Dual Gold Catalysis Research Articles

Regio‐ and Stereoselective Synthesis of Ynenamides through Gold(I)‐Catalyzed Hydroalkynylation of Ynamides

AbstractTransition metal catalysis is a useful tool for C−C bond‐forming reactions. Of special interest is the hydroalkynylation reaction of alkynes, which provides a simple method for the synthesis of enynes representing interesting structural motifs in organic chemistry. So far, there are only a few examples of gold(I)‐catalyzed hydroalkynylation reactions. Herein, we were able to show experimentally that the gold(I)‐catalyzed hydroalkynylation of ynamides leads regio‐ and stereoselectively to the corresponding ynenamides, a rather unknown type of molecule. A wide range of products could be generated with yields up to 90 % and, in contrast to many other gold‐catalyzed alkyne dimerization reactions, alkyl groups are tolerated. Quantum chemical calculations and NMR labelling experiments reveal a mechanism via dual gold catalysis.

Author Correction: Design and evolution of chimeric streptavidin for protein-enabled dual gold catalysis

Author Correction: Design and evolution of chimeric streptavidin for protein-enabled dual gold catalysis

Tetranuclear Dicationic Aurophilic Gold(I) Catalysts in Enyne Cycloisomerization: Cooperativity for a Dramatic Shift in Selectivity.

In comparison to mononuclear gold Lewis acid catalysts, digold complexes and dual-gold catalysis have illustrated a distinct and powerful potential for the activation of carbon-carbon multiple bonds. Herein, this concept is pushed further by designing novel tetranuclear gold(I) dicationic complexes structurally supported by strongly stabilizing constraint diphosphinoferrocenyl ligands and attractive closed-shell Au⋅⋅⋅Au aurophilic interactions. The use of a molecularly-defined tetranuclear dicationic aurophilic gold(I) precatalyst for the selectivity-challenging cycloisomerization of low-substituted 1,6-enynes favors the formation with high selectivity of strained azabicyclo[4.1.0]hept-4-enes - even in the complete absence of activating/orienting substituents on alkyne and olefin reactive functions. This selectivity is not achieved by the reported phosphine- and carbene-stabilized mono- and dinuclear cationic gold(I) complexes, including the ones formed from the same ligands. More importantly this selectivity differs also from nanoparticles and heterogeneous gold catalysts reported to date. DFT studies correlated to experimental mechanistic investigations support an unprecedented "cluster-like" reactivity from polynuclear cooperation at the origin of this peculiar selectivity where the aurophilic interactions preexist, and pre-organize, gold cluster reactive intermediates.

Design and evolution of chimeric streptavidin for protein-enabled dual gold catalysis

Artificial metalloenzymes result from anchoring an organometallic catalyst within an evolvable protein scaffold. Thanks to its dimer of dimers quaternary structure, streptavidin allows the precise positioning of two metal cofactors to activate a single substrate, thus expanding the reaction scope accessible to artificial metalloenzymes. To validate this concept, we report herein on our efforts to engineer and evolve an artificial hydroaminase based on dual gold activation of alkynes. Guided by modelling, we designed a chimeric streptavidin equipped with a hydrophobic lid shielding its active site, which enforces the advantageous positioning of two synergistic biotinylated gold cofactors. Three rounds of directed evolution using Escherichia coli cell-free extracts led to the identification of mutants favouring either the anti-Markovnikov product (an indole carboxamide with 96% regioselectivity, 51 turnover numbers), resulting from a dual gold σ,π-activation of an ethynylphenylurea substrate, or the Markovnikov product (a phenyl-dihydroquinazolinone with 99% regioselectivity, 333 turnover numbers), resulting from the π-activation of the alkyne by gold.

Gold-Catalyzed Aromatizations of 3-Ene-5-siloxy-1,6-diynes with Nitrosoarenes To Enable 1,4-N,O-Functionalizations: One-Pot Construction of 4-Hydroxy-3-aminobenzaldehyde Cores.

This work describes gold-catalyzed aromatizations of 3-ene-5-siloxy-1,6-diynes with nitrosoarenes to form 4-hydroxy-3-aminobenzaldehyde derivatives, manifesting the use of nitrosoarenes as 1,4-N,O-functionalization sources. Various 3-ene-5-siloxy-1,6-diynes in benzoid and nonbenzoid types are applicable substrates. A series of 18O- and 2H-labeling experiments have been conducted to exclude gold-π-alkyne intermediates. We postulate a mechanism of dual gold catalysis involving initial formation of gold-π-alkynylgold species that activates a 1,5-hydrogen shift to form reactive 1,6-dipoles, thus furnishing intramolecular Michael-type reactions with nitrosonium electrophiles.

