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 α,β-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 PPh 3 and DABCO, shown different regioselectivity: PPh 3 gave the γ-selective product whereas DABCO led to a complete β-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, CH 2 Cl 2 , DCE, acetone, CH 3 CN, 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 β-selective allylic alkylation products with good yields (55%～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.

Asymmetric synthesis of pyrazoles and pyrazolones employing the reactivity of pyrazolin-5-one derivatives

“…The asymmetric allylic alkylation of Morita-Baylis-Hillman (MBH) carbonates 68 using pyrazolones 23 as nucleophiles catalyzed by cinchonine (XV) gave the b-selective allylic alkylation products 69 in good yields and enantioselectivities (Scheme 20). 40 However, a low yield (55%) and poor enantioselectivity (13% ee) for the MBH carbonate bearing a heteroaryl group (R 3 = 2-furanyl) were observed.…”

Chiral Bifunctional Ferrocenylphosphine‐Catalyzed Enantioselective Allylic Alkylation of Morita−Baylis−Hillman Carbonates with Pyrazolin‐5‐ones

“…[15] However, the phosphine catalyzed asymmetric transformation of pyrazolone derivatives was rarely exploited. [18] Herein, we report a novel chiral bifunctional ferrocenylphosphine catalyzed asymmetric γ-addition of pyrazolin-5-ones with MBH carbonates, providing the acetylated pyrazoles after in situ treatment with AcCl/Et 3 N in moderate to good yields (up to 80%) with high enantioselectivities (up to 98% ee) (Scheme 1d). [16] Inspired by our previous work on developing chiral bifunctional ferrocenylphosphine catalysts, [17] we become interested in applying our designed catalysts in asymmetric synthesis of chiral pyrazolone derivatives by treatment of MBH carbonates with pyrazolones.…”

Pd(II)/β-ICD-Cocatalyzed Asymmetric Route to Oxindole Scaffold via Cascade Reaction of Diazoacetamides and MBH-Carbonates

“…MBH reaction is a kind of high-efficiency method of building C–C bond, that meanwhile retains the easily modified double bond; the derived MBH adducts are a kind of practical synthon in modern organic synthesis system . Very recently, the use of these MBH carbonates for asymmetric allylic alkylation (AAA) with high enantioinduction has attracted much attention (Scheme a) . Moreover, the MBH reaction mechanism has also been well studied with cinchona alkaloid derivatives, β-ICD.…”