- Sulfamate Esters Guide Selective Radical-Mediated Chlorination of Aliphatic C?H Bonds
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Masked alcohols are particularly appealing as directing groups because of the ubiquity of hydroxy groups in organic small molecules. Herein, we disclose a general strategy for aliphatic γ-C(sp3)?H functionalization guided by a masked alcohol. Specifically, we determine that sulfamate ester derived nitrogen-centered radicals mediate 1,6-hydrogen-atom transfer (HAT) processes to guide γ-C(sp3)?H chlorination. This reaction proceeds through a light-initiated radical chain-propagation process and is capable of installing chlorine atoms at primary, secondary, and tertiary centers.
- Short, Melanie A.,Blackburn, J. Miles,Roizen, Jennifer L.
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- Practical and Selective sp3 C?H Bond Chlorination via Aminium Radicals
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The introduction of chlorine atoms into organic molecules is fundamental to the manufacture of industrial chemicals, the elaboration of advanced synthetic intermediates and also the fine-tuning of physicochemical and biological properties of drugs, agrochemicals and polymers. We report here a general and practical photochemical strategy enabling the site-selective chlorination of sp3 C?H bonds. This process exploits the ability of protonated N-chloroamines to serve as aminium radical precursors and also radical chlorinating agents. Upon photochemical initiation, an efficient radical-chain propagation is established allowing the functionalization of a broad range of substrates due to the large number of compatible functionalities. The ability to synergistically maximize both polar and steric effects in the H-atom transfer transition state through appropriate selection of the aminium radical has provided the highest known selectivity in radical sp3 C?H chlorination.
- McMillan, Alastair J.,Sieńkowska, Martyna,Di Lorenzo, Piero,Gransbury, Gemma K.,Chilton, Nicholas F.,Salamone, Michela,Ruffoni, Alessandro,Bietti, Massimo,Leonori, Daniele
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supporting information
p. 7132 - 7139
(2021/03/03)
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- δ-C-H Mono- And Dihalogenation of Alcohols
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Alkoxy radicals have long been known to enable remote C-H functionalization via 1,5-hydrogen atom abstraction. However, methods for their generation traditionally have relied upon highly oxidizing metals, ultraviolet radiation, or preformed peroxide intermediates, which has prevented the development of many desirable transformations. Herein we report a new bench-stable precursor that decomposes to free alkoxy radicals via a previously unreported single-electron oxidation pathway. This new precursor enables the fluorination and chlorination of remote C-H bonds under exceptionally mild conditions with exceedingly high monoselectivity. Iterative use of this precursor enables the introduction of a second halogen atom, granting access to remote dihalide motifs, including CF2 and CFCl.
- Herron, Alastair N.,Liu, Dongxin,Xia, Guoqin,Yu, Jin-Quan
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supporting information
p. 2766 - 2770
(2020/02/13)
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- Site-Selective Aliphatic C-H Chlorination Using N-Chloroamides Enables a Synthesis of Chlorolissoclimide
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Methods for the practical, intermolecular functionalization of aliphatic C-H bonds remain a paramount goal of organic synthesis. Free radical alkane chlorination is an important industrial process for the production of small molecule chloroalkanes from simple hydrocarbons, yet applications to fine chemical synthesis are rare. Herein, we report a site-selective chlorination of aliphatic C-H bonds using readily available N-chloroamides and apply this transformation to a synthesis of chlorolissoclimide, a potently cytotoxic labdane diterpenoid. These reactions deliver alkyl chlorides in useful chemical yields with substrate as the limiting reagent. Notably, this approach tolerates substrate unsaturation that normally poses major challenges in chemoselective, aliphatic C-H functionalization. The sterically and electronically dictated site selectivities of the C-H chlorination are among the most selective alkane functionalizations known, providing a unique tool for chemical synthesis. The short synthesis of chlorolissoclimide features a high yielding, gram-scale radical C-H chlorination of sclareolide and a three-step/two-pot process for the introduction of the β-hydroxysuccinimide that is salient to all the lissoclimides and haterumaimides. Preliminary assays indicate that chlorolissoclimide and analogues are moderately active against aggressive melanoma and prostate cancer cell lines.
- Quinn, Ryan K.,K?nst, Zef A.,Michalak, Sharon E.,Schmidt, Yvonne,Szklarski, Anne R.,Flores, Alex R.,Nam, Sangkil,Horne, David A.,Vanderwal, Christopher D.,Alexanian, Erik J.
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supporting information
p. 696 - 702
(2016/02/03)
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- Oxidation of aliphatic alcohols with the lead tetraacetate - Metal halide system under mechanical activation
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The mechanochemical oxidation of n-pentanol, n-hexanol, and n-octanol with the Pb(OAc)4 - MHal system (M = Li, K; Hal = Cl, Br) in the absence of a solvent affords esters, and secondary alcohols with the composition C8H17OH and C9H19OH give ketones.
- Kapustina,Sokova,Makhaev,Borisov,Nikishin
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p. 1842 - 1845
(2007/10/03)
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- FUNCTIONALIZATION OF THE δ-CARBON ATOM BY THE FERROUS ION INDUCED DECOMPOSITION OF ALKYL HYDROPEROXIDES IN THE PRESENCE OF CUPRIC SALTS
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In the ferrous ion induced decomposition of alkyl hydroperoxides in the presence of cupric halides or pseudohalides, intramolecular functionalization with ligand transfer from cupric salts to δ-carbon atom, is achieved.
- Cekovic, Zivorad,Cvetkovic, Milutin
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p. 3791 - 3794
(2007/10/02)
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