Triply catalytic aldehydes to ketones

Ketone compounds are not only widely found in natural products, but also in synthetic compounds such as organic materials, drugs, photosensitizers, flavoring agents and aromatics In addition, ketone is a multifunctional structural unit in the field of synthetic organic chemistry, which can be used in various powerful bonding reactions The classical methods of ketone synthesis include: (1) addition of organometallic reagents with carbonyl containing amides, anhydrides, acyls, etc.; (2) aryl substitution strategies, such as Friedel crafts acylation; (3) coupling reaction of acyl chloride with aryl, alkylstantane and borate catalyzed by transition metals Recently, Professor David W C Macmillan and Zhang Xiaheng from Merck catalytic center of Princeton University used nickel, hydrogen atom transfer (HAT) and redox to catalyze the C-H bond of aldehydes directly for aromatization and alkylation to obtain a series of ketones Relevant papers were published online in J am Chem SOC (DOI: 10.1021 / JACS 7b07078) Inspired by the coupling of metal catalyzed aryl iodides and aldehydes to form ketones, and combined with the previous research on the direct arylation and alkylation of amines and ethers by redox, nickel and hat triple catalysis, the author proposed the idea of triple catalysis for the aromatization and alkylation of aldehydes sp 2h-c (o) bond to form ketones The reaction mechanism is divided into three parts: redox catalytic cycle, organic catalytic cycle and nickel catalytic cycle Firstly, IR (III) (2), a strong oxidant, was formed by IR [DF (CF 3) PPy] 2 (dtbbpy) pf 6 (1), which was activated to oxidize quinine ring (3) to cation radical 4, and at the same time, it was reduced to IR (II) complex 5 4 and n-boc-4-piperidialdehyde (6) undergo hydrogen atom transfer In view of the negative charge of hydrogen atom in the formyl C-H bond and the relatively weak bond, the author assumes that hat generates acyl radical 7 At the same time, the oxidation addition of LNNI 0 and aryl bromine (10) results in the formation of aryl NiII (11) The author hopes that 7 can be rapidly inserted into 11 to form the aryl niiii complex 12 After that, the target products ketone (14) and NII (13) were obtained after 12 reduction and elimination The key step in the whole process is the single electron transfer between IR II complex 5 and Ni I complex 13 Only in this process can the nickel catalytic cycle and redox catalytic cycle be reversed simultaneously Finally, the inorganic base deprotonates the quinine ring cation 8 and regenerates it into quinine ring catalyst After finishing the design of reaction mechanism, the author started a series of reaction conditions screening with n-boc-4-piperidialdehyde and 5-bromo-2-trifluoromethylpyridine as reaction substrate The experimental results show that 1,4-dioxane as the reaction solvent can significantly improve the yield of the target ketone product, while reducing the load of nickel catalyst has little effect on the yield The results show that photocatalyst, nickel catalyst and light are indispensable With the optimum reaction conditions, the universality of the substrate was investigated The results show that the electronic rich aromatics, electron deficient aromatics and bicyclic aromatics have good reactivity, and the steric hindrance effect of ortho substituents has no obvious effect on the reaction Alkenyl and alkyl bromine were also competent for this reaction, and the coupling of alkyl bromine and aldehyde was first reported Different aldehydes react with 5-bromo-2-trifluoromethylpyridine, and the yield is over 70% The volatilization of acetaldehyde and the coupling reaction of aromatic aldehyde and aromatic halide all affect the yield Finally, the author used this reaction to synthesize the antipsychotic drug haloperidol Summary: David W C Macmillan and his team designed and realized the direct arylation and alkylation of aldehyde C-H under triple catalysis The reaction is based on the available aldehydes and bromines The conditions are mild, the operation is simple, and the substrate has wide applicability, providing a new choice for the synthesis of ketones.