JACS: malcolmson group of Duke University realizes the reduction coupling of aldimine and ketimine to anti-1,2-diamine catalyzed by asymmetric copper

O-diamine groups are widely found in drugs, natural products and chiral ligands Therefore, the development of asymmetric catalytic synthesis of o-diamine is an important goal in synthetic chemistry Although the synthesis method of o-diamine has been reported by researchers, its application (scheme 1) is limited due to the limitation of substrate range or poor reaction selectivity (source: J am Chem SOC.) in recent years, asymmetric copper catalyzed reductive coupling of unsaturated hydrocarbons with various carbon electrophilic reagents has become an effective way to prepare chemical structures containing adjacent stereocenters Recently, Steven J malcolmson group of Duke University reported that 2-azadiene and n-diphenylphosphonyl (DPP) imine can be reduced and coupled to form anti-1,2-diamine with ortho chiral center with high efficiency and chemical selectivity, and most of the products are single stereoisomers Relevant articles were published on J am Chem SOC (DOI: 10.1021 / JACS 8b04750) under the title of "enioselective synthesis of anti-1,2-diamines by Cu catalyzed reductive couplings of azadienes with aldimines and KETIMINES" In order to solve the problems in the synthesis of o-diamine, the author attempts to develop a method to connect two N-containing reagents by asymmetric catalytic C-C bond formation This strategy has the following advantages: 1) more diversified 1,2-diamines will be obtained, including 1,2-diamines containing nitrogen substituted quaternary carbon chiral centers; 2) the difference between the two amino groups in the product is obvious, which is conducive to the subsequent derivation; 3) free amines can be obtained without severe reduction conditions At the beginning of the study, the author began to explore the reductive coupling reaction with terminal 2-azadiene 1a and DPP aldehyde imine 2A as the substrate Through a lot of conditions screening, it was found that using dimethoxysilane as reducing agent, t-BuOH as additive, (s, s) - ph-bpe as ligand, copper acetate as catalyst, 3 equivalent 1a and 2A react at 5 ℃ for 1 hour, the effect is the best, and single anti diastereomeric diamine 3a and reducing product 4a (entry 1) can be obtained in 82% and 15% yield respectively Besides DPP, the imine active groups (such as ts and BOC) can not get the product 3A (entry 2) The increase of reaction temperature will lead to the decrease of chemical selectivity and produce more by-products 4a, but the stereoselectivity will not be affected (entry 3) Lack of t-BuOH will not only reduce the efficiency of the catalyst, but also have an adverse effect on chemical selectivity (entry 4) Copper catalysts derived from other ligands can reduce the reaction efficiency (entries 6-8) (source: J am Chem SOC.) under the optimal reaction conditions, the scope of application of the reaction substrate was investigated A variety of aldimines are coupled with azadiene 1a to form a single enantiomer anti diamine 3 (Table 2) A variety of aryl substituted imines can react with electron rich substrates to obtain the corresponding diamines in the highest yield Halogens or other substituents with electron deficient groups are also compatible with this condition (source: J am Chem SOC.) next, the author investigated whether 1,2-diamine containing quaternary carbon chiral center can be synthesized by reduction coupling of ketimine and azadiene It is gratifying that terminal azadiene 1a, aryl alkyl and diaryletoneimine can form diamine 6a-h in 84-92% yield (Table 3) No matter what the structure of imine is, the reaction can take place smoothly with a chemical selectivity of > 98%, and the diamine can be obtained with a value of > 20:1 Dr Diphenylketimine with steric hindrance can also be successfully reacted and diamine can be obtained in 86% yield for 6h (source: J am Chem SOC.) in addition, ketimine can be reduced coupled with 4-substituted 2-azadiene, and diamine 6i-r (Table 4) of a single non enantiomer can be obtained with good chemical selectivity and excellent enantioselectivity Despite the influence of steric hindrance, the reaction can be completed within 6 hours at 5 ℃ When the amount of catalyst was increased to 10 mol%, the yield of the product was increased (source: J am Chem SOC.) two amino groups in the reduction coupling product of azadiene imine are significantly different (scheme 2), because one is the double protected imine (red) and the other is the single protected phosphinamide (blue) Both of them can be hydrolyzed to amines, which makes any amino group can be functionalized selectively For example, the deprotonation and alkylation of N-H of 3A give compound 7 in 84% yield, while preserving the imine structure Or, the imine is hydrolyzed under weak acid condition, and then the free amine is functionalized to form benzyl carbamate 8 (the two-step yield is 85%); then the phosphoamide can be cracked with stronger acid, and then the released amine is functionalized to obtain tert Butyl carbamate 9 (the two-step yield is 80%) (source: J am Chem SOC.) conclusion: Steven J malcolmson's research group has developed an effective and highly stereoselective reduction coupling reaction for the construction of o-diamine This method forms ortho heteroatom substituted ortho center through asymmetric reduction coupling of imine and copper catalytic reduction coupling Diamine in the product is easy to distinguish and is beneficial to further transformation Corresponding author: Steven J malcolmson, Ph.D Steven J malcolmson, studied at Boston University, under the guidance of Amir hoveyda He studied at Harvard University under the guidance of Christopher Walsh The research directions are: (1) design and development of new catalysts; (2) development of new catalytic reactions; (3) synthesis of bioactive molecules