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Iridium-Catalyzed Silylation of Five-Membered Heteroarenes: High Sterically Derived Selectivity from a Pyridyl-Imidazoline Ligand.

ABSTRACT: The steric effects of substituents on five-membered rings are less pronounced than those on six-membered rings because of the difference in bond angles. Thus, the regioselectivities of reactions that occur with selectivities dictated by steric effects, such as the borylation of C-H bonds, have been poor in many cases. We report that the silylation of five-membered ring heteroarenes occurs with high sterically derived regioselectivity when catalyzed by the combination of [Ir(cod)(OMe)]₂ and a phenanthroline ligand or a new pyridyl-imidazoline ligand that further increases the regioselectivity. The silylation reactions with these catalysts produce high yields of heteroarylsilanes from functionalization at the most sterically accessible C-H bonds of these rings under conditions that the borylation of C-H bonds with previously reported catalysts formed mixtures of products or products that are unstable. The heteroarylsilane products undergo cross-coupling reactions and substitution reactions with ipso selectivity to generate heteroarenes that bear halogen, aryl and perfluoroalkyl substituents.

SUBMITTER: Karmel C

PROVIDER: S-EPMC7566956 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Iridium-Catalyzed Silylation of C-H Bonds in Unactivated Arenes: A Sterically Encumbered Phenanthroline Ligand Accelerates Catalysis.

Project description:We report a new system for the silylation of aryl C-H bonds. The combination of [Ir(cod)(OMe)]2 and 2,9-Me2-phenanthroline (2,9-Me2-phen) catalyzes the silylation of arenes at lower temperatures and with faster rates than those reported previously, when the hydrogen byproduct is removed, and with high functional group tolerance and regioselectivity. Inhibition of reactions by the H2 byproduct is shown to limit the silylation of aryl C-H bonds in the presence of the most active catalysts, thereby masking their high activity. Analysis of initial rates uncovered the high reactivity of the catalyst containing the sterically hindered 2,9-Me2-phen ligand but accompanying rapid inhibition by hydrogen. With this catalyst, under a flow of nitrogen to remove hydrogen, electron-rich arenes, including those containing sensitive functional groups, undergo silylation in high yield for the first time, and arenes that underwent silylation with prior catalysts react over much shorter times with lower catalyst loadings. The synthetic value of this methodology is demonstrated by the preparation of key intermediates in the synthesis of medicinally important compounds in concise sequences comprising silylation and functionalization. Mechanistic studies demonstrate that the cleavage of the aryl C-H bond is reversible and that the higher rates observed with the 2,9-Me2-phen ligand are due to a more thermodynamically favorable oxidative addition of aryl C-H bonds.

| S-EPMC6839914 | biostudies-literature

Mechanistic Studies of Cobalt-Catalyzed C(sp2)-H Borylation of Five-Membered Heteroarenes with Pinacolborane.

Project description:Studies into the mechanism of cobalt-catalyzed C(sp2)-H borylation of five-membered heteroarenes with pinacolborane (HBPin) as the boron source established the catalyst resting state as the trans-cobalt(III) dihydride boryl, (iPrPNP)Co(H)2(BPin) (iPrPNP = 2,6-(iPr2PCH2)2(C5H3N)), at both low and high substrate conversions. The overall first-order rate law and observation of a normal deuterium kinetic isotope effect on the borylation of benzofuran versus benzofuran-2-d1 support H2 reductive elimination from the cobalt(III) dihydride boryl as the turnover-limiting step. These findings stand in contrast to that established previously for the borylation of 2,6-lutidine with the same cobalt precatalyst, where borylation of the 4-position of the pincer occurred faster than the substrate turnover and arene C-H activation by a cobalt(I) boryl is turnover-limiting. Evaluation of the catalytic activity of different cobalt precursors in the C-H borylation of benzofuran with HBPin established that the ligand design principles for C- H borylation depend on the identities of both the arene and the boron reagent used: electron-donating groups improve catalytic activity of the borylation of pyridines and arenes with B2Pin2, whereas electron-withdrawing groups improve catalytic activity of the borylation of five-membered heteroarenes with HBPin. Catalyst deactivation by P-C bond cleavage from a cobalt(I) hydride was observed in the C-H borylation of arene substrates with C-H bonds that are less acidic than those of five-membered heteroarenes using HBPin and explains the requirement of B2Pin2 to achieve synthetically useful yields with these arene substrates.

| S-EPMC5822728 | biostudies-literature

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| S-EPMC3135680 | biostudies-literature

Iridium Complex-Catalyzed Transfer Hydrogenation of N-Heteroarenes and Tentative Asymmetric Synthesis.

