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

Abstract

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.

Aryl Bromides and Aryl Chlorides for the Direct Arylation of Benzylic Amines Mediated by Ruthenium(II)

“…N ‐Benzyl‐3‐phenylpyridin‐2‐amine (1b): 21 The reaction was carried out according to general procedure I with N ‐benzyl‐3‐chloropyridin‐2‐amine obtained from the above protocol (219 mg, 1 mmol, 1 equiv. ), phenylboronic acid (366 mg, 3 mmol, 3 equiv.…”

“…3‐Methyl‐ N ‐[4‐(trifluoromethyl)benzyl]pyridin‐2‐amine (1g): 21 The reaction was carried out according to general procedure I with 2‐chloro‐3‐methylpyridine (128 mg, 1 mmol, 1 equiv. ), [4‐(trifluoromethyl)phenyl]methanamine (210 mg, 1.2 mmol, 1.2 equiv.…”

“…N ‐{[4‐( tert ‐Butyl)phenyl](phenyl)methyl}‐3‐methylpyridin‐2‐amine (3h): 21 The reaction was carried out according to general procedure III with 1a (99 mg, 0.5 mmol, 1 equiv. ), 1‐bromo‐4‐( tert ‐butyl)benzene (160 mg, 0.75 mmol, 1.5 equiv.…”

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

“…A very useful and general method to achieve catalytic C–H activation is cyclometalation, which employs the aid of a nearby coordinating group to direct the catalyst selectively to one specific C–H bond to be activated and functionalized. 4 Our group recently reported several useful methods for the C–H activation of benzylic sp 3 C–H bonds directed by 3-substituted pyridin-2-yls, including Ru(0)-catalyzed arylation employing arylboronates 5 and Ru(II)-catalyzed arylation of benzylic amines with aryl halides. 6 Herein, we report detailed mechanistic investigations into a Rh(I)-catalyzed method to alkylate benzylic amines using either alkyl bromides or alkenes.…”

Direct synthesis of ruthenium catalyst precursors from ammonium (oxide) chloride salts via hydrothermal reaction

“…One of the major ruthenium catalysts/intermediates is polymeric di-l-chloro(g 4 -1,5-cyclooctadiene)ruthenium(II), [RuCl 2 (COD)] x , which has been used to catalyze many reactions including cyclizations [12], arylation [13][14][15], amidation [16], and hydrogenations [17]. In addition, ruthenium alkylidene complexes typical of ''Grubbs-type'' olefin metathesis catalysts are synthesized from [RuCl 2 (COD)] x (Scheme 2) [18].…”