Name: a two-step protocol for umpolung functionalization of ketones via enolonium species
Uploaded: 2018-08-16T13:30:00.000+00:00
Duration: 8 min 12 s
Description: Watch this Scientific Journal Video about A Two-Step Protocol for Umpolung Functionalization of Ketones Via Enolonium Species at JoVE.com

アリエル大学と ISF 個別研究助成から創業助成金 (1914/15) AMS には感謝して承諾します。

1 Enolonium 種の準備
警告: プロトコルを実行する前に、すべての試薬、溶剤の MSDS をご相談します。
注: すべての新しい試薬は、商業ソースから受け取ったとして使用されました。ホウ素三フッ化 etherate が格納されている場合は、使用する前に蒸留します。
<ol><li>丸底フラスコ電磁攪拌用隔壁と磁石装備乾燥 Koser の試薬を追加 (1.5 当量)、窒素またはアルゴンとフラスコをフラッシュします。</li>
	<li>0.234 mol/L の正式な濃度の懸濁液を与える乾燥ジクロロ メタンを追加します。</li>
	<li>-78 ° c ドライアイス/アセトン浴または冷たい指楽器/アセトン浴を使用して懸濁液を冷却します。</li>
	<li>きちんとした BF3OEt2を追加 (1.5 当量) ゆっくりと。</li>
	<li>黄色の溶液を形成するまで部屋の温度に異種混合物を温めます。通常、これは 5 分以内に発生します。</li>
	<li>クール-78 ° C への解決策</li>
	<li>冷却ソリューションに追加トリメチルシリル enolether (1 当量、0.313 mol/L) 乾燥ジクロロ メタンの滴 (規模) に応じて 2 10 分以上。シリル エノール エーテル添加が完了すると、enolonium 種の形成が完了します。 注: enolonium 種のソリューションは-78 ° c 少なくとも 30 分収率で劣化させることがなく左ことができます。Enolonium 種は報告された NMR 研究6で示されるようにこの時間の間に安定しました。</li>
</ol>2. Enolonium 種の機能化
<ol><li>塩化物の陰イオンと塩素化
	<ol>
<li>Enolonium 種の調製した溶液、塩化ベンジル-ジメチル-decylammonium を追加 (2.0 当量、1.25 mol/L) ドロップ賢明な方法で乾燥ジクロロ メタン。-55 ° C 以下温度のままそのレートでこのソリューションを追加します。0.5 - 2 モルのスケール、また 5 分以上は満足。</li>
		<li>5 分間-78 ° C で反応混合物を残します。</li>
		<li>冷却槽を取り外して、部屋の温度に達するまで反応混合物を許可します。</li>
		<li>20 分間室温で反応を残します。</li>
		<li>(ジクロロ メタン enolonium 種の準備で使用されるの半分の量) 反応混合物に水を追加します。</li>
		<li>三度ジクロロ メタンで抽出します。通常、0.5-2 各抽出で 2-3 回反応体積を使用モル小規模。</li>
		<li>塩水で 2 回した有機層を洗ってください。通常、複合反応ボリュームとして塩水の同じボリュームを使用します。</li>
		<li>30 分間、無水硫酸ナトリウムで乾燥。</li>
		<li>(例えば、セライト プラグ) を硫酸ナトリウムをフィルター処理します。</li>
		<li>ロータリーエバポレーター 40 ° C、減圧下での溶媒を除去します。</li>
		<li>ヘキサン及び酢酸エチルの溶離液を使用して、溶剤を除去した後、純粋な対応する α アジドフェニル ケトンを余裕するシリカゲル カラムクロマトグラフィーにより粗製品を浄化します。 注: のトリメチルシリル エノラートの 2 モルに 0.5 モルのスケールで、15 cm の高さ (長さ) で標準的なシリカゲル 60 を使用して直径 2 cm のガラスカラムにカラム ・ クロマトグラフィを実行します。ボリュームは、他のスケールの内容を変更する必要があります。</li>
	</ol></li>
	<li>TMS アジとアジド 注意: 有機アザイド一般に爆発は、処理と製品を準備する。TMS アジは有毒であります。使用前に MSDS を参照してください。<ol>
<li>-78 ° c の enolonium 種の準備のソリューションにきちんとした azidotrimethylsilane を追加 (2.5 当量) 滴下方式で。-55 ° C 以下の温度のまま、速度でこのソリューションを追加します。0.5 - 2 モルのスケール、加えて 2-3 分以上は満足。</li>
		<li>-78 ° C で 15 分間反応混合物をかき混ぜる</li>
		<li>-55 ° C に反応混合物を熱し、2 に 3 時間この温度で残します。</li>
		<li>(ジクロロ メタン enolonium 種の準備で使用されるの半分の量) 反応混合物に水を追加します。</li>
		<li>三度ジクロロ メタンで抽出します。通常、0.5-2 各抽出で 2-3 回反応体積を使用モル小規模。</li>
		<li>塩水で 2 回した有機層を洗ってください。通常、複合反応ボリュームとして塩水の同じボリュームを使用します。</li>
		<li>30 分間、無水硫酸ナトリウムで抽出物を乾燥させます。</li>
