Nickel-Catalyzed Homocoupling of Aryl Ethers with Magnesium Anthracene Reductant

Abstract

Nickel-catalyzed reductive homo-coupling of aryl ethers has been achieved with Mg(anthracene)(thf)3 as a readily available low-cost reductant. DFT calculations provided a rationale for the specific efficiency of the diorganomagnesium-type two-electron reducing agent. The calculations showed that the dianionic anthracene-9,10-diyl ligand reduces the two aryl ether substrates resulting in the homo-coupling reaction through supplying the electrons to the Ni-Mg bimetallic system to form organomagnesium nickel(0)-ate complexes, which cause two sequential C–O bond cleavage reactions. The calculations also showed cooperative actions of Lewis-acidic magnesium atoms and electron-rich nickel atoms in the C–O cleavage reactions.

Elements-Continuous-Flow Platform for Coupling Reactions and Anti-viral Daclatasvir API Synthesis

“…The organic phase was dried over anhydrous sodium sulfate and concentrated to finally give product 3. The extracted waste aqueous layer was further extracted with DCM and analyzed by GC-MS which showed no product and was also confirmed by the absence of the corresponding peaks in the crude NMR analysis ( 1 H and 13 C NMR spectra). The extracting solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane/ethyl acetate) to give product 3.…”

“…However, to our surprise, 4 mA current was efficient in completing the conversion and offered excellent selectivity for the synthesis of 3a. On the contrary, 6 mA, 8 mA, and 10 mA could not convert the reactants into the product efficiently (Table 1, entries [13][14][15]. We examined the solvent effect, and dimethylacetamide (DMA) or dimethylformamide (DMF) was found to be efficient for complete conversion and excellent selectivity for the synthesis of 3a, whereas tetrahydrofuran, acetonitrile, and water were not successful in producing the product (Table 1, entries [16][17][18][19].…”

“…Chemical shifts for 1 H NMR are expressed in parts per million (ppm) relative to tetramethylsilane ( 0.00 ppm). Chemical shifts for 13 C NMR are expressed in ppm relative to CDCl 3 ( 77.0 ppm). For scanning electron microscopy, gold sputter coating was carried out on desired samples at a pressure ranging between 1 and 0.1 Pa. LC-MS was conducted on a Shimadzu LCMS-8040 instrument equipped with a LUNA C8 column (250 × 4.6 mm, 5.0 m) and inbuilt triple quadrupole detector.…”

“…1 H NMR (400 MHz, CDCl 3 ):  = 7.34 (t, J = 7.9 Hz, 2 H), 7.17 (dd, J = 7.6, 0.7 Hz, 2 H), 7.11 (t, J = 2.4 Hz, 2 H), 6.90 (dd, J = 8.2, 0.9 Hz, 2 H), 3.85 (s, 6 H). 13…”

“…The commercial manufacturing process for daclatasvir (trade name Daklinza) involves multistep reaction protocols such as a C-C coupling reaction to make the core biphenyl moiety, bromination, N-Boc-L-proline coupling, imidazole formation, Boc deprotection, and Moc-L-valine coupling, and then conversion into the corresponding dihydrochloride salt. 1,2 For the synthesis of the biaryl core moiety, several C-C coupling reactions have been extensively studied in the presence of transition metals, including Au, 3 Pd, [4][5][6][7][8] Rh, 9 Ru, 10 Ir, 11 Ni, [12][13][14] and Cu. 15 Additionally, external oxidants such as benzoquinone or copper acetate 4 and reductants such as zinc, magnesium, hydroquinone, or ascorbic acid 4 are needed for changing the oxidation state of the transition-metal catalyst and initiating the formation of the aryl intermediate involving an electron-transfer pro-cess.…”