Nickel-Catalyzed Enantioselective C(sp ³ )–H Arylation of Ketones with Aryl Ethers via Selective C _Ar –O Cleavage to Construct All-Carbon Quaternary Stereocenters

Abstract

The nickel-catalyzed enantioselective C(sp 3 )-H arylation of ketones with phenol-derived aryl pyrimidyl ethers is designed via selective cleavage of C(aryl)-O bond to construct all-carbon quaternary stereocenters. This method exhibits good functional group compatibility and broad substrate scope. Drug molecule donepezil could directly transform into corresponding highly optically pure derivatives with this developed methodology.Mechanistic studies reveal that C(aryl)-O cleavage of aryl pyrimidyl ether is probably proceeded by an anionic organo-Ni(0) intermediate.

Metal-Catalyzed Enantioconvergent Transformations

“…Martin and co-workers 207 described for the first time the asymmetric α-arylation of cyclic ketones with aryl pivaloyl esters under Ni(cod) 2 /tol-Binap catalysis. Recently, Li and Wang 208 Enantioconvergent α-arylation of amides to give enantioenriched oxindoles was first described by Lee and Hartwig 209 using Pd(dba) 2 and a chiral N-heterocyclic carbene (NHC) as catalyst. Later, Buchwald and co-workers 210 developed enantioconvergent α-arylation of 3-alkyl oxindoles with aryl bromides under Pd/chiral biaryl monophosphine ligand catalysis.…”

“…Martin and co-workers described for the first time the asymmetric α-arylation of cyclic ketones with aryl pivaloyl esters under Ni­(cod) 2 /tol-Binap catalysis. Recently, Li and Wang reported the same transformation using cyclic ketones 299 and aryl pyrimidyl ethers 300 under Ni­(cod) 2 /Josiphos 301 catalysis (Scheme ). The corresponding α-arylated ketones 302 were obtained with good yields and enantioselectivities in the presence of N -Boc- l -phenylalanine and Zn­(OTf) 2 in p -xylene at 130 °C.…”

Synthesis of α‐Aryl Carbonyls via Photoinduced Formation of C−C Bonds

“…[4] The common pathway to achieve such structures is by arylation of carbonyls nowadays recognized as the elective key-strategy for constructing C(sp 2 )À C(sp 3 ) bonds and has been widely used to have access to natural products, pharmaceuticals and biomacromolecules. [5][6][7][8] Traditional approaches often involves the use of transition metal-based complexes [9][10][11][12][13][14][15][16][17] (Pd, Ni, Cu, Fe), especially in the widely known (and used) palladiumcatalyzed α-arylation protocols proposed by Hartwig, [9] Buchwald [10] and Miura, [11] although often the cost of the catalyst, the need for strong bases and ligands as well as of high temperatures [17] is a significant limitation to the scale-up of the process. On the other hand, most transition metal-free strategies (that made use of nitroaromatics, [18] hypervalent iodine derivatives, [19,20] Ar 3 Al [21] and aryl diazonium salts [22] as the arylation agents) suffer from poor functional group tolerance and specific reaction conditions that limit their application.…”

Enantioselective Alkylation of Unactivated C–O Bond: Solvent Molecule Affects Competing β-H Elimination and Reductive Elimination Dynamics

“…In 2014, a nickel-catalyzed stereoselective alkylative cross-coupling of the benzylic etheric C–O bond in the presence of achiral bidentate dppe as the ligand has been reported for the formation of tertiary stereocenters by Jarvo and co-workers, and this transformation was realized through enantiospecific cleavage of the benzylic C–O bond; the installation of a preexisting stereogenic center was required (Scheme A) . Later, by using aryl pivalate and aryl pyrimidyl ether as C–O electrophiles, elegant nickel-catalyzed formation of quaternary stereogenic centers via the asymmetric C–C bond forming reaction was demonstrated by the groups of Martin and Wang, and these processes were realized through enantioselective arylation of the cyclic ketone C­(sp 3 )–H bond, and in-situ-generated prochiral ketone enolates were employed as nucleophiles (Scheme B) . In sharp contrast, the synthesis of chiral compounds through transition-metal-catalyzed enantioselective alkylative activation of the C–O bond with β-H-containing nucleophiles has not yet been described in the literature.…”