Ruthenium(0)-Catalyzed sp³ C–H Bond Arylation of Benzylic Amines Using Arylboronates

A Ru-catalyzed direct arylation of benzylic sp³ carbons of acyclic amines with arylboronates is reported. This highly regioselective and efficient transformation can be performed with various combinations of <i>N</i>-(2-pyridyl) substituted benzylamines and arylboronates. Substitution of the pyridine directing group in the 3-position proved to be crucial in order to achieve high arylation yields. Furthermore, the pyridine directing group can be removed in high yields via a two-step protocol

Ruthenium(II)-Catalyzed sp³ C–H Bond Arylation of Benzylic Amines Using Aryl Halides

A ruthenium(II)-catalyzed protocol for the direct arylation of benzylic amines was developed. Employing 3-substituted pyridines as directing groups, arylation was achieved using aryl bromides or aryl iodides as the aryl source. Potassium pivalate proved to be an important additive in this transformation. The arylation took place selectively in the benzylic sp³ position, and no significant competitive sp² arylation was observed. Arylated imines were observed as byproducts in minor amounts. Additionally, reaction conditions for cleaving the pyridine group were established, enabling access to bis-arylated methylamines

Cross-Coupling of Remote <i>meta</i>-C–H Bonds Directed by a U‑Shaped Template

<i>meta</i>-C–H arylation and methylation of 3-phenylpropanoic acid and phenolic derivatives were developed using an easily removable nitrile template. The combination of a weakly coordinating U-shaped template and mono-protected amino acid ligand was crucial for the cross-coupling of C–H bonds with organoborons

Mechanistic Investigations and Substrate Scope Evaluation of Ruthenium-Catalyzed Direct sp³ Arylation of Benzylic Positions Directed by 3‑Substituted Pyridines

A highly efficient direct arylation process of benzylic amines with arylboronates was developed that employs Ru catalysis. The arylation takes place with greatest efficiency at the benzylic sp³ carbon. If the distance to the activating aryl ring is increased, arylation is still possible but the yield drops significantly. Efficiency of the CH activation was found to be significantly increased by use of 3-substituted pyridines as directing groups, which can be removed after the transformation in high yield. Calculation of the energy profile of different rotamers of the substrate revealed that presence of a substituent in the 3-position favors a conformation with the CH₂ group adopting a position in closer proximity to the directing group and facilitating C–H insertion. This operationally simple reaction can be carried out in argon atmosphere as well as in air and under neutral reaction conditions, displaying a remarkable functional group tolerance. Mechanistic studies were carried out and critically compared to mechanistic reports of related transformations

Monoselective <i>o</i>‑C–H Functionalizations of Mandelic Acid and α‑Phenylglycine

Pd-catalyzed C–H functionalization of mandelic acid and α-phenylglycine is reported. We have developed different protocols for the arylation, iodination, acetoxylation, and olefination of these substrates based on two different (Pd­(II)/Pd­(IV) and Pd­(II)/Pd(0)) catalytic cycles. Four crucial features of these protocols are advantageous for practical applications. First, the α-hydroxyl and amino groups are protected with simple protecting groups such as acetates (Ac, Piv) and carbamates (Boc, Fmoc), respectively. Second, these protocols do not involve installation and removal of a directing group. Third, monoselectivity is accomplished. Fourth, no epimerization occurs at the vulnerable α-chiral centers

Mechanistic and Kinetic Studies of the Direct Alkylation of Benzylic Amines: A Formal C(sp³)–H Activation Proceeds Actually via a C(sp²)–H Activation Pathway

Mechanistic investigations of a Rh­(I)-catalyzed direct C–H alkylation of benzylic amines with alkenes, formally an C­(sp³)–H activation, reveal this reaction to proceed via imine intermediates and, hence, via C­(sp²)–H activation. The reaction shows a primary kinetic isotope effect of 4.3 at the benzylic C–H position together with a reversible H–D exchange at the same position, which indicates that there are at least two distinct steps in which the corresponding C–H bonds are broken. The imine intermediates are shown to be converted to the final product under the reaction conditions, and a time course analysis of the alkylated imine intermediate shows that it is formed before the final amine product in the course of the reaction