Dinuclear Gold Complexes Supported by Wide Bite Angle Diphosphines for Preorganization-Induced Selective Dual-Gold Catalysis

The synthesis, reactivity, and potential of well-defined dinuclear gold complexes as precursors for dual-gold catalysis is explored. Using the preorganizing abilities of well-known wide bite angle diphosphine ligands, DBFPhos and DPEPhos, dinuclear Au(I)–Au(I) complexes 1 and 2 are used as precursors to form well-defined monocationic species with either a chlorido- or acetylido-ligand bridging the two gold centers. These compounds are active catalysts for the dual-gold heterocycloaddition of a urea-functionalized alkyne, and the preorganization of both Au-centers affords efficient σ,π-activation of the substrate, even at high dilution, significantly outperforming benchmark mononuclear catalysts.

Gold Vinylidenes as Useful Intermediates in Synthetic Organic Chemistry

Gold vinylidenes have recently emerged as useful intermediates in synthetic organic chemistry. These species, which can principally be accessed by a 1,2-migration process from a gold-activated alkyne or by dual gold catalysis on a diyne substrate, can react with nucleophilic partners or by C–H insertion to produce a variety of functionalized (poly)cyclic compounds. This short review covers the synthetic approaches developed so far to access gold vinylidenes and the different reactivities these species can exhibit.1 Introduction2 1,2-Migration Processes3 Dual Gold Catalysis4 Other Processes5 Conclusion

Dual gold catalysis - an update.

This review summarizes the recent developments in the field of dual gold activation chemistry. New developments including synthetic strategies, latest mechanistic insights, computational studies and the identification and isolation of key intermediates, are discussed.

Gold-Catalyzed Formal Dehydro-Diels-Alder Reactions of Ene-Ynamide Derivatives Bearing Terminal Alkyne Chains: Scope and Mechanistic Studies.

A new protocol for the synthesis of a variety of N-containing aromatic heterocycles by a formal gold-catalyzed dehydro-Diels-Alder reaction of ynamide derivatives has been developed. Deuterium-labeling experiments and kinetic studies support the involvement of a dual gold catalysis mechanism in which a gold acetylide moiety adds onto an aurated keteneiminium.

Gold‐Catalyzed Formal Dehydro‐Diels–Alder Reactions of Ene‐Ynamide Derivatives Bearing Terminal Alkyne Chains: Scope and Mechanistic Studies

AbstractA new protocol for the synthesis of a variety of N‐containing aromatic heterocycles by a formal gold‐catalyzed dehydro‐Diels–Alder reaction of ynamide derivatives has been developed. Deuterium‐labeling experiments and kinetic studies support the involvement of a dual gold catalysis mechanism in which a gold acetylide moiety adds onto an aurated keteneiminium.

Different Selectivities in the Insertions into C(sp2 )-H Bonds: Benzofulvenes by Dual Gold Catalysis Competition Experiments.

An unprecedented, often almost quantitative access to tricyclic aromatic compounds by dual gold catalysis was developed. This synthetic route expands the scope of benzofulvene derivatives through a C(sp2 )-H bond insertion in easily available starting materials. The insertion takes place with an exclusive chemoselectivity with respect to the competing aromatic C-H positions. A bidirectional synthesis with two competing ortho-aryl C-H bonds in the selectivity-determining step also shows perfect selectivity; this result is explained by a computational investigation of the two conceivable intermediates. The intramolecular competition of two non-equivalent aryl C-H bonds with a benzylic methyl group also showed perfect selectivity.

Detection of Intermediates in Dual Gold Catalysis Using High-Resolution Ion Mobility Mass Spectrometry

We have probed for reaction intermediates involved in the dual-gold-catalyzed activation of a conjugated 1,5-diyne substrate and its further coupling to benzene in the liquid phase. This was done by sampling the reaction mixture by electrospray ionization followed by high-resolution ion mobility mass spectrometry—under conditions allowing for the resolution of structural isomers differing in their collision cross sections by less than 0.5%. For the cationic mass corresponding to catalyst + diyne (activation stage) we resolve four isomers. At the mass corresponding to catalyst + diyne + benzene, two isomers are observed. By comparing the experimentally obtained cross sections to those inferred for model structures derived from density functional computations, we find our measurements to be consistent with the proposed solution mechanism. This constitutes the first direct observation of intermediates in dual gold catalysis and supports the previous inference that the mechanism involves cooperative interacti...

Dual Gold Catalysis: Bidirectional Processes and Tandem sp3 -C-H Insertion Reactions.

