Name: synthesis and purification of iodoaziridines involving quantitative selection of the optimal stationary phase for chromatography
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Description: Watch this Scientific Journal Video about Synthesis and Purification of Iodoaziridines Involving Quantitative Selection of the Optimal Stationary Phase for Chromatography at JoVE.com

For finansiel støtte, vi takker EPSRC (Career Acceleration Fellowship til JAB, EP/J001538/1) Ramsay Memorial Trust (Research Fellowship 2009-2011 til JAB) og Imperial College London. Tak til professor Alan Armstrong for generøs støtte og rådgivning.

1.. Udarbejdelse af Iodoaziridines med Diiodomethyllithium <ol><li> Flame tørre en 100 ml rundbundet kolbe indeholdende en omrørerstav og forsynet med et septum, under en strøm af argon, og derefter afkøles til stuetemperatur under en argonatmosfære. BEMÆRK: Glas tørret i en ovn natten over (125 ° C) og afkølet til stuetemperatur på en analog måde, er også passende. </li><li> Til kolben tilsættes 5,7 ml vandfrit THF og 2,7 ml vandfrit Et2O via en sprøjte, og frisk destilleret hexameth...

<ol>
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M., Vedejs, E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Metalated+aziridines+for+cross-coupling+with+aryl+and+alkenyl+halides+via+palladium+catalysis.">Metalated aziridines for cross-coupling with aryl and alkenyl halides via palladium catalysis.</a> Org. Lett. 12 (22), 5085-5087 (2010).</li><li>Theddu, N., Vedejs, E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Stille+coupling+of+an+aziridinyl+stannatrane.">Stille coupling of an aziridinyl stannatrane.</a> J. Org. Chem. 78 (10), 5061-5066 (2013).</li><li>Hughes, M., Boultwood, T., Zeppetelli, G., Bull, J. 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A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Highly+cis-selective+synthesis+of+iodo-aziridines+using+diiodomethyllithium+and+in+situ+generated+N-Boc-imines.">Highly cis-selective synthesis of iodo-aziridines using diiodomethyllithium and in situ generated N-Boc-imines.</a> Chem. Commun. 48 (100), 12246-12248 (2012).</li><li>Boultwood, T., Affron, D. P., Trowbridge, A. D., Bull, J. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Synthesis+of+cis-C-iodo-N-tosyl-aziridines+using+diiodomethyllithium:+reaction+optimization,+product+scope+and+stability,+and+a+protocol+for+selection+of+stationary+phase+for+chromatography.">Synthesis of cis-C-iodo-N-tosyl-aziridines using diiodomethyllithium: reaction optimization, product scope and stability, and a protocol for selection of stationary phase for chromatography.</a> J. Org. Chem. 78 (13), 6632-6647 (2013).</li><li>Bull, J. A., Charette, A. B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Improved+procedure+for+the+synthesis+of+gem-diiodoalkanes+by+the+alkylation+of+diiodomethane.+scope+and+limitations.">Improved procedure for the synthesis of gem-diiodoalkanes by the alkylation of diiodomethane. scope and limitations.</a> J. Org. 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En procedure til diastereoselektiv fremstilling af cis - N-Ts-iodoaziridines er beskrevet, sammen med en stabilitet forsøgsprotokollen for kvantitativt at angive den bedste stationære fase til oprensning af potentielt ustabile forbindelser ved flashsøjlekromatografi. Det forudses, at adgangen til iodoaziridines gennem denne tilgang vil gøre det muligt for metoder til at få adgang til en bred vifte af aziridiner der skal udvikles, ved derivatisering af det intakte ringen. <p class="jove_content...