		<li>硫酸ナトリウムをフィルター処理します。</li>
		<li>ロータリーエバポレーター 40 ° C、減圧下での溶媒を除去します。</li>
		<li>ヘキサン及び酢酸エチルの溶離液を使用して、溶剤を除去した後、純粋な対応する α アジドフェニル ケトンを余裕するシリカゲル カラムクロマトグラフィーにより粗製品を浄化します。</li>
	</ol></li>
	<li>アゾールとの反応
	<ol>
<li>-78 ° c の enolonium 種の調製した溶液、アゾール系を追加 (4 に 5 当量, 1 mol/L) 滴ファッションにジクロロ メタン 5 mL に溶解しました。0.5 - 2 モルのスケール、また 5 分以上は満足。 注: テトラゾール系化合物など難溶性アゾールの場合に、ジクロロ メタンの代わりに 0.5 mol/L の濃度でアセトニ トリルを使用します。-55 ° C 以下の温度のまま、速度でこのソリューションを追加します。</li>
		<li>-78 ° C で 15 分間反応混合物をかき混ぜる</li>
		<li>-55 ° C に反応混合物を熱し、4 に 8 時間この温度で残します。</li>
		<li>(Enolonium 種の準備で使用される有機溶剤の半分の量) 反応混合物に水を追加します。</li>
		<li>三度ジクロロ メタンで抽出します。通常、0.5-2 各抽出で 2-3 回反応体積を使用モル小規模。</li>
		<li>塩水で 2 回した有機層を洗ってください。通常、複合反応ボリュームとして塩水の同じボリュームを使用します。</li>
		<li>30 分間、無水硫酸ナトリウムで抽出物を乾燥させます。</li>
		<li>硫酸ナトリウムをフィルター処理します。</li>
		<li>ロータリーエバポレーター 40 ° C、減圧下での溶媒を除去します。</li>
		<li>ヘキサン及び酢酸エチルの溶離液を使用して、溶剤を除去した後、純粋な対応する α-アゾール系ケトンを余裕するシリカゲル カラムクロマトグラフィーにより粗製品を浄化します。</li>
	</ol></li>
	<li>アリル化、crotylation、cinnamylation、およびプレニル化アリル シランを使用して
	<ol>
<li>きちんとしたアリル、クロチル、シンナミル、追加またはプレニル トリメチルシラン (2 当量)-78 ° C でゆっくりと-55 ° C 以下の温度のまま、速度でこのソリューションを追加します。0.5 - 2 モルのスケール、加えて 2-3 分以上は満足。</li>
		<li>-78 ° C で 10 分間反応混合物をかき混ぜる</li>
		<li>ゆっくりと室温に冷却槽を外して暖かいに反応混合物を許可します。20 分間室温で反応を残します。</li>
		<li>(ジクロロ メタン enolonium 種の準備で使用されるの半分の量) 反応混合物に水を追加します。</li>
		<li>三度ジクロロ メタンで抽出します。通常、0.5-2 各抽出で 2-3 回反応体積を使用モル小規模。</li>
		<li>塩水で 2 回した有機層を洗ってください。通常、複合反応ボリュームとして塩水の同じボリュームを使用します。</li>
		<li>30 分間、無水硫酸ナトリウムで抽出物を乾燥させます。</li>
		<li>硫酸ナトリウムをフィルター処理します。</li>
		<li>ロータリーエバポレーター 40 ° C、減圧下での溶媒を除去します。</li>
		<li>ヘキサン及び酢酸エチルの溶離液を使用して、溶剤を除去した後、純粋な対応する α-アリル製品を買う余裕するシリカゲル カラムクロマトグラフィーにより粗製品を浄化します。</li>
	</ol></li>
	<li>Arylation メモ: arylation、使用して BF3OEt2等価な 3 enolonium 種の準備の間に主要な側面の反作用として enolonium 種の tosylation を避けるために。一般に、芳香族基質のみ 1.6 相当が必要です。ただし、芳香族基質、pyrane、チオフェン、またはピロール、最良の結果を芳香族基質の 5 の同等を使用して達成されています。<ol>
<li>準備された enolonium の溶液に種は乾燥ジクロロ メタン芳香族基質のソリューションを追加 (1.6 当量、0.5 mol/L) 滴下方法で。-55 ° C 以下の温度のまま、速度でこのソリューションを追加します。0.5 - 2 モル スケール添加 5-10 分以上は満足。</li>
		<li>芳香族基質の添加が完了後、-55 ° C への混合物の温度を上げるし、20 分間この温度で混合物を残します。</li>
		<li>(ジクロロ メタン enolonium 種の準備で使用されるの半分の量) 反応混合物に水を追加します。</li>
		<li>三度ジクロロ メタンで抽出します。通常、0.5-2 各抽出で 2-3 回反応体積を使用モル小規模。</li>
		<li>塩水で 2 回した有機層を洗ってください。通常、複合反応ボリュームとして塩水の同じボリュームを使用します。</li>
		<li>30 分間、無水硫酸ナトリウムで抽出物を乾燥させます。</li>
		<li>硫酸ナトリウムをフィルター処理します。</li>
		<li>ロータリーエバポレーター 40 ° C、減圧下での溶媒を除去します。</li>
		<li>ヘキサン及び酢酸エチルの溶離液を使用して、溶剤を除去した後、純粋な対応する α-arylated のケトンを余裕するシリカゲル カラムクロマトグラフィーにより粗製品を浄化します。</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>

