C-O cross coupling reaction of aryl electrophilic reagents and aliphatic alcohols catalyzed by auxiliary ligands

C (SP 2) - O-C (SP 3) linkage is widely found in natural products and active pharmaceutical intermediates, so the synthesis of aliphatic primary alcohols and secondary alcohols of aromatic ethers has attracted extensive attention Some of these ethers can be prepared by S N 2 chemistry of phenol and alkyl electrophilic reagents, such as Williamson ester synthesis method Complementary methods using (heteroaryl) electrophilic reagents are also popular because they can utilize readily available fatty alcohols There are few successful examples of preparing alkyl (hetero) aryl ethers by s NAR chemistry or copper Catalysis (Ullmann ether synthesis), and such methods usually need active (hetero) aryl bromine or iodine and strong reaction conditions In contrast, palladium catalyzed cross coupling reactions between (hetero) aryl electrophilic reagents and primary / secondary aliphatic alcohols have sprung up in large numbers, which enables relatively cheap and abundant (hetero) aryl chlorine to participate in the transformation Suitable auxiliary ligands and palladium formed l NPD (aryl) (alkoxide) type catalytic intermediates can promote the reduction and elimination of C (SP 2) - O bonds and avoid the unnecessary elimination of β - H (Fig 1a) Phosphine ligands, such as rockphos, ad bippyphos and josiphos cypf-t Bu, which are electron rich and have high steric hindrance, are particularly effective (Fig 1b) Despite the significant progress in palladium catalytic methods, researchers are still developing other methods to replace expensive and scarce palladium with more abundant transition metals Fig 1 The cross coupling of aliphatic alcohol and (heteroaryl) halide (source: J am Chem SOC.) can be seen from the cross coupling reaction of C (SP 2) - N catalyzed by nickel (acc chem Res 2015, 48, 1717-1726), compared with palladium catalytic method, in the cross coupling reaction of aliphatic alcohol and (heteroaryl) chlorine catalyzed by nickel, the oxidation addition of C (SP 2) - Cl bond is milder, and β - H elimination is less likely to occur Macmillan and his colleagues reported that nickel catalyzed C (SP 2) - O cross coupling was promoted by photo oxidation-reduction Catalysis (Fig 1c) Aliphatic primary alcohol and secondary alcohol were successfully used in this reaction, but electrophilic reagents were only limited to (hetero) aryl bromine (nature 2015, 524, 330-334) Mark stradiotto team from Dalhousie University in Canada developed pad dalphos auxiliary ligand (Figure 1D) in early stage and used it to catalyze C (SP 2) - N cross coupling reaction with nickel (NAT Commun 2016, 7, 11073) Recently, the research group also reported the nickel catalyzed C (SP 2) - O coupling reactions involving the auxiliary ligands pad dalphos and cypad dalphos A series of aliphatic primary, secondary, tertiary alcohols and (hetero) aryl (pseudo) halides can successfully participate in such reactions Relevant papers were published on J am Chem SOC (DOI: 10.1021/jacs.8b01800) At the beginning of the study, different auxiliary ligands and inorganic bases were screened by the reaction of 1-chloronaphthalene (1a) with 4-methyl-1-pentanol (2a) or 2-propanol (2b) (Fig 2) The experimental results show that the pre catalyst C1 and C2 have obvious advantages, especially C1; the inorganic base naotbu has the best effect; the reaction activity of substrate 2b is lower than 2A; the conversion of electrophilic reagent to 1-bromonaphthalene or the increase of 2B equivalent can improve the yield of product 4a Figure 2 Reaction condition screening (source: J am Chem SOC.) next, the author used the above optimized conditions to screen the reaction substrate It can be seen that fatty alcohol and aryl electrophilic reagent are widely used (Figure 3, 4) Figure 3 (hetero) cross coupling of aryl electrophilic reagent with primary alcohol (source: j.am Chem SOC.) Figure 4 (hetero) cross coupling of aryl electrophilic reagent with secondary and tertiary alcohol (source: j.am Chem SOC.) Summary: Stradiotto group realized the C (SP 2) - O cross coupling reaction of aliphatic primary, secondary, tertiary alcohol and (hetero) aryl electrophilic reagent by using pad dalphos and cypad dalphos assisted nickel pre catalyst, which provided other options for such reactions besides palladium catalysis and photo oxidation reduction catalysis Corresponding author: Professor Mark stradiotto