peri-Disubstituted naphthalenes exhibit interesting physical properties and unique chemical reactivity, due to the parallel arrangement of the bonds to the two peri-disposed substituents. Regioselective installation of a functional group at the position peri to 1-substituted naphthalenes is challenging due to the steric interaction between the existing substituent and the position at which the second one would be installed. We report an iridium-catalyzed borylation of the C-H bond peri to a silyl group in naphthalenes and analogous polyaromatic hydrocarbons. The reaction occurs under mild conditions with wide functional group tolerance. The silyl group and the boryl group in the resulting products are precursors to a range of functional groups bound to the naphthalene ring through C-C, C-O, C-N, C-Br and C-Cl bonds.

Enantioselective reactions that install functional groups at the positions of unactivated C-H bonds can be envisioned to produce intermediates for the synthesis of the active ingredients in pharmaceuticals and agrochemicals directly from simple feedstocks. Among these C-H bond functionalization reactions, those that form carbon-silicon (C-Si) and carbon-boron (C-B) bonds have been pursued because the products of these reactions can be converted to those containing a wide range of functional groups and because compounds containing silicon and boron possess unique properties that can be valuable for medicinal and materials chemistry. Although the silylation and borylation of C-H bonds have undergone extensive development during the past two decades, enantioselective versions of these reactions were not known until a few years ago. In this Minireview, we present the rapid development of enantioselective silylation and borylation of C-H bonds, with an emphasis on the design and development of the types of chiral ligands needed to achieve these reactions and an intention to inspire an expansion of these types of transformations.

We report highly enantioselective intramolecular, silylations of unactivated, primary C(sp³)-H bonds. The reactions form dihydrobenzosiloles in high yields with excellent enantioselectivities by functionalization of enantiotopic methyl groups under mild conditions. The reaction is catalyzed by an iridium complex generated from [Ir(COD)OMe]₂ and chiral dinitrogen ligands that we recently disclosed. The C-Si bonds in the enantioenriched dihydrobenzosiloles were further transformed to C-Cl, C-Br, C-I, and C-O bonds in final products. The potential of this reaction was illustrated by sequential C(sp³)-H and C(sp²)-H silylations and functionalizations, as well as diastereoselective C-H silylations of a chiral, natural-product derivative containing multiple types of C-H bonds. Preliminary mechanistic studies suggest that C-H cleavage is the rate-determining step.

The functionalization of unactivated C(sp³)-H bonds of aliphatic amines catalyzed by transition-metal complexes is important because amine-based functionality is present in a majority of biologically active molecules and commercial pharmaceuticals. However, such reactions are underdeveloped and challenging to achieve in general because the basicity and reducing properties of alkylamines tends to interfere with potential reagents and catalysts. The functionalization of C-H bonds β to the nitrogen of aliphatic amines to form prevalent 1,2-amino functionalized structures is particularly challenging because the C-H bond β to nitrogen is stronger than the C-H bond α to nitrogen, and the nitrogen in the amine or its derivatives usually directs a catalyst to react at more distal γ- and δ-C-H bonds to form 5- or 6-membered metallacyclic intermediate. The enantioselective functionalization of a C-H bond at any position in amines also has been vexing and is currently limited to reactions of specific, sterically hindered, cyclic structures. We report iridium-catalyzed, β-selective silylations of unactivated C(sp³)-H bonds of aliphatic amines to form silapyrrolidines that are both silicon-containing analogs of common saturated nitrogen heterocycles and precursors to 1,2-amino alcohols by Tamao-Fleming oxidation. These silylations of amines are accomplished by introducing a simple methylene linker between the heteroatom and silicon that has not been used previously for the silylation of C-H bonds. The reactions occur with high enantioselectivity when catalyzed by complexes of new chiral, pyridyl imidazoline ligands, and the rates of reactions with catalysts of these highly basic ligands are particularly fast, occuring in some cases at or even below room temperature.

