Copper(II)-Catalyzed Direct C–H (Hetero)arylation at the C3 Position of Indoles Assisted by a Removable N,N-Bidentate Auxiliary Moiety

Abstract

The regioselective arylation of inert C3−H bonds in indoles reacting with arylboronates via effective copper-mediated catalysis with the aid of a facile and removable 2-pyridinylisopropyl (PIP) group without ligand participation is reported. This newly established method features high compatibility with diverse functional groups between coupling partners, including both indole substrates and arylboron reagents, consequentially leading to operational simplicity and providing access to generate the desired arylated products in good to excellent yields of up to 97%. Synthetically, the PIP-derived amide moiety could subsequently be readily removed under mild reaction conditions to produce useful indole carboxylic acids for further transformation.

Copper‐Catalyzed C(sp2)−C(sp2) Bond Formation via Single C(sp2)−H Activation

“…During the same year, Chen and co-workers [40] developed a method for C3 arylation of substituted indoles 111 with aryl boronates 112 in a regioselective manner. The inexpensive ligand free copper catalyst was employed with amide-2pyridinylisopropy (PIP) as facile directing group and Ag 2 O as an oxidizing agent, under mild inert reaction conditions.…”

Regioselective Direct C−H Bond (Hetero)arylation of Thiazoles Enabled by a Novel Iminopyridine-Based α‐Diimine Nickel(II) Complex Evaluated by DFT Studies.

“…71 Regarding these optimized conditions, we only observed the C5 selectivity of thiazole derivatives upon direct C-H bond heteroarylation (see Figure S14 in SI), as observed in other studies, including the electrophilic palladation at C5 of thiazoles. 17,26,[29][30][31] Scheme 2. Evaluation of catalytic performance.…”

“…[1][2][3][4][5] Direct C−H bond arylation of heteroaromatics through transition metal catalytic systems has recently drawn significant attention. [2][3][6][7][8][9][10][11][12][13][14][15][16][17] Compared to traditional Negishi, Suzuki, or Stille cross-coupling for making (hetero)aryl compounds, direct arylation offers atom-economical and facile synthetic methods. 3,8,[18][19] Consequently, this synthetic tool has emerged as the most desirable technique for synthesizing small molecules, and building blocks containing five-membered heteroaromatics including thiazoles.…”

Regioselective Direct C–H Bond Heteroarylation of Thiazoles Enabled by an Iminopyridine-Based α-Diimine Nickel(II) Complex Evaluated by DFT Studies

“…However, the environmental and financial costs associated withPd systems have led the research community to explore more sustainable choices. Accordingly, Ni-based systems are gaining popularity because of their reduced toxicity and cost. - Nonetheless, many Pd- and Ni-catalyzed systems are air- and moisture-sensitive. ,,, Moreover, both Pd and Ni systems often require in situ catalyst generation from expensive precursors. , Furthermore, these systems greatly suffer from a high catalyst loading (5–10 mol %), longer reaction time (12–36 h), high temperature (100–150 °C), , and time-consuming ligand synthesis …”