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

Et starttilskud fra Ariel Universitet og en ISF individuelle forskning tilskud (1914/15) til AMS er taknemmeligt anerkendt.

1. forberedelse af Enolonium arter
Forsigtig: Før du gennemfører protokollen, konsultere sikkerhedsdatablade for alle reagenser og opløsningsmidler.
Bemærk: Alle nye reagenser blev brugt som modtaget fra kommercielle kilde. Hvis boron trifluoride etherate er blevet gemt, destillere det før brug.
<ol><li>I en tør runde rundbundet kolbe forsynet med en septum og en magnet for magnetisk omrøring, tilsæt Kosers reagens (1,5 ækvivalent) og skyl kolben med nitr...

<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>

Vellykket forberedelse af enolonium arter fra TMS-enolater er afhængig af en række faktorer. Den store side reaktion taktfast forberedelse er homo kobling af råvaren ved reaktion af et molekyle dannet enolonium arter med et molekyle af TMS-enolate. Kravet om reaktionsbetingelser er således, at undgå denne dimerization ved at sikre hurtig reaktion Lewis syre aktiveret hypervalente jod reagens med tilføjet TMS-enolate i forhold til antallet af dimerization. Dette opnås i protokollen ved at aktivere og solubilizing d...

Enolater er klassisk carbon nukleofiler i organisk kemi og blandt de mest udbredte. Umpolung af enolater til at oprette elektrofil enolonium arter giver værdifulde alternative måder at producere α-functionalized ketoner samt aktivere roman reaktioner ikke muligt via klassisk enolate kemi. Enolonium arter er blevet foreslået som mellemprodukter i talrige reaktioner i særlige reaktioner der involverer hypervalente jod reagenser. Disse reaktioner omfatter α-halogenation, iltning og undersøgelsesområde1 samt andre reaktioner2,3,4,5.
Områder af disse reaktioner var dog altid begrænset af den forbigående karakter af reaktive enolonium arter. Denne transiency krævede nogen nukleofil at være til stede i reaktionsblandingen under reaktionen af carbonyl enolater med stærkt oxiderende hypervalente jod reagens. Således kunne enhver nukleofil udsat for oxidation, som elektron rige aromatiske forbindelser (heterocycles) og alkener, ikke anvendes.
I det sidste år, har vi overvinde disse begrænsninger ved at udvikle betingelser, hvor enolonium arter er dannet som en diskret mellemprodukt i ét trin efterfulgt af tilsætning af nukleofil i et andet trin. Denne protokol tillader ikke kun den klassiske type af functionalization såsom chlorering6, men også anvendelsen af oxiderbare carbon nukleofiler, såsom allylsilanes6,8, enolater1,6, 7, og elektron rige aromatiske forbindelser9, hvilket resulterer i C-C bond dannelse. Metoden allylation er indstillet til dannelsen af Kvartære og tertiære Centre. Keton arylation metode udgør formel C-H functionalization af aromatiske sammensatte uden behov for en ledelse gruppe9. For nylig, har vi rapporteret tilsætning af azoles og azider10 som godt11. Detaljeret præsentation af protokollen forventes at hjælpe i indførelsen af disse metoder i den daglige værktøjskasse af de syntetiske organiske kemiker.

<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

Α-Functionalization af ketoner via umpolung af enolater af hypervalente jod reagenser er et vigtigt begreb i syntetisk organisk kemi. For nylig, har vi udviklet en to-trins strategi for keton enolate umpolung, der har aktiveret udviklingen af metoder til chlorering, azidation og undersøgelsesområde ved hjælp af azoles. Derudover har vi udviklet C-C bond – danner arylation og allylation reaktioner. Kernen i disse metoder er forberedelsen af den mellemliggende og meget reaktive enolonium arter inden tilsætning af en reaktiv nukleofil. Denne strategi er dermed minder om forberedelse og brug af metal enolater i klassisk syntetisk kemi. Denne strategi tillader brug af nukleofiler, der ellers ville være uforenelig med stærkt oxiderende hypervalente jod reagenser. I dette papir, vi præsenterer en detaljeret protokol til chlorering, azidation, N-heteroarylation, arylation og allylation. Produkterne omfatter motiver fremherskende i medicinsk aktive produkter. Denne artikel vil i høj grad hjælpe andre i at bruge disse metoder.

Repræsentative resultater, opnået efter protokollen, er anført i figur 1 og er beskrevet i afsnittet diskussion. Navnlig, kan et meget stort udvalg af forskellige ketoner anvendes med succes i reaktionen til at give produkterne i gode udbytter, som det kan ses for azidation11. Omfanget af reaktion for at indføre azoles i α-position af ketoner omfatter de fleste af de fælles mono-cyklisk og bicykliske nitrogen indeholdende heteroc...

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

En to-trins one-pot protokol for umpolung af keton enolater enolonium arter og tilsætning af en nukleofil til α-position er beskrevet. Nukleofiler omfatter chlorid, indeholder, azoles, allylisothiocyanat-silaner og aromatiske forbindelser.

En to-trins protokol til Umpolung Functionalization af ketoner Via Enolonium arter

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

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