The selective functionalization of strong, typically inert carbon-hydrogen (C-H) bonds in organic molecules is changing synthetic chemistry. However, the undirected functionalization of primary C-H bonds without competing functionalization of secondary C-H bonds is rare. The borylation of alkyl C-H bonds has occurred previously with this selectivity, but slow rates required the substrate to be the solvent or in large excess. We report an iridium catalyst ligated by 2-methylphenanthroline with activity that enables, with the substrate as limiting reagent, undirected borylation of primary C-H bonds and, when primary C-H bonds are absent or blocked, borylation of strong secondary C-H bonds. Reactions at the resulting carbon-boron bond show how these borylations can lead to the installation of a wide range of carbon-carbon and carbon-heteroatom bonds at previously inaccessible positions of organic molecules.

Background

Th1 cells play an essential role in immune protection against tuberculosis. Th17 cells might be involved with immune pathology in active human tuberculosis (TB). The balance between Th1 and Th17 cells in patients with cavitary tuberculosis needs to be clarified which might help understanding the immunological basis of pathologic pathogenesis in TB.

Method

Initially treated pulmonary TB (PTB) patients with or without cavities were recruited before chemotherapy. We isolated peripheral blood mononuclear cells, stimulated with phytohemagglutinin (PHA), PPD, or ESAT-6 antigens, and assayed supernatant IFN-γ and IL-17 by ELISA after 24 or 72 hours incubation, respectively. Cells were also stained with antibodies to CD3, CD4, CD8, IFN-γ or IL-17 and the proportion of stained cells was measured by flow cytometry.

Results

We found wide variation of IFN-γ response in active PTB patients, but less subject-to-subject variation of IL-17 was observed as we previously reported. There were no significant differences in IFN-γ and IL-17 between cavitary and non-cavitary PTB; however, we found decreased IFN-γ secretion in severe cavitary PTB compared to mild lesion non-cavitary PTB (p < 0.05). We also found a decrease in the proportion of CD3+CD4+ T cells in the blood of severe cavitary PTB patients (p < 0.05).

Conclusions

IL-17 seemed to have no association with the formation of cavities in active PTB from the study of PBMC. Impaired IFN-γ without IL-17 enhancement occurs in peripheral blood during severe cavitary PTB. Our results demonstrate that M. tuberculosis antigen-specific Th1 response is decreased when PTB lesions develop to severe cavities.

Site-selective functionalizations of C-H bonds are often achieved with a directing group that leads to five- or six-membered metallacyclic intermediates. Analogous reactions that occur through four-membered metallacycles are rare. We report a challenging palladium-catalyzed oxidation of primary C-H bonds β to nitrogen in an imine of an aliphatic amine, a process that occurs through a four-membered palladacyclc intermediate. The success of the reaction relies on the identification, by H/D exchange, of a simple directing group (salicylaldehyde) capable of inducing the formation of this small ring. To gain insight into the steps of the catalytic cycle of this unusual oxidation reaction, a series of mechanistic experiments and density functional theory (DFT) calculations were conducted. The experimental studies showed that cleavage of the C-H bond is rate-limiting and formation of the strained four-membered palladacycle is thermodynamically uphill. DFT calculations corroborated these conclusions and suggested that the presence of an intramolecular hydrogen bond between the oxygen of the directing group and hydroxyl group of the ligating acetic acid is crucial for stabilization of the palladacyclic intermediate.

The borylation of C-H bonds catalyzed by transition metals has been investigated extensively in the past two decades, but no iridium-catalyzed enantioselective borylation of C-H bonds has been reported. We report a set of iridium-catalyzed enantioselective borylations of aromatic C-H bonds. This reaction relies on a set of newly developed chiral quinolyl oxazoline ligands. This process proceeds under mild conditions with good to excellent enantioselectivity, and the borylated products can be converted to enantioenriched derivatives containing new C-O, C-C, C-Cl, or C-Br bonds.

Iridium catalysts containing dative nitrogen ligands are highly active for the borylation and silylation of C-H bonds, but chiral analogs of these catalysts for enantioselective silylation reactions have not been developed. We report a new chiral pyridinyloxazoline ligand for enantioselective, intramolecular silylation of symmetrical diarylmethoxy diethylsilanes. Regioselective and enantioselective silylation of unsymmetrical substrates was also achieved in the presence of this newly developed system. Preliminary mechanistic studies imply that C-H bond cleavage is irreversible, but not the rate-determining step.