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

아리엘 대학과 ISF 개별 연구 보조금에서 시작 그랜트 (1914/15) AMS를 기꺼이 인정 된다.

1입니다. Enolonium 종 준비
주의: 프로토콜을 수행 하기 전에 모든 시 약 및 용 매에 대 한 MSDS를 참조.
참고: 상용 소스 로부터 받은 모든 새로운 시 약 사용 되었다. 붕 소 trifluoride etherate를 저장 하는 경우 사용 하기 전에 그것을 증 류.
<ol><li>둥근 바닥된 플라스 크는 심장 및 자석 마그네틱 감동에 대 한 장비 건조, 추가 Koser의 시 약 (1.5 equiv.) 질소 또는 아르곤 플라스 크를 플러시.</li>
	<li>0.234 mol/L 공식 농도의 현 탁 액을 주고 건조 dichloromethane을 추가 합니다.</li>
	<li>쿨 드라이 아이스/아세톤 목욕 또는 차가운 손가락 악기/아세톤 목욕을 사용 하 여-78 ° C에 서 스 펜 션.</li>
	<li>깔끔한 BF3OEt2 추가 (1.5 equiv.) 천천히.</li>
	<li>노란 솔루션의 형성까지 실내 온도에 다른 유형의 혼합물을 따뜻한. 일반적으로,이 5 분 이내 발생합니다.</li>
	<li>-78 ° c 솔루션 쿨</li>
	<li>냉각된 솔루션에 추가 trimethylsilyl enolether (1 equiv., 0.313 mol/L)에서 건조 dichloromethane dropwise (규모)에 따라 2-10 분 이상. Silyl enol 에테르의 추가 완료 한 후 enolonium 종 형성 완료 됩니다. 참고: enolonium 종의 솔루션 수 있습니다 남아 있을 적어도 30 분 동안-78 ° C에 수확량에 더 악화. Enolonium 종 보고 NMR 연구6에 표시 된 대로이 시간 동안 안정적입니다.</li>
</ol>2입니다. Enolonium 종의 기능화
<ol><li>염화 염화 물 음이온과
	<ol>
<li>Enolonium 종 준비 솔루션, 염화 비닐 벤 질 디 메 틸 decylammonium 추가 (2.0 equiv., 1.25 mol/L) 건조 dichloromethane 드롭 현명한 방식에서에. -55 ° c 온도 유지 되도록이 솔루션에 추가 0.5-2 mmol 규모 또한 5 분 이상 만족입니다.</li>
		<li>5 분 동안-78 ° C에서 반응 혼합물을 남겨 주세요.</li>
		<li>냉각 목욕을 제거 하 고 실내 온도 도달 하는 반응 혼합물을 허용.</li>
		<li>20 분 동안 실 온에서 반응을 남겨 주세요.</li>
		<li>반응 혼합물 (enolonium 종의 준비에 사용 되는 dichloromethane의 절반 볼륨)에 물을 추가 합니다.</li>
		<li>Dichloromethane을 몇 번이 고 압축을 풉니다. 일반적으로 2-3 시간 반응 볼륨을 사용 하 여 0.5-2 각 추출에 mmol 작은 규모.</li>
		<li>결합 된 유기 레이어 두 번 소금물을 씻어. 일반적으로, 소금물의 동일한 볼륨을 사용 하 여 결합된 반응 볼륨으로.</li>
		<li>30 분 동안 무수 황산 나트륨으로 건조.</li>
		<li>(예를 들어, 통해 Celite 플러그) 나트륨 황산 염을 필터링 합니다.</li>
		<li>감압 및 40 ° c.에서 회전 증발 기에 용 매를 제거</li>
