Indium(III)-Catalyzed Stereoselective Synthesis of Tricyclic Frameworks by Cascade Cycloisomerization Reactions of Aryl 1,5-Enynes.

Ramón E Millán,Enrique Gómez-Bengoa,Jaime Rodríguez,José Pérez Sestelo,Luis A Sarandeses

doi:10.1021/acs.joc.1c00825

Ramón E Millán, Enrique Gómez-Bengoa + Show 3 more

Open Access

https://doi.org/10.1021/acs.joc.1c00825

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Abstract

The indium(III)-catalyzed cascade cycloisomerization reaction of 1,5-enynes with pendant aryl nucleophiles is reported. The reaction proceeds in cascade under mild reaction conditions, using InI3 (5 mol %) as a catalyst with a range of 1,5-enynes furnished with aryl groups (phenyl and phenol) at alkene (E and Z isomers) and with terminal and internal alkynes. Using 1-bromo-1,5-enynes, a one-pot sequential indium-catalyzed cycloisomerization and palladium-catalyzed cross-coupling with triorganoindium reagents were developed. The double cyclization is stereospecific and operates via a biomimetic cascade cation-olefin through 1,5-enyne cyclization (6-endo-dig) and subsequent C-C hydroarylation or C-O phenoxycyclization. Density functional theory (DFT) computational studies on 1,5-enynyl aryl ethers support a two-step mechanism where the first stereoselective 1,5-enyne cyclization produces a nonclassical carbocation intermediate that evolves to the tricyclic reaction product through a SEAr mechanism. Using this approach, a variety of tricyclic heterocycles such as benzo[b]chromenes, phenanthridines, xanthenes, and spiroheterocyclic compounds are efficiently synthesized with high atom economy.

Highlights

The design of synthetic methodologies based on catalytic cascade reactions constitutes an ideal tool for the construction of complex molecules with high chemo, regio, and stereoselectivity.[1]
Our investigation started with the cycloisomerization reaction of (E)-1,5-enynyl aryl ether 1a under In(III) catalysis
We found that the reaction of 3,5dimethoxyphenyl 1,5-enynyl N-tosylamine (E)-3a with InI3 (5 mol %) in toluene at 60 °C gave the phenanthridine trans-4a in 90% yield in just 2 h as the only diastereoisomer detected by 1H NMR (Table 3, entry 1)

Summary

Introduction

The design of synthetic methodologies based on catalytic cascade reactions constitutes an ideal tool for the construction of complex molecules with high chemo-, regio-, and stereoselectivity.[1]. Cascade polyene cyclizations are one of the most impressive biosynthetic transformations known, and their chemical emulation represents a major challenge in modern synthetic chemistry.[2] Usually, these transformations involve the epoxide activation in a polyenic compound using oxophilic Lewis acids under stoichiometric or catalytic conditions.[3] Alternatively, electrophilic alkyne activation under metal catalysis has been recently envisaged as a different synthetic approach to promote catalytic cascade polyenynic πcyclizations.[4] The catalytic electrophilic activation of alkynes promotes the addition of nucleophiles and allows the formation of new carbon−carbon and carbon−heteroatom bonds in an intermolecular and intramolecular manner This methodology has been associated with the use of carbophilic late precious transition metals such as platinum[5] or gold[6] as catalysts, main group metals such as gallium[7] or indium[8] have been shown as valuable alternatives (Scheme 1a)

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