Organic Base Enabled Nickel‐Catalyzed Mono‐α‐Arylation of Feedstock Solvents

Abstract

We report on our successful development of the first metal-catalyzed mono-α-arylation of carbonyl compounds employing a soluble organic base. The scope of these Ni/DalPhos-catalyzed transformations encompasses a range of (hetero)aryl halides (Cl, Br, I) and phenol-derived electrophiles (sulfonates, carbonates, carbamates, sulfamates), in-cluding active pharmaceutical ingredients (chloroquine, clozapine), in combination with the typically problematic feedstock small molecule substrates acetone, dimethylacetamide, and for the first time with any metal catalyst/ base, ethyl acetate.

Probing the Impact of Added Al(OTf)3 on DalPhos/Nickel‐Catalyzed N‐Arylations of Amides with (Hetero)aryl Chlorides

“…Given the success of PAd2-DalPhos (L1) and CyPAd-DalPhos (L2) in our prior studies of Ni-catalyzed amide N-arylation (vide supra), we focused our attention on screening the catalytic abilities of the derived pre-catalysts C1A/B, and also C2A/B, in the presence and absence of aluminum triflate (Figures 1 and 2). Notably, the relatively new pre-catalyst C2B, while useful in challenging Ni-catalyzed alpha arylation chemistry, [13] had not been examined in the cross-coupling of amides and (hetero)aryl halides. In our screenings featured herein, we opted to employ low (1 mol % Ni) pre-catalyst loadings (cf � 5 mol % in previous reports [8,[11][12] ) so as to present challenging conditions where the aluminum triflate additive may suitably augment catalytic performance.…”

Visible light-induced Ni-catalyzed C–heteroatom cross-coupling of aryl halides via LMCT with DBU to access a Ni(i)/Ni(iii) cycle

“…Notably, the choice of base also significantly affects the success of the reaction. 21 Inorganic bases were entirely ineffective in the reaction (entries [10][11][12], and inexpensive DBU outperformed all other tested organic bases (Table S2 in the ESI †). DMF, MeCN and EtOAc can also be used as the solvent to afford the product in moderate yields (entries 13-15).…”

“…Satisfactorily, this reaction also possessed a broad scope with respect to aryl iodides. Electron-poor (20,21), electron-neutral (22,23) and electron-rich aryl iodides (24, 25) were all found to be amenable substrates for effectively generating C-N cross-coupled products.…”

“…A broad range of synthetically useful functional groups, including fluoride (21,35), chloride (27, 50), ether (25, 31), ketone (11,46), sulfone (47), trifluoromethyl (10,48), alkene (13) and cyano (20,42) groups, could be well tolerated in both amination and esterification reactions. Interestingly, the boronic ester functional handle in 36 and 45 was left unscathed after the esterification.…”

Nickel-Catalyzed N-Arylation of Sulfinamides: A Comparative Study versus Analogous Sulfonamide Cross-Couplings

“…Improved catalytic performance was observed when using this precatalyst (85%, entry 1) versus the L1 /NiCOD 2 system, and ( L2 )­Ni­( o -tol)­Cl also offered excellent conversion to 3a (82%, entry 2). In changing the quantity and choice of base with ( L1 )­Ni­( o -tol)­Cl, we documented the following trends (entries 3–9): (i) Decreasing the amount of NaO t Bu from 2.0 to 1.5 equiv resulted in a dramatic decrease in overall conversion (85% vs 43%, entries 1 and 3), and (ii) alternative bases, including Cs 2 CO 3 , the “dual-base” system BTPP or DBU with the halide abstractor NaTFA (TFA – = trifluoroacetate), K 3 PO 4 , or Li­(HMDS), each proved inferior to NaO t Bu under analogous conditions. Furthermore, a small decrease in yield was noted when 1,4-dioxane was replaced with toluene (85% vs 80%, entries 1 and 10), and the use of conditions (entry 11) that proved to be effective in our sulfonamide C–N cross-couplings proved to be inferior in this test reaction.…”