		<li>칼럼 크로마토그래피는 용 매 제거 후 순수 해당 α-azido 케 톤을 감당할 헥 산 및 에틸 아세테이트 eluents를 사용 하 여 실리 카 젤에 의해 원유 제품을 정화. 참고: trimethylsilyl enolate의 2 mmol 0.5 m m o l의 비늘에 2 cm 직경 15 cm의 높이 (길이)에 표준 실리 카 젤 60을 사용 하 여 유리 열에 열 크로마토그래피 수행 합니다. 볼륨 다른 비늘에 대 한 다양 한 필요 합니다.</li>
	</ol></li>
	<li>TMS-아 지 드와 Azidation 주의: 유기 azides 일반적으로 폭발성 고 주의 처리 및 제품을 준비 한다. TMS-아 지 드 독성이 있다. 사용 하기 전에 MSDS를 참조 하십시오.<ol>
<li>Enolonium 종-78 ° C에서의 준비 된 솔루션에 추가 하는 깔끔한 azidotrimethylsilane (2.5 equiv.) dropwise 방식에서. 되도록 온도가-55 ° c에이 솔루션 추가 0.5-2 mmol 규모, 추가 2-3 분 이상 만족 이다.</li>
		<li>-78 ° c.에 15 분 동안 반응 혼합물을 저 어</li>
		<li>-55 ° C에 반응 혼합물이 열 하 고 2 ~ 3 h에 대 한이 온도에 둡니다.</li>
		<li>반응 혼합물 (enolonium 종의 준비에 사용 되는 dichloromethane의 절반 볼륨)에 물을 추가 합니다.</li>
		<li>Dichloromethane을 몇 번이 고 압축을 풉니다. 일반적으로 2-3 시간 반응 볼륨을 사용 하 여 0.5-2 각 추출에 mmol 작은 규모.</li>
		<li>결합 된 유기 레이어 두 번 소금물을 씻어. 일반적으로, 소금물의 동일한 볼륨을 사용 하 여 결합된 반응 볼륨으로.</li>
		<li>건조 30 분 무수 황산으로 추출.</li>
		<li>나트륨 황산 염을 필터링 합니다.</li>
		<li>감압 및 40 ° c.에서 회전 증발 기에 용 매를 제거</li>
		<li>칼럼 크로마토그래피는 용 매 제거 후 순수 해당 α-azido 케 톤을 감당할 헥 산 및 에틸 아세테이트 eluents를 사용 하 여 실리 카 젤에 의해 원유 제품을 정화.</li>
	</ol></li>
	<li>Azoles와 반응
	<ol>
<li>Enolonium 종-78 ° C에서의 준비 된 솔루션에 추가할 azole (4 ~ 5 equiv., 1 mol/L)에 dropwise 패션 dichloromethane의 5 mL에 용 해. 0.5-2 mmol 규모 또한 5 분 이상 만족입니다. 참고: tetrazoles 같은 가난 하 게 녹는 azoles 경우 dichloromethane 대신 0.5 mol/L의 농도에서 이기를 사용 합니다. 되도록 온도가-55 ° c에이 솔루션 추가</li>
		<li>-78 ° c.에 15 분 동안 반응 혼합물을 저 어</li>
		<li>-55 ° C에 반응 혼합물이 열 하 고 4 ~ 8 h에 대 한이 온도에 둡니다.</li>
		<li>반응 혼합물 (enolonium 종의 준비에 사용 된 유기 용 제의 절반 볼륨)에 물을 추가 합니다.</li>
		<li>Dichloromethane을 몇 번이 고 압축을 풉니다. 일반적으로 2-3 시간 반응 볼륨을 사용 하 여 0.5-2 각 추출에 mmol 작은 규모.</li>
		<li>결합 된 유기 레이어 두 번 소금물을 씻어. 일반적으로, 소금물의 동일한 볼륨을 사용 하 여 결합된 반응 볼륨으로.</li>
		<li>건조 30 분 무수 황산으로 추출.</li>
		<li>나트륨 황산 염을 필터링 합니다.</li>
		<li>감압 및 40 ° c.에서 회전 증발 기에 용 매를 제거</li>
		<li>칼럼 크로마토그래피는 용 매 제거 후 순수 해당 α azole 케 톤을 감당할 헥 산 및 에틸 아세테이트 eluents를 사용 하 여 실리 카 젤에 의해 원유 제품을 정화.</li>
