Nat. Commun.: Professor Kang Yanbiao from University of science and technology of China and Professor Qu Jianping from Nantong University of technology jointly develop copper catalyzed oxidation and cyclization of benzyl C-H bond

Recently, alkali promoted C-H bond breaking without transition metal catalyst has become a research hotspot (Fig 1a) This method provides a practical and cheap alternative for C-H bond breaking based on precious metal or free radical initiator It is well known that metal oxidants such as Cu (II) can promote the free radical addition reaction between carbon anion and unsaturated bond such as C ≡ n or C ≡ C (Fig 1b), but these reactions need stoichiometric oxidants At present, there is no copper salt catalyzed anion radical oxidation relay reaction On the other hand, imino radicals are usually produced by the break of N-O bond induced by light or initiator They have been widely used as intermediates (Fig 1c) for the construction of nitrogen-containing heterocycles (such as indole and pyridine rings) However, there are few reports on transition metal catalyzed intermolecular carbon anion radical relay reactions to prepare imino radicals (source: Nat Commun.) recently, Professor Kang Yanbiao of University of science and technology of China and Professor Qu Jianping of Nanjing University of technology jointly developed a method to construct indole derivatives through alkali promoted C-H bond cleavage and copper catalyzed carbon anion redox relay Relevant articles were published on NAT Commun (DOI: 10.1038/s41467-019-08849-z) At the beginning of the reaction, the C-H bond of benzyl was broken by alkali to produce benzyl anion a, which formed free radical B through Cu (II) - mediated oxidation reaction B and phcn are added by intermolecular radicals to produce imino radical C, which is trapped by aromatic ring to form D D is reduced to indole by Cu (I), and Cu (II) is regenerated (Fig 2a) The mechanism experiments showed that tempo completely inhibited the reaction and did not produce the by-products of Ullmann type intramolecular cyclization, which further indicated that the free radical pathway was reasonable (Fig 2C and 2D) (source: Nat Commun.) at the beginning of the study, the author optimized the reaction conditions (Table 1) The effects of various copper salts on the cyclization of toluene 1a and nitriles 2A were investigated CuSO4 was the best catalyst and the yield was 77% (entries 1-6) Compared with other solvents, the reaction was the best in octane (entries 6, 9-11) The yield was further increased to 85% (entries 12-13) by increasing the reactant concentration and reducing the catalyst loading to 2 mol% (source: Nat Commun.) under the optimal reaction conditions, the author investigated the substrate range of the method (Fig 3) The corresponding indole products (3b-3d, 3I and 3L) can be successfully obtained from a variety of 2-halotoluene under standard conditions, and the halogens can be retained under alkaline conditions The substrates with hydroxyl and carboxyl groups can be cyclized directly without protecting groups (3f and 3G) These reactions can also be used to prepare 7-azaindole 3q and 3R In order to further prove the practicability of the reaction, the gram level synthesis of BACE1 inhibitor 4B has been realized in three steps (Fig 4) (source: Nat Commun.) (source: Nat Commun.), in addition, by further optimizing the reaction conditions, the author synthesized a series of C3 substituted indole derivatives (Fig 5) using the above strategies Indole (6a-6d) with C3 substituents (such as phenyl, heteroaryl, phenoxy and phenylthiol) can be obtained in excellent yields It is worth noting that there are still limited methods for the synthesis of 3-sulfinyindole, which provides a powerful tool for the preparation of 3-sulfinyindole (6d-6p, 6s-6t) And most functional groups (such as halogen, hydroxyl, carboxyl, amide, ester, etc.) can be compatible in the reaction system It is gratifying that C 2-alkyl substituted indoles can also be prepared in medium to good yields (6u-6z), which may be related to the steric hindrance of nitriles (source: Nat Commun.) conclusion: Professor Kang Yanbiao and Professor Qu Jianping have jointly developed a method to generate imino radicals in situ through intermolecular carbon anion free radical redox relay reaction catalyzed by cheap copper salt The strategy is realized by the oxidation-reduction reaction of carbon anion radical catalyzed by CuSO 4 in series with C-H bond breaking promoted by alkali This method can produce imino radicals without N-O / N-N bond splitting or free radical initiation, and provides a green and practical synthesis way for indole.