3-(o-Trifluoroacetamidoaryl)-1-propargylic esters: common intermediates for the palladium-catalyzed synthesis of 2-aminomethyl-, 2-vinylic, and 2-alkylindoles
Graphical abstract
Introduction
The indole nucleus is prevalent in a vast array of biologically active natural and unnatural compounds. In view of this, the development of efficient and versatile methods for the construction of this structural unit is a subject of great interest in drug discovery and palladium catalysis has provided an almost unique tool to develop a wide range of synthetic strategies.1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g) In attempting to further extend our palladium-catalyzed alkyne-based synthesis of indoles,2 we observed and previously communicated that ethyl 3-(o-trifluoroacetamidoaryl)-1-propargylic carbonates 13 could be used as precursors of 2-aminomethyl-4 and 2-alkylindoles5 via trapping of π-allylic palladium intermediates generated in situ with amines and formate anions, respectively. We wish at this time to report full details on this very useful new synthetic approach to indoles, including its extension to the preparation of 2-vinylic indoles.
Section snippets
Results and discussion
Ethyl 3-(o-trifluoroacetamidoaryl)-1-propargylic carbonates 1 were prepared from o-(iodo)trifluoroacetanilides via Sonogashira cross-coupling with propargylic alcohols followed by an esterification step (Scheme 1). This protocol was typically used with neutral or electron-rich o-(iodo)trifluoroacetanilides. Alternatively, particularly when the preparation of ethyl 3-(o-trifluoroacetamidoaryl)-1-propargylic carbonates containing electron-poor aromatic rings was required, they were synthesized
Conclusions
In summary, we have developed a convenient straightforward approach for the construction of the functionalized pyrrole ring incorporated into the indole system from 3-(o-trifluoroacetamidoaryl)-1-propargylic esters. In particular, these compounds have been shown to be useful common synthetic intermediates for the preparation of a variety of 3-unsubstituted 2-substituted indoles. Depending on reaction conditions and the substitution pattern, they can be converted into 2-aminomethylindoles,
General
Melting points were determined with a Büchi apparatus and are uncorrected. All of the reagents and solvents are commercially available and were used as purchased, without further purification. Compounds 1a and 1b, 2-vinylic indoles 5, and 2-alkylindoles 6 were purified on axially compressed columns, packed with SiO2 25–40 μm (Macherey Nagel), connected to a Gilson solvent delivery system and to a Gilson refractive index detector, and eluting with n-hexane/AcOEt mixtures. 2-Aminomethylindoles
Acknowledgements
Work carried out in the framework of the National Projects ‘Stereoselezione in Sintesi Organica. Metodologie ed Applicazioni’ and supported by the Ministero dell'Università e della Ricerca and by the University ‘La Sapienza’.
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