Name: a two-step protocol for umpolung functionalization of ketones via enolonium species
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Bir start-up hibe Ariel Üniversitesi ve ISF bireysel araştırma bursu (1914/15) için AMS minnetle kabul edilmektedir.

1. Enolonium türler hazırlanması
Dikkat: Protokolü gerçekleştirmeden önce MSDS tüm reaktifler ve solventler için başvurun.
Not: Tüm yeni reaktifler ticari kaynağından alınmış olarak kullanılmıştır. Bor trifluoride etherate depolanmış olsa, kullanmadan önce damıtmak.
<ol><li>Kaynatıp şişesi bir septum ve bir mıknatıs manyetik karıştırma için donatılmış yuvarlak kuru, Koser'ın reaktif ekleyin (1.5 eşdeğeri) ve azot veya argon şişeye boşalt.</li>
	<li>Bir süspansiyon konsantrasyon 0,234 mol/L resmi vermek kuru diklorometan ekleyin.</li>
	<li>-78 ° c Kuru buz/aseton banyo veya soğuk parmak enstrüman/aseton banyo kullanarak süspansiyon ne yapıyorsun?</li>
	<li>Temiz BF3OEt2 ekleyin (1.5 eşdeğeri) yavaş yavaş.</li>
	<li>Oda sıcaklığında heterojen karışım sarı çözüm oluşumuna kadar sıcak. Genel olarak, bu 5 dk içinde gerçekleşir.</li>
	<li>Çözüm-78 ° C'ye serin</li>
	<li>Soğutmalı, trimethylsilyl-enolether ekleyin (1 eşdeğeri, 0.313 mol/L) içinde kuru diklorometan dropwise üzerinde 2-10 dk (bağlı olarak ölçek). Silyl enol eter eklenmesi tamamlandıktan sonra enolonium türlerin oluşumu tamamlanmış olur. Not: Enolonium tür çözüm için en az 30 dk-78 ° C'de verim hiçbir bozulma ile bırakılabilir. Enolonium türler bildirilen NMR çalışmalar6tarafından belirtildiği gibi bu süre boyunca stabildir.</li>
</ol>2. functionalization Enolonium türlerin
<ol><li>Klorlama ile klorür anyon
	<ol>
<li>Hazır enolonium türlerin, Benzil-dimetil-decylammonium klorür ekleyin (2.0 eşdeğeri, 1,25 mol/L) bir damla bilge şekilde Kuru diklorometan içinde. Sıcaklığı-55 ° c altında kalır bir oranda bu çözüm eklemek 0,5-2 mmol ölçek, ek 5 dk tatmin edici olduğunu.</li>
		<li>-78 ° c 5 min için tepki karışımı bırak.</li>
		<li>Soğutma banyo kaldırmak ve oda sıcaklığında ulaşmak tepki karışım izin verin.</li>
		<li>Reaksiyon, oda sıcaklığında 20 dakika bırakın.</li>
		<li>Su (yarım ses düzeyini enolonium türler hazırlanmasında kullanılan diklorometan) tepki karışıma ekleyin.</li>
		<li>Üç kez diklorometan ile ayıklayın. Genellikle, her ayıklama 0,5-2 2 - 3 kez tepki birim kullanılır mmol küçük ölçekli.</li>
		<li>Kombine organik katmanları iki kez tuzlu su ile yıkayın. Genellikle, aynı tuzlu su hacmi kombine tepki birim olarak kullanılır.</li>
		<li>30 dk için susuz sodyum sülfat ile kuru.</li>
		<li>Sodyum sülfat (örneğin, üzerinden bir CELITE fiş) kapalı filtre.</li>
		<li>Düşük basınçta ve 40 ° C'de rotary Evaporatör üzerinde çözücü kaldırmak</li>
		<li>Sütun Kromatografi silika jel, çözücüler, çıkarıldıktan sonra saf karşılık gelen α-azido keton göze hekzan ve etil asetat eluents kullanarak tarih tarafından ham ürün arındırmak. Not: Standart silika jel 60 bir yükseklikte 15 cm (uzunluk) kullanarak 2 cm çapında bir cam sütunu sütun Kromatografi için trimethylsilyl enolate 2 mmol 0.5 mmol ölçeklerde yürütmek. Birimin diğer ölçekler için çeşitli olabilir gerekir.</li>
	</ol></li>
	<li>TMS-azid ile Azidation Dikkat: Organik azides genel olarak patlayıcı ve işleme ve ürünleri hazırlama özen gösterilmelidir. TMS-azid zehirlidir. MSDS kullanmadan önce danışın.<ol>
<li>Hazır-78 ° C'de enolonium türlerin, düzgün azidotrimethylsilane ekleyin (2.5 eşdeğeri) dropwise bir moda. Sıcaklığı-55 ° c altında kalır bir oranda bu çözüm eklemek 0,5-2 mmol ölçek, ek 2-3 dk tatmin edici olduğunu.</li>
		<li>-78 ° C'de 15 dakika tepki karışımı heyecan</li>
		<li>Reaksiyon karışımı-55 ° c ısı ve 2-3 h için bu sıcaklıkta bırakın.</li>
		<li>Su (yarım ses düzeyini enolonium türler hazırlanmasında kullanılan diklorometan) tepki karışıma ekleyin.</li>
		<li>Üç kez diklorometan ile ayıklayın. Genellikle, her ayıklama 0,5-2 2 - 3 kez tepki birim kullanılır mmol küçük ölçekli.</li>
		<li>Kombine organik katmanları iki kez tuzlu su ile yıkayın. Genellikle, aynı tuzlu su hacmi kombine tepki birim olarak kullanılır.</li>
		<li>Özleri 30 dk için susuz sodyum sülfat ile kuru.</li>
		<li>Sodyum sülfat filtre.</li>
		<li>Düşük basınçta ve 40 ° C'de rotary Evaporatör üzerinde çözücü kaldırmak</li>
