Enabling synthesis in fragment-based drug discovery by reactivity mapping: photoredox-mediated cross-dehydrogenative heteroarylation of cyclic amines

Grainger, Rachel; Heightman, Tom D.; Ley, Steven V.; Lima, Fabio; Johnson, Christopher N.

doi:10.1039/c8sc04789h

Cited by 90 publications

(77 citation statements)

References 57 publications

(49 reference statements)

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“…As imilar procedure was adopted by Grainger,J ohnson and co-workers in their high throughput reactivity mapping for fragment-based drug discovery. [92] Most recently,H ea nd Chen developed am ethod for the highly selective abstraction of methylene C À Hb onds for Minisci-type reactions (Scheme 28). [93] Upon proposed reduction by excited Ru II ,h ypervalent iodine reagent PFBI-OH loses hydroxide and forms ah ighly electrophilic carboxyl radical, capable of abstracting aliphatic CÀHbonds.The high methylene selectivity is thought to be aided by an orthofluorine substituent on the aryl ring, perhaps affecting conformation in the C À Ha bstraction transition state.T he scope is very broad and the reaction displays such high selectivity for methylene positions that amino acid derivative 23 and steroid derivative 24 are formed by reaction of only one aliphatic CÀHb ond.…”

Section: Angewandte Chemiementioning

confidence: 99%

Recent Advances in Minisci‐Type Reactions

2019

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Reactions that involve the addition of carbon‐centered radicals to basic heteroarenes, followed by formal hydrogen atom loss, have become widely known as Minisci‐type reactions. First developed into a useful synthetic tool in the late 1960s by Minisci, this reaction type has been in constant use over the last half century by chemists seeking to functionalize heterocycles in a rapid and direct manner, avoiding the need for de novo heterocycle synthesis. Whilst the originally developed protocols for radical generation remain in active use today, they have been joined in recent years by a new array of radical generation strategies that allow use of a wider variety of radical precursors that often operate under milder and more benign conditions. The recent surge of interest in new transformations based on free radical reactivity has meant that numerous choices are now available to a synthetic chemist looking to utilize a Minisci‐type reaction. Radical‐generation methods based on photoredox catalysis and electrochemistry have joined approaches which utilize thermal cleavage or the in situ generation of reactive radical precursors. This review will cover the remarkably large body of literature that has appeared on this topic over the last decade in an attempt to provide guidance to the synthetic chemist, as well as a perspective on both the challenges that have been overcome and those that still remain. As well as the logical classification of advances based on the nature of the radical precursor, with which most advances have been concerned, recent advances in control of various selectivity aspects associated with Minisci‐type reactions will also be discussed.

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Section: Angewandte Chemiementioning

confidence: 99%

Recent Advances in Minisci‐Type Reactions

2019

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“…(2)]. [69] Forexample,W ang and co-workers reported the Minisci-like direct alkylation of azines,a sw ell as of azoles (see Section 2.2.4. for details) with cyclic and acyclic amines under iridium-catalyzed photoredox conditions to afford the desired alkylated heterocycles in fair to good yields [Scheme 23, Eq. [68b] Finally,a ctivation of CÀHb onds a to an itrogen atom in (cyclic) amines has also been recently exploited to promote the direct alkylation of electron-deficient N-heteroarenes.…”

Section: Alkylation By Cross-dehydrogenative Coupling With Alkanes Ementioning

confidence: 99%

“…[68b] Finally,a ctivation of CÀHb onds a to an itrogen atom in (cyclic) amines has also been recently exploited to promote the direct alkylation of electron-deficient N-heteroarenes. [69] Forexample,W ang and co-workers reported the Minisci-like direct alkylation of azines,a sw ell as of azoles (see Section 2.2.4. for details) with cyclic and acyclic amines under iridium-catalyzed photoredox conditions to afford the desired alkylated heterocycles in fair to good yields [Scheme 23, Eq. (3)].…”

Section: Alkylation By Cross-dehydrogenative Coupling With Alkanes Ementioning

confidence: 99%

Beyond Friedel and Crafts: Directed Alkylation of C−H Bonds in Arenes

2019

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The alkylation of arenes is one of the most fundamental transformations in chemical synthesis leading to privileged scaffolds in many areas of science. Classical methods for the introduction of alkyl groups to arenes are mostly based on the Friedel-Crafts reaction, radical additions, metallation or pre-functionalization of the arene: these methods however suffer from limitations in scope, efficiency and selectivity. Moreover, they are based on the innate reactivity of the starting arene, favoring the alkylation at a certain position and rendering the introduction of alkyl chains at other positions much more challenging. This can be addressed by the use of a directing group facilitating, in the presence of a metal catalyst, the regioselective alkylation of a C-H bond. These directed alkylations of C-H bonds in arenes are overviewed, in a comprehensive manner, in this review article.

