Highly efficient and diastereoselective gold(I)-catalyzed synthesis of tertiary amines from secondary amines and alkynes: substrate scope and mechanistic insights

An efficient method for the synthesis of tertiary amines through a gold(I)‐catalyzed tandem reaction of alkynes with secondary amines has been developed. In the presence of ethyl Hantzsch ester and [{(tBu)₂(o‐biphenyl)P}AuCl]/AgBF₄ (2 mol %), a variety of secondary amines bearing electron‐deficient and electron‐rich substituents and a wide range of alkynes, including terminal and internal aryl alkynes, aliphatic alkynes, and electron‐deficient alkynes, underwent a tandem reaction to afford the corresponding tertiary amines in up to 99 % yield. For indolines bearing a preexisting chiral center, their reactions with alkynes in the presence of ethyl Hantzsch ester catalyzed by [{(tBu)₂(o‐biphenyl)P}AuCl]/AgBF₄ (2 mol %) afforded tertiary amines in excellent yields and with good to excellent diastereoselectivity. All of these organic transformations can be conducted as a one‐pot reaction from simple and readily available starting materials without the need of isolation of air/moisture‐sensitive enamine intermediates, and under mild reaction conditions (mostly room temperature and mild reducing agents). Mechanistic studies by NMR spectroscopy, ESI‐MS, isotope labeling studies, and DFT calculations on this gold(I)‐catalyzed tandem reaction reveal that the first step involving a monomeric cationic gold(I)–alkyne intermediate is more likely than a gold(I)–amine intermediate, a three‐coordinate gold(I) intermediate, or a dinuclear gold(I)–alkyne intermediate. These studies also support the proposed reaction pathway, which involves a gold(I)‐coordinated enamine complex as a key intermediate for the subsequent transfer hydrogenation with a hydride source, and reveal the intrinsic stereospecific nature of these transformations observed in the experiments.     

Application of the gold(I)-Catalyzed aldol reaction to a stereoselective synthesis of (2S, 3R, 4R, 6E)-3-Hydroxy-4-methyl-2-(methylamino)oct-6-enoic Acid ( = MeBmt), Cyclosporin's unusual amino acid

The title compound 8 was prepared in three steps starting from the optically pure aldehyde (2R, 4E)-2-methyl-hex-4-enal ( 3 ), thus constituting the shortest synthetic approach reported. Two of the three stereogenic centers in the product were generated in a coupling reaction of 3 with ethyl isocyanoacetate, catalyzed by a gold(I)/chiral ferrocenylphosphine system, giving the dihydrooxazole 5 in 85% diastereoselectivity (mismatchedcase). The weak effect of double stereodifferentiation in this reaction (matched case 90% ds) is discussed. N-Methylation and hydrolytic ring opening of 5 gave the protected form 7 of MeBmt, The X-ray diffraction study carried out on 7 confirms the absolute configuration of the two stereogenic centers formed in the gold(I)-catalytic reaction.     

Synthesis of Highly Substituted N‐(Furan‐3‐ylmethylene)benzenesulfonamides by a Gold(I)‐Catalyzed Oxidation/1,2‐Alkynyl Migration/Cyclization Cascade

A variety of N‐(furan‐3‐ylmethylene)benzenesulfonamides were obtained by a gold(I)‐catalyzed cascade reaction from easily accessible starting materials. The reaction pathway involves a rarely observed 1,2‐alkynyl migration onto a gold carbenoid. This observation further enriches gold carbenoid chemistry with regard to group migration.     

Synthesis of Polycyclic Indole Skeletons by a Gold(I)‐Catalyzed Cascade Reaction

The conversion of simple, easily available urea‐substituted 3‐phenylpropargyl alcohols catalyzed by a simple IPr–gold(I) catalyst in a gold(I)‐catalyzed cascade reaction composing of a gold‐catalyzed nucleophilic addition and a subsequent gold‐catalyzed substitution reaction delivers 1H‐imidazo[1, 5?a]indol‐3(2 H)‐ones. Other gold(I) catalysts or silver catalysts gave lower yields and often gave other side products. Gold(III) and copper(II) catalysts decomposed the starting material. Twelve examples, including donor and acceptor substituents on the distal nitrogen of the urea substructure, are provided. An X‐ray crystal structure analysis confirmed the structural assignment. The mechanistic investigation including isolation and further conversion of intermediates and reactions with enantiopure starting materials indicated that after the nucleophilic‐addition step, the substrate undergoes an S_N1‐type benzylic substitution reaction at the indolyl alcohol intermediate or an intramolecular hydroamination reaction of the 2‐vinylindole intermediate.     

