Angelw: the dauban group of Paris Thackeray university has realized the catalytic asymmetric intermolecular benzyl C (SP3) - H amination

Chiral benzylamines are widely found in drugs (rivastigmine, cinacalcet), agricultural chemicals (indazifalam), chiral promoters and catalyst ligands (Figure 1) Catalytic asymmetric C (SP 3) - H functionalization is an effective method for the synthesis of optically pure organic compounds, but the asymmetric conversion of C-H bonds is still challenging In recent years, the design of chiral transition metal complexes has promoted the discovery of catalytic asymmetric amination of C (SP 3) -H, which is mainly related to the azides or the presence of I (III) oxidants (picture source: angelw Chem Int ed.) at present, in the presence of chiral RH, Ru, IR and Co complexes or mutant P450 enzyme, the intramolecular asymmetric C (SP 3) - H amination has been realized; in contrast, the corresponding intermolecular reactions are less studied After M ü ller developed the chiral Rh (II) complex, Hashimoto and Davies reported a new catalyst for the amination of asymmetric benzyl C (SP 3) - h However, this method requires an excessive substrate and limited enantiomeric control Subsequently, Bach developed a supramolecular method inspired by RH 2 (ESP) 2 complex, but its yield and enantioselectivity are general and its application scope is limited to 3-benzylquinolones Recently, the Philippe dauban research group of Paris Thackeray University in France has realized the catalytic asymmetric intermolecular C (SP 3) - H amination (scheme 1) of various benzyl substrates by using the new benzyl sulfamate as the precursor of azone and the chiral Rh (II) complex as the catalyst This achievement has been published on angel Chem Int ed (DOI: 10.1002 / anie 201902882) (picture source: angelw Chem Int ed.) firstly, the author studied the reaction of ethyl benzene 1A with benzyl sulfamate 3A under the catalysis of chiral complex [RH 2 (s-tfpttl) 4] (4a) (Table 1) The preliminary results show that benzyl sulfamate can be used as a source of high active azone Next, the author screened all kinds of sulfamate esters by the amination of ethyl benzene under the catalysis of 4A, and found that benzylsulfamate azone has high reactivity, among which the effect of 5F benzylsulfamate 3E is the best Therefore, 3e was selected as a precursor for further study (image source: angelw Chem Int ed.) Secondly, the effects of solvents on Yield and enantioselectivity were evaluated, and it was found that trifluoromethyl had the best effect (yield: 92%; E.R., 82:18) At the same time, the author screened all kinds of rhodium (II) complexes and revealed the key effect of perfluorobenzoyl protecting group on enantioselectivity Next, the effect of amino acid side chain on the reaction process was studied (Table 2), and it was found that the enantioselectivity increased with the increase of the volume of ligand side chain Therefore, when the substituents are converted from methyl to tert butyl, adamantyl or 3,5-dimethyladamantyl, the reaction yield and enantioselectivity can be improved Among them, Rh 2 (s-tfptad) 4 (4b) is more effective in improving enantioselectivity Finally, the amount of catalyst loading was reduced to 1 mol% or 0.1 mol%, and the reactivity and selectivity of the reaction remained the same level Therefore, the author chose 8 and 9 conditions to study the amination range of asymmetric benzyl C (SP 3) - H (scheme 2) (image source: angelw Chem Int ed.) then, the authors evaluated various substrates with optimized reaction conditions When the complex 4B (1 mol%) was used, the yield of separation was as high as 99% (E.R., 92:8), and the reaction could be carried out on the scale of mmol, and the E.R value (E.R., 94.5:5.5) could be slightly improved, but in some cases, the yield decreased by about 5-15% It is also found that C (SP 3) - H amination can tolerate electron absorption and electron substitution, and the electron rich substrate has higher conversion In addition, increasing the volume of substituents (such as tert butyl or aryl) can improve the selectivity of the reaction However, for compounds 2Ge and 2je, ethyl substituents are more favorable for regional selectivity In addition, the substrate with long side chain was also studied Although it has good yield (40-81%), the selectivity is greatly reduced (image source: angel Chem Int ed.) then, the author applied RH 2 (s-tfptad) 4 (4b, 1 mol%) to more complex substrates (Figure 2) On the one hand, the single isomer 2UE (65%) was obtained by using methyl dehydroabienate analogues On the other hand, Shubatan derivative 2ve and cinnamic acid 2We showed excellent chemical selectivity, and the reaction only occurred in the benzyl ethyl part (picture source: angelw Chem Int ed.) finally, the author carried out the C (SP 3) - H amination reaction (scheme 3) on the scale of gram, and obtained 2me (E.R., 94.5:5.5) with 1 m as the substrate in 90% yield, and found that RH 2 (s-tfptad) 4 complex can induce the production of (s) - enantiomer Under mild conditions [75 ℃, solvent: acetonitrile / water (2:1), alkali: pyridine], the sulfamoyl group can be removed to obtain free amines in quantitative yield Conclusion: Philippe dauban research group has developed the catalytic asymmetric intermolecular C (SP 3) - H amination with the participation of pentafluorobenzyl sulfamate (3e) / chiral rhodium complex RH 2 (s-tfptad) 4 (4b) The reaction has a wide range of substrates, excellent yield (up to 99%) and enantioselectivity (up to 89%) In addition, the high reactivity of benzyl sulfamate as a source of Azone was revealed.