Nickel‐Catalyzed Reductive Cross‐Coupling of Aryl Halides with Monofluoroalkyl Halides for Late‐Stage Monofluoroalkylation

Abstract

A combinatorial nickel-catalyzed monofluoroalkylation of aryl halides with unactivated fluoroalkyl halides by reductive cross-coupling has been developed. This method demonstrated high efficiency, mild conditions, and excellent functional-group tolerance, thus enabling the late-stage monofluoroalkylation of diverse drugs. The key to success was the combination of diverse readily available bidentate and monodentate pyridine-type nitrogen ligands with nickel, which in situ generated a variety of readily tunable catalysts to promote fluoroalkylation with broad scope with respect to both coupling partners. This combinatorial catalysis strategy offers a solution for nickel-catalyzed reductive cross-coupling reactions and provides an efficient way to synthesize fluoroalkylated druglike molecules for drug discovery.

Nickel‐Catalyzed 1,1‐Difluoroethylation of (Hetero)aryl Halides with 1,1‐Difluoroethyl Chloride (CH3CF2Cl)

“…Furthermore, we examined the influence of additives and solvent. As previously reported,–− pyridine and its derivatives could facilitate Ni‐catalyzed reductive coupling reactions. Therefore, various pyridine derivatives were examined and the yield of 3 a was increased to 25% in the presence of 4‐( N , N ‐dimethylamino)pyridine (DMAP) (Table , entry 8).…”

“…Therefore, various pyridine derivatives were examined and the yield of 3 a was increased to 25% in the presence of 4‐( N , N ‐dimethylamino)pyridine (DMAP) (Table , entry 8). On the contrary, 4‐cyanopyridine (4‐CN−Py), used in nickel‐catalyzed monofluoroalkylation of aryl halides, resulted in little product 3 a (Table , entry 11). For solvent screening, it was found that DMSO is better than DMF, DMA and NMP (Table , entries 8, 13–15).…”

Nickel‐Catalyzed Reductive Coupling for Transforming Unactivated Aryl Electrophiles into β‐Fluoroethylarenes

“…[14] We found that the b-fluoroalkyl electrophile (FCH 2 CH 2 I) kept untouched under the treatment of manganese powderi nN MP at 80 8C( Scheme 5d)o ru nder the standard condition A in the absence of aryl chloride (Scheme5e). [14] We found that the b-fluoroalkyl electrophile (FCH 2 CH 2 I) kept untouched under the treatment of manganese powderi nN MP at 80 8C( Scheme 5d)o ru nder the standard condition A in the absence of aryl chloride (Scheme5e).…”

“…Attempts to improve the reaction outcomev ia employing combinatorial ligand system [14] were unsuccessful by screening within as eries of pyridinyl monodentate ligandsw hich are decorated by either electron-donating or electron-withdrawingg roups ( Table 1, entries [8][9][10][11][12][13]. Further interrogation on the structuralm otifs of bidentate nitrogen ligands indicated that the electron-rich 4,4'-dimethoxy-2,2'-bipyridine (dmobpy) with steric-unhinderedc oordination site was optimal and improved the coupling yield to 77 % ( Table 1, entries [14][15][16][17][18]. Finally,c ontrol experiment indicated that both the nickel salts and supporting ligands werei ndispensablefor the success of this coupling (Table 1, entry 19).…”

“…[11,12] Unlike the conventional couplings which relied on the union of nucleophilic carbon (C dÀ or "R-[M]") and electrophilic carbon (C d + or "R-[X]"), the reductivec ross-coupling reactions provide the linkages of two electrophilic carbon based on the turnover of transiton metal catalysts in the presence of sacrificial reductant. [14] Their reaction was highlighted by utilizing gem-dihaloalkane as startingm ateriala nd bypassing the generation of elusive Y-M-CHFR metallicn ucleophiles. [13] Recently,W ang group disclosed an ickel-catalyzed reductive monofluoroalkylation reactionf or access to benzylic fluorides (ArCHFR, R = Ho ralkyl)f rom Ar-X (X = Br or I) andY CHFR (Y = Br or I) electrophiles (Scheme 1a).…”