Gold-catalyzed Alkyne Oxidation Research Articles

Enantioselective Oxidative Cyclization/Mannich Addition Enabled by Gold(I)/Chiral Phosphoric Acid Cooperative Catalysis

An enantioselective Mannich-type reaction of 3-butynol and nitrones is described, which affords dihydrofuran-3-ones in good yields and with excellent enantioselectivities. The reaction is initiated by gold-catalyzed alkyne oxidation and modification of the resulting gold carbene species with a tethered hydroxy group to form enolate species; the reaction terminates with an enantioselective Mannich-type addition with the assistance of chiral phosphoric acid (CPA) and hydrogen bonding. This novel pattern of alkyne transformation involving chemical bond cleavage, and a fragment modification and reassembly process, provides an atom- and step-economic method, and is the first example of cooperative asymmetric catalysis in gold-catalyzed alkyne oxidations via an α-oxo gold carbene route.

A Non-Diazo Approach to α-Oxo Gold Carbenes via Gold-Catalyzed Alkyne Oxidation

For the past dozen years, homogeneous gold catalysis has evolved from a little known topic in organic synthesis to a fully blown research field of significant importance to synthetic practitioners, due to its novel reactivities and reaction modes. Cationic gold(I) complexes are powerful soft Lewis acids that can activate alkynes and allenes toward efficient attack by nucleophiles, leading to the generation of alkenyl gold intermediates. Some of the most versatile aspects of gold catalysis involve the generation of gold carbene intermediates, which occurs through the approach of an electrophile to the distal end of the alkenyl gold moiety, and their diverse transformations thereafter. On the other hand, α-oxo metal carbene/carbenoids are highly versatile intermediates in organic synthesis and can undergo various synthetically challenging yet highly valuable transformations such as C–H insertion, ylide formation, and cyclopropanation reactions. Metal-catalyzed dediazotizations of diazo carbonyl compounds are the principle and most reliable strategy to access them. Unfortunately, the substrates contain a highly energetic diazo moiety and are potentially explosive. Moreover, chemists need to use energetic reagents to prepare them, putting further constrains on operational safety.In this Account, we show that the unique access to the gold carbene species in homogeneous gold catalysis offers an opportunity to generate α-oxo gold carbenes if both nucleophile and electrophile are oxygen. Hence, this approach would enable readily available and safer alkynes to replace hazardous α-diazo carbonyl compounds as precursors in the realm of gold carbene chemistry.For the past several years, we have demonstrated that alkynes can indeed effectively serve as precursors to versatile α-oxo gold carbenes. In our initial study, we showed that a tethered sulfoxide can be a suitable oxidant, which in some cases leads to the formation of α-oxo gold carbene intermediates. The intermolecular approach offers excellent synthetic flexibility because no tethering of the oxidant is required, and its reduced form is not tangled with the product. We were the first research group to develop this strategy, through the use of pyridine/quinolone N-oxides as the external oxidants. In this manner, we can effectively make a C–C triple bond a surrogate of an α-diazo carbonyl moiety in various gold catalyses. With terminal alkynes, we demonstrated that we can efficiently trap exclusively formed terminal carbene centers by internal nucleophiles en route to the formation of cyclic products, including strained oxetan-3-ones and azetidin-3-ones, and by external nucleophiles when a P,N-bidentate ligand is coordinated to gold. With internal alkynes, we generated synthetically useful regioselectivities in the generation of the α-oxo gold carbene moiety, which enables expedient formation of versatile enone products. Other research groups have also applied this strategy en route to versatile synthetic methods. The α-oxo gold carbenes appear to be more electrophilic than their Rh counterpart, which many chemists have focused on in a large array of excellent work on metal carbene chemistry. The ease of accessing the reactive gold carbenes opens up a vast area for developing new synthetic methods that would be distinctively different from the known Rh chemistry and promises to generate a new round of “gold rush”.

Generation of gold carbenes in water: efficient intermolecular trapping of the α-oxo gold carbenoids by indoles and anilines

The efficient intermolecular reaction of gold carbene intermediates, generated via gold-catalyzed alkyne oxidation, with indoles and anilines has been realized in aqueous media.

Gold-catalyzed oxazoles synthesis and their relevant antiproliferative activities

Nine 5-aryl-2-methyloxazole derivatives were synthesized via gold-catalyzed alkyne oxidation. All of the compounds have been screened for their antiproliferative activities against MCF-7 cell (human breast carcinoma), A549 cell (human lung carcinoma) and Hela cell (human cervical carcinoma) lines in vitro. The results revealed that compounds 1b, 1c and 1d exhibited strong inhibitory activities against the MCF-7 cell lines (with IC50 values of 4.6, 9.7 and 2.2 μmol/L, respectively).

Rapid Access to Chroman‐3‐ones through Gold‐Catalyzed Oxidation of Propargyl Aryl Ethers

Only two steps? Chroman-3-ones are important intermediates for organic synthesis and medicinal chemistry. However, their syntheses require multiple steps and are not efficient. By using gold-catalyzed alkyne oxidation, this versatile heterocycle can be prepared in only two steps from readily available phenols and with mostly high efficiencies.

An Efficient [2 + 2 + 1] Synthesis of 2,5-Disubstituted Oxazoles via Gold-Catalyzed Intermolecular Alkyne Oxidation

The first efficient intermolecular reaction of gold carbene intermediates generated via gold-catalyzed alkyne oxidation has been realized using nitriles as both the reacting partner and the reaction solvent, offering a generally efficient synthesis of 2,5-disubstituted oxazoles with broad substrate scope. The overall reaction is a [2 + 2 + 1] annulation of a terminal alkyne, a nitrile, and an oxygen atom from an oxidant. The reaction conditions are exceptionally mild, and a range of functional groups are easily tolerated. With complex and/or expensive nitriles, only 3 equiv could be sufficient to achieve serviceable yields in the absence of any solvent and using only 1 mol % BrettPhosAuNTf(2) as the catalyst.