Various tetrayne systems were converted under dual gold-catalyzed conditions. For symmetric tetraalkynyl-substituted thiophenes, bearing two alkyl-substituted alkynes and two terminal alkyne units, bidirectional cyclizations led to the efficient formation of dibenzothiophene systems. In all cases, selective CH activation of the C-H bond of the alkyl substituent was observed leading to cyclopentane moieties annelated to the newly formed aromatic cores. If two thiophene moieties were tethered over the attached non-terminal alkynes, depending on the length of the connecting alkyl tether, either bidirectional processes or tandem processes can be addressed leading to interesting molecular structures, such as spiro compounds or isolated benzothiophenes connected by a C-C bond. Other electron-rich heterocycles also reacted. While the reactions even worked for some mixed systems, other cases only delivered the products of a mono-cyclization.

Front Cover Picture: Dual Gold Catalysis: Synthesis of Fluorene Derivatives from Diynes (Adv. Synth. Catal. 2/2017)

Front Cover Picture: Dual Gold Catalysis: Synthesis of Fluorene Derivatives from Diynes (Adv. Synth. Catal. 2/2017)

Dual gold and photoredox catalysis: visible light-mediated intermolecular atom transfer thiosulfonylation of alkenes.

Regioselective difunctionalization of alkenes has attracted significant attention from synthetic chemists and has the advantage of introducing diverse functional groups into vicinal carbons of common alkene moieties in a single operation. Herein, we report an unprecedented intermolecular atom transfer thiosulfonylation reaction of alkenes by combining gold catalysis and visible-light photoredox catalysis. A trifluoromethylthio group (SCF3) and other functionalized thio groups together with a sulfonyl group were regioselectively introduced into alkenes in the most atom economical manner. A detailed mechanism study indicated that a synergistic combination of gold catalysis and photoredox catalysis is crucial for this reaction.

The preference for dual-gold(i) catalysis in the hydro(alkoxylation vs. phenoxylation) of alkynes.

Dinuclear gold complexes and their use in catalysis have received significant recent attention, but there are few critical comparisons of mono- versus dual gold-catalysed pathways. Herein we study the hydroalkoxylation and hydrophenoxylation of alkynes using density functional theory calculations, and compare two possible mechanisms that have been proposed previously on the basis of theoretical and experimental studies, which unravel different preferences because of both the nature of the alkyne and alcohol and the non-innocent role of the counter-anion of a dual gold based catalyst. Entropy is found to have a significant effect, rendering the nucleophilic attack of the monoaurated intermediate [Au(L)(η2-alkyne)]+ difficult both kinetically and thermodynamically; this mechanism cannot easily form only the trans-alkene product that is observed experimentally. Instead, a reaction via a dual gold catalysed mechanism presents much lower barriers. In addition, for the sake of direct comparison with recent results by Belanzoni and Zuccaccia, oversimplification of the N-heterocyclic carbene (NHC) ligand in the calculations might decrease the enthalpy barrier and lead to results that are not directly applicable to experiments. Moreover, the alkylic or arylic nature of the alkyne and/or alcohol is also tested.

Fluorescence resonance energy transfer (FRET) for the verification of dual gold catalysis.

Fluorescence resonance energy transfer (FRET) in appropriately tagged NHC-gold complexes can be utilized to in situ observe the formation of digold species, which are known to be catalytically relevant intermediates in various gold catalyzed reactions.

Recent Advances in Dual Visible Light Photoredox and Gold-Catalyzed­ Reactions

In a dual visible light photoredox and gold catalysis system, Au(I) is oxidized in a stepwise fashion by photogenerated aryl radicals leading to cationic Au(III) species, a process which is incorporated into various domino functionalization/coupling reactions. This article presents an overview of the major contributions reported in this field, emphasizing those involving aryldiazonium or diaryliodonium salts as general radical sources. 1 Introduction 2 Domino Nucleophilic Addition/Arylation 3 Domino Rearrangement/Arylation 4 Cross-Coupling 5 Conclusion

Dual Gold Catalysis: Synthesis of Fluorene Derivatives from Diynes

Abstract1,5‐Diyne systems bearing one terminal and one benzyl‐ or allyl‐substituted alkyne attached to an aromatic backbone were converted in the presence of a gold catalyst. In a dual gold‐catalyzed process, gold vinylidenes are formed that selectively undergo formal CH insertion into the C(sp2)–H bond of the offered unsaturated systems. If H atoms are present in the propargylic position, a subsequent isomerization to the aromatic system takes place leading to 9H‐fluorene and 11H‐benzo[b]fluorene derivatives as final products. In the case of a quaternary carbon in the propargylic position no further aromatization is observed and 10H‐benzo[b]fluorene derivatives are obtained in high yield.magnified image

Jarl Ivar van der Vlugt

Jarl Ivar van der Vlugt