Chapter 2 Radical additions to pyridines, quinolines and isoquinolines

Harrowven, David C.; Sutton, Benjamin J.

doi:10.1016/s0959-6380(05)80044-3

Cited by 56 publications

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References 89 publications

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“…and Nature Chem., the results were described as "conceptual breakthroughs" [1,3] because no metal catalyst was needed.Here we suggest that these exciting results are not best viewed in terms of C À H activation or organocatalysis, but instead in terms of homolytic radical aromatic substitution (HAS). [5][6][7][8][9] Although the results may not be conceptual breakthroughs from that viewpoint, they could well herald new opportunities for making organic molecules through organic radical and radical anion reactions.Kwong, Lei, and co-workers discovered that heating aryl iodides in benzene at 80 8C with one equivalent of potassium tert-butoxide and 20 mol % N,N'-dimethylethylenediamine (DMEDA, the organocatalyst) gave biaryls in good yields (60-85 %, Scheme 1). [3] The research groups of Shirakawa/ Hayashi [2] and Shi [1] described similar bimolecular reactions in comparable yields, although their organocatalyst was 1,10phenanthroline (or a substituted analogue) and used at a level of 20 and 40 mol %, respectively.…”

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“…Here we suggest that these exciting results are not best viewed in terms of C À H activation or organocatalysis, but instead in terms of homolytic radical aromatic substitution (HAS). [5][6][7][8][9] Although the results may not be conceptual breakthroughs from that viewpoint, they could well herald new opportunities for making organic molecules through organic radical and radical anion reactions.…”

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Organocatalysis and CH Activation Meet Radical‐ and Electron‐Transfer Reactions

2011

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aryl radicals · CÀH activation · homolytic radical substitutions · organocatalysis · radical anionsThe research groups of Shi, [1] Shirakawa/Hayashi, [2] and Kwong/Lei [3] have recently reported independently on the construction of biaryl compounds from unactivated aromatic rings by direct CÀH activation with the aid of organocatalysts.[4] Published in J. Am. Chem. Soc. and Nature Chem., the results were described as "conceptual breakthroughs" [1,3] because no metal catalyst was needed.Here we suggest that these exciting results are not best viewed in terms of C À H activation or organocatalysis, but instead in terms of homolytic radical aromatic substitution (HAS). [5][6][7][8][9] Although the results may not be conceptual breakthroughs from that viewpoint, they could well herald new opportunities for making organic molecules through organic radical and radical anion reactions.Kwong, Lei, and co-workers discovered that heating aryl iodides in benzene at 80 8C with one equivalent of potassium tert-butoxide and 20 mol % N,N'-dimethylethylenediamine (DMEDA, the organocatalyst) gave biaryls in good yields (60-85 %, Scheme 1).[3] The research groups of Shirakawa/ Hayashi [2] and Shi [1] described similar bimolecular reactions in comparable yields, although their organocatalyst was 1,10-phenanthroline (or a substituted analogue) and used at a level of 20 and 40 mol %, respectively. In addition, Shi and co-workers reported an example of a cyclization: heating 2-iodophenyl benzyl ether (1) in mesitylene with potassium tert-butoxide (3 equiv) and 1,10-phenanthroline provided benzochromene 2 in 75 % yield.In 2008, Itami and co-workers reported that potassium tert-butoxide (1.5 equiv) alone effected the addition of aryl iodides and bromides to pyridizine and other electron-poor aromatic rings. [10,11] These results are reminiscent of the Minisci reaction (addition of alkyl and other radicals to electron-poor heterocycles), [12] except that Minisci reactions are usually conducted under acidic conditions rather than basic conditions. The research groups [1,3,4] discovered these transformations through control experiments while trying to develop metal-catalyzed C À H activation reactions. They observed that with certain "ligands" and KOtBu, the metal was not needed at all to effect the conversion of the aryl halide into the biaryl. Extensive control experiments and trace analyses (Shi and co-workers, [1] Itami and co-workers [10] ) were performed to ensure that the conditions were indeed metal-free. Coming from this direction, the processes look like organocatalylic CÀH activation reactions.In all these reports there are suggestions that aryl radicals are intermediates. The scope and conditions of the reactions (large excess of acceptor needed) and the H/D isotope effects are consistent with aryl radicals being involved. The addition of 2,2,6,6-tetramethyl-1-piperidinoxyl (TEMPO) and other inhibitors blocked the reactions, [1,3,10] and the successful cyclization of 1 to 2 is consistent with an aryl radical intermediate. Final...