Formålet med denne metode er at forberede iodoaziridines der tilbyder potentiale for yderligere funktionalisering til aziridin derivater. Metoden indeholder en protokol til kvantitativ udvælgelse af den optimale stationære fase til kromatografi. Aziridiner, som tre-leddede ringe, besidder iboende ring stamme, der gør dem vigtige byggesten i organisk kemi 1. De udviser en bred vifte af reaktivitet ofte involverer aziridinring åbning 2,3, især som mellemprodukter i syntesen af funktionaliserede aminer 4,5, eller dannelse af andre nitrogenholdige heterocykliske 6,7. Syntesen af en række aziridin derivater ved funktionalisering af en forløber indeholdende en intakt aziridinring har vist sig som en levedygtig strategi 8. Funktionel gruppe-metal-udveksling, til at generere en aziridinyl anion, og omsætning med elektrofiler har vist sig at være effektive <sup&gt; 9,10,11, og for nylig regio-og stereoselektiv deprotonation af N-beskyttede aziridiner er også opnået 12-15. For ganske nylig, palladium katalyseret krydskoblingsreaktioner metoder til dannelse af aryl aziridiner fra funktionaliserede aziridin forstadier er blevet udviklet af Vedejs 16,17, og selv 18. Kemi heteroatom erstattet aziridiner åbner fascinerende spørgsmål reaktivitet og stabilitet 19.. Vi har været interesseret i udarbejdelse af iodoaziridines som en ny funktionel gruppe, der giver mulighed for at give forløbere for en bred vifte af derivater med komplementær reaktivitet eksisterende aziridin funktionalisering reaktioner. I 2012 rapporterede vi det første fremstillingen af aryl N-BOC-iodoaziridines 20, og for nylig rapporteret til fremstilling af aryl-og alkyl-substitueret N-Ts-iodoaziridines 21. Metoden til at access iodoaziridines bruger diiodomethyllithium, et reagens, der for nylig også været ansat i forberedelsen af diiodoalkanes 22,23, diiodomethylsilanes 22,24, og vinyl jodider 25-27. Den carbenoid-lignende karakter af dette reagens kræver forberedelse og brug ved lave temperaturer 22,28. De teknikker og betingelser, der anvendes til frembringelse af diiodomethyllithium i fremstillingen af ​​iodoaziridines er beskrevet nedenfor. Mens silica har vist sig som det foretrukne materiale til kromatografi 29, det viste sig at være uegnet til rensning af N-TS-iodoaziridines. Silica gel er generelt den første og eneste fastfasemateriale ansat i flashkromatografi i organisk kemi på grund af tilgængelighed og effektive separationer. Den sure karakter af silicagel kan imidlertid forårsage nedbrydning af følsomme substrater under oprensning, hvilket forhindrer isolationen af ​​det ønskede materiale. Mens andre stationary faser eller modificerede silicageler er tilgængelige for kromatografi 30, var der ingen måde at vurdere foreneligheden af målmolekylet for disse forskellige materialer. På grund af den følsomme karakter af de iodoaziridines, vi etableret en protokol til at vurdere stabiliteten af en forbindelse til en række stationære faser 21, hvilket påvises her. Dette har potentiale til anvendelse i syntesen af ​​en lang række forbindelser med følsomme funktionelle grupper. Følgende protokol giver effektiv adgang til N-Ts iodoaziridines, så diastereoselektiv syntese af både alkyl-og aromatiske cis-iodoaziridines i højt udbytte.

<table border="0" cellpadding="0" cellspacing="0" width="871">
	<tbody>
		<tr height="42">
			<td height="42" style="height:42px;width:209px;">Hexamethyldisilazane</td>
			<td style="width:273px;">999-97-3</td>
			<td style="width:197px;">Alfa Aesar</td>
			<td style="width:192px;">Distill from KOH under argon prior to use.</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:209px;">n-Butyllithium</td>
			<td style="width:273px;">109-72-8</td>
			<td style="width:197px;">Sigma Aldrich</td>
			<td style="width:192px;">2.5 M in hexanes, titrate prior to use.</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:209px;">Diiodomethane</td>
			<td style="width:273px;">75-11-6</td>
			<td style="width:197px;">Alfa Aesar</td>
			<td style="width:192px;">Contains copper as a stabilizer.</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:209px;">1,3,5-Trimethoxybenzene</td>
			<td style="width:273px;">621-23-8</td>
			<td style="width:197px;">Sigma Aldrich</td>
			<td style="width:192px;"></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:209px;">Silica</td>
			<td style="width:273px;">112945-52-5</td>
			<td style="width:197px;">Merck</td>
			<td style="width:192px;"></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:209px;">Basic alumina</td>
			<td style="width:273px;">1344-28-1</td>
			<td style="width:197px;">Sigma Aldrich</td>
			<td style="width:192px;"></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:209px;">Neutral alumina</td>
			<td style="width:273px;">1344-28-1</td>
			<td style="width:197px;">Merck</td>
			<td style="width:192px;"></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:209px;">Florisil</td>
			<td style="width:273px;">1343-88-0</td>
			<td style="width:197px;">Sigma Aldrich</td>
			<td style="width:192px;"></td>
		</tr>
		<tr height="22">
			<td height="22" style="height:23px;width:209px;">THF</td>
			<td colspan="3" rowspan="3" style="width:663px;">All anhydrous solvents were dried through activated alumina purification columns.&#160;</td>
		</tr>
		<tr height="25">
			<td height="25" style="height:25px;width:209px;">Et2O</td>
		</tr>
		<tr height="25">
			<td height="25" style="height:25px;width:209px;">CH2Cl2</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">NMR spectrometer</td>
			<td>Bruker AV 400&#160;</td>
			<td>n/a</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:209px;">NMR processing software</td>
			<td>MestReNova&#160;</td>
			<td>7.0.2-8636</td>
			<td></td>
		</tr>
	</tbody>
</table>

synthesis and purification of iodoaziridines involving quantitative selection of the optimal stationary phase for chromatography