		<li>Sütun Kromatografi silika jel, çözücüler, çıkarıldıktan sonra saf karşılık gelen α-azido keton göze hekzan ve etil asetat eluents kullanarak tarih tarafından ham ürün arındırmak.</li>
	</ol></li>
	<li>Azoles ile reaksiyonu
	<ol>
<li>Hazır-78 ° C'de enolonium türlerin, azole ekleyin (4-5 eşdeğeri, 1 mol/L) 5 ml diklorometan bir dropwise moda çözünmüş. 0,5-2 mmol ölçek, ek 5 dk tatmin edici olduğunu. Not: 0,5 mol/L diklorometan yerine bir konsantrasyon, Asetonitril tetrazoles gibi kötü çözünür azoles söz konusu olduğunda kullanın. Sıcaklığı-55 ° c altında kalır bir oranda bu çözüm eklemek</li>
		<li>-78 ° C'de 15 dakika tepki karışımı heyecan</li>
		<li>Reaksiyon karışımı-55 ° c ısı ve 4-8 h için bu sıcaklıkta bırakın.</li>
		<li>Su (yarım ses düzeyini enolonium türler hazırlanmasında kullanılan organik çözücüler) tepki karışıma ekleyin.</li>
		<li>Üç kez diklorometan ile ayıklayın. Genellikle, her ayıklama 0,5-2 2 - 3 kez tepki birim kullanılır mmol küçük ölçekli.</li>
		<li>Kombine organik katmanları iki kez tuzlu su ile yıkayın. Genellikle, aynı tuzlu su hacmi kombine tepki birim olarak kullanılır.</li>
		<li>Özleri 30 dk için susuz sodyum sülfat ile kuru.</li>
		<li>Sodyum sülfat filtre.</li>
		<li>Düşük basınçta ve 40 ° C'de rotary Evaporatör üzerinde çözücü kaldırmak</li>
		<li>Sütun Kromatografi silika jel, çözücüler, çıkarıldıktan sonra saf karşılık gelen α-azole keton göze hekzan ve etil asetat eluents kullanarak tarih tarafından ham ürün arındırmak.</li>
	</ol></li>
	<li>Allylation, crotylation, cinnamylation ve prenilasyon allil-silanes kullanarak
	<ol>
<li>Ekle düzgün alil,-, crotyl-, cinnamyl, veya prenyl-trimethylsilane (2 eşdeğeri)-78 ° C'de yavaş yavaş Sıcaklığı-55 ° c altında kalır bir oranda bu çözüm eklemek 0,5-2 mmol ölçek, ek 2-3 dk tatmin edici olduğunu.</li>
		<li>-78 ° C'de 10 dakika tepki karışımı heyecan</li>
		<li>Soğutma banyo kaldırarak oda sıcaklığına kadar yavaş yavaş ısıtmak tepki karışım izin verin. Reaksiyon, oda sıcaklığında 20 dakika bırakın.</li>
		<li>Su (yarım ses düzeyini enolonium türler hazırlanmasında kullanılan diklorometan) tepki karışıma ekleyin.</li>
		<li>Üç kez diklorometan ile ayıklayın. Genellikle, her ayıklama 0,5-2 2 - 3 kez tepki birim kullanılır mmol küçük ölçekli.</li>
		<li>Kombine organik katmanları iki kez tuzlu su ile yıkayın. Genellikle, aynı tuzlu su hacmi kombine tepki birim olarak kullanılır.</li>
		<li>Özleri 30 dk için susuz sodyum sülfat ile kuru.</li>
		<li>Sodyum sülfat filtre.</li>
		<li>Düşük basınçta ve 40 ° C'de rotary Evaporatör üzerinde çözücü kaldırmak</li>
		<li>Sütun Kromatografi silika jel, çözücüler, çıkarıldıktan sonra saf karşılık gelen α-allil ürün göze hekzan ve etil asetat eluents kullanarak tarih tarafından ham ürün arındırmak.</li>
	</ol></li>
	<li>Arylation Not: arylation için bir büyük yan tepki olarak enolonium türlerin tosylation önlemek için enolonium türler hazırlanması sırasında BF3OEt2 3 eşdeğerleri kullanın. Genel olarak, sadece 1,6 aromatik substrat denk gereklidir. Ancak, aromatik substrat pyrane, tiyofen veya pyrrole ise, en iyi sonuçları 5 aromatik substrat karşılıkları kullanılarak elde edilir.<ol>
<li>Hazır enolonium, türler aromatik substrat çözeltisi içinde kuru diklorometan ekleyin (1.6 eşdeğeri, 0,5 mol/L) dropwise bir şekilde. Sıcaklığı-55 ° c altında kalır bir oranda bu çözüm eklemek 0,5-2 mmol ölçek, ek 5-10 dk tatmin edici olduğunu.</li>
		<li>Aromatik substrat ilavesi tamamlandıktan sonra karışımı-55 ° c sıcaklık artışı ve 20 dk için bu sıcaklıkta karışımı bırak.</li>
		<li>Su (yarım ses düzeyini enolonium türler hazırlanmasında kullanılan diklorometan) tepki karışıma ekleyin.</li>
		<li>Üç kez diklorometan ile ayıklayın. Genellikle, her ayıklama 0,5-2 2 - 3 kez tepki birim kullanılır mmol küçük ölçekli.</li>
		<li>Kombine organik katmanları iki kez tuzlu su ile yıkayın. Genellikle, aynı tuzlu su hacmi kombine tepki birim olarak kullanılır.</li>
		<li>Özleri 30 dk için susuz sodyum sülfat ile kuru.</li>
		<li>Sodyum sülfat filtre.</li>
		<li>Düşük basınçta ve 40 ° C'de rotary Evaporatör üzerinde çözücü kaldırmak</li>
		<li>Sütun Kromatografi silika jel, çözücüler, çıkarıldıktan sonra saf karşılık gelen α-arylated keton göze hekzan ve etil asetat eluents kullanarak tarih tarafından ham ürün arındırmak.</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>

