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

一项由爱丽大学提供的创业补助金和一份独立研究补助金 (1914/15) 给 AMS 的致谢。

1. Enolonium 种的制备
注意: 在执行该协议之前, 请查阅所有试剂和溶剂的 MSDS。
注: 所有新试剂均使用从商业来源收到。如果已经储存了三氟化硼乙醚, 在使用前先蒸馏。
<ol><li>在一个干燥的圆底烧瓶, 装有隔膜和磁铁搅拌, 添加科泽的试剂 (1.5 equiv), 并冲洗瓶与氮气或氩气。</li>
	<li>添加干二氯甲烷, 使悬浮0.234 摩尔/L 正式浓度。</li>
	<li>使用干冰/丙酮浴或?...

<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>

从 TMS-enolates 成功地制备 enolonium 物种取决于许多因素。在制备步骤中的主要副反应是由形成的 enolonium 分子与烯醇负离子分子的反应产生的起始材料的人偶联。因此, 反应条件的要求是避免这种二聚化通过确保快速反应的刘易斯酸活化高价碘试剂与增加 TMS 烯醇负离子相对于二聚化率。这是在协议中通过活化和溶解科泽试剂使用化学计量 BF3。许多高价碘试剂包括科泽试剂在标准有机溶剂中...

Enolates 是经典的碳亲核试剂在有机化学和其中最广泛使用。极性转换 enolates 创造亲 enolonium 物种允许有价值的替代方法, 以产生α功能性酮, 并使新的反应不可能通过经典的烯醇负离子化学。Enolonium 种在许多反应中被建议为中间体, 特别是涉及高价碘试剂的反应。这些反应包括α卤化, 氧合和胺化1以及其他反应2,3,4,5。
然而, 这些反应的范围总是受到反应 enolonium 物种瞬态性质的限制。这顷刻要求在反应混合物中存在任何亲核试剂在羰基 enolates 反应期间与强氧化高价碘试剂。因此, 任何亲核试剂易氧化, 如电子丰富的芳香化合物 (杂环化合物) 和烯烃, 不能使用。
在过去的一年里, 我们通过发展条件来克服这些限制, enolonium 物种在一个步骤中形成一个离散的中间, 然后在第二步加入亲核试剂。该协议不仅允许经典类型的功能化, 如氯化6, 而且使用氧化碳亲核试剂, 如 allylsilanes6,8, enolates1,6, 7、和电子丰富的芳香化合物9, 导致碳-碳键形成。烯丙基方法适合于第四纪和第三纪中心的形成。酮 arylation 法构成芳香化合物的正式 C H 功能化, 不需要指导组9。最近, 我们报告增加了唑类药物和叠氮化合物10以及11。该议定书的详细表述可望有助于将这些方法引入合成有机化学家的日常工具箱中。

<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

高价碘试剂 enolates 极性转换酮的α功能化是合成有机化学的一个重要概念。最近, 我们已经制定了两个步骤的战略, 酮烯醇负离子极性转换, 这使得发展的方法, 氯化, azidation 和胺化使用唑类药物。此外, 我们还开发了 c-bond–forming arylation 和烯丙基反应。这些方法的核心是在添加反应性亲核试剂之前制备中间和高活性 enolonium 种。这一策略使人联想到在古典合成化学中金属 enolates 的制备和使用。这种策略允许使用亲核试剂, 否则将与强烈氧化高价碘试剂不相容。本文提出了氯化、azidation、n-heteroarylation、arylation 和烯丙基的详细协议。产品包括在药用活性产品中流行的图案。本文将极大地帮助其他人使用这些方法。

图 1给出了根据该议定书取得的代表性成果, 并在讨论部分进行了讨论。值得注意的是, 很大范围的不同的酮可以成功地用于反应, 使产品的良好的产量, 可以看到的 azidation11。在酮α位置引入唑类药物反应的范围包括大多数常见的单循环和笼含杂环化合物氮。烯丙基过程的范围包括烯丙基、crotyl 和梨醇-trimethylsilane6?...

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

本文介绍了极性转换酮 enolates 到 enolonium 种的两步单锅协议, 并对α位亲核试剂的添加进行了描述。亲核试剂包括氯、叠氮化物、唑类药物、烯丙基烷和芳香化合物。

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

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