	</ol></li>
	<li>Allylation, crotylation, cinnamylation, 및 prenylation 사용 하 여 알릴 실
	<ol>
<li>추가 하는 깔끔한 알릴-, crotyl, cinnamyl, 또는 prenyl trimethylsilane (2 equiv.)-78 ° c.에 천천히 되도록 온도가-55 ° c에이 솔루션 추가 0.5-2 mmol 규모, 추가 2-3 분 이상 만족 이다.</li>
		<li>-78 ° c.에서 10 분에 대 한 반응 혼합물을 저 어</li>
		<li>천천히 냉각 목욕을 제거 하 여 실내 온도를 따뜻하게 반응 혼합물을 허용 한다. 20 분 동안 실 온에서 반응을 남겨 주세요.</li>
		<li>반응 혼합물 (enolonium 종의 준비에 사용 되는 dichloromethane의 절반 볼륨)에 물을 추가 합니다.</li>
		<li>Dichloromethane을 몇 번이 고 압축을 풉니다. 일반적으로 2-3 시간 반응 볼륨을 사용 하 여 0.5-2 각 추출에 mmol 작은 규모.</li>
		<li>결합 된 유기 레이어 두 번 소금물을 씻어. 일반적으로, 소금물의 동일한 볼륨을 사용 하 여 결합된 반응 볼륨으로.</li>
		<li>건조 30 분 무수 황산으로 추출.</li>
		<li>나트륨 황산 염을 필터링 합니다.</li>
		<li>감압 및 40 ° c.에서 회전 증발 기에 용 매를 제거</li>
		<li>칼럼 크로마토그래피는 용 매 제거 후 순수 해당 α-알릴 제품을 감당할 헥 산 및 에틸 아세테이트 eluents를 사용 하 여 실리 카 젤에 의해 원유 제품을 정화.</li>
	</ol></li>
	<li>Arylation 참고: arylation, 사용 3 해당 BF3OEt2 의 enolonium 종의 준비 하는 동안 주요 측면으로는 enolonium의 tosylation를 피하기 위하여. 일반적으로, 향기로운 기판만 1.6 상응이 필요 합니다. 그러나, 경우 아로마 기판은 pyrane, thiophene, 또는 pyrrole, 최상의 결과 향기로운 기판의 5 항목을 사용 하 여 달성 된다.<ol>
<li>준비 된 enolonium의 솔루션 종 건조 dichloromethane에 향기로운 기판의 솔루션 추가 (1.6 equiv., 0.5 mol/L) dropwise 방식에서. 되도록 온도가-55 ° c에이 솔루션 추가 0.5-2 mmol 규모, 추가 5-10 분 이상 만족 이다.</li>
		<li>향기로운 기판의 추가 완료 되 면-55 ° C에 혼합물의 온도 증가 하 고 20 분 동안이 온도에 혼합물을 두고.</li>
		<li>반응 혼합물 (enolonium 종의 준비에 사용 되는 dichloromethane의 절반 볼륨)에 물을 추가 합니다.</li>
		<li>Dichloromethane을 몇 번이 고 압축을 풉니다. 일반적으로 2-3 시간 반응 볼륨을 사용 하 여 0.5-2 각 추출에 mmol 작은 규모.</li>
		<li>결합 된 유기 레이어 두 번 소금물을 씻어. 일반적으로, 소금물의 동일한 볼륨을 사용 하 여 결합된 반응 볼륨으로.</li>
		<li>건조 30 분 무수 황산으로 추출.</li>
		<li>나트륨 황산 염을 필터링 합니다.</li>
		<li>감압 및 40 ° c.에서 회전 증발 기에 용 매를 제거</li>
		<li>칼럼 크로마토그래피는 용 매 제거 후 순수 해당 α-arylated 케 톤을 감당할 헥 산 및 에틸 아세테이트 eluents를 사용 하 여 실리 카 젤에 의해 원유 제품을 정화.</li>
	</ol></li>
</ol>