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“…In einer vorangegangenen Arbeit der selben Autoren ermçglicht die Bildung eines Alkoxyradikals die Wanderung einer Heteroarylgruppe entlang eines langkettigen Alkohols (Schema 26 a). [92] Vorkurzem entwickelten He und Chen eine Methode zur hoch selektiven Abstraktion von Methylen-C-H-Bindungen Der vorgeschlagene Mechanismus verläuft über die Homolyse der in situ gebildeten, hypervalenten Iodverbindung 21,i nd er der als Substrat eingesetzte Alkohol als Ligand an das Iod(III)-Zentrum gebunden vorliegt.…”

Section: Angewandte Chemieunclassified

“…Ein ähnlicher Ansatz wurde von Graigner,J ohnson und Mitarbeitern in einem Hochdurchsatzverfahren zur fragmentbasierten Wirkstoffentwicklung genutzt. [92] Vorkurzem entwickelten He und Chen eine Methode zur hoch selektiven Abstraktion von Methylen-C-H-Bindungen…”

Section: Angewandte Chemieunclassified

Neue Entwicklungen auf dem Gebiet der Minisci‐Reaktion

Proctor¹,

Phipps²

2019

Angewandte Chemie

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Reaktionen, die über die Addition von kohlenstoffzentrierten Radikalen an basische Heteroarene gefolgt von der formalen Abspaltung eines Wasserstoffatoms verlaufen, sind heute allgemein als Minisci‐Reaktionen bekannt. Als synthetisches Werkzeug erstmals in den 1960er Jahren von Minisci entwickelt, wurde diese Reaktion in den letzten fünfzig Jahren kontinuierlich genutzt, um Heterozyklen schnell und direkt zu funktionalisieren, ohne dass eine De‐novo‐Synthese von Heterozyklen nötig ist. Während die meisten der ursprünglich beschriebenen Syntheseprotokolle zur Radikalerzeugung auch heute noch genutzt werden, wurde in den vergangenen Jahren eine Reihe neuer Strategien zur Erzeugung von Radikalen entwickelt, die den Einsatz vielfältigerer Radikalvorläufer und milderer Reaktionsbedingungen ermöglichen. Das in den letzten Jahren gestiegene Interesse an neuen Umsetzungen mit freien Radikalen hat dazu geführt, dass Synthesechemikern heute eine Vielzahl von Möglichkeiten für eine Minisci‐Reaktion zur Verfügung stehen. Inzwischen sind zusätzlich zu Methoden, die die thermische Spaltung oder In‐situ‐Bildung reaktiver Radikalvorläufer nutzen, auch die Photoredoxkatalyse und die Elektrochemie als Strategien zur Radikalerzeugung etabliert. Dieser Aufsatz deckt die bemerkenswert umfangreiche Literatur ab, die in den letzten Jahren auf diesem Gebiet erschienen ist, und unternimmt so den Versuch, Chemikern eine Orientierungshilfe zu geben und gleichzeitig eine Perspektive über die Herausforderungen zu bieten, die bereits bewältigt wurden und offen bleiben. Neben den logischen Klassifizierungen dieser Fortschritte entsprechend der Art des jeweiligen Radikalvorläufers, auf die sich die meisten Arbeiten konzentrieren, werden in diesem Aufsatz auch aktuelle Fortschritte in der Kontrolle verschiedener Selektivitätsaspekte von Minisci‐Reaktionen diskutiert.

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Enabling synthesis in fragment-based drug discovery by reactivity mapping: photoredox-mediated cross-dehydrogenative heteroarylation of cyclic amines

Cited by 90 publications

References 57 publications

Recent Advances in Minisci‐Type Reactions

Recent Advances in Minisci‐Type Reactions

Beyond Friedel and Crafts: Directed Alkylation of C−H Bonds in Arenes

Neue Entwicklungen auf dem Gebiet der Minisci‐Reaktion

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