from a single intermediate. The complexity of a two-step method is compensated by the overall short reaction time (2 h for the larger reaction time), and mild reaction conditions (25 &#176;C to 80 &#176;C and 1 to 3 atm of CO2).

Versatile CO2 Transformations into Complex Products: A One-pot Two-step Strategy

CO2 transformations are conducted in a one-pot two-step procedure for the synthesis of complex molecules. The selective 4 e- reduction of CO2 with a hydroborane reductant affords a reactive and versatile bis(boryl)acetal intermediate which is subsequently involved in condensation reaction or carbene-mediated C-C coupling generation.

CO2 transformations using a one-pot two-step method are presented herein. The purpose of the method is to give access to a variety of value-added products ...

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.

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 ...

Reactivity of Enols

Enols are a class of compounds where a hydroxyl group is attached to a carbon&#8211;carbon double bond, which implies that it is a vinyl alcohol. A carbonyl compound with an &#945; hydrogen undergoes keto&#8211;enol tautomerism and remains in equilibrium with its tautomer, the enol form. Usually, the keto tautomer is present in a higher concentration than the enol tautomer due to the higher bond energy of C=O compared to C=C. Moreover, the direction of the keto&#8211;enol equilibrium is governed by factors like conjugation, intramolecular hydrogen bonding, and aromatic energy. Recall that tautomers are constitutional isomers with distinct atomic arrangements, while resonance forms are different representations of one molecule. This tautomerization is reversibly catalyzed by both acids and bases involving protonation and deprotonation steps. While protonation precedes deprotonation in presence of an acid leading to enols, the reverse order is followed in base-catalyzed enolization that yields enolates.
Enols are electron-rich and hence nucleophilic in nature, like other compounds containing carbon&#8211;carbon double bonds. Due to the strong electron-donating resonance effect of the hydroxyl group, a second resonance structure of the enol can be drawn where the negative charge is on the &#945; carbon. Consequently, this carbon atom is especially nucleophilic and reacts with electrophiles (E+) to form a new C&#8211;E bond. Loss of a proton in the next step leads to a neutral product. The net result amounts to the substitution of hydrogen by an electrophile on the &#945; carbon. Therefore, carbonyl compounds are halogenated at the &#945; position by halogens, such as bromine, in both acidic and basic solutions. This results in the formation of different products under various reaction conditions.
When a carbonyl compound with at least one &#945; hydrogen is dissolved in D2O, to which DCl or NaOD are added, the &#945; hydrogens are gradually replaced by deuterium (D) atoms via enol formation. If this carbonyl compound is chiral owing to a stereogenic center at the &#945; carbon, its chirality is destroyed by rapid interconversion between keto and enol forms through a planar, achiral enol intermediate. The spontaneous racemization prevents the synthesis of chiral &#42933;-keto esters whose only stereogenic center lies in between the two keto groups.

Enols are a class of compounds where a hydroxyl group is attached to a carbon&#8211;carbon double bond, which implies that it is a vinyl alcohol. A ...