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TMS-enolates enolonium tür başarılı hazırlanması bir dizi faktöre bağlıdır. Homo kaplin tarafından kurulan enolonium tür bir molekül molekül TMS-enolate ile reaksiyon başlangıç malzemenin hazırlık adımda büyük yan tepkidir. Böylece, reaksiyon koşulları gereği bu dimerization Lewis asit harekete geçirmek hypervalent iyot reaktif ile eklenen TMS-enolate dimerization oranı göreli olarak hızlı reaksiyon sağlayarak kaçınmaktır. Bu protokol etkinleştirme ve stokiometrik BF3kullana...

Enolates klasik karbon nucleophiles organik kimya ve arasında en çok kullanılan vardır. Umpolung enolates, electrophilic enolonium türler oluşturmak için α-functionalized Ketonlar üretmek için yanı sıra roman reaksiyonlar klasik enolate Kimya mümkün değil etkinleştirmek için değerli alternatif yollar sağlar. Enolonium türler belirli tepkiler hypervalent iyot reaktifler içeren çok sayıda reaksiyonlarda ara ürün olarak önerilmiştir. Bu tepkiler α-halogenation, oksijen ve amination1 yanı sıra diğer tepkiler2,3,4,5içerir.
Ancak, bu tepkiler kapsamını her zaman reaktif enolonium tür geçici doğası gereği antlaşmasına neredeyse uygundu. Bu transiency herhangi bir nucleophile karbonil enolates şiddetle oksitleyici hypervalent iyot reaktif ile reaksiyon sırasında reaksiyon karışımı bulunması gerekli. Böylece, herhangi bir nucleophile elektron zengin aromatik bileşikler (heterocycles) ve alkenes, gibi oksidasyon eğilimli kullanılamadı.
Geçen yıl, biz hangi enolonium türler olarak ikinci adımda nucleophile ilavesi ve ardından tek adımda ayrı bir orta olarak kurulan koşulları geliştirerek bu sınırlamalar üstesinden geldiler. Bu iletişim kuralı sadece functionalization klorlama6gibi klasik türünü, aynı zamanda allylsilanes6,8, enolates1,6gibi oxidizable karbon nucleophiles kullanımı sağlar, 7ve elektron zengin aromatik bileşikler9C-C bağı oluşumu sonucu,. Allylation, Kuvaterner ve üçüncül merkezler oluşumuna müsait bir yöntemdir. Keton arylation yöntemi resmi C-H functionalization aromatik bileşik bir yönetmenlik grup9için gerek kalmadan, kabul ettiğiniz anlamına gelir. Son zamanlarda, azoles ve azides10 ek olarak iyi11bildirdin. Detaylı tanıtım iletişim kuralı bu yöntemleri giriş sentetik organik kimyacı günlük araç kutusu içine yardımcı bekleniyor.

