Copper-Catalyzed Chan-Lam Cyclopropylation of Phenols and Azaheterocycles.

Small molecules containing cyclopropane-heteroatom linkages are commonly needed in medicinal chemistry campaigns yet are problematic to prepare using existing methods. To address this issue, a scalable Chan-Lam cyclopropylation reaction using potassium cyclopropyl trifluoroborate has been developed. With phenol nucleophiles, the reaction effects O-cyclopropylation, whereas with 2-pyridones, 2-hydroxybenzimidazoles, and 2-aminopyridines the reaction brings about N-cyclopropylation. The transformation is catalyzed by Cu(OAc)2 and 1,10-phenanthroline and employs 1 atm of O2 as the terminal oxidant. This method is operationally convenient to perform and provides a simple, strategic disconnection toward the synthesis of cyclopropyl aryl ethers and cyclopropyl amine derivatives bearing an array of functional groups.

Nickel-Catalyzed ß,γ-Dicarbofunctionalization of Alkenyl Carbonyl Compounds via Conjunctive Cross-Coupling.

A nickel-catalyzed conjunctive cross-coupling between non-conjugated alkenes, aryl iodides, and alkylzinc reagents is reported. Excellent regiocontrol is achieved utilizing an 8-aminoquinoline directing group that can be readily cleaved to unmask net ß,γ-dicarbofunctionalized carboxylic acid products. Under optimized conditions, both terminal and internal alkene substrates provided the corresponding alkyl/aryl difunctionalized products in moderate to excellent yields. The methodology developed herein represents the first three-component 1,2-dicarbofunctionalization of non-conjugated alkenes involving a C(sp3)-C(sp3) reductive elimination step.

Palladium(II)-Catalyzed Directed anti-Hydrochlorination of Unactivated Alkynes with HCl.

A regioselective anti-hydrochlorination of unactivated alkynes is reported. The reaction utilizes in situ generated HCl as the source of both the Cl- and H+ and is catalyzed by palladium(II) acetate, with loadings as low as 25 ppm. Removable picolinamide and 8-aminoquinoline bidentate directing groups are used to control the regioselectivity of the chloropalladation step and stabilize the resulting alkenylpalladium(II) intermediate for subsequent protodepalladation. This method provides access to a broad array of substituted alkenyl chlorides in excellent yields and with high regioselectivity. The products from this transformation were successfully derivatized via Stille coupling to a variety of trisubstituted alkene products. Reaction progress kinetic analysis was performed, shedding light on a possible mechanism for this catalytic process.