Borylated pyrrole

An iridium(l) complex, generated from l/2[Ir(OMe)(COD)]2 and 4,4 -di-/-butyl-2,2 -bipyridine (dtbpy), catalyzed the direct borylation of 2-substituted pyrroles in stoichiometric amounts relative to 2,2 -bi-l,3,2-dioxaborolane 785 in hexane at room temperature (Equation 188) <2003ASC1103>. The pyrrolylborates 786 from regioselective C-H activation at the 5-position were formed in high yields. Similar borylation of unsubstituted pyrrole with an equimolar amount of borolane 785 regioselectively provided 2,5-bis(boryl)pyrrole 787 (Equation 189). 

Borylated pyrrole 88 was prepared by Oestreich by treatment of the corresponding pyrrole with pinacolborane and a ruthenium(II) thiolate complex. The direct synthesis of 88 promises to find wide utility in medicinal chemistry and was applied to a variety of substituted indoles (13JA10978). N-Methylpyrrole was directly arylated at room temperature by photoredox catalysis with diaryliodonium salts to furnish 89 in 84% yield (13SL507). 

Interestingly, a similar method can be used for the synthesis of 3-borylated pyrroles 24 from enamides and internal alkyne AT-methyliminodiacetic acid (MIDA) boronates (Eq, (5.23)) [17]. Product 24a undergoes Suzuki-Miyaura coupling with bromobenzene to give 24c in good yield, with a concomitant removal of the acetyl group. 

Scheme 11.10 Pyrrole borylation in the synthesis of rhazinicine by Gaunt...

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... 

The C-H coupling of aromatic heterocycles with bis(pinacolato)di-borane(4) was carried out in octane at 80-100 °C in the presence of a half equivalent [IrCl(COD)]2-(4,4 -di-tert-butyl-2,2 -bipyridine) catalyst (3 mol%). The reactions of five-membered substrates such as thiophene, furan, pyrrole, and their benzo-fused derivatives exclusively produced 2-borylated... 

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>. 

The formation of borylated heterocyclic componnds has attracted mnch interest with regard to their use as starting materials for cross-conpling reactions, the possible formation of interesting macrocyclic species, and their applications in optoelectronic materials. Several synthetic routes are available for the borylation of the five-membered heterocycles thiophene, furan, pyrrole, and related componnds (101-103 ... 

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. 

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

They found that combination of the Ir(T) catalyzed C-H borylation and Suzuki coupling sequence led to a two-step, one-pot C-H Suzuki arylation that enabled direct transformation of the N-Boc pyrrole to the C3 arylated intermediate in 78% yield. Following installation of the required acyl group, an application of their oxidative Pd-catalyzed C-H alkenylation reaction enabled formation of the key structural architecture of the natural deliver the natural product. The orthogonal selectivity characteristics displayed by these C-H functionalization processes makes possible iterative functionalization of the heteroaromatic pyrrole core. Utilization of the highly versatile C-H borylation - Suzuki coupling to install the aromatic functionality opens up possibilities of facile analogue synthesis via this route. 

In terms of C-3 substitution reactions, the regioscleclive borylation of 1-triisopropylsilyl-pyrrole (77) was achieved providing a valuable reagent for cross-coupling reactions <01OL2831>. Thus, reaction of 77 with the rhodium precatalyst shown in the presence of pinacolborane affords the C-3 substituted derivative 78. 

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. ... 

The iridium-catalyzed borylation of C—H bonds has established itself as a reliable method for heteroaromatic functionalization. The borylation of pyrrole tends to occur at the most acidic C—H bond treatment of l f-pyrrole (1) with B2pin2 (pin = Me4C202) occurs at the C2 position to afford heteroarylboronate 26 in 80% yield (Scheme 10.7). Traditional cross-coupling methods can then be used to convert the C—B bond into a C—C bond. A one-pot, two-step process for this transformation was realized in 2008 by Miyaura and co-workers 26 could be prepared in situ from reaction of 177-pyrrole (1) and an alkoxyborane (either B2pin2 or HBpin), and subsequently trapped with 2-bromothiophene to allow access to bis-heterocycle 27 in 93% yield. ... 

It has been previously shown that the regioselectivity of pyrrole borylation can be switched from C2 to C3 if the nitrogen is TIPS or Boc protected. More recently, however, Maleczka and Smith described a very useful method that circumvents the installation and removal steps required for pyrrole protection (Scheme 10.8). The researchers demonstrated that 177-pyrrole (1) could be exclusively borylated at the C3 position (29) when Bpin was employed as a traceless directing group. As the AH of pyrrole is not particnlarly acidic, triethylamine was added to the reaction mixture to make the B—H bond in HBpin more hydridic and ensure successful A-borylation. 

Beyond arylation, pyrroles can also be borylated with iridium catalysts using either pinacol borane or bis(pinacolato)diboron (eq 14). These products can then be carried on for further functionalization. In this case, a-ketoesters are also thought to coordinate to zirconium in a bidentate fashion. 

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