Enantioselective C-H alkylation of Aniline Derivatives Catalyzed by JACS: Pd / s, O ligands

Aromatic amines are widely found in natural products, drugs, fluorescent dyes and organic functional materials Therefore, it is of great significance to realize the selective functionalization of aniline In recent years, metal catalyzed C-H functionalization has become a powerful tool for efficient construction of functional molecules Most of the C-H functionalization reactions of aniline derivatives need the guiding group connected with nitrogen atom to produce ortho functionalized products However, the selective remote C-H functionalization of aniline derivatives is rarely reported In some specific cases, only unsubstituted aniline or aniline with electron donating substituent can perform metal catalyzed para-c-h functionalization (scheme 1a) Recently, Ru (II) catalyst was used to realize the para difluoromethylation of ester or halogen substituted aniline In addition, the gaunt group reported the highly para selective copper (II) catalytic aromatization of electron rich and electron deficient aniline (scheme 1b) At present, there are only two cases of PD catalyzed para-c-h olefinization of unsubstituted tertiary aniline, and the conditions are complex Recently, the team of M hengeles fern á ndez IB á ñ EZ, University of Amsterdam, the Netherlands, reported the para selective C-H alkylation of Aniline Derivatives Catalyzed by Pd / s, O ligands This method is simple, efficient and mild (scheme 1D) Relevant research results were published on J am Chem SOC (DOI: 10.1021 / JACS 9b01908) (source: J am Chem SOC.) recently, the authors found that bidentate s, O ligands can promote palladium catalyzed C-H olefinization of non oriented aromatics (ACS catalyst 2017, 7, 6342-6346) The selectivity of the reaction site is mainly determined by the substrate and controlled by the electrical effect The most electron rich sites in aromatics are preferentially functionalized In addition, in addition to accelerating the reaction, the presence of S, O ligands will also affect the site selectivity of the process Therefore, the authors speculate that the alkylation reactivity and site selectivity of C-H alkenes of aniline derivatives can be enhanced by using Pd / s and O ligand catalysts In order to verify the above conjecture, the feasibility of the reaction of N, N-dimethylaniline 1a and ethyl acrylate 2 was investigated under the standard conditions of C-H olefinization of non oriented aromatics (5 mol% PD (OAC) 2, 5 mol% 3-methyl-2 - (phenylthio) butyric acid (L), 1 equivalent phco3tbu as oxidant and reacting in AcOH at 100 ℃ for 6 hours) Unfortunately, under the above conditions, no olefin products were formed Then, through the selection of solvent, temperature, reaction stoichiometry, oxidant, concentration and ligand, the author found that the olefin product 3A can be obtained by the reaction of N, N-dimethylaniline 1a and ethyl acrylate 2 in DCE at 40 ℃ with 71% separation yield and excellent para selectivity (P: O > 19:1) The results showed that s, O ligands are the key to high para selectivity (source: J am Chem SOC.) in order to study the substrate range of the reaction, the author first investigated the universality of aniline derivatives (Table 1) The alkyltertiary aniline derivatives can obtain the product 3B - 3G with good yield and high para selectivity The N, N-dimethylaniline with electron absorption or electron substitution can be successfully obtained with medium to high yield and good to excellent para selectivity However, the substrates with para - and meta-methyls are not suitable for this system (source: J am Chem SOC.) in the presence of Pd / s, o-ligand catalysts, ortho substituted n-benzylaniline derivatives can efficiently carry out the allylation reaction (Table 2) The reaction of n-benzylaniline derivatives 1q-1v, which were substituted by methyl, methoxy, chlorine, trifluoromethyl, ester and carbonyl, showed excellent para selectivity, and p-alkenylation products were obtained in good yield (47-70%) The C-H olefinization can be carried out successfully even for the two or three substituted anilines with different substituents, and the product 3w-3y can be obtained in good yield (57-75%) (source: J am Chem SOC.) finally, the compatibility of the catalytic system with primary aniline was investigated (Table 3) The reaction efficiency of primary aniline depends on the substituents on the aromatic ring One ortho group of aniline has ester group and the other ortho group has other substituents The product 3aE - 3AI can be obtained in high yield and has excellent para selectivity O-cf3 and o-ome substituted aniline can also obtain the corresponding product 3aj in medium yield (source: J am Chem SOC.) next, the author studied the application scope of olefins (Table 4) The product 4a-4c was obtained by the reaction of N, N-Diethylaniline with methyl, cyclohexyl and phenylacrylate in high yield (85-96%) and selectivity α - methylene - γ - butyrolactone was mixed with 4 DA and 4 dB in the ratio of 1.4:1 Similarly, other activated alkenes are also suitable for the reaction system, and the product 4E - 4H can be obtained in good yield (source: J am Chem SOC.) Summary: the first case of Pd / s, O-Ligands catalyzed para selective C-H alkylation of aniline derivatives has been developed The reaction conditions are mild and the substrate is widely used In this catalytic system, a total of 42 aniline derivatives can be olefinized with p-selective C-H in good yield The preliminary mechanism study shows that s, O ligands promote C-H bond breaking, which is the decisive step of the reaction.