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    Home > JACS: trifluoromethylation of C-H bond at benzyl site in aqueous phase

    JACS: trifluoromethylation of C-H bond at benzyl site in aqueous phase

    • Last Update: 2018-11-05
    • Source: Internet
    • Author: User
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    Because of its high electronegativity and Teflon like stability, trifluoromethyl has been widely used in drug discovery, agricultural chemicals and material synthesis In recent years, the emergence of some new trifluoromethylation reagents has provided new opportunities for the rapid trifluoromethylation of organic molecules Ruppert Prakash, togni, umemoto, Langlois, grushin, Chen, Shibata, Baran and other reagents provide chemists with many trifluoromethyl synthons with unique properties Compared with trifluoromethylation of aromatic compounds (mainly including metal mediated McLoughlin – thrower coupling or free radical addition of electron deficient aromatic rings), the development of trifluoromethylation of aliphatic compounds is relatively backward Although fluoroform has a suitable acidity (PKA = 28), it is not easy to introduce trifluoromethyl into aliphatic compounds by simple SN2 reaction because CF 3 anion is easy to decompose into monomer fluoride and Difluorocarbene Recent studies have shown that compared with metal mediated coupling, the free radicals produced by aliphatic carboxylic acids, esters or halides are more convenient for trifluoromethylation of aliphatic compounds The direct trifluoromethylation of csp3-h bond is undoubtedly the most efficient method (source: J am Chem SOC.) recently, Silas P cook group, University of Indiana, USA, used the grushin reagent to realize the photocatalysis of trifluoromethylation of C-H bond at the benzyl position The hydrogen atom with the smallest steric hindrance in the substrate can carry out the monotrifluoromethylation with high selectivity The reaction can be carried out in an environment-friendly acetone / water solvent system and can be used for the later modification of drug molecules (j.am.chem.soc 2018, 140, 12378) Firstly, toluene (1a) was used as the model substrate to optimize the reaction conditions (Table 1) In the preliminary screening, the author found that the target product 3A could be obtained by the reaction of ammonium persulfate and grushin reagent (2a) in toluene at 50 ℃ Because UV light can promote the halogenation of C-H bond, the yield can be increased to 58% when the reaction is exposed to 365 nm LED light Finally, in the presence of ammonium persulfate / triesopropylsilane (3 equivalent), trifluoroacetic acid (8 equivalent) and 2A (1 equivalent), using acetone / water as solvent, 1A can yield 3A (Table 1, entry 1) Among them, acid can promote the cleavage of grushin reagent through the protonation of ligands, and triisopropylsilane can inhibit the competitive trifluoromethylation of aromatic compounds (source: J am Chem SOC.) after determining the optimal reaction conditions, the author studied the substrate range of the reaction (Table 2) The first-order benzyl C-H bond is faster than the second-order benzyl C-H bond In addition, even if there are more than one C-H bond reaction site at the same benzyl position in a molecule, the reaction can only selectively obtain the monotrifluoromethylation product The reaction can tolerate a series of functional groups, including halide (3C, 3O, 3S and 3cc), pseudo halide (3b), ketone (3I, 3aa-3cc and 3ee), ester (3Y and 3BB), amide (3j-3r, 3Z and 3dd), nitrile (3x), phthalimide (3V and 3W), pyridine (3q and 3T), pyrimidine (3U) and silane (3e) (source: J am Chem SOC.) further, the author studied the reaction mechanism of trifluoromethylation of C-H bond at the first, second and third benzyl positions (Figure 2) By calculating the relative energy of the first-order (1P), second-order (1s) and third-order (1t) radicals, it is found that bipycu (CF3) 2 (4) tends to recombine with the first-order (1P) and second-order (1s) radicals in thermodynamics, while the steric hindrance is not conducive to the formation of 5T The author proposed the reaction mechanism of Wohl Ziegler reaction by analogy (Figure 3) UV light plays a variety of roles in the reaction, including promoting the cleavage of 2a and persulfate to form active Cu (II) species (4) and CF 3 radicals Silane can inhibit trifluoromethylation of aromatic compounds by quenching trifluoromethyl radicals Since the energy barrier of recombination of 4 and 1-rad is about 4 kcal / mol, the author has excluded the mechanism that the energy barrier is larger than 61 kcal / mol (i.e 1-rad directly grabs CF 3) Finally, 5 was reduced to eliminate the formation of target product 3 and non reactive 6 The kinetic isotope effect (KIE) observed by the intermolecular competitive reaction of toluene and toluene-d 8 is K H / k d = 2.8, which indicates that the C-H bond cleavage or the previous step is the decisive step of the reaction According to the results of intramolecular competition reaction (KH / Kd = 4.2) of monodeuterium p-xylene, it can be concluded that the most likely rate determining step is the uniform splitting of persulfate under 365 nm light (source: J am Chem SOC.) (source: J am Chem SOC.) finally, the author studied the late stage trifluoromethylation (scheme 1) of several bioactive small molecules All the protected 4-methyl-phenylglycine, meclizine and celecoxib can be obtained by trifluoromethylation (source: J am Chem SOC.) conclusion: Professor Silas P cook, University of Indiana, USA, has developed an environmentally friendly photocatalysis of trifluoromethylation of C-H bond at benzyl site This method can tolerate a variety of functional groups and can be used in the later stage of trifluoromethylation of bioactive molecules.
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