Asymmetric synthesis of allylic amines via hydroamination of allenes with benzophenone imine

Rhodium-catalyzed highly regio- and enantioselective hydroamination of allenes is reported.

Step 2, Hydrolysis: To the hydroamination reaction mixture of step 1 was added Et 2 O (2.0 ml) and HCl aq. Step 3, Amide formation: To the resulting allylic amine HCl salt curde mixture of step 2 was added CH 2 Cl 2 (2.0 ml) and Et 3 N (223 μl, 161.9 mg, 1.6 mmol, 4.0 equiv) and corresponding acyl/sulfonyl chlorides or anhydride (0.6 mmol, 1.5 equiv) sequentially. The reaction mixture was stirred for 3 hours. The volatiles were removed and the residue was purified by FCC to give the desired allylic amides.
Step 2, Hydrolysis: To the hydroamination reaction mixture of step 1 was added Et 2 O (30 ml) and HCl aq. (30 ml, 2.0 M, 4 mmol) sequentially. The reaction was stirred at r.t for 24 hours. The volatiles were removed under vacuum.
Step 3, Purification: The two phase mixture was separated, the aqueous phase was extracted with Et 2 O (20 ml x 3). 1) The combined organic phase was concentrated via rotary evaporation, and the organic residue was purified via FCC to recycle the benzophenone (EA/CH = 1/15, 1.05 g, 96% yield). 2) Water in the aqueous phase was removed via azeotropic distillation with toluene. The resulted solid was washed with cold Et 2 O then pentane to obtain the desired HCl salt (R)-6-phenylhex-1-en-3-aminium chloride (4) as a white solid (1.10 g, 86% yield). The ee value of compound 4 was measured via its amide derivative (4ee) after benzoyl protection following the scope condition. The enantiomeric excess of compound 4ee is the same with 1e (95% ee).
When the solution remained light blue about 5 min, indicating excess ozone, the ozone flow was stopped and N 2 was bubbled for 15 min to remove excess of ozone. To the reaction mixture was added PPh 3 (104.9 mg, 0.4 mmol) at -78 o C, and the resulting solution was stirred at r.t. for 2 hours. The crude reaction mixture was concentrated and purified by FCC on silica gel (EA/CH = 1/4, R f = 0.33) to afford the product as a yellowish solid (94.3 mg, 85 %). The ee value of 5b was obtained according to the ee of its derivative (5a).

S7-2
3 Synthesis of (R)-2-((tert-butoxycarbonyl)amino)-5-phenylpentanoic acid (5c) The reaction was performed according to the modified literature procedure. [6b] Allylic amine 2a (70.0 mg, 0.25 mmol) was dissolved in a mixture of CH 3 CN/CCl 4 /H 2 O (2.0 ml/2.0 ml/3.0 ml), then NaIO 4 (219.2 mg, 1.025 mmol, 4.1 equiv) and ruthenium trichloride hydrate (1.1 mg, 0.0055 mmol, 2.2%) were added subsequently. The reaction mixture was vigorously stirred at room temperature for 2 hours. The CH 2 Cl 2 (10 ml) was added and the phases were separated. The upper aqueous phase was extracted three times with CH 2 Cl 2 . The combined organic extracts were dried over MgSO 4 , filtered and concentrated. The crude mixture was purified by FCC on silica gel (CH 3 OH/CH 2 Cl 2 = 1/16, R f = 0.30) to afford the product as a yellowish oil (60.0 mg, 82 %). The ee value of 5c was obtained according to the ee of its derivative (5a). 4 Synthesis of (R)-tert-butyl (1-hydroxy-6-phenylhexan-3-yl)carbamate (5d) The reaction was performed according to the modified literature procedure. [6a] Allylic amine 2a (251.0 mg, 0.9 mmol) was dissolved in THF (10 ml) and cooled to -78 o C, then 9-BBN (4.6 ml, 272.5 mg, 2.25 mmol, 0.5 M in THF) was slowly added. The reaction was stirred for 15 min at 0 o C, and then slowly warmed up to room temperature, at which it was stirred overnight. The reaction mixture was cooled to -10 o C, then EtOH (1.0 ml), NaOH (1.0 ml, 2 M) and H 2 O 2 (1.0 ml, 30% in H 2 O) were added slowly in the given order. The reaction was warmed up to room temperature and stirred for 3 hours. The reaction mixture was diluted with dichloromethane and transferred into a separation funnel. The aqueous phase was extracted with dichloromethane (3x), the combined organic layers were dried over Na 2 SO 4 , filtered and concentrated by rotary evaporation. The crude product was purified by FCC on silica gel (EA/CH = 1/2, R f = 0.33) to afford the product as a white solid (252.0 mg, 95 %).

S7-3
The reaction was performed according to the modified literature procedure. [6c] To a solution of 5d (58.7 mg, 0.2 mmol) in DMSO (0.5 ml) was added Et 3 N (80 µl, 0.6 mmol). The solution was cooled to 0 o C and sulfur trioxide pyridine complex (95.0 mg, 0.6 mmol) in DMSO (0.5 ml) was added. The mixture was stirred at r.t. for 1 hour, then poured into ice-water and extracted with ethyl acetate. The combined organic layers were washed with acetic acid (10%), water, NaHCO 3 (5%) and brine. The organic residue was dried over MgSO 4 , filtered and concentrated.
The ee value of 5f was obtained according to the ee of its precursor (5d).

Mechanistic Investigations 1 Isotopic-labeling experiments
The reactions were performed according to the scope procedure using deuterated samples. The crude products were purified by flash column chromatography on silica gel (EA / CH = 1:30, R f = 0.35) to afford the deuterated products.