Professor Yan Hong, Associate Professor Wang Yi and Associate Professor Han Jianlin of NANDA University reported the cross electrophilic coupling reaction of deamination of katritzky salt and halide catalyzed by Ni

Transition metal catalyzed radical cross coupling is one of the basic transformations in materials science, biology and organic chemistry Although remarkable progress has been made in this field, the formation of SP 3 hybrid carbon center is still full of challenges due to its weak nucleophilic reactivity and difficult coordination with metals In recent years, a variety of alkyl precursors, such as halides, silicones, dihydropyridines, carboxylic acids and sulfones, have been used for free radical cross coupling reactions (Fig 1a) Primary amines are commonly found in bioactive natural products and drug molecules As a cheap and abundant synthetic block, amines are widely used in synthetic chemistry Recently, Watson group converted primary amines into redox active alkylpyridine (katritzky pyridine) to react with arylboric acid, and realized Suzuki miyaara and Negishi cross coupling reaction of primary amines Subsequently, glorious, Shi and other research groups have successively realized the Minisci reaction and deamination boration reaction of alkylation using katritzky pyridine salt (Fig 1b) However, there are no reports about amines used as alkyl electrophilic precursors for cross electrophilic coupling of radicals, especially for the direct construction of C (SP 3) - C (SP 3) and C (SP 3) - C (SP) bonds Recently, Professor Yan Hong, Associate Professor Wang Yi and Associate Professor Han Jianlin of Nanjing University reported the first cross electrophilic coupling reaction of alkylpyridinium salt and halide activated by C-N bond (Fig 1b) Relevant research results were published on SCI Adv (DOI: 10.1126/sciadv.aaw9516) (source: SCI Adv.) at the beginning of the study, the author used 4-iodotoluene 1a and pyridine salt 1 derived from 2 - (benzo [D] [1,3] dioxolapentene-5-yl) ethyl-1-amine and 2,4,6-triphenylpyranotetrafluoroborate as model substrate to screen the reaction conditions The results showed that in the presence of 2.5 equivalent zinc powder, 10 mol% NIBR 2 catalyst and 10 mol% tridentate ligand L3, the target product (entry1, FIG 1c) was obtained in 77% yield for 1a and 1 in argon atmosphere Under the optimal reaction conditions, the substrate universality of the cross electrophilic coupling reaction was investigated (Fig 2) The aryl iodide with electron acceptor and electron acceptor (such as methyl, phenyl, chlorine, etc.) is tolerated in this reaction system, and the coupling product 1 - 8 is obtained in good yield A variety of substituted pyridinium salts with alkyl and thiazolyl groups were also successfully obtained in the yield of 44% - 73% Secondary amines can also be used as electrophilic reagents to obtain secondary alkyl substituted aromatic hydrocarbons (19 and 20) in 67% and 71% yields, respectively It is found that the substrate can be extended to alkynyl halides to form C (SP 3) - C (SP) bond (Fig 2b) Tips substituted bromoacetylene can react with a series of tetrafluoroborate pyridines, and the corresponding alkyl substituted alkynes 23 - 28 can be obtained in 52% to 71% yield In addition, alkylbromide can also be coupled with katritzky pyridine salt to form C (SP 3) - C (SP 3) bond, and the corresponding product 29 - 33 (Fig 2C) can be obtained in medium yield (source: SCI Adv.) the author also applied this strategy to the synthesis of (+ - compact and (+ - mevinolin lactones In the past, it needs 10 steps to synthesize, further proving its practicability Starting from 34 on the market, the key intermediate 35 can be obtained by introducing phenyl in two steps, with a yield of 55% (source: SCI Adv.) based on mechanism experiments and previous literature reports, the author speculated that the reaction was a free radical cross coupling pathway through C-N bond cleavage and reduction elimination (Fig 4) At first, Ni (II) salt was reduced to active Ni (0) catalyst by zinc powder, and the intermediate r-ni (II) XA was obtained by C-X bond of halide 2 and oxide addition Then a was reduced to r-ni (I) intermediate B by zinc powder, which was added with pyridinium salt 1 for the second oxidation This step may be carried out by a step-by-step single electron transfer to obtain intermediate C, and then r-ni (III) (alkyl) x intermediate D The product 3 and Ni (I) species E were obtained by reduction of D, which were reduced by zinc to promote the next catalytic cycle (source: SCI Adv.) in a word, the author has developed a new cross electrophilic coupling reaction using alkylpyridine tetrafluoroborate derived from alkylamine as coupling agent The reaction conditions are mild and can tolerate a variety of substrates including highly active alkynyl bromide The electrophilic cross coupling strategy will have a good application prospect in the installation of alkyl substituents and the later functionalization of SP 3 carbon.