PD catalyzed para selective alkylation of electron deficient aromatic hydrocarbons

Aromatics are widely used in bioactive natural products, drugs and functional materials In the study of aromatics functionalization, site selective alkylation is an important topic Friedel crafts alkylation is a kind of electrophilic aromatic substitution reaction, which is often used because alkylating reagents are easy to obtain For aromatics substrates, the neutral and electron rich aromatic ring reactions of phenol and aniline are good, but the products of over alkylation and primary alkylation are often obtained, while the reaction of electron deficient aromatics is poor In recent years, great progress has been made in the ortho alkylation of aromatics catalyzed by transition metals assisted by guiding groups, but there are few examples of remote site alkylation, especially the para selective alkylation of aromatics Recently, Nakao et al Reported that nickel catalyzed para alkylation of benzamide, diaryletone and arylsulfone This reaction needs to be carried out under the action of a large volume of aluminum complex, and only primary alkyl and deicing flake can be introduced from the olefin substrate (Fig 1a) Recently, Professor Jianrong Steve Zhou from Nanyang University of technology in Singapore reported the first case of PD catalyzed para selective alkylation of electron deficient benzene and naphthalene derivatives with halogenated hydrocarbons (Fig 1b) Relevant papers were published on angelw Chem Int ed (DOI: 10.1002 / anie 201801967) Fig 1 Para selective alkylation of electron deficient aromatics (source: angelw Chem Int ed.) the author first tried the model reaction of iodo cyclohexane (1) and 1-formylnaphthalene (2a), and found that the combination of PD (PPh3) 4 and dpephos can make the yield of C4 selective alkylation reach 74% Nickel and copper catalysts have no effect on this kind of alkylation reaction, and other auxiliary ligands can not improve the yield and selectivity The by-products are cyclohexene, naphthalene, monosubstituted and dialkylated naphthalene The addition of anisole can effectively inhibit the elimination of halogenated hydrocarbons and excessive alkylation Next, the alkylation reaction of electron deficient naphthalene derivatives was expanded by the substrate (Fig 2) The alkylation of 2-formylnaphthalene occurs mainly at C1 (Fig 2a), while the alkylation of 2-formylnaphthalene occurs mainly at C4 (Fig 2a) In addition to iodohexane, other cyclic and noncyclic secondary alkyl iodides also have good reaction results (Fig 2b) In addition, when ki is added to the reaction, some secondary alkyl bromides can also react smoothly (Fig 2C) Figure 2 Alkylation of naphthalene derivatives (source: angelw Chem Int ed.) in addition to naphthalene derivatives, the author also studied alkylation of benzene derivatives (Figure 3) For benzene derivatives containing an electron withdrawing substituent, it is necessary to increase the equivalent number of the substrate and enhance the alkalinity of the inorganic base, so that the reaction yield can reach a medium to good level, and the alkyl group is mainly substituted in the opposite position of the electron withdrawing substituent (Fig 3, top) Difluorobenzene and electron rich dimethoxybenzene have also been shown to be involved in such alkylation reactions The reaction activity of benzene derivatives substituted by double electron absorption groups is higher, but increasing the steric resistance of substituents will decrease the yield, and the steric resistance of substituents will affect the regioselectivity of alkylation (Fig 3, bottom) Figure 3 Alkylation of benzene derivatives (source: angelw Chem Int ed.) inspired by palladium catalyzed alkylation of vinyl aromatics and heterocyclic aromatics at room temperature promoted by blue LED (angelw Chem Int ed 2017, 56, 14212; J am Chem SOC 2017, 139, 18307; angelw Chem Int ed 2017, 56, 15683), the author explored the alkylation of electron deficient aromatics under blue LED irradiation (Fig 4) The results show that the ideal yield can be achieved at 40 ℃ after the introduction of blue LED, so many by-products caused by heating conditions can be avoided Primary alkyl iodide can also be used as alkylation reagent, but the yield of the product is low In addition, the equivalent number of benzene derivatives substituted by single electron absorption group can be reduced under the blue LED condition Figure 4 Alkylation of aromatics under blue LED irradiation (source: angelw Chem Int ed.) Finally, the possible catalytic cycle process is given by the author through mechanism study experiment (Figure 5) The reaction undergoes a key free radical addition step, and then the base removes a proton from the aromatic center free radical to form a free radical anion The electron deficient group plays a role in stabilizing the free radical anion Figure 5 Reaction mechanism (source: angelw Chem Int ed.) Summary: Professor Zhou Jianrong's research group reported the para selective alkylation of electron deficient aromatics The aromatics substrate type and site selectivity of this method are opposite to the classical Friedel crafts alkylation.