JACS: the Tobias Ritter group of the German Mapu Institute synthesized benzyl alcohol by C-H oxidation

In order to diversify the small molecule candidate drugs, it is necessary to develop the method of selective oxidation of C-H bond at benzyl position to alcohol At present, benzyl alcohol is mainly synthesized by the reduction of benzophenone, but there are few reports about the direct oxidation of benzyl alcohol by C-H bond at benzyl position The latter can solve the problem of selective reduction of benzophenone to alcohol in the presence of other carbonyl functional groups, and can also tolerate olefins, alkynes and basic amines sensitive to oxidation conditions In general, bis (methylsulfonyl) peroxides (1) can be used for benzyl oxidation, and the substrate is converted to benzyl alcohol (scheme 1) through the intermediate of benzyl methylsulfonate (photo source: J am Chem SOC.) first, groves et al Reported asymmetric benzyl monooxidation of simple substrates such as ethylbenzene, in which chiral iron and manganese porphyrin catalysts and iodobenzene were limited reagents; later, Lawrence que team developed various non porphyrin ligands to avoid oxidation of ligands; in 2007, white team used n, n ′ - (2-pyridylmethyl ）The iron (II) complex with diamine ligand and H 2O 2 as oxidant realizes the selective oxidation of tertiary C-H bond However, the above methods are prone to over oxidation Sukbok Chang Group has developed a method for the synthesis of benzyloxyphthalimide by benzyl monooxidation; recently, Stahl and Yoon reported the selective benzyl alkoxylation of various alcohols Recently, the Tobias Ritter research group of Max Planck Institute in Germany reported a new method of C-H oxidation to benzyl alcohol by bis (methylsulfonyl) peroxide (1), which was recently published in J am Chem SOC (DOI: 10.1021 / JACS 9b09496) In the presence of hexafluoroisopropanol (HFIP) / H 2O, the benzyl methanesulfonate prepared by cuoac, peroxide 1 and tmsoac was converted into corresponding alcohol (Table 1) The substituent range of the benzyl position of the substrate covers the electron rich 4-methoxyphenylene and the electron absorbing 4-cyanophenylene, and the electric range is wider than previously reported The reaction is also compatible with alkenes and alkynes which are sensitive to oxidation conditions If the C-H bonds of TERT, allyl and propargyl still exist in the substrate, the functionalization only occurs at the benzyl position When TFA (1 equivalent) is added, the reaction can tolerate basic amines, such as tertiary amines or pyridines Although this method has a wide range of tolerance (can tolerate carbamates, esters, imides and epoxides, etc.), it also has its limitations: when the substrate has electronic rich C-H bond at the primary benzyl position, it is easy to produce the corresponding aldehyde by peroxide; when it has electronic rich C-H bond at the secondary benzyl position, a small amount of peroxide products can be observed Dichloromethane is the best solvent, cuoac is the initiator of free radical, tmsoac is the alkali reagent In the presence of methanesulfonic acid, secondary benzyl methanesulfonate is easy to eliminate and produce corresponding styrene, and then react with 1 to form dimethoxy substituted adduct In addition, for electron rich substrates, benzyl cations can exist stably and benzyl methanesulfonate can be ionized In this case, methanesulfonate is replaced by acetate in situ to produce stable benzyl acetate For electroneutral and electron deficient aromatics, the substitution reaction slows down, resulting in the mixture of acetate and methanesulfonate By using 2,6-di-tert-butylpyridine, benzyl methanesulfonate can be selectively obtained The conditions for the formation of benzyl alcohol depend on whether methanesulfonate or acetate products are obtained in the oxidation reaction (photo source: J am Chem SOC.) another feature of the reaction is that if there is an appropriate functional group, the reaction can achieve high enantioselectivity conversion, such as (s) - phenylalanine derivative 22 can be converted into a single enantiomer alcohol 14 (scheme 2) The results show that the substitution reaction follows the S N 1 pathway and is mediated by the ortho group of lone pair electrons on the ortho oxygen atom (photo source: J am Chem SOC.) in order to reveal the reaction mechanism, the author conducted Hammett analysis and intermolecular kinetic isotope effect (KIE) experiment (scheme 3) The Hammett slope (ρ = - 2) indicates that the positive charge increases in the transition state, which determines the selectivity of the reaction, and the slope (ρ = - 1) is larger than that of the pathway through hydrogen capture (HAA) to generate benzyl radicals The inter molecular KIE (1.8) was lower than the typical KIE value (KH / KD ≥ 5) of the oxygen center free radical for HAA The observed increase of KIE value and positive charge is consistent with the synergetic transition state, in which electrons transfer from π - system of aryl substituents and protons originate from scheme 4 Because the single electron and proton transport process involves the intermediate of high energy barrier, i.e aromatic radical cation or benzyl anion, it will be inconsistent with the wide range of substrates, so the multi-step pathway can be excluded Density functional theory (DFT) calculation is consistent with the predicted proton coupled electron transfer (PCET) pathway: the CT interaction between methylsulfonyloxy radicals and aromatics is better than PCET transition state, and the transfer of positive charge (0.4) on benzyl hydrogen to methylsulfonyloxy oxygen unit is more like proton transfer than hydrogen atom transfer However, due to the low spin density (~ 0.2) of carbon and oxygen atoms involved in hydrogen migration, part of HAA characteristics cannot be excluded The mechanism proposed by the authors can also explain the selectivity of monooxidation: the second PCET slows down due to the electron absorption effect on the aromatic ring For electron rich substrates, this effect is not obvious, and peroxidation can be observed In contrast, HAA is less sensitive to the electron density of aromatics because the charge increase of transition state is smaller than that of PCET The resulting benzyl radical reacts further with another peroxide to obtain the expected benzyl methanesulfonate and another oxygen methanesulfonate radical Because the added ethanesulfonic acid reacts with tmsoac instantaneously, it will not produce benzyl ethanesulfonate, so the possibility of further oxidation of benzyl radical intermediate to benzyl cation can be ruled out, which will lead to the nucleophilic attack of methanesulfonic acid (photo source: J am Chem SOC.) (photo source: J am Chem SOC.) conclusion: Tobias Ritter research group has developed a method to synthesize benzyl alcohol by selective monooxidation of alkyl substituted benzene to alkylmethanesulphonate Compared with the previous method, this method has a wider range of substrate application and functional group tolerance, and can be widely used in the synthesis of drugs and agricultural chemicals.