何を開示する必要があります。

TMS レート産 enolonium 種の成功の準備はいくつかの要因に依存しています。準備の手順で主要な側の反応は、TMS エノラートの分子で形成された enolonium 種の分子との反応によって原料のホモ結合です。したがって、反応条件の要件は二量体化の率を基準にして追加された TMS エノラートとルイス酸活性化超原子価ヨウ素試薬の高速反応させるこの二量化を避けるためです。これはアクティブに?...

レートは、古典的な炭素求核試薬有機化学の中で最も広く使用されています。求 enolonium 種を作成するレートの極性転換では、貴重な方法 α 修飾ケトンを生成するし、古典的なエノラート化学経由で可能ではない新規反応を有効にすることができます。Enolonium 種は、超原子価ヨウ素試薬を含む特定の反応における多くの反応中間体として提案されています。これらの反応は、他の反応の2,の3,4,の5と同様に、α-ハロゲン化、酸素化、アミノ化1に含まれます。
しかし、これらの反応の範囲常に反応 enolonium 種の過渡的な性質によって制限されていました。このさせますは、強く酸化超原子価ヨウ素試薬カルボニル レートの反応反応混合物内に存在する任意の求核剤を必要な。したがって、電子豊富な芳香族化合物 (複素環化合物) など、アルケンの酸化しやすい、求核剤が使用しません。
最後の年に我々 は、enolonium 種は 2 番目のステップで求核剤の付加によって続いて 1 つのステップの離散中間体として形成される条件を開発することによりこれらの制限を克服しています。このプロトコルにより、塩素処理6などの機能化の古典的なタイプだけでなく、アリルシラン6,8レート1,6など、酸化炭素求核試薬の使用 7および電子豊富な芳香族化合物9炭素-炭素結合形成反応の結果します。アリル化方法は、第四紀と第三紀のセンターの形成に影響を受けやすいです。ケトンの arylation メソッドは、芳香族誘導グループ9を必要とせず化合物の正式な C H 官能基化を構成します。最近では、我々 はよく11としてアゾールとアザイド10の追加を報告しています。プロトコルの詳細なプレゼンテーションは、合成有機化学者の日常ツール ボックスへのこれらの方法の導入を支援する予定です。

<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

超原子価ヨウ素試薬によるレートの極性転換によるケトンの α 化、有機合成化学で重要な概念です。最近では、ケトンのエノラート極性転換アゾールを使用してアミノ化、アジド、塩素処理法の開発を有効にしているため 2 段階戦略を開発しました。さらに、炭素-炭素結合-形成 arylation とアリル化反応を開発しました。これらのメソッドの中心に反応求核剤の付加の前に中間と高反応性 enolonium 種の準備です。この戦略は準備および古典的な合成化学金属レートの使用を連想させるためです。この戦略は、そうでなければ互換性がありません強く酸化超原子価ヨウ素試薬を用いる求核試薬の使用をできます。本稿では塩素、アジド、N heteroarylation、arylation、およびアリル化のための詳しいプロトコルを提案する.製品は、薬効製品で普及しているモチーフです。この記事はこれらのメソッドを使用して他の人を容易になります。

代表的な成果、次のプロトコルは、図 1に与えられているし、ディスカッション セクションで論議されます。特に、異なるケトンの非常に大きい範囲が正常に使用する反応のアジド11の見られるかもしれないように、良好な収率で、製品を提供します。ケトンの α 位のアゾールを導入するための反応の範囲には、ほとんど一般?...