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Organocatalysis and CH Activation Meet Radical‐ and Electron‐Transfer Reactions

2011

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“…In diesem Essay schlagen wir nun vor, dass diese bemerkenswerten Reaktionen besser aus Sicht der radikalischen homolytischen aromatischen Substitution (HAS) [5][6][7][8][9] denn aus Sicht der C-H-Aktivierung oder Organokatalyse betrachtet werden sollten. Zwar können die oben genannten Resultate in unseren Augen somit nicht als "konzeptionelle Durchbrü-che" angesehen werden, wir glauben jedoch, dass sie neue Möglichkeiten zur Synthese organischer Verbindungen unter Nutzung von Radikal(anionen)chemie eröffnen.…”

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“…Dennoch finden sich sehr viele weitere HAS-Reaktionen in der Literatur zur Radikalchemie. [5][6][7][8][9] Es ist mittlerweile akzeptiert, dass ein Schlüsselschritt dieser Reaktionen die Addition (teils unter Cyclisierung) eines Arylradikals an den Arenakzeptor ist. Die aus einer Arylradikaladdition resultierenden Cyclohexadienylradikale finden nahezu immer einen Weg zur Rearomatisierung: [17][18][19][20] Es resultiert schließlich das Produkt einer "homolytischen aromatischen Substitution".…”

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Organokatalyse und C‐H‐Aktivierung treffen auf Radikal‐ und Elektronentransferreaktionen

2011

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Radikal(isch)e Perspektive: Kürzlich publizierte „organokatalytische C‐H‐Aktivierungen“ werden neu als Basen‐vermittelte homolytische Substitutionen interpretiert. Eine Sequenz aus Addition eines Arylradikals an ein Aren, Deprotonierung (siehe Schema) und Elektronentransfer ist ein Teil der Kettenreaktion. Die Arbeiten sind damit keine konzeptionellen Durchbrüche mehr, können aber gleichwohl neue Synthesemöglichkeiten unter Nutzung der Radikal(anionen)chemie eröffnen.

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“…In 1979, Wang et al reported the synthesis of ETA from 4‐cyanopyridine using a Minisci reaction, but failed to provide details of the specific steps that would be needed to further explore this synthesis route. The Minisci reaction dates to the 1890s, when chemists started to explore radical alkylation reactions . Furthermore, in 1968, Dyall and Pausacker found that the reaction of pyridine N‐oxides with phenyl radicals provided the corresponding alkylation products with good yields and selectivity.…”

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Design and scale‐up of an alkylated Minisci reaction to produce ethionamide with 4‐cyanopyridine as raw materials

Liang

Wang

et al. 2017

Can J Chem Eng

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Tuberculosis is a serious bacterial infection in developing countries, especially in areas with drug resistance. The development of the anti‐tuberculosis drug ethionamide (ETA) is therefore particularly important. We have designed a new route for ETA synthesis and considered the drug's amenability to large‐scale manufacture. We evaluated different routes for the synthesis of ETA and selected the most suitable process for the industrial production of this material, which involved the Minisci reaction of 4‐cyanopyridine with propionic acid using a AgNO3/(NH4)2S2O8 catalyst system under acidic conditions. The effects of different parameters on the reaction were studied, and the production of the intermediate of 2‐ethyl‐4‐cyanopyridine was twice recrystallized from methanol to obtain pure ETA. In the Minisci reaction, the system was stirred for an additional 20 min at 80 °C after the addition of ammonium persulphate solution. The subsequent formation of thioamide was conducted at 40 °C to 60 °C for 1.5 h with a 1:5:2 molar ratio of 4‐cyanopyridine, propionic acid, and ammonium sulphide. The purity of the crude ETA reached 98.77 % after two recrystallization steps. This process could be scaled up on a much larger scale (1 kg), leading to the yield of alkylation reaction and overall yield of the production process as 44.06 % and 31.26 %, respectively.

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Chapter 2 Radical additions to pyridines, quinolines and isoquinolines

Cited by 56 publications

References 89 publications

Organocatalysis and CH Activation Meet Radical‐ and Electron‐Transfer Reactions

Organocatalysis and CH Activation Meet Radical‐ and Electron‐Transfer Reactions

Organokatalyse und C‐H‐Aktivierung treffen auf Radikal‐ und Elektronentransferreaktionen

Design and scale‐up of an alkylated Minisci reaction to produce ethionamide with 4‐cyanopyridine as raw materials

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