Angelw: Professor Zhang Xiaoxiang's research group of Boston University realizes enantioselective amination of C (SP3) - H bond through catalytic free radical process

Free radical chemistry, with its unique reactivity and selectivity, is an important synthetic tool for building new organic molecules, which complements ion chemistry However, stereoselectivity, especially enantioselectivity, is difficult to control Recently, researchers have found that CO (II) - porphyrin complex is an effective catalyst for homogeneous activation of diazo compounds and organic azides to produce α - CO (III) - alkyl radicals and α - CO (III) - amino radicals, respectively In addition to the controllable reactivity, CO (II) - MRC based on CO (II) can control the stereoselectivity by using D 2 - symmetric chiral amide porphyrin as ligand CO (II) - MRC has been used for the homolysis activation of sulfamoyl azide to produce corresponding α - CO (III) - amino radical I, which can be transferred by 1,6-hydrogen atom to get ζ - CO (III) - alkyl radical II (scheme 1) After the substitution of intramolecular free radicals, II was converted into six membered cyclic sulfonamide by C-N bond formation process, and CO (II) - metal free radical catalyst was regenerated Although metal catalyzed intramolecular C-H amination provides an effective method for the construction of N-heterocycles, the control of enantioselectivity has always been challenging Recently, the team of Professor X Peter Zhang of Boston University realized the intramolecular enantioselective 1,6-c (SP 3) - H radical amination of sulfamoyl azide for the first time through CO (II) - MRC strategy This reaction not only has excellent enantioselectivity, but also has a wide range of functional group tolerance In addition to benzyl C-H bond, it is also suitable for allyl, propargyl, inactive and electron deficient C-H bond The related papers were published on angel.chem.int.ed (DOI: 10.1002/anie.201808923) (picture source: angel Chem Int ed.) firstly, the author selected sulfamoyl azide 1A as the model substrate, and selected scheme 2 for intramolecular 1,6-c (SP 3) - H radical amination by CO (II) - MRC The results show that MTBE is the best solvent and [CO (P4)] is the best catalyst Under these conditions, the yield of 1a is 93% and EE is 90% (picture source: angelw Chem Int ed.) under optimized conditions, [CO (P4)] catalytic system is applicable to intramolecular 1,6-c (SP 3) - H free radical amination of various sulfamoyl azides (Table 1) In addition to n-benzylsulfonyl azide, N-ethyl and n-isopropylaminosulfonyl azide can also tolerate the reaction Sulfamoyl azides derived from indole can be aminated to obtain cyclosulfonamides containing heterocycles Moreover, CO (II) - MRC can be extended to the chemical selective amination of allyl and propargyl C-H bonds, and the corresponding cyclic sulfonamide can be obtained with high yield and excellent enantioselectivity without affecting the saturation of C = C and C ≡ C For example, the β - C-H bond of hydroxyl group, Weinreb amide, allylamide and oxazolidinone imide can undergo regioselective 1,6-amination without α - C-H bond amination This indicates that the corresponding α - CO (III) - amino radical I tends to undergo 1,6-rather than 1,7-or 1,5-hydrogen atom transfer In addition, metal free radical process has a wide range of functional group tolerance, olefin, alkyne, alcohol, indole, oxazolidinone, amide and other functional groups are resistant (picture source: angelw Chem Int ed [CO (P4)] catalytic system can also realize the enantioselective amination of various electron deficient C-H bonds (Table 2) For example, it can realize the α - C-H amination of ketazide, and the substrate can obtain optically active α, γ - n-diaminone derivatives with high yield and excellent enantioselectivity In addition, ester azides can be aminated by electron deficient α - C-H bond to obtain α, γ - diamino esters; azides containing different N-substituted amides can produce α, γ - diamino amides by α - C-H bond amination; cyano azides can obtain α, γ - diamino nitriles by α - C-H bond enantioselective amination (image source: angelw Chem Int ed.) in order to prove the practicability of the above method, the author selected 2T enriched by enantiomer as model substrate, and prepared chiral 1,3-diamine derivatives (scheme 3) by desulfonylation and protection strategy Firstly, 2T was protected by BOC to obtain 3T cyclic sulfonamide, then 3T was selectively debenzylated to obtain 4T n-boc-protected α, γ - diamino ester, and then CBZ was used to protect primary amine to obtain 5T n, n '- protected 1,3-diamine, the optical purity of the compound remained unchanged in the whole process 1,3-diamine 4T and 5T can be used as chiral synthons for subsequent conversion to prepare optically active α, γ - amino acid derivatives (image source: angelw Chem Int ed.) next, the author studied the potential mechanism of amination (scheme 4) First of all, the author aminated the monodeuterium azide 1a-d with an achiral catalyst [CO (P5)] to determine the intramolecular kinetic isotope effect (scheme 4a) The K H / k d = 6.6, indicating that the C-H bond splitting is carried out by hydrogen atom transfer Secondly, the CO (III) - amino radical I produced by the reaction of 1A with [CO (P5)] can be detected by EPR spectrum and HRMS Finally, the free radical trapping agent tempo (scheme 4b) was added to the reaction of 1A with [CO (P5)] and [CO (P4)], respectively The reaction catalyzed by [CO (P5)] resulted in a lower yield of (±) - 2A and a sulfonamide containing tempo (±) - 3A; while the reaction catalyzed by [CO (P4)] resulted in a higher yield of (-) - 2A and a small amount of 3A The difference in the activity of [CO (P4)] and [CO (P5)] indicates that the steric hindrance of P4 promotes the free radical substitution of intermediate II, which is consistent with the mechanism previously proposed (scheme 1) (picture source: angelw Chem Int ed.) conclusion: Professor X Peter Zhang's research group first realized the intramolecular enantioselective 1,6-c (SP 3) - H free radical amination of sulfamoyl azide through CO (II) - MRC strategy The reaction not only has excellent enantioselectivity, but also has a wide range of functional group tolerance Besides benzyl C-H bond, it is also suitable for allyl, propargyl, inactive and electron deficient C-H bond.