Synthesis Of 2-Acylated Indoles Via Pd-Catalysis

Acylated indoles are important substructures in the chemical industry, they have also been frequently used as valuable intermediates for the synthesis of dyes, pharmaceuticals compounds and biologically active natural products. Some of them are shown to possess antidiabetic, anticancer and anti-HIV activities.Compared with 2-acylindoles, 3-acylindoles can be conveniently synthesized via Friedel-Crafts reaction, Vilsmeier-Haack reaction, indole Grignard reaction and transition metal catalyzed formylation. In addition they can be prepared via alternative procedures such as transition metal catalyzed formylation or acylations. For example, Wang recently disclosed an elegant copper-promoted decarboxylative C3-selective acylation of N-substituted indoles with ?-oxocarboxylic acids.The most common method for preparation of 2-acylindole is the Katritsky procedure. It involves the use of CO2 to protect the indole N-atom after the hydrogen on the nitrogen atom is abstracted with an organolithium reagent. This in situ protected indole will react further with a strong base such as t-Bu Li to generate a carboanion at the C2-position and the carboanion will subsequently react with an acyl electrophile to generate the desired 2-acylindole. Though the C2-acylation transformation is very efficient and can be run in one-pot fashion, the need to use CO2 and organolithium reagent makes it require stringent exclusion of air and moisture, thus making the reaction less user friendly. Moreover, the use of strong base can severely limit its reaction scope.Our main purpose is to use the high efficient catalyst of Pd for the synthesis of C2-Acylated indoles, it has a wide horizon of development in the rising market.This paper mainly describes: C2-Acylated indoles were synthesized in good yields via Pd-catalyzed dehydrogenative coupling of N-pyrimidine protected indoles using aldehydes or ethyl glyoxylate as the source of acyl reagent and TBHP as the oxidant. The major work and results are listed as following.(1) The author summarized the previous studies of synthesising 3-acylindoles and 2-acylindoles.(2) After examining various reaction conditions including solvent, reaction temperature, catalyst and ligands, the optimized reaction conditions for synthesis of2-acylindoles can be established as: 1 equiv of indoles, 1.5 equiv of p-methylbenzaldehyde, 2 ml of Et OAc as solvent, 10 mol% Pd(OAc)2 as catalyst, 2.0equiv of TBHP(anhydrous) as oxidant, under 125 o C and N2 for 24 hours.(3) With the optimized protocol in hand, we next set out to explore the scope and the limitation of the reaction. Based on literature and experimental results weproposed a possible mechanism to explain the reaction mechanism and then draw a conclusion.