Ni(II)-catalyzed asymmetric alkenylations of ketimines

Chiral allylic amines are not only present in many bioactive compounds, but can also be readily transformed to other chiral amines. Therefore, the asymmetric synthesis of chiral allylic amines is highly desired. Herein, we report two types of Ni(II)-catalyzed asymmetric alkenylation of cyclic ketimines for the preparation of chiral allylic amines. When ketimines bear alkyl or alkoxycarbonyl groups, the alkenylation gives five- and six-membered cyclic α-tertiary allylic amine products with excellent yields and enantioselectivities under mild reaction conditions. A variety of ketimines can be used and the method tolerates some variation in alkenylboronic acid scope. Furthermore, with alkenyl five-membered ketimine substrates, an alkenylation/rearrangement reaction occurs, providing seven-membered chiral sulfamide products bearing a conjugated diene skeleton with excellent yields and enantioselectivities. Mechanistic studies reveal that the ring expansion step is a stereospecific site-selective process, which can be catalyzed by acid (Lewis acid or Brønsted acid).

12 N HCl (4 mL) were added to the solution. The solvent was evaporated in vacuo and the aqueous layer was extracted with dichloromethane (3 × 100 mL). The combined organic phases were dried over anhydrous Na2SO4. The solvent was evaporated in vacuo to give the aryl sulfonamide 20 as a yellow solid without further purification. (c) A yellow suspension of the above products 20 in polyphosphoric acid (100 mL) was heated (150 °C) for 15 min while mixing manually with a spatula. The thick syrup was poured (hot) in a thin stream onto an excess of crushed ice which was vigorously stirred. Filtration of the solid and a thorough wash with water gave the product 21 as a gray solid without further purification. (d) To a 250 mL Schlenck flask equipped with a condenser, septum and magnetic stirring bar was added a solution of saccharin 21 (11 mmol) in THF (120 mL). The flask was cooled to -78 °C and methyl lithium (22 mmol) was carefully added by syringe. The reaction was stirred at -78 °C overnight. H2O (100 mL) and NH4Cl (2 g) was then added, and the reaction mixture was warmed to room temperature. Removal of the solvent in vacuo, filtration of the solid and a thorough wash with water gave the product 22 as a white solid without further purification. (e) Piperidine (2 drops) and acetic acid (2 drops) were added to a solution of cyclic N-sulfonylimines 22 (2 mmol) and t-BuCHO (4.4 mmol) in EtOH and the mixture was heated at reflux overnight. The mixture was cooled to 0 °C and the solvent was evaporated. Then H2O (20 ml) and EtOAc (40 ml) was added and extracted. The solvent was evaporated and purified by column chromatography (PE:EA = 7:1) to afford the desired products. Figure 4: Synthesis of alkenyl substituted five-membered ketimines (2) Piperidine (5 drops) and acetic acid (5 drops) were added to a solution of cyclic N-sulfonylimines 23 (8 mmol) and aldehyde 24 (17.6 mmol) in EtOH and the mixture was heated at reflux overnight. The mixture was cooled to 0 °C and the solvent was evaporated. Then H2O (40 ml) and EtOAc (80 ml) was added and extracted. The solvent was evaporated and purified by column chromatography (PE:EA = 7:1) to afford the desired product.
The product was purified by column chromatography using n-hexane/ethyl acetate (6:1) as eluent to give the desired products.

Ni(II)/DiPh-BOX-catalyzed asymmetric alkenylation of ketimines
A test tube (100 mL, 25 * 250 mm) was charged with Ni(OTf)2 (3.6 mg, 0.010 mmol, 0.050 equiv), L2 (8.1 mg, 0.015 mmol, 0.075 equiv) and unpurified TFE (1.0 mL). The solution was stirred at reflux for 5 min, then substrate (0.20 mmol, 1.0 equiv) and alkenylboronic acid (0.30 mmol, 1.5 equiv) were added into the tube. The wall of the tube was rinsed with an additional portion of TFE (1.0 mL). After stirring at reflux for 24 h in air, the reaction mixture was cooled to room temperature and the solvent was removed by rotary evaporation. The residue was purified by preparative TLC on silica gel (petroleum ether/EtOAc = 5/1) to give the product.
(Racemic ligand rac-L2 was used for racemic products and the procedure is the same as above.)

Condition screening for asymmetric alkenylation/ring-expansion of ketimines
Supplementary   (Racemic ligand rac-L2 was used for racemic products and the procedure is the same as above.)

Supplementary Note 2 Preliminary DFT computational study of racemization processes
All computations were carried out using the WB97XD method, as implemented in the Gaussian 09 software package. 15 All atoms were modeled at the 6-31G(d,p) level of theory. Geometry optimizations were performed with the account of the solvent effects (SMD, 2,2,2-Trifluoroethanol) without applying any geometry Constraints (C1 symmetry). Althouth the rotation of C1-C2 bond and C2-C3 bond is difficult, we calculated these two processes as well. The results show that C1-C2 bond rotation leads to a methyl migration intermediate SI-5 through an energy barrier of 31.1 kcal/mol and an eight-membered ring product could be formed. However, the eight-membered ring product was not observed throughout the experiments, indicating that C1-C2 bond rotation is not possible. During the scanning calculation process, C2-C3 bond rotation led to the formation of intermediate SI-1, the energy of which is 31.0 kcal/mol lower than SI-2. The above results indicate that the ring-expansion step is a stereospecific process.  To a mixture of 3ta (210 mg, 0.64 mmol) and K2CO3 (106 mg, 0.77 mmol) in DMF (7 mL) was added allyl bromide (155 mg, 1.28 mmol). The mixture was stirred at room temperature overnight and diluted with water and the mixture was The reaction was carried out using a modified procedure reported by Lam. 18 To a solution of the alkenylation product 3aa (137 mg, 0.397 mmol) in THF (2 mL) at room temperature was added LiAlH4 (1.0 M in THF, 1.59 mL, 1.59 mmol) dropwise over 2 min. The mixture was heated at 60 °C overnight, cooled naturally to room temperature, and then to 0 °C with an ice bath. The reaction was quenched carefully with EtOAc (5 mL) followed by EtOH (5 mL