Regioselective Ru(ii)-catalyzed C-H alkenylation and annulation of indoles: a direct approach to fused lactone scaffolds

Abstract

In this work, we offer a method for selectively alkenylating C5-H and then annulating indole-4-carboxylic acid derivatives using ruthenium(ii) as a catalyst. Our approach facilitates the effective formation of fused lactone structures by employing a weakly coordinating carboxylic acid group at the C4 position as a guiding group. The reaction process starts with an alkenylation at the C5 position of the indole ring, followed by an intramolecular Michael addition to produce annulated lactones in high yields. This is the first report of ruthenium-catalyzed lactone synthesis at the C5 position of indoles via a carboxylic acid directing group. We anticipate that because of its simplicity, high regioselectivity, and use of readily available starting materials, this process will open up new options for constructing functionalized lactone scaffolds that could be immensely valuable in medical and pharmacological studies.

Fig. 1. Pharmaceutically active compounds containing indole and lactone derivatives.

Scheme 1. Comparison with previous works.

Scheme 2. Scope of indole derivatives and acrylates^a,b. ^aReaction conditions: 1 (1.0 equiv.), 2 (1.1 equiv.), [RuCl₂(p-cymene)]₂ (2.5 mol%), Cu(OAc)₂·H₂O (1.5 equiv.), KOAc (0.5 equiv.), dioxane (0.2 M), 80 °C, 6 h. ^bIsolated yields; (Me = methyl, Et = ethyl, tBu-t-butyl, Bn = benzyl, Ph = phenyl).

Scheme 3. C5-alkenyation–annulation of indole derivatives with various alkenes. ^aReaction conditions: 1 (1.0 equiv.), 2 (1.1 equiv.), [RuCl₂(p-cymene)]₂ (2.5 mol%), Cu(OAc)₂·H₂O (1.5 equiv.), KOAc (0.5 equiv.), dioxane (0.2 M), 80 °C, 6 h. ^bIsolated yields; (Me = methyl, Et = ethyl, tBu-t-butyl, Bn = benzyl, Ph = phenyl).

Scheme 4. C5-annulation and C3-olefination of indole derivatives with different acrylates and various alkenes ^a,b. ^aReaction conditions: 1 (1.0 equiv.), 2 (5.0 equiv.), [RuCl₂(p-cymene)]₂ (10 mol%), Cu(OAc)₂·H₂O (1.5 equiv.), KOAc (0.5 equiv.), n-BuOH (0.2 M), 120 °C, 24 h. ^bIsolated yields; (Me = methyl, Et = ethyl, tBu-t-butyl, Bn = benzyl, Ph = phenyl).

Scheme 5. Synthetic transformations of C5-annulated indole derivatives.

Scheme 6. Mechanistic studies of site-selectivity of the ruthenium-catalysed C–H functionalization.

Scheme 7. Plausible mechanism.