<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

Α-Functionalization yolu ile umpolung enolates tarafından hypervalent iyot reaktifler, ketonlar, Sentetik Organik Kimyada önemli bir kavramdır. Son zamanlarda, klorlama, azidation ve azoles kullanarak amination Yöntem geliştirme sağladı keton enolate umpolung için iki aşamalı bir strateji geliştirdik. Buna ek olarak, C-C bağ-şekillendirme arylation ve allylation reaksiyonlar geliştirdik. Bu yöntemler kalbinde bir reaktif nucleophile eklenmesi önce Orta ve büyük ölçüde reaktif enolonium türlerin hazırlıktır. Bu strateji böylece hazırlık ve klasik sentetik Kimya metal enolates kullanımı anımsatır. Bu strateji Aksi durumda kuvvetle oksitleyici hypervalent iyot reaktifleri ile uyumsuz olacak nucleophiles kullanımına izin verir. Bu yazıda biz klorlama, azidation, N-heteroarylation, arylation ve allylation için detaylı bir iletişim kuralı mevcut. Motifler medicinally aktif ürünler, yaygın olarak karşılaşılan bazı ürünler; Bu makalede büyük ölçüde bu yöntemleri kullanarak diğerleri yardımcı olacaktır.

Protokol sonrası elde temsilcisi sonuçları Şekil 1 ' de verilen ve tartışma bölümünde ele alınmıştır. Özellikle, çok sayıda farklı Ketonlar başarılı bir şekilde tepki ürünleri iyi verimleri için azidation11görülebilir olarak vermek için kullanılabilir. Azoles konumundaki α-Ketonlar tanıtmak için tepki kapsamı heterocycles içeren ortak mono döngüsel ve bicyclic azot çoğunu içerir. Allylation yordam ...

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

Keton enolates enolonium türler umpolung ve bir nucleophile α-konuma eklenmesi için iki adım bir pot protokolü tanımlanır. Nucleophiles klorür, azid, azoles, allil-silanes ve aromatik bileşikler bulunmaktadır.

Ketonlar ile Enolonium türler Umpolung Functionalization için bir iki adım iletişim kuralı

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

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Aldehydes and Ketones

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9.9K Görüntüleme.  Ariel University. Keton enolates enolonium türler umpolung ve bir nucleophile α-konuma eklenmesi için iki adım bir pot protokolü tanımlanır. Nucleophiles klorür, azid, azoles, allil-silanes ve aromatik bileşikler bulunmaktadır.

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.

Fonksiyonel Monoorganozinc Bromides Conjugate Ilavesi ile tüm karbon Dörernary merkezlerinin verimli sentezi

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

Kimya

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.

Çok Yönlü CO2 Karmaşık Ürünlere Dönüşümler: Tek potlu İki Aşamalı Strateji

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.

Geçiş Metal Kataliz Kullanarak Ketonların Mikrodalga Destekli Doğrudan Heteroarylasyon

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.

Enollerin reaktivitesi

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 ...

Organik Kimya

α - Karbon Kimyası: Enoller, Enolatlar ve Enaminler

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>

Enolat İyonlarının Reaktivitesi

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.

Enolatların Bölgesel Seçici Oluşumu

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

Aldehitlerin ve ketonların asit katalizli α-halojenasyonu

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.

Aldollerin Enonlara Dehidrasyonu: Asit Katalizli Aldol Yoğunlaşması

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;" />

Aminli Aldehitler ve Ketonlar: Enamin Oluşum Mekanizması

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

Aldehitler ve Ketonlar

&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.

Ketonlar ile Enolonium türler Umpolung Functionalization için bir iki adım iletişim kuralı

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