Stereospecific Nickel-Catalyzed Cross-Coupling Reactions of Benzylic Ethers and Esters

Abstract

ConspectusThis Account presents the development of a suite of stereospecific alkyl–alkyl cross-coupling reactions employing nickel catalysts. Our reactions complement related nickel-catalyzed stereoconvergent cross-coupling reactions from a stereochemical and mechanistic perspective. Most reactions of alkyl electrophiles with low-valent nickel complexes proceed through alkyl radicals and thus are stereoablative; the correct enantioselective catalyst can favor the formation of one enantiomer. Our reactions, in contrast, are stereospecific. Enantioenriched ethers and esters are cleanly converted to cross-coupled products with high stereochemical fidelity. While mechanistic details are still to be refined, our results are consistent with a polar, two-electron oxidative addition that avoids the formation of radical intermediates. This reactivity is unusual for a first-row transition metal.The cross-coupling reactions engage a range of benzylic ethers and esters, including methyl ethers, tetrahydropyrans, tetrahydrofurans, esters, and lactones. Coordination of the arene substituent to the nickel catalyst accelerates the reactions. Arenes with low aromatic stabilization energies, such as naphthalene, benzothiophene, and furan, serve as the best ligands and provide the highest reactivity. Traceless directing groups that accelerate reactions of sluggish substrates are described, providing partial compensation for arene coordination.Kumada, Negishi, and Suzuki reactions provide incorporation of a broad range of transmetalating agents. In Kumada coupling reactions, a full complement of Grigard reagents, including methyl, n-alkyl, and aryl Grignard reagents, are employed. In reactions employing methylmagnesium iodide, ligation of the nickel catalyst by rac-BINAP or DPEphos provides the highest yield and stereospecificity. For all other Grignard reagents, Ni(dppe)Cl2 has emerged as the best catalyst. Negishi cross-coupling reactions employing dimethylzinc are reported as a strategy to increase the functional group tolerance of the reaction. We also describe Suzuki reactions using arylboronic esters. These reactions provided the first example in the series of a switch in stereochemical outcome. The reactions maintain stereospecificity, but reactions employing different achiral ligands provide opposite enantiomers of the product. Use of an N-heterocyclic carbene ligand, SIMes, provides inversion, consistent with our prior work in Kumada and Negishi coupling reactions. Use of the electron-rich phosphine PCy3, however, provides retention with stereospecificity, signaling a change in the mechanistic details.Potential applications of the reported cross-coupling reactions include the synthesis of medicinal agents containing the 2-arylalkane and 1,1-diarylalkane moieties, which are pharmacophores in medicinal chemistry. These moieties are found in compounds with activity against a broad range of indications, including cancer, heart disease, diabetes, osteoporosis, smallpox, tuberculosis, and insomnia. We highlight representative exa...

Parameterization of phosphine ligands demonstrates enhancement of nickel catalysis via remote steric effects

“…Notably, phthalan and dioxolane acetals 18 and 20 , which were completely unreactive with PCy 3 , undergo C–C bond formation using L17 to afford α-arylated ethers 19 and 21 in good yield. The products 21 and 23 possess an alcohol tether capable of undergoing further functionalization, including serving as a directing group for additional Ni-catalysed coupling to give bioactive triarylmethane products 30,31 . Acetal 22 (1.3:1 d.r.)…”

Ethereal C–O Bond Cleavage Mediated by Ni(0)-Ate Complex: A DFT Study

“…Based on this work, together with our previous mechanistic study on etheric Kumada-Tamao reaction, we identify and characterize a novel catalytic cycle for cross-coupling mediated by Ni(0)-ate complex.Key words cross-coupling; ether; nickel catalyst; organolithium; organozinc; density functional theory (DFT) calculation Efficient and selective cleavage and transformation of C-O bonds, particularly by means of cross-coupling methods, has attracted great interest, since compounds containing C-O moieties occur widely in nature and are also extensively utilized in industry.1-8) Among C-O compounds, ethers are particularly attractive, [1][2][3][4][5][6][7][8] as they offer the advantages of 1) high atom economy/conversion efficiency (the use of ethers as simple as MeO as substrates affords fewer by-products compared with tosylate, mesylate, triflate, phosphate, etc. ), 2) environmental compatibility (cleavage of the C-O moiety in ether releases non-halogen-containing waste), and 3) excellent stability, easy accessibility and wide diversity.…”

“…1-8) Among C-O compounds, ethers are particularly attractive, [1][2][3][4][5][6][7][8] as they offer the advantages of 1) high atom economy/conversion efficiency (the use of ethers as simple as MeO as substrates affords fewer by-products compared with tosylate, mesylate, triflate, phosphate, etc. ), 2) environmental compatibility (cleavage of the C-O moiety in ether releases non-halogen-containing waste), and 3) excellent stability, easy accessibility and wide diversity.…”

Enantioselective Synthesis of Oxetanes Bearing All‐Carbon Quaternary Stereocenters via Iridium‐Catalyzed C−C Bond‐Forming Transfer Hydrogenation

“…1). Unlike related nickel catalyzed processes, [11] stereospecific C-O oxidative addition is followed by olefin insertion and C-C reductive elimination to form cyclopropane 7 a single diastereomer. Beyond the synthesis of oxetanes, the present methodology also provides facile access to enantiomerically enriched trisubstituted azetidines.…”