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

Abstract

A Ru-catalyzed direct arylation of benzylic sp(3) carbons of acyclic amines with arylboronates is reported. This highly regioselective and efficient transformation can be performed with various combinations of N-(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.

Ligand‐Promoted meta‐C−H Functionalization of Benzylamines

“…It is worth noting that the loading of Pd catalyst can be reduced to 2.5 mol% at this scale. Importantly, the directing group can be easily removed following a modified known procedure 9 to afford the N -Boc benzylamine 7 in 91% yield, a key intermediate to access the RPR 128515 analogues. 6a …”

Palladium-Catalyzed Benzylic C–H Arylation of Azaarylmethylamines

“…Transition-metal-catalyzed cross-coupling reactions also represent an attractive approach. 7d The direct C–H functionalization of amino alkyl moieties (R’C H 2 NR 2 ), however, is challenging 9 . Therefore, activated substrates, such as Boc-protected amines, ketimines, and ( η 6 -benzylamine)Cr(CO) 3 complexes, have been employed to facilitate deprotonation of C–H bonds adjacent to nitrogen (Figure 2).…”

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

“…However, intensive screening of the conditions afforded no higher conversion until we discovered that the installation of a substituent in the 3-position of pyridine enhanced the conversion significantly, which was described in our previously published study containing preliminary results (Scheme 2). 10 The crucial role of the substituent in 3-position was also described by Jun and co-workers. 11 When the direct arylation was carried out with 4a , a much higher conversion (85%) could be achieved compared to the reaction with 1a .…”

“…10 This ester is also most convenient in the reaction workup since it can be hydrolyzed easily to the boronic acid, facilitating chromatographic purification of the product.…”