Dinuclear gold(I)-N-heterocyclic carbene complexes: Synthesis,characterization, and catalytic application for hydrohydrazidation of terminal alkynes

Dinuclear gold(I)-N-heterocyclic carbene complexes were developed for the hydrohydrazidation of terminal alkynes. The gold(I)-N-heterocyclic carbene complexes 2a-2b were synthesized in good yields from silver complexes synthesized in situ, which in turn were obtained from the corresponding imidazolium salts with Ag₂O in dichloromethane as a solvent. The new air-stable gold(I)-NHC complexes, 2a - 2b, were characterized using NMR spectroscopy, elemental analysis, infrared, and mass spectroscopy studies. The gold(I) complex 2a was characterized using X-ray crystallography. Bis-N-heterocyclic carbene–based gold(I) complexes 2a - 2b exhibited excellent catalytic activities for hydrohydrazidation of terminal alkynes yielding acylhydrazone derivatives. The working catalytic system can be used in gram-scale synthesis. In addition, the catalytic reaction mechanism of the hydrohydrazidation of terminal alkynes by gold(I)-NHC complex was studied in detail using density functional theory.     

Single‐Crystal‐to‐Single‐Crystal Transformation and Solvochromic Luminescence of a Dinuclear Gold(I)–(Aza‐[18]crown‐6)dithiocarbamate Compound

The treatment of [AuCl(SMe₂)] with an equimolar amount of NaO₅NCS₂ (O₅NCS₂=(aza‐[18]crown‐6)dithiocarbamate) in CH₃CN gave [Au₂(O₅NCS₂)₂] ? 2 CH₃CN ( 2? 2 CH₃CN), and its crystal structure displays a dinuclear gold(I)‐azacrown ether ring and an intermolecular gold(I) ??? gold(I) contact of 2.8355(3) Å in crystal lattices. It is noted that two other single crystals of 2 ?tert‐butylbenzene?H₂O and 2? 0.5 m‐xylene can be successfully obtained from a single‐crystal‐to‐single‐crystal (SCSC) transformation process by immersing single crystals of 2? 2 CH₃CN in the respective solvents, and both also show intermolecular gold(I) ??? gold(I) contacts of 2.9420(5) and 2.890(2)–2.902(2) Å, respectively. Significantly, the emissions of all three 2 ?solvates are well correlated with their respective intermolecular gold(I) ??? gold(I) contacts, where such contacts increase with 2? 2 CH₃CN (2.8355(3) Å)< 2? 0.5 m‐xylene (2.890(2)–2.902(2) Å)< 2? tert‐butylbenzene?H₂O (2.9420(5) Å), and their emission energies increase with 2? 2 CH₃CN (602 nm)< 2? 0.5 m‐xylene (583 nm)< 2? tert‐butylbenzene?H₂O (546 nm) as well. In this regard, we further examine the solvochromic luminescence for some other aromatics, and finally their emissions are within 546–602 nm. Obviously, the above results are mostly ascribed to the occurrence of intermolecular gold(I) ??? gold(I) contacts in 2 ?solvates, which are induced by the presence of various solvates in the solid state, as a key role to be responsible for their solvochromic luminescence.     

Gold(I)‐Catalyzed Enantioselective Intermolecular Hydroarylation of Allenes with Indoles and Reaction Mechanism by Density Functional Theory Calculations

Chiral binuclear gold(I) phosphine complexes catalyze enantioselective intermolecular hydroarylation of allenes with indoles in high product yields (up to 90 %) and with moderate enantioselectivities (up to 63 % ee). Among the gold(I) complexes examined, better ee values were obtained with binuclear gold(I) complexes, which displayed intramolecular Au^I Au^I interactions. The binuclear gold(I) complex 4c [(AuCl)₂( L3 )] with chiral biaryl phosphine ligand (S)‐(−)‐MeO‐biphep ( L3 ) is the most efficient catalyst and gives the best ee value of up to 63 %. Substituents on the allene reactants have a slight effect on the enantioselectivity of the reaction. Electron‐withdrawing groups on the indole substrates decrease the enantioselectivity of the reaction. The relative reaction rates of the hydroarylation of 4‐X‐substituted 1,3‐diarylallenes with N‐methylindole in the presence of catalyst 4c [(AuCl)₂( L3 )] / AgOTf [ L3 =(S)‐(−)‐MeO‐biphep], determined through competition experiments, correlate (r²=0.996) with the substituent constants σ. The slope value is −2.30, revealing both the build‐up of positive charge at the allene and electrophilic nature of the reactive Au^I species. Two plausible reaction pathways were investigated by density functional theory calculations, one pathway involving intermolecular nucleophilic addition of free indole to aurated allene intermediate and another pathway involving intramolecular nucleophilic addition of aurated indole to allene via diaurated intermediate E2 . Calculated results revealed that the reaction likely proceeds via the first pathway with a lower activation energy. The role of Au^I Au^I interactions in affecting the enantioselectivity is discussed.     

