Single-Flask Multicomponent Synthesis of Highly Substituted α-Pyrones via a Sequential Enolate Arylation and Alkenylation Strategy

Abstract

Trisubstituted α-pyrones are obtained by a Pd-catalyzed three-component, single-flask operation via an α-arylation, subsequent α-alkenylation, alkene isomerization, and dienolate lactonization. A variety of coupling components under mild conditions afforded isolated yields of up to 93% of the pyrones with complete control of regioselectivity. Metal dependence was noted for three of the steps of the pathway. Utility of the pyrone products was demonstrated by further transformations providing convenient access to polyaromatic compounds, exhibiting broad molecular diversity.

Figure 1.

Proposed multicomponent pathway to α-pyrones.

Figure 2.

Examination of reaction conditions for the combination of α-alkenylation and subsequent isomerization/lactonization. ^a Yield based on NMR internal standard.

Figure 3.

Investigation of the three-component synthesis of α-pyrones using methyl ketones with aryl or alkenyl bromides and bromoacrylates. Reactions were conducted on a 0.5 mmol scale. Isolated yields are reported. ^a Conducted on a 4.5 mmol scale. ^b The second part of the sequence was conducted at 40 °C. ^c The entire reaction sequence was conducted at 40 °C. ^d The corresponding ethyl acrylate was employed.

Figure 4.

Further reactions of initially obtained α-pyrones. (i) PhI(OCOCF₃)₂ (1.1 equiv), BF₃·OEt₂ (2.2 equiv), DCM, −40 °C. (ii) PhI(OCOCF₃)₂ (1.1 equiv), BF₃·OEt₂ (2.2 equiv), DCM, −40–22 °C, 12 h. (iii) R¹CCR¹ (3 equiv), 1,2-dichlorobenzene, 200 °C, 48 h. (iv) PhI(OCOCF₃)₂ (2.1 equiv), BF₃·OEt₂ (4.2 equiv), DCM, −40 °C, 5 h. (v) AcOH, H₂SO₄, 120 °C, 24 h. Isolated yields are shown. X-ray diffraction structures are shown for 10a and 11 without hydrogens for clarity (red = O, green = F). ^a Yield is based on PhI(OCOCF₃)₂ as the limiting reagent.