Pd(ii)-Catalyzed arylation of unactivated methylene C(sp³)–H bonds with aryl halides using a removable auxiliary

Abstract

A Pd(II)-catalyzed arylation of methylene C(sp(3))-H bonds in aliphatic amides directed by our newly developed PIP directing group with aryl iodides/bromides has been achieved. Arylation occurs efficiently with a broad range of aryl halides and amides.

Palladium(II)‐Catalyzed Enantioselective Arylation of Unbiased Methylene C(sp3)−H Bonds Enabled by a 2‐Pyridinylisopropyl Auxiliary and Chiral Phosphoric Acids

“…To achieve high enantioselectivity, the chiral ligands should be capable of creating a steric environment that induces stereocontrol and of accelerating or enabling the cleavage of C−H bonds . We previously disclosed a Pd‐catalyzed arylation of secondary C(sp 3 )−H bonds with aryl bromides assisted by our newly developed 2‐pyridinylisopropyl (PIP) auxiliary . The use of PivOH as the ligand significantly improved the reactivity [Eq.…”

“…To test this hypothesis, we commenced our investigations by replacing PivOH with L2 under reaction conditions that we had previously reported (Table ) . Thus, upon using butyric amide 1 a and p ‐acetylbromobenzene ( 2 a ) as the model system, the desired β‐arylation product 3 aa was afforded in 55 % yield and 30:70 e.r.…”

Intermolecular Amination of Unactivated C(sp3)−H Bonds with Cyclic Alkylamines: Formation of C(sp3)−N Bonds through Copper/Oxygen‐Mediated C(sp3)−H/N−H Activation

“…Next, we evaluated the potential of other known directing groups in assisting this transformation, including the perfluoroaniline, 2‐(pyridine‐2‐yl)‐isopropylamine, 2‐methylthioaniline, picolinamide, 2‐aminopyridine N ‐oxide, and 2‐(4,4‐dimethyl‐4,5‐dihydrooxazol‐2‐yl)aniline . We found that none of those groups were effective in directing the amination under the reaction conditions (see the Supporting Information).…”

α,α-Dimethyl-2-pyridinemethanamine

“…An alternative, yet reliable and scalable, procedure for the preparation of PIPamine was established according to the modification of a reported procedure using MeMgBr as the nucleophilic reagent. 2 To a solution of 2-cyanopyridine (33.0 g, 0.32 mol) in 500 mL of toluene was added CH 3 MgBr (3.2 M in 2-methyltetrahydrofuran, 300 mL, 0.96 mol) slowly at 0 • C under nitrogen (eq 2). Upon completion of the addition, the mixture was refluxed overnight.…”

“…12 Bromoalkynes can be used as the alternative alkynylation reagents when nickel was used as the catalyst. The nickelcatalyzed alkynylation of a broad range of benzamides with bromoalkynes proceeded efficiently with low nickel loading (0.5 mol % Ni(OTf) 2 More recently, a nickel-catalyzed oxidative alkynylation of (hetero)aromatic C-H bonds with terminal alkynes under atmospheric pressure of oxygen assisted by PIP auxiliary was disclosed. Relative to the previous copper-mediated oxidative alkynylation, this protocol features the use of catalytic amount of nickel as catalyst and oxygen as the sole oxidant.…”