Den meget diastereoselektiv fremstilling af cis - N-Ts-iodoaziridines ved reaktion af diiodomethyllithium med N-Ts aldiminer beskrevet. Diiodomethyllithium fremstilles ved deprotonering af diiodmethan med LiHMDS i en THF / diethylether blanding ved -78 ° C i mørke. Disse betingelser er afgørende for stabiliteten i Lichi 2 reagens genereres. Den efterfølgende dråbevis tilsætning af N-Ts aldiminer til den præformede diiodomethyllithium løsning giver en amino-diiodide mellemprodukt, der ikke isoleres. Hurtige opvarmning af reaktionsblandingen til 0 ° C fremmer ringdannelse til opnåelse iodoaziridines med eksklusive cis-diastereoselektivitet. Tilsætningen og ringslutningsprocedurer stadier af reaktionen medieres i en reaktionskolbe ved omhyggelig temperaturkontrol. På grund af følsomheden af ​​de iodoaziridines rensning, vurdering af egnede metoder til purification er påkrævet. En protokol til at vurdere stabiliteten af ​​følsomme forbindelser til stationære faser for søjlekromatografi beskrives. Denne metode er egnet til at gælde for nye iodoaziridines eller andre potentielt følsomme nye forbindelser. Derfor kan denne metode finde anvendelse inden for rækkevidde af syntetiske projekter. Denne procedure indebærer første vurderingen af reaktionsudbyttet før oprensning ved 1H NMR-spektroskopi med sammenligning med en intern standard. Dele af urent produkt blanding udsættes derefter for opslæmninger af forskellige stationære faser egnede til kromatografi, i et opløsningsmiddel, der er egnet som eluent flash kromatografi. Efter omrøring i 30 min for at efterligne kromatografi, efterfulgt af filtrering, prøverne analyseres ved 1H NMR-spektroskopi. Beregnede udbytter for hver stationær fase sammenlignes derefter, der oprindeligt stammer fra den rå reaktionsblanding. De opnåede resultater giver en kvantitativ vurdering af than stabilitet af forbindelsen til de forskellige stationære faser; dermed kan vælges optimalt. Valget af basisk alumina modificeret til aktivitet IV, som en egnet stationær fase har tilladt isolation af visse iodoaziridines i fremragende udbytte og renhed.

Den beskrevne procedure giver cis - (±)-2-iod-3-(4-tolyl) -1 - (4-tolylsulfonyl) aziridin som en enkelt diastereoisomer og med fremragende renhed (figur 1). Før oprensning blev et udbytte på 59% af iodoaziridine produkt beregnes ved 1H NMR-spektroskopi. Men denne iodoaziridine var særligt udfordrende at rense og gennemgik en betydelig nedbrydning på silica. Oprensning på basisk aluminiumoxid (aktivitet IV) som bestemt ved den stationære skærm fase tilladt at produktet kan iso...

Watch this Scientific Journal Video about Synthesis and Purification of Iodoaziridines Involving Quantitative Selection of the Optimal Stationary Phase for Chromatography at JoVE.com

Synthesis and Purification of Iodoaziridines Involving Quantitative Selection of the Optimal Stationary Phase for Chromatography

Syntese og oprensning af Iodoaziridines Inddragelse kvantitativ udvælgelse af det optimale stationære fase til kromatografi

En protokol til diastereoselektiv forberedelse af cis one-pot - N-TS-iodoaziridines beskrives. Den generation af diiodomethyllithium, tilføjelse til N-Ts aldiminer og ringslutning af amino perle-diiodide mellemliggende til iodoaziridines demonstreres. Også inkluderet er en protokol til hurtigt og kvantitativt vurdere den mest hensigtsmæssige stationære fase til oprensning ved kromatografi.

The highly diastereoselective preparation of cis-N-Ts-iodoaziridines through reaction of diiodomethyllithium with N-Ts aldimines is described. ...

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