Project description:An iridium-catalyzed transfer hydrogenation of N-heteroarenes to access a series of substituted 1,2,3,4-tetrahydroquinoline derivatives in excellent yields is disclosed. This transformation is distinguished with water-soluble and air-stable iridium complexes as the catalyst, formic acid as the hydrogen source, mild reaction conditions, and broad functional group compatibility. Most importantly, a tentative chiral N,N-chelated Cp*Ir(III) complex-catalyzed enantioselective transfer hydrogenation is also presented, affording chiral products in excellent yields and good enantioselectivities.

| S-EPMC8153796 | biostudies-literature

A Chiral Nitrogen Ligand for Enantioselective, Iridium-Catalyzed Silylation of Aromatic C-H Bonds.

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| S-EPMC5293510 | biostudies-literature

Sterically Controlled C-H Olefination of Heteroarenes.

Project description:The regioselective functionalization of heteroarenes is a highly attractive synthetic target due to the prevalence of multiply substituted heteroarenes in nature and bioactive compounds. Some substitution patterns remain challenging: While highly efficient methods for the C2-selective olefination of 3-substituted five-membered heteroarenes have been reported, analogous methods to access the 5-olefinated products have remained limited by poor regioselectivities and/or the requirement to use an excess of the valuable heteroarene starting material. Herein we report a sterically controlled C-H olefination using heteroarenes as the limiting reagent. The method enables the highly C5-selective olefination of a wide range of heteroarenes and is shown to be useful in the context of late-stage functionalization.

| S-EPMC7384109 | biostudies-literature

Palladium-catalyzed amination of unprotected five-membered heterocyclic bromides.

Project description:An efficient method for the palladium-catalyzed amination of unprotected bromoimidazoles and bromopyrazoles is presented. The transformation is facilitated by the use of our newly developed Pd precatalyst based on the bulky biarylphosphine ligand tBuBrettPhos (L4). The mild reaction conditions employed allow for the preparation of a broad scope of aminoimidazoles and aminopyrazoles in moderate to excellent yields.

| S-EPMC3983327 | biostudies-literature

Phosphorus(III)-assisted regioselective C-H silylation of heteroarenes.

Project description:Heteroarenes containing carbon-silicon (C-Si) bonds are important building blocks that play an important role in the construction of natural products, pharmaceuticals, and organic materials. In this context, the C-H silylation of heteroarenes is a topic of intense interest. Indole C-H silylation can preferentially occur at the nucleophilic C3 and C2 position (pyrrole core), while accessing the C4-C7 positions (benzene core) of the indole remains highly challenging. Here, we show a general strategy for the regioselective C7-H silylation of indole derivatives. Mainly, the regioselectivity is determined by strong coordination of the palladium catalyst with phosphorus (III) directing group. Using this expedient synthetic strategy, the diverse C7-silylated indoles are synthesized effectively which exhibits the broad functional group compatibility. Moreover, this protocol also been extended to other heteroarenes such as carbazoles. The obtained silylated indoles have been employed in various transformations to enable the corresponding differently functionalized indole derivatives. Significantly, a cyclopalladated intermediate is successfully synthesized to test the hypothesis about the P(III)-directed C-H metalation event. A series of mechanistic experiments and density functional theory (M06-2X) calculations has shown the preferred pathway of this directed C-H silylation process.

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Photocatalytic C-H silylation of heteroarenes by using trialkylhydrosilanes.

Project description:The efficient and selective C-H silylation of heteroarenes, especially the pharmaceutically relevant electron-deficient heteroarenes, represents a great challenge in organic synthesis. Herein we wish to report a distinctive visible light-promoted photocatalytic C-H silylation approach that enables the direct coupling of trialkylhydrosilanes with both electron-deficient and -rich heteroarenes as well as with cyano-substituted arenes in moderate to high yields and with good regioselectivity. The protocol features operational simplicity, mild reaction conditions, and the use of safe and readily available Na2S2O8, bis(trimethylsilyl) peroxide (BTMSPO) or iPr3SiSH as the radical initiators. Notably, the challenging bulky and inert trialkylhydrosilanes, such as (t-butyldimethyl)silane ( t BuMe2SiH) and (triisopropyl)silane (iPr3SiH), work smoothly with the protocol. Moreover, despite the higher stability of t BuMe2Si silylation products, our studies revealed their great reactivity and versatility in diverse C-Si-based chemical transformations, providing an operationally simple, low-cost, and environmentally benign synthetic technology for molecule construction and elaboration.

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