JACS: hull group of University of Illinois Urbana Champaign and Merck Schultz et al. Realize RH catalyzed asymmetric hydrogenation of allylamine

Chiral amines (such as chiral 1,2-diamine) are widely found in drugs and ligands for asymmetric catalysis (Figure 1) Synthesis of chiral amines by asymmetric hydrogenation of alkenes is the most atom economical method However, the problem of intermolecular variation is still an unsolved challenge The asymmetric hydroamination of norbornadiene, styrene and diene has good enantioselectivity, while the unactivated alkene can be directly hydrogenated, but its enantioselectivity is low Recently, copper catalyzed hydroamination of olefins with electrophilic amines and silanes has been reported, which shows excellent enantioselectivity The team of Beauchemin reported that the asymmetric synthesis of 1,2-diamine was realized by the hydrogenation amination of organic catalyst; however, the first generation of catalyst is prone to racemization, which makes the enantioselectivity unstable (scheme 1) Recently, Kami L hull group of the University of Illinois Urbana Champaign and Danielle M Schultz et al Of Merck reported on J am Chem SOC A method for the synthesis of chiral 1,2-diamine by hydrogenation of allylimine and amine (DOI: 10.1021 / JACS 8b09811) (photo source: J am Chem SOC.) (photo source: J am Chem SOC.) first, the hydrogenation of allylamine 1a and morpholine catalyzed by RH (NBD) 2BF 4 was studied The chiral bidentate ligands were screened (Table 1) Meo-bipep ligands L6 and Rh were found The reaction catalyzed by the complex has good yield and excellent enantioselectivity Next, the author screened and optimized the reaction solvent, substrate concentration and catalyst dosage, and found that the reaction effect was the best when the concentration of DME was reduced and 5 mol% catalyst was added Under the optimized conditions, the yield of 2a was 92% (96.6:3.4er) It is worth mentioning that at the scale of 2.0 mmol, 2.5 mol% RH catalyst was used to obtain 2a in 75% yield, and the enantioselectivity was not decreased (photo source: J am Chem SOC.) after obtaining the optimized reaction conditions, the author explored the application scope of allylamine (Table 2) The enantioselectivity of the reaction is not affected when the substrate contains aromatic and heterocyclic aromatic groups with different electrical properties The reaction has a wide range of functional group tolerance and can be compatible with aryl ether, tertiary amine, trifluoromethyl, aryl bromine, ester and heterocycle containing moderate Lewis base The single ortho substituent on the aromatic ring has little effect on the reactivity When the aromatic ring contains 2,4,6-trimethoxybenzyl substituents with high resistance, the reaction can also be carried out The secondary amine group without π system (such as aliphatic substitution) can also make the reaction proceed smoothly, which has little effect on the yield or enantioselectivity However, when primary amines and α - branched amines were used as guiding groups, the required products were not obtained Although n-allylimine can be hydrogenated, its enantioselectivity is significantly reduced (photo source: J am Chem SOC.) then, the author evaluated the applicable range of nucleophiles suitable for this transformation (Table 3) The results show that n-methylbenzylamine, dimethylamine, Quaternary, penta and hexa cyclic secondary amines are all effective nucleophiles However, the substrates with steric hindrance such as 3,5-dimethylmorpholine and tetrahydroisoquinoline need to increase the reaction concentration and catalyst loading to produce good reactivity When 1-pyrimidinypiperazine with Lewis base is used as nucleophile, it has similar reactivity and selectivity to piperidine; 1 - (2-hydroxyethyl) piperazine and 1-boc-piperazine are also good nucleophiles 1,4-dioxa-8-azaspiro [4,5] decane is also an effective nucleophilic reagent When diethylamine, the substrate containing strong Lewis basic group or strong chelating functional group were used as nucleophilic reagent, no hydroamination product was obtained (photo source: J am Chem SOC.) in addition, the author used this method to rapidly construct challenging 1,2-propanediamine fragments to synthesize the methylated derivative (EQ 1) of the antidepressant moclobemide This simple and highly diversified synthesis method proves that this method has the ability to synthesize drug analogues effectively (photo source: J am Chem SOC.) asymmetric hydroamination of non activated olefins has been a challenge in the development of synthesis methods and catalysis It was found that the combination of MEO bipep ligand L6 and Rh could promote the hydrogenation of allylamine, and the corresponding 1,2-diamine was obtained with high yield and excellent enantioselectivity The conversion is suitable for various cyclic secondary amines, methylbenzylamines and dimethylamine nucleophiles In addition, the reaction can also be used to construct 1,2-diamine fragments in known bioactive molecules, which is more effective than other methods Conclusion: Kami L hull and Danielle M Schultz et al developed a enantioselective hydrogenation method of allylamine catalyzed by RH using chiral bipep type ligands This method can obtain the corresponding chiral 1,2-diamine with good yield and excellent enantioselectivity, which is suitable for a variety of nucleophiles and allylamine guiding groups In addition, 1,2-diamine fragments in drug molecules can be constructed quickly by this method, which simplifies the synthesis route.