Organocatalyzed Asymmetric Allylic Alkylation of MBH-Carbonates with Pyrazolones

Abstract

The asymmetric allylic alkylation (AAA) reaction is one of the important transformations in asymmetric synthesis, which was intensively studied in the last decade. Recently, the use of Morita-Baylis-Hillman (MBH) carbonates as electrophiles for the AAA reaction has attracted much attention. Pyrazole is an important pharmacophore, which often exhibit various biological and pharmacological activities. In the last years, the asymmetric synthesis using pyrazolones as the nucleophiles were reported by several research groups. However, the work were mainly focused on the asymmetric conjugate addition of pyrazoles to alpha,beta-unsaturated compounds, and other types of enantioselective reactions were seldom studied. Herein, we report the first example of AAA reaction of MBH carbonates using pyrazolones as nucleophiles. In the reaction, we found that different Lewis basic catalyst, namely PPh3 and DABCO, shown different regioselectivity: PPh3 gave the.-selective product whereas DABCO led to a complete beta-selectivity. During the catalyst screening, cinchonine gave the best result. The enantioselectivity heavily relied on the choice of solvent: MeOH was superior compared to EtOH, CH2Cl2, DCE, acetone, CH3CN, toluene, m-xylene and PhCl. In the substrate scope study, all the reactions were proceeded smoothly under mild conditions by using cinchonine as the catalyst (20 mol%) and give the beta-selective allylic alkylation products with good yields (55%similar to 91%) and high enantioselectivities (up to 93% ee). Based on our experimental results and previous reports, a preliminary mechanism of bifunctional catalysis was proposed. A representative procedure for the asymmetric allylic alkylation of MBH-carbonates with pyrazolones is as follows: to a flask equipped with a magnetic stirring bar was charged with pyrazolone 1 (0.1 mmol) and MBH-carbonate 2 (0.12 mmol) in methanol (2 mL), and then, the cinchonine catalyst (6 mg, 20 mol%) was added under air. The reaction solution was stirred at room temperature for 72 to 96 hours. Then, the mixture was concentrated and purified through a flash chromatography (silica gel, PE/EtOAc, V : V=7 : 1) to give the corresponding products 3.