Diels-Alder Cycloadditions of Oxacyclic Allenes and α-Pyrones

Abstract

Reactions of α-pyrones with oxacyclic allenes in Diels-Alder trappings are described. We investigate regioselectivity trends and perform competition experiments to assess the influence of structural and electronic features on relative reaction rates. We also demonstrate the stereospecific trapping of an oxacyclic allene, which proceeds in high optical yield. This study provides insight into strained cyclic allene reactivity, as well as new synthetic tools for the rapid construction of complex, heterocyclic scaffolds.

Figure 1.

Overview of scaffolds accessible from strain-promoted Diels–Alder cycloadditions of intermediates 3 or 6 with furans 2 or pyrones 4.

Figure 2.

Scope of the DA cycloaddition with methyl-substituted oxa- and azacyclic allenes (12) and pyrones 15–18. Conditions unless otherwise stated: silyl triflate substrate (1.0 equiv), pyrone (5.0 equiv), CsF (5.0 equiv), acetonitrile (0.1 M) at 23 °C. Yields reflect the average of two experiments. ^aYield determined by ¹H NMR analysis using 1,3,5-trimethoxybenzene as an external standard. ^bSee reference for conditions. ^cReaction performed with 2.5 equiv TBAF in THF for 16 h.

Figure 3.

Cycloaddition reactions with α-pyrone (15) and 2,5-dimethylfuran (29) with ester-substituted oxacyclic allene 27 and disubstituted oxacyclic allene 31. Conditions: silyl triflate substrate (1.0 equiv), pyrone (5.0 equiv), CsF (5.0 equiv), acetonitrile (0.1 M) at 23 °C. ^aYield determined by ¹H NMR analysis using 1,3,5-trimethoxybenzene as an external standard. ^bA constitutional isomer of 32 was also observed in ~20% yield; see the SI for further details.

Figure 4.

Competition experiments with allene precursors 11b and 34 with 2,5-dimethylfuran (29) and α-pyrone (15). Conditions unless otherwise stated: silyl triflate substrate (1.0 equiv), CsF (5.0 equiv), acetonitrile (0.1 M) at 23 °C. ^aYield determined by ¹H NMR analysis using 1,3,5-trimethoxybenzene as an external standard.

Figure 5.

Synthesis of silyl bromide (+)-37 and Diels–Alder cycloaddition employing (+)-37 to provide (−)-26. Conditions for Diels–Alder cycloaddition: silyl triflate substrate (1.0 equiv), pyrone (5.0 equiv), CsF (5.0 equiv), Bu₄NBr (40 mol%), acetonitrile (0.1 M) at 0 → 23 °C. Yield of cycloadditions determined by ¹H NMR analysis using 1,3,5-trimethoxybenzene as an external standard.