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... 

As one might expect from its inherent reactivity for the metallation of indole, the selective iridium-catalyzed monoborylation of indole at the C2 position proceeded efficiently to afford the corresponding boronate ester in 92% yield. A later report outlined the C7-borylation of indole in systems where the C2 position had been blocked with an alkyl or ester substituent. The need for a C2 substituent to achieve exclusive C7 borylation was obviated when a landmark report from the Hartwig laboratory detailed that indoles 92 could undergo C7-borylation when a silyl-directed... 

One year later Van der Eycken and Dehaen described the smooth microwave-assisted borylation of 4, 5, 6 and 7-bromo-lff-indole using PdCl2(dppf) as a precatalyst and KOAc as a base (Scheme 30) [48]. With 5, 6, and 7-bromo-lH-indole, DMSO was used as solvent at a temperature of 150 °C (with a set power of 150 W) for 17-27 min, resulting in the corresponding boronate esters in good yields. For 4-bromo-lH-indole, DME gave a better result at the same temperature (with a set power of 250 W). 

The Ir-catalyzed borylation of the indole nucleus is another important development that promises to find widespread use in complex molecule synthesis. Early reports include the functionalization of C(7) and also of C(2), reported by Malezcka and Smith and by Hartwig, respectively [39, 40]. In a report in 2011, Movassaghi, Miller, and coworkers demonstrated the borylation of tryptamine derivative 61 to afford 62 in 70 % yield [41]. This material was subjected to Suzuki-Miyaura cross coupling with 7-bromoindole (63) to set the stage for studying the oxidative rearrangement of 64, which would eventually provide diketopiperazine indole alkaloids such as asperazine (Scheme 11.11). 

The [Ir(OMe)(COD)]2/dtbpy catalytic system borylates indole selectively at the 2-position (Scheme 6). Smith and coworkers reported that borylation of N-unprotected 2-substituted indoles exclusively occurs at 7-position (Scheme 6) [85, 86]. It has been suggested that nitrogen interaction with the iridium center or possibly the empty p-orbital of boron in a boryl ligand induces the observed regioselectivity. Borylation of other heteroarenes have been reported using the same or similar Ir(I) and bipyridine combination [85, 87-90]. 

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... 

Iridium complexes generated from [IrCl(COD)]2 and 2,2 -bipyridine (bpy) catalyze the borylation of pyrrole and indole derivatives to yield the borylated products 788 in moderate to good yields (Equation 190) <2004JM021>. 

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. 

As mentioned in a previous section, the iridium-catalyzed borylation of 2-(substituted)indoles gave 7-(borylated)indoles [291]. 

Scheme 29 Ir-catalyzed C2-borylation and C3-borylation of IH-indole via a traceless Bpin directing group.

The reactive boronium ion (88) has been prepared from l,8-bis(dimethylamino) naphthalene and has been shown to be effective in the borylation of pyrrole and indole derivatives. Catechol-ligated borenium cations, such as (89), have also been used in the borylation of a range of anilines, thiophenes, and (V-heterocycles. ... 

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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