ACS catalyst: Zhang Xingang group of Shanghai organic Research Institute realized the difluoroalkylation alkylation reaction of enamide catalyzed by nickel

Transition metal catalyzed fluoroalkylation is an efficient and valuable method for the selective synthesis of fluorinated compounds In recent years, among all kinds of transition metal catalysts, due to their cheap price and abundant reserves, nickel catalyzed fluoroalkylation has attracted more and more attention In this context, Zhang Xingang's research group has previously developed a chelating group assisted strategy (CGA) for nickel catalyzed series reactions, and effectively prepared fluorine-containing compounds (scheme 1a) Later, the strategy has been extended to a fluorine-free substrate, which provides an effective method for organic synthesis (scheme 1b) However, most of the reported methods focus on aromatization / alkylation, while the Dialkylation of olefins has not been developed It is still very challenging to synthesize fluorine-containing compounds by CGA strategy with aliphatic nucleophiles Two of the key problems are how to avoid the elimination of β - hydrides of alkyl nickel species and how to inhibit the competitive cross coupling between fluoroalkyl halides and aliphatic nucleophiles Recently, Zhang Xingang, a researcher of Shanghai Institute of organic science, Chinese Academy of Sciences, solved the above problems They used nickel to catalyze the series reaction of N-vinyl-2-pyrrolidone with difluoroalkyl bromide and dialkyl zinc reagent to realize the Dialkylation of olefins, and synthesized a variety of 2-pyrrolidone difluoride derivatives Relevant research results were published on ACS catalyst (DOI: 10.1021 / acscalal 9b02488) (source: ACS catalyst.) firstly, the reaction of n-vinyl-2-pyrrolidone-1 with difluoropropane bromide 2a and alkylzinc reagent 3 (1) catalyzed by nickel was studied When tripyridine was used as the ligand, the cross coupling product 6a of 2a and 3 was observed, while when diamine or other bidentate ligands were used, heck type by-product 5 was obtained (source: ACS catalyst.) in order to overcome the above problems, the author speculates that the use of more active dialkyl zinc reagent 8A may be conducive to the series reaction of difluoroalkylation alkylation In the presence of NiCl2 · DME (5 mol%) and phen (5 mol%), 1,2a (1.5eq) and 8A (1.5eq) were reacted in DMA at room temperature with 4% yield It is gratifying that at - 20 ℃, 9a and a small amount of byproducts 5 and 6B were obtained in 53% yield After optimizing the nickel catalyst, the author found that the activity of NiCl2 (DPPE) was the highest, and 9 A was obtained in 60% yield When the load of 2a was increased from 1.5 EQ to 2 EQ, the yield of 9A was further increased to 91% (source: ACS catalyst.) under the best reaction conditions, the author first studied the scope of application of difluoroalkyl bromide 2 (scheme 2a) The bifluoropropynyl bromide substrate containing silalkyl protection or alkyl substitution is suitable for the reaction, and the product 9A - 9j is obtained in good to excellent yield In addition to the bifluoropropynyl bromide, ethyl difluoroacetate and bromodifluoromethyl substituted benzoxazole and thiazole can also successfully obtain the Dialkylation product 9K - 9N Then, the author investigated the substrate range (scheme 2b) of dialkyl zinc reagent Dimethylzinc reagent showed good tolerance to a series of difluoroalkyl bromides, and the corresponding fluorinated product 10A - 10I was obtained in good yield Other dialkyl zinc reagents with long chain are also suitable for this kind of reaction, but the yield of 10J - 10q is slightly reduced, which may be due to the serious defluorination of 2A It is worth noting that N-vinyl oxazolidinone and N-vinyl acetamide are also compatible with the reaction, and the product 10r-10s is obtained in medium yield (source: ACS catalyst.) based on the results of control experiments and free radical clock experiments and previous literature reports, the author proposed two possible nickel (I / III) catalytic cycle mechanisms (scheme 5) The reaction in path I was initiated by species (a) of nickel (I), which was produced by the centrifugation of nickel (II) and in situ nickel (0) The nickel (I) species reacts with dialkyl zinc reagent to obtain alkylnickel complex B B and difluoroalkyl bromide were transferred to form difluoroalkyl radical and nickel (II) complex C by single electron transfer Then, the difluoroalkyl radicals were trapped by N-vinyl-2-pyrrolidone to produce new alkyl radicals With the aid of the carbonyl group of pyrrolidone to chelate the nickel complex C, the key intermediate, nickel (III) complex D, was obtained by recombination of the newly formed alkyl radical with C Finally, dealkylation products were obtained from D by reduction and elimination, and a was regenerated at the same time Alternatively, the reaction may be initiated by nickel (II) (path II) The reaction begins with the conversion of the nickel (II) species to the C obtained from the dialkyl zinc reagent Subsequently, C reacts with the newly formed alkyl radical e to form the key intermediate D D is eliminated by reduction to produce the final product and release nickel (I) (a) A reacts with difluoroalkyl bromide to form difluoroalkyl radical, which is captured by N-vinyl-2-pyrrolidone to obtain alkyl radical E and regenerate nickel (II) (source: ACS catalyst.) Summary: nickel catalyzed difluoroalkylation alkylation of alkenylamides has been developed The reaction conditions were mild and resistant to various difluoroalkyl bromides and dialkyl zinc reagents Considering the simplicity and practicability of the synthesis and the important application of 2-pyrrolidone and difluoromethyl group in medicine, the series process catalyzed by nickel will have potential application value in medicine chemistry.