<ol>
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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>

공개 하는 것이 없다.

TMS enolates에서 enolonium의 성공적인 준비는 여러 가지 요인에 따라 달라 집니다. 준비 단계에서 주요 측 반응은 TMS enolate의 분자 형성된 enolonium의 분자의 반응에 의해 시작 물자의 호모 커플링 이다. 따라서, 반응 조건의 요구 이합체 화의 속도 기준으로 추가 TMS enolate와 루이스 산 활성화 hypervalent 요오드 시 약의 빠른 반응 함으로써이 이합체 화를 방지 하는. 이 프로토콜에 활성화 하 고 solubilizing Kos...

Enolates 클래식 탄소 nucleophiles 유기 화학에서 그리고 중 가장 널리 사용 되는. Electrophilic enolonium 종 만들려고 enolates의 Umpolung는 귀중 한 대체 방법으로 α-기능성된 ketones을 생산으로 소설 반응 클래식 enolate 화학을 통해 불가능을 가능 하 게 하 수 있습니다. Enolonium 종 hypervalent 요오드 시 약을 포함 하는 특정 반응에 많은 반응에서 중간체도 제안 되었습니다. 이러한 반응에는 α-halogenation, 산소, 그리고 amination1 뿐만 아니라 다른 반응2,3,,45포함 됩니다.
그러나, 이러한 반응의 범위는 항상 반응 enolonium 종의 과도 특성에 의해 제한 되었다. 이 transiency 필요 어떤 nucleophile 강하게 산화 hypervalent 요오드 시 약으로 생성 enolates의 반응 동안 반응 혼합물에 있어야 합니다. 따라서, 어떤 nucleophile 전자 부유한 향기로운 화합물 (heterocycles) 및 알 켄와 같은 산화 하는 경향이 사용할 수 없습니다.
작년에 우리 뒤에 두 번째 단계에서 nucleophile의 추가 1 단계에서 개별 중급으로 enolonium 종 형성은 조건 개발 하 여 이러한 한계를 극복 했다. 이 프로토콜 허용 기능화 염소6, 등의 고전 형식 뿐만 아니라 산화 탄소 nucleophiles allylsilanes6,8, enolates1,6,등의 사용 7, 그리고 전자 부유한 향기로운 화합물9, C-C 유대 형성의 결과. Allylation 메서드는 의무가 제 사기 및 3 차 센터의 형성. 케 톤 arylation 방법의 향기로운 감독 그룹9에 대 한 필요 없이 복합 형식 C H 기능화를 구성합니다. 최근에, 우리는 뿐만 아니라11로 azoles 및 azides10 의 추가 보고 있다. 프로토콜의 상세한 프레 젠 테이 션 합성 유기 화학자의 나날 도구 상자에 이러한 방법의 소개에 지원 예정입니다.

<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-기능화 hypervalent 요오드 시 약에 의해 enolates의 umpolung 통해 ketones의 합성 유기 화학에서 중요 한 개념 이다. 최근에, 우리는 케 톤 enolate umpolung 수돗물, azidation, 및 amination azoles를 사용 하 여 메서드의 개발 활성화를 위한 2 단계 전략을 개발 했습니다. 또한, C C 본드-형성 arylation와 allylation 반응 개발 했습니다. 이러한 방법의 중심에는 반응 nucleophile의 추가 이전 중간과 높은 반응 enolonium 종의 준비 합니다. 이 전략은 따라서 준비 및 고전적인 합성 화학 금속 enolates의 사용의 연상 이다. 이 전략 nucleophiles 것 그렇지 않으면 호환 되지 않을 수 강하게 산화 hypervalent 요오드 시 약의 사용을 허용 한다. 이 문서에서 우리는 염소, azidation, N-heteroarylation, arylation, 및 allylation에 대 한 자세한 프로토콜 제시. 제품 모티브 medicinally 활성 제품에 포함 됩니다. 이 기사 크게 이러한 메서드를 사용 하 여 다른 사람을 도움이 됩니다.

대표 실적, 프로토콜, 다음 그림 1 에 그리고 토론 섹션에서 설명 됩니다. 특히, 다른 ketones의 아주 큰 범위 사용할 수 있습니다 성공적으로 반응에서에 대해서 제품 좋은 수익률 azidation11볼 수 있습니다. 소개 azoles ketones의 α-위치에 대 한 반응의 범위 heterocycles 포함 된 일반적인 모노 주기적와 bicyclic 질소의 대부분 포함. Allylation 절?...

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 종 케 톤 enolates의 umpolung와 α-위치에 nucleophile의 추가 대 한 2 단계 한 냄비 프로토콜 설명 되어 있습니다. Nucleophiles 염화 물, 아 지 드, azoles, 알릴-실, 그리고 향기로운 화합물 포함.

Enolonium 종 통해 Ketones의 Umpolung 기능화에 대 한 2 단계 프로토콜

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

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Organic Chemistry

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Unit 1

Aldehydes and Ketones

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9.9K 조회수.  Ariel University. Enolonium 종 케 톤 enolates의 umpolung와 α-위치에 nucleophile의 추가 대 한 2 단계 한 냄비 프로토콜 설명 되어 있습니다. Nucleophiles 염화 물, 아 지 드, azoles, 알릴-실, 그리고 향기로운 화합물 포함.

비디오: 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.

관 능 적 모노 아연 브로 미 데스의 결합체 첨가를 통한 전 탄소 4 급 센터의 효율적인 합성

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

연구

화학

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.

다재다능한CO2를 복합 제품으로 전환: 원포트 2단계 전략

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.

전이 금속 촉매를 이용한 케톤 전자레인지 보조 직접 이질화

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.

Enols의 반응성

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 ...

교육

유기화학

&alpha;-Carbon Chemistry: Enols, Enolates, and Enamines

주요 용어 및 개념

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>

Enolate 이온의 반응성

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.

Enolates의 위치 선택적 형성

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

알데히드와 케톤의 산 촉매 α-할로겐화

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.

Aldols에서 Enones로의 탈수: 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.

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;" />

아민을 함유한 알데히드와 케톤: 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 ...

&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 종 통해 Ketones의 Umpolung 기능화에 대 한 2 단계 프로토콜

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