The latest achievement of Yu Jin Quan Group: asymmetric C (SP3) - H arylation of free carboxylic acid catalyzed by Pd (II)

The author of the paper: danyan has a wide range of symmetric prochiral C (SP 3) - H bonds in most organic molecules, so the method of C-H activation and desymmetry to construct chiral centers has potential application value Recently, the combination of weak coordination guiding group and chiral bidentate ligands has made it possible for PD (II) to catalyze the enantioselective intermolecular C (SP 3) - H activation At the same time, the development of chiral bidentate quinoline ligands has realized the enantioselective functionalization of methylene C (SP 3) - H bond in acyclic n-perfluoroaryl formamide, and then successfully constructed β (SP 3) - H bond -In addition, the bidentate oxazoline ligands can functionalize the C (SP 3) - H enantioselectivity of n-perfluoroaryl or methoxyformamide to construct α - chiral centers However, the substrates involved in these reactions need to introduce guiding groups in advance, and the introduced groups (scheme1) need to be removed after C-H functionalization Following the principle that free groups do not need to be protected, Professor Yu Jinquan's research group of Scripps Institute in the United States started to study the enantioselective C-H activation of carboxylic acids without the use of foreign guiding groups Recently, Pd (II) catalyzed asymmetric C (SP 3) - H arylation of free carboxylic acids has been realized by the research group, and relevant research results have been published on J am Chem SOC (DOI: 10.1021 / JACS 8b03509) (photo source: J am Chem SOC.) the C (SP 3) - H activation reactivity of free carboxylic acids is low due to the weak ability of carboxylic groups to guide In addition, the conformation of metal carboxylic acid complex is more variable than that of metal amide complex, which may lead to stereo control problems The bidentate aminoethyl quinoline ligands previously developed by the authors can only act on 1-aminocyclopropane carboxylic acid Therefore, the authors set out to develop a novel ligand to effectively control the enantioselectivity of free carboxylic acids Since chiral cyclopropane is widely used in bioactive natural products and drugs, the author chose cyclopropane carboxylic acid as the ligand development model substrate (scheme 1) Based on the previous experience of chiral ligands, a series of mono protected aminoethylamine (mpaam) ligands were synthesized to realize the enantioselective C (SP 3) - H functionalization of free carboxylic acids (Table 1) The n-alkyltertiary amine ligands were first tested The results of L1 to L4 showed that steric hindrance on tertiary amines decreased the reactivity of ligands, while the reactivity and enantioselectivity of L5 and L6 were poor In addition, substitution of acetyl group with other protecting group will lead to complete loss of reactivity of ligands The ligands with different side chains were also examined Among the different substituents, benzyl group has the best result, the yield can reach 82%, the ratio of enantiomers can reach 97:3; the yield and enantioselectivity of isopropyl, SEC butyl, tert butyl and isobutyl are slightly lower The yield of phenyl substituted ligands is only 20%, and the enantioselectivity is low The mono benzyl group with low steric hindrance also reduces the reactivity and selectivity In addition, when the substituent is introduced into the para or ortho position of phenyl and the naphthyl is used to replace phenyl, the yield will be reduced (photo source: J am Chem SOC.) next, the author screened the application scope of aryl iodide (Table 2) The experimental results show that most of the aryl iodides containing electron absorbing and electron donating groups can obtain the desired products with high yield and high enantioselectivity (ER value up to 98:2) The yield of aryl iodides containing electron withdrawing substituents such as p-methoxycarbonyl, p-acetyl, p-trifluoromethyl, m-trifluoromethyl and o-methoxycarbonyl is slightly higher than that of other aryl iodides However, the yield of nitro substituted aryl iodide is only 53% (ER 90:10); the yield of iodobenzene is also low, but it has high enantioselectivity In addition, aryl iodides containing bromine, phosphonates and aldehydes can obtain the target products with high yield and good enantioselectivity In addition to phenyl iodides, heteroaryl iodides such as 2-acetyl-5-iodothiophene and 5-iodo-2-furfural can also be tolerated in this reaction, resulting in medium yield and high er value (photo source: J am Chem SOC.) later, the author also used methyl iodobenzoate as coupling substrate to screen the application scope of α - substituted cyclopropane carboxylic acid (Table 3) 1-aryl-1-cyclopropane carboxylic acid is an important structural unit in pharmaceutical chemistry The yield and enantioselectivity of its arylation are good Interestingly, C (SP 2) - H arylation of α - phenyl did not occur In this reaction, the tolerance of chlorine, bromine and trifluoromethyl on the benzene ring in the substrate was better α - alkylcyclopropane carboxylic acid is also a suitable reaction substrate The aromatization of α - ethyl, butyl and chloropentyl cyclopropane carboxylic acids at 60 ℃ also produced monoaromatization products in good yields However, the yield of α - phenylpropyl substituted products is only 58% Benzyl protected 1-hydroxymethylcyclopropane carboxylic acid and o-phthaloyl protected 1-aminomethylcyclopropane carboxylic acid have good yield and excellent enantiomer ratio (photo source: J am Chem SOC.) next, the author further evaluated the performance of the new chiral ligand in the enantioselective arylation of 2-aminoisobutyric acid (Table 4) This reaction can provide a simple way for the synthesis of various chiral α - amino acids Although the yields of aryl iodides with different substituents are similar, the enantioselectivity is quite different The enantioselectivity of aryl iodide substituted by neutral group is better than that of aryl iodide containing electron donor group Because aryl iodide does not participate in the C-H activation process, it may be that the lower reactivity of the oxidation addition step promotes the enantioselectivity of the reaction A more detailed mechanism of the reaction is under study (photo source: J am Chem SOC.) in order to further prove the practicability of this new method, the author used it in the later stage C-H functionalization of itanapraced, a drug candidate for neurological diseases The reaction proceeded smoothly, and the derivative products were obtained with high yield and high enantioselectivity (photo source: J am Chem SOC.) conclusion: the author developed a chiral ligand of mpaam based on the main chain of ethylenediamine, and used it for the enantioselective C (SP 3) - H arylation between cyclopropane carboxylic acid and 2-aminoisobutyric acid catalyzed by palladium The reaction does not need the external directional group The new ligands provide a new bond breaking method for the preparation of various chiral carboxylic acids from simple raw materials.