JACS: late oxygen functionalization of aromatic C-H bonds

Aromatic electrophilic substitution (SAR) reactions, such as nitrification or halogenation, have a wide range of substrates, and have become widely used as a favorable tool for the construction of C-N or C-X bonds For similar C-O bond formation reactions, only natural methods can achieve such a wide range of substrates Cytochrome P450 enzyme (CYP) can catalyze the electrophilic hydroxylation of aromatic compounds to phenol during the first phase metabolism Therefore, CYP is usually used as a catalyst for the direct synthesis of oxygen-containing metabolites in vitro However, the nonenzymatic c-h-bond oxygen functionalization is usually not carried out on complex small molecules The known c-o-bond formation reaction of aromatics is very rare, especially the late oxygen functionalization of small molecules with complex structure has not yet been realized Recently, a new strategy of C-O bond formation for aromatics, heteroaromatics and complex molecules has been developed by Professor Tobias Ritter of Max Planck Coal Research Institute in Germany The reaction uses bis (methylsulfonyl) peroxides as oxidants, which are suitable for electron rich, electron deficient and heteroaromatics For highly functionalized substrates, the reaction also has excellent functional group tolerance The reaction products can be cracked to form aryl fluorides or phenols under mild conditions Relevant research results were published in J am Chem SOC (DOI: 10.1021 / JACS 8b09208) (source: J am Chem SOC.) first, two different reaction conditions were developed to expand the range of substrates Solvent hexafluoroisopropanol (HFIP) is very important for high yield The reaction is easy to operate and can be compatible with various functional groups, such as electron rich amides, sulfonamides, alcohols and even olefins If there are nucleophilic amines, in situ protonation of TFA or tfoh can protect the nucleophilic nitrogen atoms from oxidation In addition, if there is an acid sensitive sensory group, such as the electron rich alkyne (15) in the antiretroviral drug favelon, the by-product of methanesulfonic acid can be neutralized in situ by adding a phosphate buffer (1.0m, pH = 7.2) to the reaction Electron rich heterocycles, such as quinoline in hydroquinine (9), thiophene in clopidogrel (10) and pyrazol C-H bond in celecoxib derivative 18, can also successfully achieve oxygen functionalization With acetonitrile as solvent and 2.5 mol% of [Ru (bpy) 3] (PF 6) 2 as catalyst, the range of heteroaromatics can be extended Pyridine (3), pyrrole (4), quinoxaline (5) and pyrimidine (7) derivatives can all react to obtain the desired products For electron deficient aromatics (such as methyl benzoate (12), nitrobenzene (17) and pycnomycin (19) are also suitable for this reaction, but pyridine without substituents at position 2 can not be converted into the desired product Therefore, this reaction is the first one that can functionalize aromatic C-H bonds and is suitable for electron rich and electron deficient aromatics or heteroaromatics Although some of the reactions are isomer mixtures, they provide a new way to synthesize several oxygenated products by one pot reaction (source: J am Chem SOC.) then, the cracking of the reaction products was studied At - 78 ℃, diisopropylaminolithium (LDA) can selectively cleave aryl methanesulfonate and install phenol groups on complex molecules Tetrabutylammonium fluoride (TBAF) can effectively convert aromatic methanesulfonate without O-H or N-H bond into phenol The hydroxylated heteroaromatics (22,23) and the metabolite 8-hydroxyeferene (24) can also be synthesized by these methods It is also found that aryl methanesulfonate can also undergo C-F bond transformation, and 4 '- OMS flurbiprofenmethyl ester can undergo fluorination to obtain product 25 Flurbiprofen methyl ester is the prodrug of flurbiprofen and can be metabolized at 4 'position, where fluorination may block this metabolic pathway These embodiments highlight the versatility of the aromatic methanesulfonate functional group, and the related complex small molecules can be obtained without the need of de novo synthesis (source: J am Chem SOC.) conclusion: a new C-O bond formation strategy for aromatics, heteroaromatics and complex compounds has been developed by Professor Tobias Ritter of Max Planck Institute of coal research in Germany The reaction uses bis (methylsulfonyl) peroxide as oxidant The reaction products are easy to split under appropriate mild conditions to form aryl fluoride and phenol.