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    Home > Pt (II) - catalyzed enantioselective fluorination of C (SP3) - H

    Pt (II) - catalyzed enantioselective fluorination of C (SP3) - H

    • Last Update: 2018-06-15
    • Source: Internet
    • Author: User
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    At present, more than 25% of pesticides and 20% of drug molecules on the market contain at least one C-F bond in the structure The existence of C-F bonds affects the physical and biological properties of molecules, including conformation, lipophilicity and metabolic stability Therefore, the introduction of fluorine atoms is a common method to regulate the molecular properties In recent years, significant progress has been made in the field of organic molecular fluorination There are many asymmetric methods to directly construct C (SP 3) - f stereocenters, including α - fluorination of enols, fluorination of alkenes, and asymmetric addition of nucleophilic fluorides and carbon electrophilic reagents As an alternative to the above methods, the direct enantioselective fluorination of C (SP 3) - H bonds is very attractive Although the palladium inserted C (SP 3) - H fluorination method has been reported, its asymmetric form still needs to be expanded Free radical mediated direct C (SP 3) - H fluorination is a highly efficient strategy to introduce fluorine atoms However, asymmetric benzyl C-H fluorination has only been reported, and the enantioselectivity of this method is low Recently, Yu Jinquan group of Scripps Research Institute has realized the first metal inserted PD (II) catalyzed enantioselective C (SP 3) - H fluorination (Fig 1) by using the strategy of transient oriented basis In this method, the transient guiding group is used as the chiral ligand to control the stereochemistry in the C-H insertion step and promote the formation of C (SP 3) - f bond in the reduction and elimination step Relevant articles were published on NAT Chem (DOI: 10.1038/s41557-018-0048-1) (source: Nat Chem.) in the early stage of the research group, the enantioselective C (SP 3) - H arylation catalyzed by Pd (II) was developed by using chiral amino acids as transient guiding groups This discovery prompted the author to explore a new chiral transient guiding group to realize enantioselective C (SP 3) - H fluorination The main challenge of PD (II / IV) catalytic fluorination of C (SP 3) - H bond is that the C-F reduction of PD (IV) species is relatively slow, which makes [F +] an effective oxidant (Fig 1a) for the reduction of other C (SP 3) - C (SP 3) bonds or C (SP 3) - heteroatom bonds In addition, it has been reported that C (SP 3) - [PD (IV) (LN)] - f species can react with various oxygen and nitrogen nucleophiles in the form of S N 2, forming C (SP 3) - O and C (SP 3) - N bonds instead of C (SP 3) - f bonds In view of the above challenges, the author expects to change the ligand environment of PD (IV) - f intermediates to selectively fluorinate them At the beginning of the study, the author found that the acetoxylation product 2a and the fluorination product 3A (9.7:1) could be formed by the reaction of benzaldehyde 1A with n-fluoro-2,4,6-trimethylpyrinium salt ([F +]) in AcOH solution with simple glycine as the transient guiding group, of which [F +] was mainly used as oxidant (Table 1, entry 1) With the increase of the steric hindrance of amino acid transient guiding group, the author observed that the yield of 3A increased while that of 2A decreased It is worth noting that the E.E value of product 2a is 88% and the E.E value of product 3a is 90% (Table 1, entry 3) when the chiral tdg3 is used as the guiding group, which means that C-H insertion has high stereoselectivity Then the diethylamide tdg4 derived from amino acids was prepared, and the product 3A was obtained for the first time with high enantioselectivity In order to further improve the chemical selectivity of fluorination reaction, the author continued to investigate a variety of solvents The results showed that when benzene and AcOH were used as solvents, the selectivity of fluorination reaction increased by 1:6.7 Through the selection of acid additives, the author found that c6f5co2h is the most effective carboxylic acid, which can promote the fluorination reaction in medium yield, and the product has good chemical selectivity and excellent enantioselectivity