Mechanistic Insight Leads to a Ligand Which Facilitates the Palladium‐Catalyzed Formation of 2‐(Hetero)Arylaminooxazoles and 4‐(Hetero)Arylaminothiazoles

Abstract

Using mechanistic insight, a new ligand (EPhos) for the Pd-catalyzed C–N cross-coupling between primary amines and aryl halides has been developed. Employing an isopropoxy group at the C3-position favors the C-bound isomer of ligand-supported Pd(II) complexes and leads to significantly improved reactivity. The use of a catalyst system based on EPhos with NaOPh as a mild homogeneous base proved to be very effective in the formation of 4-arylaminothiazoles and highly functionalized 2-arylaminooxazoles. Previously, these were not readily accessible using Pd-catalyzed methodology.

PAd2‐DalPhos Enables the Nickel‐Catalyzed C−N Cross‐Coupling of Primary Heteroarylamines and (Hetero)aryl Chlorides

“…Prior to our work herein, no base‐metal catalyst capable of effecting the cross‐coupling of primary five‐membered ring heteroarylamines and (hetero)aryl chlorides with synthetically useful scope had been disclosed in the literature. In the context of Pd catalysis, a 2017 report from Buchwald and co‐workers describing the C−N cross‐coupling of (hetero)aryl chlorides and bromides with 2‐aminooxazole and 4‐aminothiazole using a Pd/EPhos catalyst (2.0–7.5 mol % Pd; 100 °C) represents the state‐of‐the‐art for this type of transformation. In light of these considerations, we compared the performance of C1 and C2 , as well as related pre‐catalysts featuring JosiPhos CyPF‐Cy, DPPF, or XantPhos, which have each been employed successfully in alternative C−N cross‐coupling applications, in the cross‐coupling of 2‐aminooxazole and 4‐chlorobenzophenone to give 2 a (2.5 mol % Ni, 80 °C; Scheme ).…”

“…Encouraged by the utility of C2 in the cross‐coupling of 2‐aminooxazole leading to 2 a , we turned our attention toward exploring the scope of reactivity with other heteroarylamines and (hetero)aryl chlorides (Scheme ). To avoid substrate‐specific optimization, the diastereomeric mixture of C2 ( meso and rac ) was employed at 5 mol % (that is, the mid‐point loading of the Pd/EPhos catalyst employed by Buchwald and co‐workers). 2‐Aminooxazole, 2‐aminothiazole, 5‐amino‐1,3‐dimethyl‐1 H ‐pyrazole, and 2‐aminopyridine were each employed successfully as nucleophiles in combination with our C2 pre‐catalyst, affording products 2 a – 2 l in synthetically useful isolated yield.…”

Cross-Coupling Reactions of Nitroarenes

“…We thus focused our efforts on promoting the reductive elimination because the other half of the catalytic cycle, namely, the oxidative addition of the C–NO 2 bond and the subsequent nitrite–phenoxide exchange, should proceed analogous to the reactions discussed above (vide supra). In principle, the reductive elimination can be accelerated by just increasing the conformational rigidity and the steric demand of the supporting ligands as shown in Scheme a, , but this would facilitate the reductive elimination of both product (Ar–O–Ar′) and substrate (Ar–NO 2 ) (vide supra). In accordance with this hypothesis, the use of ligands bearing t Bu groups on the phosphorus atom delivered barely any target product (Scheme b).…”

Intriguing Behavior of an Apparently Simple Coupling Promoter Ligand, PPh2(p-C6H4–C6F5), in Their Pd Complexes

“…We hypothesized that ligand fluorination at the distal aryl of the biphenyl might increase their similarity with our PEWO-F ligands. Although some partially fluorinated biaryl phosphines have already been reported and their catalytic performance was not particularly good when compared with that of nonfluorinated analogues, − these results are not necessarily informative about the reductive elimination step. In this context, we decided to synthesize and examine the behavior of a new PR 2 (biaryl) ligand fluorinated at the distal aryl group, L HF (Figure , right) and immediately set to estimate its coupling potential, measuring Δ G ‡ Pf–Pf with the standard protocol reported in ref .…”