PhPAd‐DalPhos: Ligand‐Enabled, Nickel‐Catalyzed Cross‐Coupling of (Hetero)aryl Electrophiles with Bulky Primary Alkylamines

Abstract

The base metal‐catalyzed C−N cross‐coupling of bulky α,α,α‐trisubstituted primary alkylamines with (hetero)aryl electrophiles represents a challenging and under‐developed class of transformations that is of significant potential utility, including in the synthesis of lipophilic active pharmaceutical ingredients. Herein, we report that a new, air‐stable Ni(II) pre‐catalyst incorporating the optimized ancillary ligand PhPAd‐DalPhos enables such transformations of (hetero)aryl chloride, bromide, and tosylate electrophiles to be carried out for the first time with substrate scope rivalling that achieved using state‐of‐the‐art Pd catalysts, including room temperature cross‐couplings of (hetero)aryl chlorides that are unprecedented for any catalyst (Pd, Ni, or other).

Overcoming limitations in dual photoredox/nickel-catalysed C–N cross-couplings due to catalyst deactivation

“…With the optimized conditions in hand, the versatility of the semiheterogeneous catalytic system was evaluated (Table 2). The reaction of methyl 4-bromobenzoate with cyclic secondary amines generally gave high yields for the corresponding aryl amines (1,(4)(5)(6)(7). A secondary amine with low steric hindrance also resulted in the desired aryl amine ( 8), but the majority of acyclic secondary amines did not react under these conditions (see Supplementary Information).…”

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

“…[11] In 2016 we disclosed the new ligand PA d-DalPhos (L1,S cheme 1B), featuring trioxaphosphaadamantane (PCg) and di(o-tolyl)phosphino donor fragments spanned by an o-phenylene bridge. [12] Thederived Ni II pre-catalyst (L1)Ni(o-tol)Cl has proven effective in ad iversity of CÀN cross-coupling applications,i ncluding the monoarylation of ammonia, [12] unhindered primary alkylamines, [12] primary amides, [13] and lactams, [13] with aw ide range of (hetero)aryl electrophiles.V ariation of the PR 2 group in PA d-DalPhos has enabled other challenging C À Ncross-couplings,including the N-arylation of cyclopropylamine [14] and hindered primary alkylamines [15] (Scheme 1B). We have also demonstrated that replacing the phenylene backbone of L1 with a3 ,4-thiophenylene linker (ThioPAd-DaPhos) affords Ni catalysts for the C À Nc ross-coupling of unhindered primary alkylamines that operate under mild conditions (25 8 8C, < 1mol %N i),i n amanner that is competitive with BHA.…”

Overcoming Limitations in Dual Photoredox/Nickel catalyzed C–N Cross-Couplings due to Catalyst Deactivation

“…1 Nickel is an attractive alternative to palladium due to its higher abundance, but the air-sensitive Ni(0) complexes, sophisticated ligands, strong reductants, and bases required for C-N bond formations have hampered its use. [2][3][4] Air-stable nickel pre-catalysts have been developed, but require harsh conditions and have a limited substrate scope (Figure 1, a). [5][6][7][8] In combination with electrochemistry, ligated Ni(II) salts catalyze the C-N cross-coupling under mild conditions (Figure 1, b).…”