Zinc (II)-Mediated Selective O-Benzylation of 2-Oxo-1,2-Dihydropyridines Systems

The selective O-benzylation of 2-oxo-1,2-dihydropyridines plays a critical role in organic synthesis of natural products and biological active molecules. Herein we report a novel ternary system of ZnO, ZnCl2 and N,N-diisopropylethylamine (DIEA), that is highly effective for selective O-benzylation of 2-oxo-1,2-dihydropyridines using abundant substituted benzyl halides and related substituted 2-oxo-1,2-dihydropyridines compounds. This process allows access to a variety of O-benzyl products under mild reaction conditions, which are important synthetic intermediates in the protection of functional groups, and represents a new method toward the development for the O-benzylation of 2-oxo-1,2-dihydropyridines.


General procedures
All of the starting materials, reagents, and solvents are commercially available and used without further purification. The microwave-assisted reactions were performed using a CEM Discover System 908010 microwave apparatus (Matthews, NC, USA).
Melting points were determined with a X-4 apparatus and were uncorrected. The nuclear magnetic resonance (NMR) spectra were recorded on a Bruker 600 MHz spectrometer in CDCl3 or DMSO-d6 using tetramethylsilane (TMS) as an internal standard. Electrospray ionization mass spectrometry (ESI-MS) analyses were recorded in an Agilent 1100 Series MSD Trap SL (Santa Clara, CA, USA). The reactions were monitored by thin-layer chromatography (TLC: HG/T2354-92, GF254), and compounds were visualized on TLC with UV light.

Microwave-assisted synthesis of 3a
To a solution of 1a (0.20 g, 1.35 mmol), zinc oxide (0.12 g, 1.48 mmol), zinc chloride (0.20 g, 1.48 mmol), N,N-diisopropylethylamine (0.19 g, 1.48 mmol), 1,4-dioxane (3 mL) was added benzyl chloride (0.2 g, 1.61 mmol). The mixture was irradiated at 110 °C for 60 min in a dedicated CEM-Discover system, operating at a frequency of 2.45 GHz with continuous irradiation power from 0 to 300 W. After completion of the reaction, the insoluble residue was filtered off through celite, and the cake was wash with ethyl acetate (30 mL). The filtrate was washed with water (10 mL×2), once with brine (10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford crude product. The product was purified by column chromatography on silica gel (ethyl acetate: petroleum ether=1:20) to afford O-benzylation in 65% yield and N-benzylation in 21% yield.

General procedures for the synthesis of substituted aromatic lactam of 1a-1k
A substituted alkyl methy ketone or cyclic ketone (1 equiv) and ethyl formate or 2 / 47 ethyl acetic (1 equiv) was added dropwise to absolute ether solution of sodium metal (1 equiv) for 1 hour while maintained below 20 o C. After the addition, the reaction was allowed to stir at ice bath until the sodium metal was disappeared. The precipitate was filtered, washed with absolute ether and dried to give the corresponding compound which was directly used next step without purification.
To a solution of previous product (1 equiv), and cyanoacetamide (1.05 equiv) in water was stirred 6 minutes at room temperature. The mixture was added dropwise piperidine acetate solution (0.3 equiv), which was prepared from piperidine (1 equiv), acetic acid (1 equiv) and water (5 equiv). The solution was heated to reflux for 2 hours. Then, the reactor was cooled to room temperature, and adjusted to pH 4 by 4 N hydrochloric acid. The resulting solid was filtered, respectively washed with water and ether, and dried to give the corresponding compound which was purified by recrystallizing using menthol as solvent.

General procedures for the synthesis of 3a-3m
To a solution of substituted aromatic lactam (3.36 mmol), zinc oxide (0.30 g, 3.70 mmol), zinc chloride (0.50 g, 3.70 mmol), N,N-diisopropylethylamine (0.48 g, 3.70 mmol), 1,4-dioxane (15 mL) was added benzyl chloride (0.58 g, 4.04 mmol) under argon atmosphere. The mixture was heated in 110 o C oil bath with rapid stirring for the indicated time. The reactor was cooled to room temperature, and the insoluble residue was filtered off through celite, and the cake was wash with ethyl acetate (30 mL). The filtrate was washed with water (10 mL×2), once with brine (10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford crude product. The product was purified by column chromatography on silica gel (ethyl acetate: petroleum ether=1:20) to yield the corresponding compounds.

General procedures for the synthesis of 4a-4k
To a solution of 1a (0.5 g, 3.36 mmol), zinc oxide (0.30 g, 3.70 mmol), zinc chloride (0.50 g, 3.70 mmol), N,N-diisopropylethylamine (0.48 g, 3.70 mmol), 3 / 47 1,4-dioxane (15 mL) was added substituted benzyl halides (4.04 mmol) under argon atmosphere. The mixture was heated in 110 o C oil bath with rapid stirring for the indicated time. The reactor was cooled to room temperature, and the insoluble residue was filtered off through celite, and the cake was wash with ethyl acetate (30 mL). The filtrate was washed with water (10 mL×2), once with brine (10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The product was purified by column chromatography on silica gel (ethyl acetate: petroleum ether=1:20) to yield the corresponding compounds.