Tdg3 (entry 7) and tdg5-7 (entry 8-10), the amino acid guiding group and the amide guiding group with small steric hindrance, will make the reaction inactive and selective, which indicates that the presence of amide part and large quaternary carbon substituent in the transient guiding group is very important (source: Nat Chem.) then, the absolute stereoconfiguration (Fig 2a) of 2a and 3a was determined by X-ray diffraction Interestingly, the absolute configuration of the two products is opposite, indicating that two different reaction pathways are involved in the conversion process The configuration of 3a is consistent with that of the previous aromatization reaction, which indicates that the fluorination reaction is formed by the traditional inner sphere reduction and elimination process with the stereostructure reserved, while 2a is formed by the SN2 mechanism with the stereostructure reversed Subsequently, in order to further support the above hypothesis, a series of experiments were carried out to exclude the possibility that two different diastereomeric palladium intermediates could form 2a and 3a through the same mechanism Firstly, the deuterium experiment shows that the process of C (SP 3) - H insertion is irreversible (Fig 2b) Secondly, Pd (OAC) 2 and imine 7, which were formed in advance, reacted in acod-d 4 solvent at 70 ℃ to separate palladium ring intermediate 8, which has the same stereostructure as compound 3A (Fig 2C) Under the action of [F +] and AcOH, intermediate 8 forms 2a and 3a with opposite configuration, which is consistent with the catalytic reaction The above experimental data prove that the assumption that two non enantiomeric palladium intermediates undergo different bonding modes is unlikely (source: Nat Chem.) then, the author proposed a reasonable explanation for the chemical selectivity transition in the formation of C (SP 3) - F and C (SP 3) - O bonds (Fig 3) PD (II) catalyst and amino acid type transient guiding group (tdg1-3) form a neutral five coordinated PD (IV) intermediate (Fig 3, I-III), which makes the elimination of C (SP 3) - f reduction slow, so the C (SP 3) - O bond is mainly formed through the mechanism of SN2 When the carboxylic acid part of the transient guiding group changes to a neutral diethylamide group, a cationic five coordinated PD (IV) intermediate (Fig 3, IV) suitable for C (SP 3) - f reduction and elimination can be formed Without affecting the overall yield, the reaction selectivity tends to form C (SP 3) - f bond Finally, when using c6f5co2h instead of AcOH, the selectivity and yield of fluorination are further improved (Figure 3, V), because the poor nucleophilicity of electron deficient benzoic acid will not only reduce the formation of C (SP 3) - O bond, but also promote the reduction and elimination of C (SP 3) - F (source: Nat Chem.) under the optimal reaction conditions, the author investigated the substrate range of enantioselective fluorination (Table 2) The fluorinated product (3b-c) can be obtained from the substrate of benzaldehyde 2-linked to the longer alkyl chain with slightly lower yield and higher enantioselectivity Then, the range of substituents with electron absorbing groups was investigated Ester, ketone, nitro and halogen substituted benzaldehyde can get fluorinated products with medium yield and excellent enantioselectivity Unfortunately, the fluorination reaction system is not compatible with substrates with electron donor groups Finally, the heterocyclic substrate can also undergo fluorination reaction, and the product has high enantioselectivity (3O) In this kind of fluorination, 2-ethylbenzaldehyde (1P) with unsubstituted benzene ring not only has low yield, but also forms C (SP 2) - H activation by-product (3P) (source: Nat Chem.) conclusion: the research group of Yu Jin Quan has developed a method of enantioselective fluorination of C (SP 3) - H catalyzed by Pd (II) with the assistance of chiral transient guiding group Anionic or neutral transient guiding groups are beneficial to the formation of neutral or cationic PD (IV) intermediates, and provide an effective way to control two reduction elimination pathways The large steric hindrance of amino amide transient guiding group is conducive to the realization of high enantioselectivity and the promotion of C-F bond reduction elimination.
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