Intramolecular Aromatic 1,5-Hydrogen Transfer in Free Radical Reactions 1. Unprecedented Rearrangements in Pschorr Cyclization, Sandmeyer, and Hydro-, Hydroxy-, and Iododediazoniation Reactions

Karady, Sandor; Abramson, N. L.; Dolling, Ulf H.; Douglas, Alan W.; Mcmanemin, G. J.; Marcune, Benjamin

doi:10.1021/ja00124a052

Cited by 30 publications

(21 citation statements)

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“…This result, together with some recent observations of 1,5-hydrogen-atom-transfer reactions in aryl radicals, [24] led us to attempt a radical translocation approach with vinyl bromide 12.…”

Section: Resultsmentioning

confidence: 91%

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A General Synthetic Approach to the (20S)-Camptothecin Family of Antitumor Agents by a Regiocontrolled Cascade Radical Cyclization of Aryl Isonitriles

et al. 1998

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A general and efficient synthesis of (20S)-camptothecin (1 a) is reported. A key common intermediate containing the pyridone and lactone (DE) rings of camptothecin and most derivatives was constructed from 2-trimethylsilyl-6-methoxypyridine by a series of metalation reactions and a Heck cyclization to provide an achiral bicyclic enol ether. Sharpless asymmetric dihydroxylation followed by lactol oxidation and iododesilylation produced the key intermediate in 94 % enantiomeric excess. Alkylation with propargyl bromide and a cascade radical reaction with phenyl isonitrile then produced 1 a. About 20 other pentaand hexacyclic analogues of camptothecin with differing single or multiple substituents at C7, C9, C10, C11, and/or C12 were made by changing the propargylating agent and the isonitrile. Included among these are several drug candidates and the approved drugs topotecan and irinotecan. The synthesis of the prodrug irinotecan is a direct one that does not pass through the active metabolite. The use of ortho-trimethylsilyl-substituted isonitriles allows the regioselective synthesis of camptothecin analogues in cases where isomeric mixtures are formed from the parent isonitriles. The synthesis of the derivatives relies on the broad scope and functional group tolerance of the key cascade radical reaction.

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Section: Resultsmentioning

confidence: 91%

“…As for 24 b, dehydration of this solid (945 mg, 4.0 mmol) followed by flash chromatography (hexanes/AcOEt 9:1), provided 24 (28): N-Formylation [35] of 3-(1-hydroxyethyl)aniline (26), followed by standard TBDPSprotection, [35] provided N-3-(1-tert-butyldiphenylsilyloxyethyl)formanilide (27) …”

Section: -Tert-butyloxycarbonylaminophenyl Isonitrile (24 C)mentioning

confidence: 99%

A General Synthetic Approach to the (20S)-Camptothecin Family of Antitumor Agents by a Regiocontrolled Cascade Radical Cyclization of Aryl Isonitriles

et al. 1998

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“…47 The corresponding expression for the pre-exponential factor, A bi , of a bimolecular reaction in solution phase is given, with the same notation, by eqn. (12); here, in the second set of…”

Section: (V) Comparison Of Reaction Energeticsmentioning

confidence: 99%

“…More recently, Karady and co-workers 12 have examined the rearrangement of benzophenone-derived radicals in more detail (Scheme 2). The diazonium ion 2 was homolysed in various conditions giving rise, initially, to the corresponding radical 3 which could then undergo sequential 1,5-H-transfer reactions to produce the isomeric radicals 4 and 5.…”

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confidence: 99%

Sandmeyer reactions. Part 5. Estimation of the rates of 1,5-aryl/aryl radical translocation and cyclisation during Pschorr fluorenone synthesis with a comparative analysis of reaction energetics

Chandler

Hanson

Taylor

et al. 2001

J. Chem. Soc., Perkin Trans. 2

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During the Pschorr cyclisation of 2-aroylphenyl radicals, a rearrangement occurs reversibly by 1,5-hydrogen transfer to give 2-benzoylaryl radicals. Rate constants of (1.2 ± 0.2) × 10 6 s Ϫ1 at 293 K are estimated for both the forward and back reactions in the equilibrium between 2-(4-methylbenzoyl)phenyl and 2-benzoyl-5-methylphenyl radicals. Assuming an empirical estimate of 1.6 × 10 Ϫ2 dm 3 mol Ϫ1 s Ϫ1 for the hypothetical rate of abstraction of hydrogen from benzene by phenyl radicals, the radical translocation is calculated to occur with a statistically corrected effective molarity of 2.2 × 10 8 mol dm Ϫ3 . By contrast, the competing cyclisation, though occurring at a rate of (8.0 ± 0.9) × 10 5 s Ϫ1 , exhibits an effective molarity of only 5.3 mol dm Ϫ3 . The causes of these differences are analysed in terms of reaction mechanism.

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“…For example, the possibility of an intramolecular hydrogen transfer has been studied for an aromatic molecule. In that case, the spin density is mainly localized on the carbon-centered primary radical, being very low at the carbon that bears the migrating hydrogen [30,31]. The hydrogen transfer could justify \ /~CH.…”

Section: Hyperfine Constant Patterns In the Radicalsmentioning

confidence: 99%

Evidence for the development of persistent carbon-centered radicals from a benzyl phenolic antioxidant: an electron paramagnetic resonance study

Mendiara

Coronel

2006

Appl. Magn. Reson.

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Radicals have been generated from the benzyl phenolic antioxidant 1,3,5-trimethyl-2,4,6-tris (3,5-di-tert-butyl-4-hydroxybenzyl) benzene, carrying out oxidative and hydrogen abstraction reactions. Transient phenoxyl radicals were directly visualized but only persistent carbon-centered radicals were monitored by electron paramagnetic resonance (EPR). The experimental EPR results let us rationalize our analysis as the sum of two different radicals. One, called the methylene radical, developed from the loss of a benzylic hydrogen gave place to a doublet of triplets with ac~ ~ 2.7 mT anda H = 0.165 mT. Besides, the methyl radical, developed after an intramolecular hydrogen transfer involving a methyl group on the central aromatic ring of the molecule, formed a triplet of triplets, with a~ H around 0.060 mT and a2 H = 0.169 mT. AII the co~tact interactions were tested by EPR simulation of the experimental data.

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Intramolecular Aromatic 1,5-Hydrogen Transfer in Free Radical Reactions 1. Unprecedented Rearrangements in Pschorr Cyclization, Sandmeyer, and Hydro-, Hydroxy-, and Iododediazoniation Reactions

Cited by 30 publications

References 0 publications

A General Synthetic Approach to the (20S)-Camptothecin Family of Antitumor Agents by a Regiocontrolled Cascade Radical Cyclization of Aryl Isonitriles

A General Synthetic Approach to the (20S)-Camptothecin Family of Antitumor Agents by a Regiocontrolled Cascade Radical Cyclization of Aryl Isonitriles

Sandmeyer reactions. Part 5. Estimation of the rates of 1,5-aryl/aryl radical translocation and cyclisation during Pschorr fluorenone synthesis with a comparative analysis of reaction energetics

Evidence for the development of persistent carbon-centered radicals from a benzyl phenolic antioxidant: an electron paramagnetic resonance study

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