Gold-Catalyzed Synthesis And Reaction Pathways

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Transition metal-catalyzed addition of an amine across a C-C triple bond (hydroamination reaction) represents a powerful tool for the construction of a wide range of nitrogen heterocycles.  Intramolecular hydroaminations of 2-alkynylaniline derivatives (Compound 1) to give interesting indole heterocycles (Compound 2) have been widely investigated (Fig. 1).

Over the past decades Au, Pd, Ir, Cu, Ag and Pt catalysts have been successfully employed for this transformation, that has been carried out also in the presence of Lewis acids such as In and Zn halides. Coordination to the catalysts inverts its classical reactivity of the triple bond (that usually reacts with electrophiles) and activates it towards an intramolecular nucleophilic attack.  

Compounds (Compound 3) represents a particular class of 2-alkynylanilines, bearing an electron-withdrawing group conjugated with the triple bond. Cyclization of substrates (Compound 3) through transition-metals catalyzed reactions to give indoles (Compound 4) has not been reported so far. This is probably due to the polarization of the triple bond induced by the carbonyl, that hampers the nucleophilic attack of the nitrogen to the a-carbon.

We have recently reported (Adv. Synth. Catal. 2017, 359, 3371-3377) that in the presence of highly reactive (JohnPhosAuMeCN)SbF6  (known also as Echavarren’s catalyst), an unexpected intermolecular reaction occurs, with the formation of interesting eight-membered dibenzodiazocine derivatives (Compound 5) (Fig. 2). A variety of groups R including aryl, heteroaryl, vinyl and alkyl can be introduced in the products. Moreover, esters (R = -OMe) can be used in this reaction.

Dibenzodiazocines represent an uncommon class of heterocycles, that is of interest in medicinal chemistry and in organometallic chemistry; in material science, copolymers containing (Compound 5) find potential application as molecular actuators. Moreover, a class of analogs of (Compound 5), i.e. Tröger’s base and its derivatives, possess a chiral cleft structure that makes them interesting scaffolds in supramolecular chemistry.

The methodology described here allows an easy and efficient synthesis dibenzodiazocines with a wide range of substituents. The mechanism of the reaction has been studied: an initial intermolecular reaction affords an intermediate, that subsequently undergoes the final cyclization. Both these steps are catalyzed by the Au(I).

We hope that compound 5 will find application as precursors of new materials that can act as actuators. These are devices able convert a form of energy into motion such as light-driven molecular machines.

This study, Gold-Catalyzed Synthesis of Dibenzo[1,5]diazocines from β-(2-Aminophenyl)-α,β-ynones was recently published in the journal Advanced Synthesis & Catalysis.

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