Copper(ii)-catalyzed C5 and C7 halogenation of quinolines using sodium halides under mild conditions

Abstract

A simple and mild protocol for copper catalyzed halogenation of quinoline at C5 and C7 positions was developed, affording the desired remote C-H activation products in moderate to good yields. This reaction proceeds with low-cost sodium halides (NaX, X = Cl, Br, I) and features excellent substrate tolerance. A series of control experiments were carried out to illustrate a single-electron-transfer process which plays a vital role in the halogenation.

The Highly Regioselective Halogenation of N‐(8‐quinolinyl)amides on the C‐5 Position with Cuprous Halides Under Mild Conditions

“…When we added 3.0 equiv TEMPO (2,2,6,6‐tetramethyl‐1‐piperidinyloxy) into the reaction system, the reactiont was completely suppressed with desired product 0 % yield, indicating the radical was involved. Thus, considering above results and previous reports, we suggested plausible SET mechanism as shown in Scheme . Firstly, CuX was oxidized by NFSI into CuX 2 , which combined with quinoline to form complex aryl‐Cu II A .…”

“…Recently, the halogen introduction to quinoline scaffolds via C−H cross coupling was reported . Regarding to double halogenations on C‐5 and C‐7 position, palladium‐mediated di‐chlorination on 8‐acylaminoquinoline scaffolds utilizing N‐chlorosuccinimide as “Cl” source, and Cu(OAc) 2 ‐catalyzed di‐bromination on N‐(8‐quinolinyl) amides using NaBr as “Br” source, were reported respectively by Xie and Zhang groups. The access to highly regioselective C‐5 halogenation was described in Scheme (a) .…”

“…However, under Cu(OAc) 2 /PhI(OAc) 2 system, in particularly, only single Cl, Br or I halogen was introduced successfully, when CuCl 2 , NaX, or I 2 was used alone as halogen source . Even though diverse C−X (X= Cl, Br, I) bonds may be formed with NaX reported by Zhang group, low chlorination yield limits its wide application. Moreover, other drawbacks are obvious, such as elevated temperature, acid or base additives, were required in these protocols.…”

One‐Pot Functionalization of 8‐Aminoquinolines through the Acylation and Regioselective C5‐H Halogenation under Transition‐Metal‐Free Conditions

“…In 2013, Stahl and coworkers first reported the remote CuCl‐catalyzed C5 chlorination of 8‐amidoquinoline amides through a single electron transfer (SET) process. Since then, regioselective C5 halogenation of quinolines has been widely investigated, and various halogen sources such as NXS (X=Cl, Br or I),– halide salts,– molecular idodine, and other halogen reagents have been used for the synthesis of halogenated quinolines. Despite the significant progress, most of these methods cannot avoid the use of transition‐metals, and/or excess of oxidants and halogen sources, thus not conforming to the requirements of atom economy and green chemistry.…”

Copper(II)‐Catalyzed and Chelation‐Induced Remote C‐H Halogenation of Quinolines under Neutral Conditions

“…C‐5 halogenation of 8‐acylaminoquinolines was subsequently reported by Huang and coworkers; bromination, chlorination, and iodination of 8‐acylaminoquinolines at C‐5 positions were performed in the presence of stoichiometric copper halides (CuBr 2 , CuCl 2 , and CuI 2 ) as halogen sources and expensive PhI(OAc) 2 as oxidant under acidic conditions [Scheme (c)] . Copper‐catalyzed C‐5 halogenation of 8‐acylaminoquinolines was also successfully performed under acidic or neutral conditions in the presence of PhI(OAc) 2 and Ag 2 CO 3 as oxidants using sodium halide (NaBr, NaCl, and NaI) and N ‐halosuccinamide (NXS=NBS, NCS, and NIS) as halogen sources [Schemes 1(d) and 1(e)] . These methods are effective, but they also exhibit drawbacks, such as acidic condition requirement, use of a molar equivalent or excess amount of copper halide as halogen source, and/or expensive oxidant.…”