Cu-Catalyzed Couplings of Heteroaryl Primary Amines and (Hetero)aryl Bromides with 6-Hydroxypicolinamide Ligands

Abstract

A family of 6-hydroxypicolinamide ligands have been identified as effective supporting ligands for Cu-catalyzed couplings of heteroaryl bromides and chlorides with heteroaryl primary amines. The C−N couplings are carried out at 80−120 °C in DMSO or sulfolane using K 2 CO 3 or K 3 PO 4 as the base with 2−10 mol % CuI and supporting ligand. The strength of the base was found to have an impact on the chemoselectivity and rate. The use of K 2 CO 3 as the base enabled selective C−N coupling of aryl bromides over aryl chlorides with 2−5 mol % Cu at 80−120 °C. With K 3 PO 4 as the base, aryl chlorides are capable of undergoing C−N coupling, though 5−10 mol % Cu is required at 120−130 °C. Members of the ligand family are straightforward to prepare in one step from 6-hydroxypicolinic acid and the corresponding anilines.

pH-Dependent Degradation of T3P-Related Byproducts

“…The resulting slurry was filtered to isolate 6 as an off-white solid, which was dried in a vacuum oven at 50 °C to provide the product (13.8 g, 79% yield). Characterization data were consistent with those reported in the literature …”

“…In a second example, a family of 6-hydroxypicolinamide ligands were synthesized and evaluated for the development of Cu-catalyzed C–N coupling methodology . (Figure ) Through this work, ligand 6 emerged as optimal for C–N couplings of heterocyclic amines.…”

Kilogram-Scale Preparation of an Aminopyrazole Building Block via Copper-Catalyzed Aryl Amidation

“…We started by evaluating a total of >40 ligands (consisting of mainly amines and amides); however, many yielded very low conversion. Nevertheless, we found that using ammonium hydroxide ( 6 ) along with sterically encumbered amide-derived ligands developed by either Ma , or Singer was successful in furnishing good selectivity for the monoarylated product. Unfortunately, these noncommercial ligands were the only promising leads, and we ultimately decided to pursue the use of an ammonia surrogate ( vide infra ).…”

Flexible Synthesis and Herbicidal Activity of Fully Substituted 3‐Hydroxypyrazoles

“…Compounds containing an NH‐bridge were accessed via nitration of pyrazole 12 , followed by iron‐mediated reduction to afford aminopyrazole 22 (Scheme 5). A Buchwald‐Hartwig coupling of this intermediate with bromobenzenes provided a library of NH‐bridged analogues 23 [14] . Alkylation with iodomethane afforded the N ‐methyl derivatives 24 .…”