Dinuclear PhosphoiminoBINOL-Pd Container for Malononitrile: Catalytic Asymmetric Double Mannich Reaction for Chiral 1,3-Diamine Synthesis

A phosphoiminoBINOL ligand was designed to form a dinuclear metal complex that could hold a malononitrile molecule. The dinuclear bis(phosphoimino)binaphthoxy-Pd2(OAc)2 complex catalyzed a double Mannich reaction of N-Boc-imines with malononitrile to give chiral 1,3-diamines with high enantioselectivity. The rational asymmetric catalyst, which smoothly introduces the first coupling product to the second coupling reaction while avoiding the reverse reaction, facilitates the over-reaction into a productive reaction process.


General
Dry solvents were purchased from commercial suppliers and used without further purification.
The solvent was removed in vacuo, and the residue was purified by silicagel column chromatography (Hexane/AcOEt = 10/1) to obtain L7 as yellow oil. 1
Then, N-Boc imine (0.1 mmol) in dichloromethane (1 ml) was added over 4 hours. After being stirred for appropriate time, the reaction mixture was quenched with H2O, and then the products were extracted with dichloromethane in 3 times. The collected organic layer was dried over Na2SO4. After removal of the solvent under reduced pressure, the residue was purified by silica-gel column chromatography. The enantiomeric excesses of the products were determined by chiral stationary phase HPLC using a Daicel Chiralcel OD-H and Chiralpak IA column.
[For calculating the conversion yield of Table 1 and Fig. 4] The molar ratio between amine and diamine (1:d) was analyzed from the intensity of 1 H-NMR spectra for the mixture of products. Based on the molar ratio, each chemical yields of the amine (A mmol) and the diamine (A x d mmol) was determined on the isolated amount of the products. Finally, the conversion yield (A + A x 2d) was calculated as the consumption of imine substrates. (2,2-dicyano-1-phenylethyl) Enantiomeric excess was determined by HPLC with a Chiralpak IA column (hexane:2-propanol = 90:10, 0.5 mL/min, 254 nm) ; major enantiomer tr = 21.8 min, minor enantiomer tr = 35.0 min, 91% ee.  ( The NMR spectra was identical to those previously reported.
Then, N-Boc imine (0.25 mmol) was added. After being stirred for appropriate time, the reaction mixture was quenched with H2O, and then the products were extracted with dichloromethane in 3 times. The collected organic layer was dried over Na2SO4. After removal of the solvent under reduced pressure, the residue was purified by silica-gel column chromatography. The enantiomeric excesses of the products were determined by chiral stationary phase HPLC using a Daicel Chiralcel OD-H, Chiralpak IA, Chiralpak AD-H and Chiralpak AS-H column.