Carboxylic Acid-Promoted Single-Step Indole Construction from Simple Anilines and Ketones via Aerobic Cross-Dehydrogenative Coupling

Abstract

The cross-dehydrogenative coupling (CDC) reaction is an efficient strategy for indole synthesis. However, most CDC methods require special substrates, and the presence of inherent groups limits the versatility for further transformation. A carboxylic acid-promoted aerobic catalytic system is developed herein for a single-step synthesis of indoles from simple anilines and ketones. This versatile system is featured by the broad substrate scope and the use of ambient oxygen as an oxidant and is convenient and economical for both laboratory and industry applications. The existence of the labile hydrogen at C-3 and the highly transformable carbonyl at C-2 makes the indoles versatile building blocks for organic synthesis in different contexts. Computational studies based on the density functional theory (DFT) suggest that the rate-determining step is carboxylic acid-assisted condensation of the substrates, rather than the functionalization of aryl C−H. Accordingly, a pathway via imine intermediates is deemed to be the preferred mechanism. In contrast to the general deduction, the in situ formed imine, instead of its enamine isomer, is believed to be involved in the first ligand exchange and later carbopalladation of the α-Me, which shed new light on this indolization mechanism.

Regioselective Mercury(I)/Palladium(II)-Catalyzed Single-Step Approach for the Synthesis of Imines and 2-Substituted Indoles

“…The Pd(II)-catalyzed conversion of imines/enamines into indoles has been performed by fairly similar methods [ 89 , 90 , 91 ], previously forming imine 5 or generating it in situ as the intermediate [ 66 , 67 , 68 ] ( Scheme 1 b). In all the approaches, the mechanism seems to start from the tautomerization of imine 5 to enamine 8 , which undergoes a dehydrogenative reaction by the metal to furnish the σ-Pd(II) complex 9 ( Scheme 2 ).…”

“…The latter is oxidized back to Pd(II) by the oxidizing agent to renew the catalytic cycle. This aerobic oxidative cyclization reaction is only modestly efficient and regioselective in a one-pot reaction beginning from the aniline and the ketone [ 67 ]. With an excess of Cu(OAc) 2 , on the other hand, the reaction produces a couple of indoles in moderate yields (41–55%) [ 66 ].…”

“…Taking into account the aforementioned results as well as the role played by the catalysts through each step [ 54 , 66 , 67 , 68 ] in the one-pot process for 2a , two consecutive catalytic cycles can be suggested ( Scheme 4 ). For the first event, the triple bond of 2a would be activated by a π-Hg(I) mercurinium cation complex I , and then probably stabilized by the formation of the alkynylmercury(I) II [ 83 ].…”

“…The addition of aniline 1 to either of the two possible complexes (I or II) would generate enamino-vinylmercury(I) III, followed by tautomerization to obtain imine IV. The protonolysis of the latter [80] The second step would start with the tautomerization of imine 5 to enamine V, leading to the π-Pd(II) complex VI and the subsequent elimination of AcOH to deliver σ-Pd(II) complex VII (Scheme 4) [66][67][68]. Intramolecular aryl C-H activation would furnish palladacycle VIII, which would undergo a coupling reaction to give rise to the new C3-C3a sigma bond of heterocycle IX.…”

“…Most of them demand the use of ortho -halogenated and ortho -vinylated N-protected anilines or nitrobenzenes to build the indole A ring. Recently, imine substrates have proven valuable for indole synthesis, as demonstrated by the groups of Yoshikai [ 66 ], Xiao [ 67 ], and Zhang [ 68 ] ( Scheme 1 b).…”