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    Home > Angelw: Zhu Jieping group realizes remote C (SP3) - H arylation of amides and sulfonamides catalyzed by copper

    Angelw: Zhu Jieping group realizes remote C (SP3) - H arylation of amides and sulfonamides catalyzed by copper

    • Last Update: 2018-09-05
    • Source: Internet
    • Author: User
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    Hofmann-l ö ffler FREYTAG (HLF) reaction refers to the conversion of linear n-chloramine 1a to pyrrolidine 2 by heating or photolysis in a strong acid medium The HLF reaction experienced the production of nitrogen free radical a, selective 1,5-hydrogen atom transfer (HAT), chlorination and cyclization (scheme 1a) Recently, Knowles and rovis team have developed the remote functionalization of simple formamide and sulfonamide catalyzed by photo oxidation-reduction respectively, which uses Michael receptor to capture free radical B to form 3 Yu reported the formation of 4 by γ - halogenation of metal catalyzed imide At present, the subsequent reactions of carbon radicals formed by amido radicals via 1,5-hat are limited to atom transfer (halogenation), cyclization and Michael addition In order to further expand the application scope and application of C-H functionalization Recently, Zhu Jieping's group of Federal Institute of technology in Lausanne, Switzerland, reported a new copper catalyzed remote C (SP 3) - H arylation of n-fluoroamide and n-fluorosulfonamide Relevant articles were published on angelw Chem Int ed (DOI: 10.1002 / anie 201807623) (source: angelw Chem Int ed.) in the early stage of the study, the author found that in the presence of Cu (OTF) 2 (0.1 equivalent), 2,2 '- bipyridine (0.1 equivalent) and potassium carbonate, n-tert-butyl-n-fluoro-2-methylbenzamide 7a and 4-tert-butylbenzoic acid 9A reacted in benzene solution, only the target product 5aa (scheme 2) with a yield of 3% was obtained Then the author systematically screened the conditions of copper salt, solvent, ligand, alkali and temperature, and found that the best conditions were: 7a and 9A reacted in room temperature under the action of Cu (CF 3cochcoch 3) 2 (0.1 equivalent), 2,2 '- bipyridine (0.1 equivalent) and sodium TERT butanol (2.0 equivalent) The yield of 5aa was 87% Under the optimal reaction conditions, the substrate range of the C (SP 3) - H aromatization was investigated Firstly, the author investigated the universality of the reaction of n-fluorobenzamide 1A with different arylboronic acids (scheme 2) The aryl boric acid with electron donor, electron acceptor and halogen at different positions has good tolerance, and 1,1-diarylmethane 5aa-5aw (50% - 87%) can be obtained in good to excellent yield Furan, benzofuran, thiophene, benzothiophene, indole and other heteroaryl boric acids are also good coupling agents, and can be converted into arylation product 5AX - 5AC 'in medium yield (source: angelw Chem Int ed.) next, the author investigated the coupling reaction of different n-fluoroamides and arylboric acid (scheme 3) The n-fluorobenzamide and n-fluorothiophene formamide with different electronic properties can react smoothly, and the product 5bd '- 5LA can be obtained with medium or above yield (source: angelw Chem Int ed.) later, the copper catalyzed coupling reaction was extended to the δ - C (SP 3) - H aromatization of n-fluoroamide and n-fluorosulfonamide (scheme 4) It is gratifying that a variety of n-fluorobenzamide, n-fluorothiophene formamide and n-fluoro-p-toluenesulfonamide with different structures and electric properties can all successfully obtain the product 6ae '- 6ia with medium yield (source: angelw Chem Int ed.) in addition, in order to further prove the functional compatibility of the method, the author also studied the later functionalization of natural product derivatives (scheme 5) 9 I 'boric acid derived from diacetone-d-furoglucose and 9 J' boric acid ester derived from γ - tocopherol can be obtained corresponding arylation products 11 and 12 under standard conditions (source: angelw Chem Int ed.) after a lot of mechanism experiments, the author proposed a possible reaction pathway (scheme 7) FCU (II) x and amide free radical a were produced after reduction of n-fluoroamide 7 or 10 by Cu (I) species in situ The latter will undergo intramolecular 1,5-hat conversion to carbon free radical B The transition metallization of FCU (II) x and ARB (OH) 2 promoted by alkali will produce intermediate C, which reacts with B to form arcu (III) RX species D The remote C (SP 3) - H aromatization product 5 or 6 will be produced by D reduction and elimination, and Cu (I) species will be produced at the same time (source: angelw Chem Int ed.) Summary: Zhu Jieping group has developed the first long-range C (SP 3) - H arylation of n-fluoroamide and n-fluorosulfonamide Derivatives Catalyzed by copper, which involves the continuous formation of amide radicals, 1,5-hat and cross coupling of copper catalyzed carbon radicals with arylboric acid The reaction is not only suitable for functionalization of C (SP 3) - H bond of benzyl group, but also for functionalization of C (SP 3) - H bond of fatty chain The regioselectivity of the reaction is controlled by the 1,5-hat process with favorable kinetics.
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