Development of Au(I) Cycloadditions, Trifluoromethylation and Novel Au(I) Complexes

Abstract

The field of gold(I)-catalysed reactions in organic chemistry has been expanding rapidly in the last two decades. Gold catalyses a diverse range of transformations and is especially useful in the activation of triple bonds toward nucleophilic attack.

Gold(I)-catalysed reactions of highly reactive terminal propargyl acetals are a source of new chemistry due to novel electron-rich intermediates. Reactions between terminal propargyl acetals and vinyl esters underwent a unique [1+2]/[2+3] tandem cyclisation to give cyclopentene-cyclopropane tethered rings (yields up to 77%). Reactions of terminal propargyl acetals with alkynes produced novel fused bicyclic cyclopentene structures by a “[2+3]”/[2+3] tandem cyclisation (yields up to 60%).

Building on previous knowledge of gold(I)-nitrone chemistry, chiral nitrones were synthesised and their ability to tune gold(I) catalyst activity in reactions of non-terminal propargyl acetals was explored. NMR studies were conducted on chiral gold(I)-nitrone complexes. The crystal structure (X‑ray) was obtained for one complex, which showed coordination of the chiral nitrone to gold(I) through the oxygen atom. The chemistry of non-terminal propargyl acetals was found to give a diverse range of cycloaddition products, involving several reactive intermediates. Interestingly, reaction of non-terminal propargyl acetals and imines gave heterocyclic products via gold(I)-catalysed [2+2], [2+4] and [3+4] cycloaddition reaction pathways. Development of new methods for the introduction of trifluoromethyl groups is interesting; these groups can impart specific, pharmaceutically significant properties to compounds. Electrophilic trifluoromethyl reagents were combined with a gold(I) catalyst for the first time and a novel method of trifluoromethylation of terminal alkynes was developed (yields up to 46% with 12.5% active gold complex). Even more interesting was the discovery that the reaction pathway involved a gold(I)-Togni complex coordinated through the oxygen atom and a catalytically active dual gold(I) complex generated with the terminal alkyne substrate. Both these complexes were confirmed through X-ray crystallography and NMR studies.

Following the discovery that dual gold(I) complexes are catalytically active species, a series of JohnPhos dual gold(I) complexes was synthesised and their catalytic activity studied in known propargyl reactions. Furthermore, novel chiral bridged dual gold(I) complexes based on the (R)‑MeO‑BIPHEP ligand were generated. These chiral complexes were active in several propargyl reactions, and moderate enantioselectivity was observed by chiral HPLC (up to 52%).

The development of new and stable gold catalysts for use in organic tranformations continues to be of interest. Gold(III) complexes are rarely used in propargyl chemistry and the integration of ligated Au(III) complexes into metal-organic frameworks for use in heterogeneous chemistry has received little attention. A series of cyclometallated Au(III) complexes and the first phenylpyrimidine gold(III) MOF (synthesised by PhD candidate Volodymyr Levchenko, UiO) were shown to catalyse propargyl ester cyclopropanation (up to quantitative yields). The work presented contributes to the understanding of propargyl substrates in gold(I)-catalysed reactions, explores the possibilities of gold(I)-catalysed trifluoromethylation and investigates the reactivity of dual gold(I) and gold(III) catalysts in the chemistry of propargyl substrates.