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

KEY TERMS AND CONCEPTS

Reactivity of Enolate Ions

Enolate ions are formed by the acid&#8211;base reaction of a carbonyl compound with a base. This leads to deprotonation of the &alpha; hydrogen atom, leading to a resonance-stabilized enolate ion where one of the contributing structures is an oxyanion, which imparts additional stability. Therefore, the proton on the &alpha; carbon is more acidic in nature than that of other sp3-hybridized C&#8211;H bonds but less acidic than those in O&#8211;H bonds where the negative charge in the conjugate base is localized on the oxygen atom. This is reflected in their trend of pKa values. For example, acetic acid, ethanol, acetone, 1-propene, and ethane have pKa values of 4.8, 16, 19.2, 43, and 50, respectively.
The enolate ion is an example of an ambident nucleophile&#8212;i.e., a nucleophile with two reactive sites. The contributing structures of enolate ions show that both carbon and oxygen atoms can bear the negative charge. Hence, the enolate ion is the conjugate base of both keto and enol forms. In theory, it can react with a particular electrophile to form two different products by bond formation at the two different sites. However, an enolate ion usually reacts at the carbon end, as this is more nucleophilic than the oxygen site.
As enolate ions are Br&#248;nsted bases, they react with Br&#248;nsted acids, like protons. This leads to hydrogen exchange at the &alpha; position of carbonyl compounds with that of solvent, leading to isotope exchange in the presence of D2O and an aqueous base. An optically active aldehyde or ketone undergoes racemization if there is an asymmetric &alpha; carbon in the molecule. The loss in stereogenicity owes to the formation of an achiral enolate intermediate where all three atoms are trigonal planar due to sp2 hybridization and conjugation through p-orbital overlap. Since the pKa of an &alpha; hydrogen is very high in the case of esters, the various consequences of enolate ion formation is observed specifically for aldehydes and ketones.
Enolate ions also react as Lewis bases, where they act as nucleophiles. Therefore, they can undergo two types of reaction leading to the formation of new bonds at the &alpha; carbon:
<ol>
	<li>Substitution reactions with electrophiles to yield halogenated and alkylated products with molecular halogen (X2) in the presence of an acid or base and an alkyl halide (RX) or sulfonate ester (RSO3&#8722;), respectively.</li>
	<li>Addition reactions with carbonyl groups at the electrophilic carbon center followed by nucleophilic acyl substitution reactions depending on the structure of the carbonyl group.</li>
</ol>

Enolate ions are formed by the acid&#8211;base reaction of a carbonyl compound with a base. This leads to deprotonation of the &alpha; hydrogen atom, ...

Regioselective Formation of Enolates

As depicted in the figure below, the unsymmetrical ketones can form two possible enolates:&#160; less substituted or more substituted enolates. Usually, the thermodynamic enolates are formed from the more substituted &#945;-carbon atom, while the kinetic enolates are formed faster by deprotonation from the less substituted position. The thermodynamic enolates have lower energy, so they are&#160; more stable. But the energy required to form kinetic enolates is less.
<img alt="Figure1" src="/files/ftp_upload/12381/12381_PT_Figure_1.svg" style="text-align: center; height: 172px;" />
This regioselectivity in enolate formation is essentially an acid-base reaction and is controlled by various factors such as solvent, base, cation, and temperature. Protic solvents and weaker bases favor the formation of thermodynamic enolates, while aprotic solvents and stronger bases favor the kinetic enolates. Thermodynamic enolates are formed at higher temperatures and have longer reaction times because of the higher energy barrier. On the other hand, kinetic enolates are formed at lower temperatures with short reaction times. The conditions favoring thermodynamic enolates encourage a reversible reaction which is not the case with conditions involved for kinetic enolates intermediate.

As depicted in the figure below, the unsymmetrical ketones can form two possible enolates:&#160; less substituted or more substituted enolates. Usually, ...

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

By replacing an α-hydrogen with a halogen, acid-catalyzed α-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 α-hydrogen to form an enol tautomer. The C=C bond in an enol is highly nucleophilic because of the electron-donating nature of the –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 α-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 α-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 α-halogenation at the more substituted carbon by the preferential formation of a thermodynamic enol. As shown below, the acid-catalyzed α-halogenation reaction also works well to convert ketones to α,β‒unsaturated ketones via E2 elimination reactions forming a new π bond.
<img alt="Cyclohexanone to 2-cyclohexenone synthesis, equations, chemical process diagram, organic chemistry." src="/files/ftp_upload/12382/12382_PT_Figure_1.svg" style="text-align: center; height: 110px;" data-altupdatedat="1747908711000" data-alt="Figure1">

Acid-Catalyzed &#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 ...

