Nickel-Catalyzed C(2)–H Arylation of Indoles with Aryl Chlorides under Neat Conditions

Abstract

Nickel-catalyzed regioselective C(2)–H arylation of indoles and pyrroles with aryl chlorides is achieved under neat conditions. This method allows the efficient coupling of diverse aryl chlorides employing a user-friendly and inexpensive Ni­(OAc)2/dppf catalyst system at 80 °C. Numerous functionalities, such as halides, alkyl ether, fluoro-alkyl ether, and thioether, and substituted amines, including heteroarenes like benzothiazolyl, pyrrolyl, indolyl, and carbazolyl, are well tolerated under the reaction conditions. The preliminary mechanistic study highlights a single-electron transfer (SET) pathway for the arylation reaction.

Copper‐Catalyzed Direct Arylation of Indoles and Related (Hetero)arenes: A Ligandless and Solvent‐free Approach

“…The halide functionalities −F, −Cl and −CF 3 were well tolerated at the para position of arene and afforded the arylated products in low to moderate yields ( 3 ak – 3 am ). Notably, the −CF 3 containing aryl electrophile was unreactive under the nickel‐catalysis that was demonstrated earlier . The 1,3‐dioxolane derivative, 2 n could be employed in the arylation reaction providing 84% of the coupled product 3 an .…”

“…Interestingly, the aryl iodides containing substituted amine and N ‐heterocycles, like N ‐pyrrolyl, N ‐indolyl, N ‐carbazolyl groups reacted efficiently and afforded the desired arylated products in excellent yields. Such functionalities containing aryls have shown moderate reactivity under the nickel catalysis . Unfortunately, the current method failed to tolerate the base sensitive functionalities, such as acetyl, ester, amides and nitro groups.…”

“…The sterically hindered 3‐methyl‐indole 1 f upon reaction with 4‐iodotoluene afforded 80% of desired C‐2 arylated product 3 fa . This substrate had shown low reactivity for the arylation reaction using nickel catalyst . The 7‐azaindolepyridine could be coupled with 4‐iodotoluene in moderate activity affording 32% of 3 ga .…”

C−H Functionalization of Indoles by 3d Transition‐Metal Catalysis

“…Notably, the reaction proceeded in the absence of solvent using a strong base LiHMDS, which made this reaction more environmentally friendly. Later on, the same group came up with a new catalyst system, Ni/dppf, which could couple high‐demand and challenging aryl chlorides with indoles and pyrroles to produce C‐2 arylated indoles and pyrroles . Notably, these reactions were performed at 80 °C and demonstrated to be very useful for the tolerance of diverse functionalities like halides, alkyl ether, fluoroalkyl ether, thioether, and substituted amines, including benzothiazolyl, pyrrolyl, indolyl, and carbazolyl groups.…”

“…Later on, the same group came up with a new catalyst system, Ni/ dppf, which could couple high-demand and challenging aryl chlorides with indoles and pyrroles to produce C-2 arylated indoles and pyrroles. [20] Notably, these reactions were performed at 80°C and demonstrated to be very useful for the tolerance of diverse functionalities like halides, alkyl ether, fluoroalkyl ether, thioether, and substituted amines, including benzothiazolyl, pyrrolyl, indolyl, and carbazolyl groups. The preliminary mechanistic study suggested that the reaction proceeds via a single electron transfer (SET) pathway involving the aryl radical.…”