Nickel-Catalyzed Cross-Electrophile Coupling of Aryl Triflates with Alkyl Halides: Mechanism-Informed Design of More General Conditions.

Aryl triflates make up a class of aryl electrophiles that are available in a single step from the corresponding phenol. Despite the known reactivity of nickel complexes for aryl C-O bond activation of phenol derivatives, nickel-catalyzed cross-electrophile coupling using aryl triflates has proven challenging. Herein, we report a method to form C(sp)-C(sp) bonds by coupling aryl triflates with alkyl bromides and chlorides using phenanthroline (phen) or pyridine-2,6-bis(-cyanocarboxamidine) (PyBCam)-ligated nickel catalysts.

Alkene Carboxy-Alkylation via CO

Herein, we introduce a new platform for alkene carboxy-alkylation. This reaction is designed around CO addition to alkenes followed by radical polar crossover, which enables alkylation through carbanion attack on carbonyl electrophiles. We discovered that CO adds to alkenes faster than it reduces carbonyl electrophiles and that this reactivity can be exploited by accessing CO via hydrogen atom transfer from formate.

Mannich-Type Condensation and Domino Quinazolinone-Amidine Rearrangement Affords Ring-Fused Mackinazolinones with Anti-Amoebic Activity.

A three-step synthesis of anti-amoebic, ring-fused mackinazolinones has been developed. A Mannich-type reaction between quinazolin-4-ones and -Cbz propanal in the presence of AgOTf afforded quinazolinones (19-94% isolated yield) bearing a newly formed heterocycle with an alkylamine appendage that, upon -Cbz deprotection and basification, triggered a domino rearrangement to afford 45 separable, ring-fused products. Several compounds inhibited growth of parasites that can cause a lethal human brain infection.

Decarboxylative Cross-Coupling Enabled by Fe and Ni Metallaphotoredox Catalysis.

Decarboxylative cross-coupling of carboxylic acids and aryl halides has become a key transformation in organic synthesis to form C(sp)-C(sp) bonds. In this report, a base metal pairing between Fe and Ni has been developed with complementary reactivity to the well-established Ir and Ni metallaphotoredox reactions. Utilizing an inexpensive FeCl cocatalyst along with a pyridine carboxamidine Ni catalyst, a range of aryl iodides can be preferentially coupled to carboxylic acids over boronic acid esters, triflates, chlorides, and even bromides in high yields.

Pharmacophore Establishment and Optimization of Saturated 1,6-Naphthyridine-Fused Quinazolinones that Inhibit Meningoencephalitis-Causing .

Primary amoebic meningoencephalitis (PAM) is a human brain infection caused by with a 97% mortality rate. Quinazolinones resulting from a Mannich-coupled domino rearrangement were recently identified as inhibitors of the amoeba. Herein, we resolved the effective concentrations for 25 pilot compounds and then, using the Mannich protocol and a key late-stage, -demethylation/functionalization, we synthesized 53 additional analogs to improve potency, solubility and microsomal stability.