Synthesis of Indoles by Intermolecular Cyclization of Unfunctionalized Nitroarenes and Alkynes: One‐Step Synthesis of the Skeleton of Fluvastatin

Abstract

The addition of Ru3(CO)12, dimethyl carbonate, or both to the reaction mixture improves the selectivity of the palladium/phenanthroline‐catalyzed reaction of nitroarenes, arylalkynes, and CO to give 3‐arylindoles. When 4‐fluorophenylacetylene and nitrobenzene are used as substrates, the indole skeleton of Fluvastatin and other pharmaceutically active compounds is obtained in one step.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Transition Metal Catalyzed Reductive Cyclization Reactions of Nitroarenes and Nitroalkenes

“…The kinetic isotope effect is close to 1. All of these results paralleled those previously observed for the reactions starting from nitroarenes, [24,96,150] strongly supporting the idea that the latter are intermediately reduced to nitrosoarenes and that the cyclization reaction occurs at this stage of the reduction process in both cases. The only difference is that in the case of nitroarenes the rate-determining step of the reaction is the initial activation of the nitro group, which is even slower than the reaction between the corresponding nitrosoarene and the alkyne.…”

“…[1,58] The approach was partly successful and the addition of Ru 3 (CO) 12 to the catalytic system in a 1-1.5 mol ratio with respect to palladium increased the selectivity in indole by 8-11 %. [150] The ruthenium cluster alone was found not to catalyze the reaction under these conditions, even when activated by Ph-BIAN as a ligand, supporting the idea that it plays a role only after the initial activation of the nitroarene has been performed by palladium. Surprisingly, the addition of Ph-BIAN to the catalytic system when both metals are present decreased the selectivity, despite the fact that it strongly promotes the activity of Ru 3 (CO) 12 in the reduction of nitroarenes by CO/ H 2 O.…”

“…No specific study has been devoted to the reduction of N‐ hydroxyindoles, but analogies with the synthesis of anilines by reduction of nitroarenes by CO/H 2 , where hydroxylamines are likely to be formed, suggest that ruthenium complexes should be more active catalysts for this reaction than palladium ones . The approach was partly successful and the addition of Ru 3 (CO) 12 to the catalytic system in a 1–1.5 mol ratio with respect to palladium increased the selectivity in indole by 8–11 % . The ruthenium cluster alone was found not to catalyze the reaction under these conditions, even when activated by Ph‐BIAN as a ligand, supporting the idea that it plays a role only after the initial activation of the nitroarene has been performed by palladium.…”

“…However, the weaker alkylating agent dimethylcarbonate improved the selectivity, albeit by only 8 %. [150] Interestingly, the two approaches could be employed together, affording an absolute increase in selectivity of 16 % (36 % if measured with respect to the obtained indole).…”

(1H-Benzo[d][1,2,3]triazol-1-yl)(5-bromo-1-hydroxy-1H-indol-3-yl)methanone

“…In this latter case the indolization was employed to afford natural occurring compounds as meridianins, marine alkaloids from Aplidium meridianum, widely studied as kinase inhibitors [9]. This synthetic procedure was then studied by Ragaini and Srivastava who developed catalytic processes mediated by transition metal complexes using the respectively nitroarenes [10,11] and C-nitrosoaromatics [12,13].…”