JACS: carbon dioxide mediated C (SP2) - H arylation of primary and secondary benzylamines

Amines are widely found in polymers and drug molecules In recent years, the rapid construction of amines by C-H functionalization has attracted the attention of researchers Primary and secondary amines usually need to introduce static guiding groups to promote C-H bond activation and avoid substrate oxidation However, up to now, there is no report that the free primary and secondary benzylamines can be directly prepared by C-H activation Only in 2006, daugulis group realized the first palladium catalyzed ortho arylation of free primary and secondary benzylamines, but its harsh conditions led to the need to protect the amino group to acetamide for product separation, and the substrate range of secondary amines was limited to methylbenzylamine (org Lett., 2006, 8, 5211 – 5213) At present, the study of C-H activation has turned to the use of transient guiding groups which can be formed in situ Although the strategy is often used for aldehyde and ketone substrates, the combination of amine substrate and aldehyde guiding group can also realize C-H functionalization Recently, the Michael C young group of University of Toledo in the United States has developed a new co 2-mediated strategy for the construction of ortho arylated primary and secondary benzylamines This method has mild conditions and a wide range of substrates Relevant research results were published in J am Chem SOC (DOI: 10.1021 / JACS 9b03375) (source: J am Chem SOC.) inspired by the transient guiding group, the author used CO2 as the traceless guiding group to realize the γ - arylation of aliphatic amines (J am Chem SOC 2018, 140, 6818 − 6822) The experimental results show that the transient carbamates act as the guiding and protecting groups, thus promoting the C-H activation of amines Therefore, the author speculates that CO2 may promote the C-H activation and realize the ortho arylation of free primary and secondary benzylamines under mild conditions In order to explore the feasibility of CO 2 promoting the arylation of benzylamine γ - C (SP 2) - H, the author selected 2 - (2-fluorophenyl) butyl-2-amine as the substrate It is gratifying that under the previously reported conditions: PD (OAC) 2 as the pre catalyst, AgTFA as the additive, acetic acid as the solvent, the reaction can get the target product smoothly Then, the conditions of solvent, amount of reaction and temperature were selected (Table 1) It was found that the yield increased when the loading amount of iodobenzene was increased to 3 equivalent When the mixture of HFIP / AcOH (7:3) was used as the solvent, the reaction effect was the best, and ortho arylated aniline (entry 11) was obtained in 78% yield (source: J am Chem SOC.) after determining the optimal reaction conditions, the author next investigated the substrate range of arylhalides (Table 2) Aryl iodide (1a - 1n) with halogen and other electron deficient groups (such as ester, nitro group, ketone) can react smoothly with good yield The electron rich aryl iodide (1o - 1W) with indole ring, methyl group, methoxy group and even long conjugated aromatic hydrocarbon is also tolerant in the reaction process Surprisingly, 2-iodo-brucine was also suitable for this reaction, and the corresponding product 1x was obtained (source: J am Chem SOC.) next, the author investigated the reaction range of benzylamine substrate It is difficult to realize selective monofunctionalization due to the O-C (SP 2) - H activation between molecules Therefore, the author first investigated the 2 or 3-position benzylamine substrate (Table 3) with a locating group The reaction can be compatible with short to medium length fatty chains and aromatics, and the aromatization products 2A - 2K show excellent selectivity It is gratifying that the strategy can also be applied to the more sensitive α - primary benzylamine, and the corresponding o-biarylamine can be obtained in a better yield without the oxidation of benzylamine (2L and 2m) (source: J am Chem SOC.) in addition, the second-order benzylamine 3a-3o with a straight chain or a straight chain on the amino group can also participate in the reaction, and the corresponding arylation products can be obtained in a medium to good yield (Table 4) (source: J am Chem SOC.) it is not surprising that the author found that in the absence of substituents at position 2 or 3, when excessive aryl halides are used, the reaction can yield diaryl products with high selectivity (Table 5) α - tertiary amines and SEC benzylamines are converted into m-triphenyls (4a-4c, 4f-4h) by C-H aromatization α - primary benzylamine is also a suitable substrate (4D, 4E and 4I) (source: J am Chem SOC.) conclusion: the author has proved that CO2 can promote the ortho arylation of free benzylamine under milder conditions than the transient guiding group of aldehyde group This makes the substrate range of primary benzylamine wider, and secondary benzylamine, which is sensitive to oxidation reaction, can also participate in the reaction smoothly The role of CO2 in the above reactions is also studied.