C—H borylation of indoles

Scheme 35 Regioselective Ir(I)-catalyzed C-H borylation of indoles and pyrroles...

C—H borylation of indoles has been reported by a number of groups. Chirik and coworkers utilized pincer-ligated cobalt complexes with N-methyhndole and recorded the C-2 borylated indole (133) as the major product (2014JAC4133). The catalysts employed demonstrated high catalysis turnover and low catalytic loading and also demonstrated efficacy with other electron-rich heteroarenes (furan, thiophene, benzofuran) as well as electron-deficient pyridines. More recendy, platinum-NHC complexes have been used in the selective C—H borylation of indoles (2015JAC12211). The authors reported higher isolated yields with this... 

Scheme 16.6 Synthesis of hippadine enabled by C-H borylation of an indole at the C7 position.

Although not a palladium-catalyzed reaction, the Ir(I)-catalyzed C-H borylation reaction developed independently by Smith and Malezcka [58] and Hartwig and Miyaura [59] deserves some mention in the context of indole and pyrrole functionalization. Based on the original studies, indoles and pyrroles can be borylated (and hence cross coupled under Suzuki conditions) to form either the C2 or C3 functionalised products (Scheme 35) [60, 61]. Free (NH)-indoles and pyrroles react exclusively at the C2, whereas /V-TIPS indole and pyrroles are borylated at the C3 positions. Interestingly, Smith, Maleczka and co-workers also demonstrated that when the C2 position of indole is blocked, then the borylation reaction takes place at the C7-position of the indole nucleus [62]. They propose that an A-chelation to Ir (or B) is responsible for the observed selectivity. 

Although not fitting exactly into the scope of this book, the iridium catalyzed borylation of five membered heterocycles through C-H bond activation also deserves mentioning. A recent report by Miyaura disclosed the reaction of bis(pinacolato)diboron with heteroaromatic systems, where thiophene, fiirane and pyrrole were converted to their 2-boryl derivatives with good selectivity (6.86.), The yields presented refer to the diboron compound since the heterocycles were used in excess in all cases. Indole, benzofurane and benzothiophene were monoborylated with similar efficiency.116... 

Shen in 2012 reported an Ir/Cu synergistic catalytic C—H bond activation for the one-pot trifluoromethylation reaction (Scheme 9.19). This catalytic process involves sequential iridium-catalyzed C—activation borylation and copper-catalyzed trifluoromethylation of arenes with a variety of functional groups. This tandem procedure was successfully applied to the 2,6-disubstituted pyridine, benzofuran, benzothiazole, indole, and substituted quinoline systems. 

Interestingly, [IrCl(cod)]2 did not catalyze the reaction. The [Ir(OMe)(cod)]2]/dtbpy catalytic system in nonpolar solvents such as hexane was found to be very effective for the synthesis of arylboronates, using stoichiometric amounts of arene and pin2fi2 at room temperature (Table 1). The borylation t) ically occurs at the para or meta position with respect to the functional groups on the arene. The ortho C-H positions are less active due to the steric hindrance. In addition, the electronic effect plays a minor role, where the electron-poor carbon seems to be more active. This allows the reaction to occur regiospecifically (Table 1). For example, the borylation of 1,3-disubstituted arenes selectively occurs at the common meta position, while the borylation of heterocycles such as benzo[l)]thiophene, benzo[fc]furan, or indole occurs selectively at the 2-position (Table 1). 

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