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

Enolonium 種にケトン レートの極性転換と α-位へ求核剤の付加のための 2 つのステップ ワンポット プロトコル、説明します。求核剤には、芳香族化合物、アリル シラン、アゾール アジ化塩化物が含まれます。

Enolonium 種によるケトン類の極性転換を高機能化 2 段階のプロトコル

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

a-two-step-protocol-for-umpolung-functionalization-ketones-via

Universidad San Sebastian

Research

Education

JoVE Core

JoVE Journal

Organic Chemistry

Chemistry

Unit 1

Aldehydes and Ketones

SCIENTISTS IN ACTION

9.9K ビュー.  Ariel University. Enolonium 種にケトン レートの極性転換と α-位へ求核剤の付加のための 2 つのステップ ワンポット プロトコル、説明します。求核剤には、芳香族化合物、アリル シラン、アゾール アジ化塩化物が含まれます。

ビデオ: 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.

官能化 Monoorganozinc 臭化物の共役添加による全炭素4級センターの効率的な合成

The conjugate addition of organometallic reagents to &#945;,&#946;-unsaturated carbonyls represents an important method to generate C&#8211;C bonds in the ...

化学

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.

多彩なCO2の複雑な製品への変革:ワンポット2段階戦略

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.

遷移金属触媒を用いたケトンのマイクロ波アシスト直接ヘテロリル化

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.

エノールの反応性

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 ...

有機化学

ユニット １

α-炭素の化学: エノール、エノラート、エナミン

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>

エノラートイオンの反応性

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.

エノラートの位置選択的形成

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 &#945;-hydrogen with a halogen, acid-catalyzed &#945;-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 &#945;-hydrogen to form an enol tautomer. The C=C bond in an enol is highly nucleophilic because of the electron-donating nature of the &#8211;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 &#945;-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 &#945;-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 &#945;-halogenation at the more substituted carbon by the preferential formation of a thermodynamic enol. As shown below, the acid-catalyzed &#945;-halogenation reaction also works well to convert ketones to &#945;,&beta;&#8210;unsaturated ketones via E2 elimination reactions forming a new &#960; bond.
<img alt="Figure1" src="/files/ftp_upload/12382/12382_PT_Figure_1.svg" style="text-align: center; height: 110px;" />

Acid-Catalyzed &amp;#945;-Halogenation of Aldehydes and Ketones

酸触媒によるアルデヒドおよびケトンのα-ハロゲン化反応

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 &#946;-hydroxy ketone undergoes dehydration via an E1 elimination reaction to form an enone.
<img alt="Figure1" src="/files/ftp_upload/13063/13063-PT_Figure1.svg" style="text-align: center; height: 85px;" />
Figure 1. The dehydration reaction of a &#946;-hydroxy ketone.
Figure 2 depicts the sequential processes involved in the mechanism of the reaction. Here, the acid protonates the hydroxyl group in the &#946;-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 &alpha; carbon yields an enone as the final product.
<img alt="Figure2" src="/files/ftp_upload/13063/13063-PT_Figure2.svg" style="text-align: center; height: 95px;" />
Figure 2. The mechanism of the dehydration reaction of a &#946;-hydroxy ketone.

アルドールからエノンへの脱水:酸触媒アルドール縮合

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 &alpha; carbon to form a C=C bond in the enamine. This differs from the last step of imine formation, where the N&#8211;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&#8212;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&rsquo;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="Figure1" src="/files/ftp_upload/13216/13216_Figure_1.svg" style="text-align: center; height: 275px;" />

アルデヒドとケトンとアミン:エナミン形成機構

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

アルデヒドとケトン

&alpha;-Alkylation of Ketones via Enolate Ions

Ketones with &alpha; 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-&NoBreak;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.

Enolonium 種によるケトン類の極性転換を高機能化 2 段階のプロトコル

要約

さらに動画を探す

この動画の章