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

Abstract

By using mechanistic insight, anew ligand (EPhos) for the palladium-catalyzed CÀNc ross-coupling between primary amines and aryl halides has been developed. Employing an isopropoxy group at the C3-position favors the C-bound isomer of the ligand-supported palladium(II) complexes and leads to significantly improved reactivity.The use of acatalyst system based on EPhos with NaOPh as am ild homogeneous base proved to be very effective in the formation of 4-arylaminothiazoles and highly functionalized2 -arylaminooxazoles.P reviously,t hese were not readily accessible using palladium catalysis.

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

“…However,m etalcatalyzed CÀNc ross-coupling involving such NH nucleophiles has proven to be significantly more challenging than transformations involving alkylamines or simple anilines, owing,inpart, to the increased acidity of the amine as aresult of adjacent heteroatoms,w hich can lead to poor substrate binding and/or slow C À Nr eductive elimination. [21] 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.Inthe context of Pd catalysis,a2017 report from Buchwald and co-workers [22] describing the C À Nc ross-coupling of (hetero)aryl chlorides and bromides with 2-aminooxazole and 4-aminothiazole using aP d/EPhos catalyst (2.0-7.5 mol %P d; 100 8 8C) represents the state-of-the-art for this type of transformation. In light of these considerations,w ec ompared the performance of C1 and C2,a sw ell as related pre-catalysts featuring JosiPhos CyPF-Cy, [23] DPPF, [9a] or XantPhos, [24] which have each been employed successfully in alternative C À Nc rosscoupling applications,i nt he cross-coupling of 2-aminooxazole and 4-chlorobenzophenonet og ive 2a (2.5 mol %N i, 80 8 8C; Scheme 3).…”

“…Encouraged by the utility of C2 in the cross-coupling of 2aminooxazole leading to 2a,w et urned our attention toward exploring the scope of reactivity with other heteroarylamines and (hetero)aryl chlorides (Scheme 4). To avoid substratespecific optimization, the diastereomeric mixture of C2 (meso and rac)w as employed at 5mol %( that is,t he mid-point loading of the Pd/EPhos catalyst employed by Buchwald and co-workers [22] ). 2-Aminooxazole,2 -aminothiazole,5 -amino-1,3-dimethyl-1H-pyrazole,a nd 2-aminopyridine were each employed successfully as nucleophiles in combination with our C2 pre-catalyst, affording products 2a-2l in synthetically useful isolated yield.…”

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

“…Although some partially fluorinated biary phosphines have already been reported, their catalytic performance was not particularly good when compared with non-fluorinated analogs. [10][11][12][13][14] These results are not necessarily against our expectations for their coupling ability, since overall catalytic results are not informative of how a ligand behaves in the different steps of the cycle. In this context of activity we decided to synthesize and examine the behavior of a new PR 2 (biaryl) ligand fluorinated at the biary, L HF (Figure 1, right).…”

Unexpected Formation of Hexasubstituted Arenes Through a Twofold Palladium-Mediated Ligand Arylation

“…The characterization data were consistent with previous reports. 22 1 H NMR (500 MHz, CDCl3): δ 7.32 (t, J = 7.9 Hz, 1H), 7.07 (s, 2H), 6.92 (d, J = 8.1 Hz, 1H), 6.84 (d, J = 7.5 Hz, 1H), 3.99 (s, 3H), 2.97 (hept, J = 6.9 Hz, 1H), 2.47 (hept, J = 6.9 Hz, 2H), 1.33 (d, J = 6.9 Hz, 6H), 1.19 (d, J = 6.9 Hz, 6H), 1.05 (d, J = 6.8 Hz, 6H). 13…”