Rh(III)-Catalyzed C–H Functionalization of Indolines with Readily Accessible Amidating Reagent: Synthesis and Anticancer Evaluation

Abstract

The rhodium­(III)-catalyzed direct C–H functionalization of various indolines with 1,4,2-dioxazol-5-ones as new amidating agents is described. This transformation provides efficient preparation of C7-amidated indolines known to display potent anticancer activity. The synthetic compounds were evaluated for in vitro anticancer activity against human prostate adenocarcinoma cells (LNCaP), human endometrial adenocarcinoma cells (Ishikawa), and human ovarian carcinoma cells (SKOV3). Compound 4f was found to be highly cytotoxic, with activity competitive with that of anticancer agent doxorubicin.

Mechanism‐Driven Approach To Develop a Mild and Versatile C−H Amidation through IrIII Catalysis

“…Carboxylic acidw as found to serve as an effective directing group in the current CÀHa midation with dioxazolone. Indeed, benzoica cids, 2-thiophenecarboxylic acid, and methacrylic acid were all amidated in satisfactory yields (10)(11)(12). Again, the amidation efficiency in reactions of these carboxylic acids with azide was seen to be much poorer.I na ddition, amidationo f N,N-dimethylphenyl carbamate occurred smoothly (13).…”

“…[8a] We demonstrated that ar hodacyclicc omplex was successfully coupled with sulfonyl azides, affording CÀNc oupled Rh-amido complex at elevated temperature. [8d] This notable outcome inspired extensive subsequents tudies with dioxazolones as the amide source, especiallyf ocusing on the development of Rh III , [10] Ru II , [11] or Co III[12] catalysts, leading to broad applicationsi nt he facile preparation of synthetic valuables. Detailed mechanistic studies strongly corroborated the involvemento fo rganometallic Rh V and Ir V -imido species as the key intermediates.…”

“…Detailed mechanistic studies strongly corroborated the involvemento fo rganometallic Rh V and Ir V -imido species as the key intermediates. [8d] This notable outcome inspired extensive subsequents tudies with dioxazolones as the amide source, especiallyf ocusing on the development of Rh III , [10] Ru II , [11] or Co III[12] catalysts, leading to broad applicationsi nt he facile preparation of synthetic valuables. [13] Althoughd ioxazolones have been under the spotlightr ecently,t he origin of high catalytic activity is underexplored.…”

A comprehensive overview of directing groups applied in metal-catalysed C–H functionalisation chemistry

“…Substituted dioxazolones were instead employed for the carboxyamidation of indolines at the C7 position at room temperature (or 80 °C for several examples, Scheme 144B ). 853 The reaction proceeds giving generally good yields. Interestingly, the reaction proved efficient on tetrahydroquinoline as well, a not commonly studied substrate.…”

RuII‐Catalysed Regioselective C–N Bond Formation of Indolines and Carbazole with Acyl Azides

“…In contrast, the formation of acyl amide with indoline using C–H functionalization is limited, which may be due to the competitive Curtius rearrangement with acyl azides that can lead to C–C bond formation . Recently, Kim and co‐workers reported a Rh‐catalysed coupling of dioxazolones with indolines to give acyl amides,[10a] while Prabhu group accomplished the transformation utilizing Ru‐catalysis (Scheme a). [10b] Li group showed a few examples for the acetyl chelated direct coupling of acyl azide with indoline under Ir‐catalysis devoid of Curtius rearrangement (Scheme b).…”