Enantioselective direct Mannich-type reactions of 2-benzylpyridine N-oxides catalyzed by chiral bis(guanidino)iminophosphorane organosuperbase

2-Benzylpyridine N-oxides possessing less acidic α-protons were utilized as pronucleophiles for the first time in enantioselective addition reactions under Brønsted base catalysis.

The combined organic layer was dried over magnesium sulfate and concentrated to give the crude sulfide. The crude sulfide was dissolved in 35 mL CH 2 Cl 2 . To the solution was added m-CPBA (77 wt%, 0.79 g, 3.5 mmol). After stirred for 30 min, 10 mL aq. NaOH (1 M) was added, the phases S6 were separated, and the aqueous phase was extracted with CH 2 Cl 2 (10 mL  2). The combined organic phase was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (hexane/ethyl acetate = 2:1 as the eluent) to afford the sulfoxide.
To a solution of the sulfoxide (3.5 mmol) in 15 mL THF was added methylmagnesium bromide solution (3.0 M in THF, 3.9 mmol) dropwise at room temperature. Then the reaction mixture was stirred for 1 h. The reaction was quenched by adding 10 mL saturated aq. NH 4 Cl slowly, and the mixture was extracted with ethyl acetate (20 mL  3). The combined organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (hexane/ethyl acetate = 4:1 as the eluent) to provide S7.  To a 50 mL flask were added 2-benzylpyridine (2.0 mmol, 1.0 eq.) and 20 mL CH 2 Cl 2 . The solution was cooled to 0 ºC, and meta-chloroperoxybenzoic acid (6.0 mmol, 3.0 eq) was added portionwise.

Synthesis of 2-benzyl-4-methoxypyridine S14
After that, the mixture was warmed to room temperature and stirred for 6 h. The reaction mixture was quenched with potassium carbonate (1.24 g, 4.5 eq.) and stirred for additional 10 min. The mixture was filtrated through a celite pad. The filtrate was concentrated under reduced pressure.
The residue was purified by flash chromatography (hexane/ethyl acetate/methanol = 3:6:1 as the eluent) to afford the desired product.    All the characterization data of the mixture of diastereomers were described in this section. In the case of 4aa, the NMR spectra of two diastereomers were given respectively. [α] 27 D = 46.4 (c = 0.49, CH 3 OH).
To a 30 mL two-neck flask were added the adduct 4ga (94.0 mg, 0.20 mmol), bis(pinacolato)diboron (0.15 g, 0.60 mmol) and 4.0 mL acetonitrile. The solution was stirred at 70 ºC for 48 h. After that, the mixture was cooled to room temperature, 1.6 mL 1,2-diaminoethane was added, and the mixture was stirred at rt for 1 h. The product was extracted with CH 2 Cl 2 (10 mL  3).
The combined organic phase was dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/ethyl acetate = 4:1 as the eluent) to afford 5 as a white solid.