Indole Construction from Simple Anilines and Ketones

chem 有机方法 4.6W+ 0

Indole Construction from Simple Anilines and Ketones  第1张

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.

Experimental Procedures

Indole Construction from Simple Anilines and Ketones  第2张

1a(49.2 mg, 0.4 mmol), Pd(OAc)2 (9.0 mg, 0.04 mmol), and 4 Å MS (80 mg) were added to a 25 mL Schlenk tube equipped with a
magnetic stirrer bar. After the air was evacuated and the tube was refilled with O2 for three times or more, 2a (92.8 mg, 0.8 mmol),
AcOH (96.0 mg, 1.6 mmol), and DMSO (2.0 mL) were added via syringe. The mixture was stirred at 70 °C for 18 h. Upon cooling to
room temperature, the reaction mixture was diluted with 10 mL of ethyl acetate and filtered through a pad of Celite using 5 mL of ethyl acetate as an additional eluent. The filtrate was washed with NaCl aqueous solution (3 × 10 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified through flash column chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 30:1) to afford 3aa (75.3 mg, 86% yield).


J. Org. Chem. 2018, 83, 23, 14472–14488

标签: Indole

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