Dehydration of Aldols to Enones: Acid-Catalyzed Aldol Condensation

As shown in Figure 1, under acidic conditions, the β-hydroxy ketone undergoes dehydration via an E1 elimination reaction to form an enone.
<img alt="Organic reaction mechanism, dehydration of alcohol to ketone, formula with HCl and H2O." src="/files/ftp_upload/13063/13063-PT_Figure1.svg" style="text-align: center; height: 85px;" data-altupdatedat="1747908711000" data-alt="Figure1">
Figure 1. The dehydration reaction of a β-hydroxy ketone.
Figure 2 depicts the sequential processes involved in the mechanism of the reaction. Here, the acid protonates the hydroxyl group in the β-hydroxy ketone to form a hydrated hydroxyl group, which then departs to form a tertiary carbocation intermediate. Subsequently, the loss of the hydrogen atom from the α carbon yields an enone as the final product.
<img alt="Ketone formation via alcohol dehydration; chemical reaction diagramc; acid-catalyzed mechanism." src="/files/ftp_upload/13063/13063-PT_Figure2.svg" style="text-align: center; height: 95px;" data-altupdatedat="1747908711000" data-alt="Figure2">
Figure 2. The mechanism of the dehydration reaction of a β-hydroxy ketone.

As shown in Figure 1, under acidic conditions, the &#946;-hydroxy ketone undergoes dehydration via an E1 elimination reaction to form an enone.

Figure 1. ...

Aldehydes and Ketones with Amines: Enamine Formation Mechanism

Enamine formation involves the addition of carbonyl compounds to a secondary amine through a series of reactions. The mechanism begins with the generation of carbinolamine, a nucleophilic attack followed by several proton transfer reactions. The hydroxyl group of the carbinolamine is converted into water to make a better leaving group that can push the reaction forward by eliminating a water molecule. In enamine formation, the last step involves the abstraction of a proton from the α carbon to form a C=C bond in the enamine. This differs from the last step of imine formation, where the N–H proton was abstracted to give the imine.
Enamines are formed under mildly acidic conditions. A pH of 4.5 is ideal for the reaction.
If the pH is low or the solution is too acidic, the reaction slows down in the first step—when the lone pair on the nitrogen atom of the amine attacks the carbonyl carbon of the substrate. A low pH indicates a high concentration of the protonated form of amine. The protonated amine cannot function as a nucleophile, slowing down this step’s rate.
If the pH is high or the solution is too basic, the fourth step of the reaction mechanism is affected. This is when the hydroxyl group of the carbinolamine is protonated to generate the leaving group, water. Highly basic conditions inhibit the process of water elimination by making the protonated amine, the proton donor in this step, less available for the reaction.
<img alt="Amide hydrolysis mechanism; chemical reaction diagram illustrating the step-by-step process." src="/files/ftp_upload/13216/13216_Figure_1.svg" style="text-align: center; height: 275px;" data-altupdatedat="1747908711000" data-alt="Figure1">

Enamine formation involves the addition of carbonyl compounds to a secondary amine through a series of reactions. The mechanism begins with the generation ...

&alpha;-Alkylation of Ketones via Enolate Ions

Ketones with &#945; protons are deprotonated by strong bases like lithium diisopropylamide (LDA) to form enolate ions. The anion is stabilized by resonance, and its hybrid structure exhibits negative charges on the carbonyl oxygen and the &#945; carbon. This ambident nucleophile can attack an electrophile via two possible sites: the carbonyl oxygen, known as O-attack, or the &#945;&nbsp;carbon, known as C-attack. The nucleophilic attack via the carbanionic site is preferred. This is due to the strong interaction of the positive counterpart of the base with the anionic oxygen, which restricts the approaching electrophile, making the reaction less favorable. Also, the product obtained through C-attack is more stable than that obtained through O-attack, as the stronger C=O &#960; bond is retained in the former, whereas a weaker C=C &#960; bond is preserved in the latter.
A subsequent reaction of the enolate with electrophiles such as alkyl halides produces an &#945;-alkylated ketone via the SN2 pathway. The &#945;-alkylation of ketones is achieved with the halides of primary alkyl, benzyl, and allylic groups. With secondary and tertiary alkyl halides, elimination predominates over substitution.

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

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