Angelw: a series reaction of C-H functionalization and elimination of β - fluorine to synthesize amphiphilic alkenes

As a kind of unique structural group, amphiphilic alkenes have important applications in medicine, materials and other fields Amphiphilic alkenes have unique properties, such as regulating the metabolic stability and lipophilicity of organic molecules The strong electronegativity of fluorine and the chemical reactivity of difluoroethylene make difluoroethylene have strong electrophilicity It can be used as an irreversible inhibitor of thymidylate synthetase or other enzymes For example, 5 - (2,2-difluoroethylene) - 2 '- deoxyuridine (1) can be used as a new antiviral In addition, the difluoroethylene can also be used in oral active thrombin inhibitors such as ssr182289a (2), tubulin inhibitors (3) or amino acid derivatives (scheme 1a) Therefore, in recent years, more and more attention has been paid to the efficient synthesis of amphiphilic olefins However, the preparation of carbonyl compounds by classical reactions, including Wittig, Horner Wadsworth Emmons and so on, usually requires strong alkaline conditions and limited substrate range Recently, researchers found that Difluorocarbene is an effective precursor (scheme 1b) Only Wang Jianbo group reported the difluoroethylation of 2,2,2-trifluoroenzane with organic boric acid Inspired by this, Professor Rene M Koenigs of Aachen University of technology, Germany, reported for the first time the palladium catalyzed C-H functionalization and β - fluorine elimination reaction of indole heterocycle and diazolane fluoride in series to synthesize gemodifluoroolefins This method has the advantages of mild conditions, rapid and efficient reaction The related research results were published in angelw Chem Int ed (DOI: 10.1002/anie.201915500) (source: angelw Chem Int ed.) at first, the author used phenyl (trifluoromethyl) diazomethane 8a and 1,2-dimethylindole 7a as model substrates, NABAR F as additive, rac-binap as ligand and DCM as solvent to investigate the catalytic activity of different palladium compounds (Table 1) The results show that PD (OAC) 2 can be used to obtain the dicyclohydroolefin 9a and carbene insertion product 11a at the highest ratio of 55:18 Then, other conditions such as ligand, solvent and temperature were selected The bidentate phosphine ligands play an important role in the selectivity and yield of the reaction Using dppbe ligands, we can obtain 9-difluoroethylene-9a in 92% yield and have good selectivity (entry 6) The weak coordination of NABAR f is crucial for this transformation because acetate may inactivate Pd catalyst (entry 7) (source: angelw Chem Int ed.) determined the best conditions, and then the author examined the scope of application of the substrate (scheme 2) A variety of aliphatic substituents (including terminal alkenes) can be compatible with the reaction system, and the product 9A - 9K can be obtained with high yield The product 9L - 9p can be selectively formed from aryltrifluoroadiazoethane with different substituents in 60% - 89% yield (source: angelw Chem Int ed.) in addition, halogens or electron donor substituents at positions 5, 6 and 7 of indole have good tolerance, and can efficiently introduce 1-aryl - (2,2-difluoroethylene) group (scheme 3, 9p - 9V) at position 3 However, the electron withdrawing substituents can inhibit the reaction The substituents of indole 4 will form cyclopropane and C-H functionalized products The brominated substituents with a large steric hindrance at 4 sites will selectively yield the cyclopropane product 14b (source: angelw Chem Int ed.) the author has further studied and found that when the protecting group on nitrogen changes to phenyl, the chemical selectivity will be completely changed, and only 15A single cyclopropane product will be obtained under the same reaction conditions, which may be attributed to the low nucleophilicity of n-arylindole heterocycle (scheme 4) Various indole derivatives protected by N-aryl group can selectively obtain cyclopropanized product 15a-15h in medium yield (source: angelw Chem Int ed.) on the reaction mechanism, the author speculated that PD (II) catalyst 18 first formed PD carbene complex 19, which was then nucleophilic adducted with indole to form 20 The compound underwent β - fluorine elimination reaction to obtain cddf 9; or, after 1, The product 11 of trifluoromethylation was obtained by 2-proton transfer reaction, and Pd (II) complex was released at the same time The control reaction of the product 11a of trifluoromethylation showed that 9A was not formed, which further confirmed the importance of the β - fluorine elimination reaction pathway (scheme 6b) Finally, the intermediate 20 was broken by Pd (II) complex, and then cyclized to obtain cyclopropane product 15 (scheme 6a) (source: angelw Chem Int ed.) in short, palladium catalyzed C-H functionalization of diazoalkanes and indole heterocycles has been reported for the first time, and 1-aryl - (2,2-difluoroethylene) groups have been successfully introduced into indole heterocycles and electron rich aromatic systems This method can directly synthesize important difluoroethylenes in one step, in which the elimination of β - fluorine is the key step.