Nickel-catalyzed enantioselective arylation of pyridine

A Ni-catalyzed cross coupling of arylzinc reagents with pyridinium ions provides enantioenriched dihydropyridines, which are precursors to diverse piperidine derivatives.


II. General Procedures
Pyridinium Arylation on 0.5-mmol Scale: In a nitrogen-filled glovebox, L3 (30.1 mg, 0.0600 mmol, 0.12 equiv.) was added to a threaded 16 mm x 100 mm glass vial and dissolved in THF (0.5 mL). To this solution was added Ni(acac) 2 (12.9 mg, 0.0500 mmol, 0.10 equiv.), followed by THF (0.5 mL). Arylzinc halide (prepared as a 0.60 M solution in THF/hexanes, 2.5 mL, 1.5 mmol, 3.0 equiv.) was added to the Ni/ligand solution. Upon addition of the zinc halide, the solution immediately turned from green and translucent to dark brown and opaque. The glass vial was sealed with a plastic cap lined with a Teflon septum, wrapped with electrical tape, and removed from the glovebox.
Separately, a threaded 16 mm x 100 mm glass vial equipped with a stir bar was put under a nitrogen atmosphere. To this vial was added anhydrous pyridine (39.5 mg, 0.500 mmol, 1.0 equiv.) by weight. The pyridine was dissolved in THF (1 mL), and the Ni/ligand/nucleophile solution was added to the pyridine solution at rt via syringe. The vial containing this solution was transferred to a -40 °C Cryocool, and chloroformate (1.5 mmol, 3.0 equiv.) was added at this temperature. The reaction was left to stir at -40 °C overnight (approximately 14 h).
The reaction was quenched with ~5 mL of water and stirred for 10 min at rt. The resulting mixture was diluted with diethyl ether, and the aqueous layer was extracted with diethyl ether (3 x 30 mL). The combined organic layers were dried over MgSO 4 , and the filtrate was concentrated in vacuo. The crude mixture was purified by automated column chromatography (typically 1→10% EtOAc in hexanes) to give the product dihydropyridine.
Pyridine (0.40 mL, 5.0 mmol, 1.0 equiv.) was added under N 2 to a flame-dried, 100-mL Schlenk flask equipped with a stir bar, and dissolved in THF (10 mL). To the pyridine solution was added the Ni/ligand/ArZnBr solution via syringe. The reaction mixture was cooled to -78 °C, and i-BuOCOCl (1.9 mL, 15 mmol, 3.0 equiv.) was added at this temperature. Then, the reaction mixture was transferred to a -40 °C Cryocool, where it was allowed to stir overnight (approximately 14 h).

S-5
The reaction was quenched with water (40 mL) and allowed to stir at rt for 10 min. The solution was extracted with Et 2 O (3 x 50 mL), and the combined organic fractions were washed with brine (1 x 100 mL). The organic layer was dried over MgSO 4 and the filtrate was concentrated in vacuo. The crude material was purified by automated column chromatography (1→10% EtOAc in hexanes) to give the product dihydropyridine as an oil.
Formation of Arylzinc Bromide Solutions 3 : The following procedure was used to prepare the arylzinc bromide solutions, except where noted in Section V.
A 50-mL recovery flask equipped with a stir bar was flame dried under vacuum and put under N 2 . Bromoarene (7.5 mmol, 1.0 equiv.) was added and dissolved in THF (4 mL). The bromoarene solution was cooled to -78 °C and n-BuLi (titrated as 2.2 M in hexanes, 3.4 mL, 7.5 mmol, 1.0 equiv.) was added dropwise. The reaction mixture was allowed to stir at -78 °C for 30 min.
Meanwhile, ZnBr 2 (1.86 g, 8.25 mmol, 1.1 equiv.) was weighed into a 50-mL pear-shaped flask under N 2 . To the solid was added THF (5 mL), and the mixture was placed in a sonicator until the ZnBr 2 had completely dissolved.
After 30 min had elapsed, the ZnBr 2 solution was added in one portion to the aryllithium solution at -78 °C. After stirring for 5 min at this temperature, the solution was allowed to warm to rt. If, after warming to rt, the ArZnBr solution was biphasic, more THF was added in 0.5-mL increments with vigorous stirring until a monophasic solution resulted. The ArZnBr solution (nominally 0.6 M) was stored in a N 2 -filled glovebox.

Racemic Standards:
Racemic standards for 1-6 were prepared in one of two ways: (1) following the "pyridinium arylation on 0.5-mmol scale" procedure, except with PPh 3 (16 mg, 0.060 mmol, 0.12 equiv.) in place of L3, or (2) reaction of the appropriate pyridinium salt (prepared in situ from pyridine and chloroformate) with the appropriate Grignard reagent in THF.