A tandem Mannich addition-palladium catalyzed ring-closing route toward 4-substituted-3(2H)-furanones

Abstract

A facile route towards highly functionalized 3(2H)-furanones via a sequential Mannich addition-palladium catalyzed ring closing has been elaborated. The reaction of 4-chloroacetoacetate esters with imines derived from aliphatic and aromatic aldehydes under palladium catalysis afforded 4-substituted furanones in good to excellent yields. 4-Hydrazino-3(2H)-furanones could also be synthesized from diazo esters in excellent yields by utilising the developed strategy. We could also efficiently transform the substituted furanones to aza-prostaglandin analogues.

Keywords: 3(2H)-furanone; Mannich addition; aza-prostaglandin analogue; palladium catalysis; tandem reaction.

Figure 1

Bioactive molecules I [19], II [26], III & IV [–22] with 3(2H)-furanone moiety.

Scheme 1

Pd-catalyzed synthesis of 3(2H)-furanones from activated alkenes [40].

Scheme 2

Pd-catalyzed synthesis of 3(2H)-furanone from tosylimine 1a.

Figure 2

Generalisation with aromatic and aliphatic imines (reaction conditions: 1 (1.0 equiv), 2 (1.1 equiv), Pd₂dba₃·CHCl₃ (5 mol %), dppe (10 mol %), Na₂CO₃ (2.0 equiv), dioxane (2 mL), 50 °C, 10 h, isolated yield).

Figure 3

Thermal ellipsoid diagrams (50% probability levels) of 4-substituted-3(2H)-furanones 7 (above) and 10 (below).

Scheme 3

Mechanism of formation of the 3(2H)-furanone derivative from an imine.

Scheme 4

Pd-catalyzed synthesis of 3(2H)-furanone from diazoester 19a.

Figure 4

Generalisation with diazo esters (reaction conditions: 19 (1.0 equiv), 2 (1.1 equiv), Pd(PPh₃)₄ (5 mol %), Na₂CO₃ (2.0 equiv), dioxane (2 mL), 50 °C, 10 h, isolated yield).

Scheme 5

Synthesis of aza-prostaglandin analogue.