On the Structure of Intermediates in Enyne Gold(I)-Catalyzed Cyclizations: Formation of trans-Fused Bicyclo[5.1.0]octanes as a Case Study

The nature of cyclopropyl gold(I) carbene-type intermediates has been reexamined as part of a mechanistic study on the formation of cis- or trans-fused bicyclo[5.1.0]octanes in a gold(I)-catalyzed cascade reaction. Benchmark of DFT methods together with QTAIM theory and NBO analysis confirms the formation of distinct intermediates with carbenic or carbocationic structures in the cycloisomerizations of enynes.     

Synthesis of tetrahydrobenzo[b]furans via a gold(I)‐catalyzed rearrangement/cycloisomerization sequence of cyclic 1‐aryl‐2‐propargyl‐cyclohex‐2enols

A facile synthesis of tetrahydrobenzo[b]furans via gold(I)‐catalyzed cycloisomerization of 1‐aryl‐2‐propargylcyclohex‐2‐enols is described. The transformation is suggested to proceed through a gold(I)‐catalyzed tertiary allylic alcohol rearrangement to give a secondary allylic alcohol that underwent a 5‐exo‐dig addition of the hydroxyl group onto the gold(I)‐activated alkyne to give a vinylgold species. Protodeauration of the resulting vinylgold intermediate followed by aromatization furnished the tetrahydrobenzo[b]furans.     

Chiral Hemilabile P,N-Ligand-Assisted Gold Redox Catalysis for Enantioselective Alkene Aminoarylation

Enantioselective, intermolecular alkene arylamination was achieved through gold redox catalysis. Screening of ligands revealed chiral P,N ligands as the optimal choice, giving alkene aminoarylation with good yields (up to 80 %) and excellent stereoselectivity (up to 99 : 1 er). As the first example of enantioselective gold redox catalysis, this work confirmed the feasibility of applying a chiral ligand at the gold(I) stage, with the stereodetermining step (SDS) at the gold(III) intermediate, thus opening up a new way to conduct gold redox catalysis with stereochemistry control.     

Synthesis and Isolation of Organogold Complexes through a Controlled 1,2‐Silyl Migration

During our efforts toward the synthesis of naturally occurring polyprenylated polycyclic acylphloroglucinol using a Au^I‐catalyzed 6‐endo dig carbocyclization, we isolated stable vinyllic gold intermediates. Optimization lead to isolated yields of up to 98 %, using 2‐(di‐tert‐butylphosphino)biphenyl as the ligand. This transformation is derived from a silyl rearrangement that can be fully controlled according to the nature of the substituent on the ynone. This selective transformation does not require basic conditions to prevent protodeauration. These vinylgold complexes are the first isolated intermediates during a silyl migration with gold(I). More than 16 new organogold complexes were synthesized and characterized by single‐crystal X‐ray diffraction. Reactivity of these complexes is also presented.     

Structural diversity in the coordination of 1,4‐dihydro‐1,4‐diarsinine as a cyclic ditopic organoarsenic ligand to metal ions

A number of different complexation structures of cis‐1,4‐dihydro‐1,4‐dimethyl‐2,3,5,6‐tetrakis(t‐butoxycarbonyl)‐1,4‐diarsinine (cis‐DHDAtBu) with gold(I) and iridium(III) were synthesized and characterized by ¹H, ¹³C NMR spectra, X‐ray crystallography, and elemental analysis. Mono‐ and di‐nuclear gold(I) chloride complexes with cis‐DHDAtBu were obtained by simple addition of gold(I) chloride to cis‐DHDAtBu. A hetero‐trinuclear gold‐platinum‐gold complex (PtAu₂Cl₄(cis‐DHDAtBu)₂) was obtained by complexation of a mononuclear platinum(II) complex (trans‐PtCl₂(cis‐DHDAtBu)₂), which was obtained by complexation of cis‐DHDAtBu with a half‐equimolar amount of PtCl₂(PhCN)₂, with a twice‐equimolar amount of gold(I) chloride. An iridium(III) complex with cis‐DHDAtBu (IrCl₃(cis‐DHDAtBu)₂) was prepared from hydrated iridium(III) chloride and cis‐DHDAtBu. The complex comprises a five‐membered chelate cis‐DHDAtBu and an usual monodentate cis‐DHDAtBu. The interior angles at around the arsenic and the As–C—C bond angles were significantly varied from 113.4° to 129.4° in the present crystal. These observations suggest that the flexibility of the bond angles at around the arsenic center is inherent property in the present organoarsenic compounds. © 2011 Wiley Periodicals, Inc. Heteroatom Chem 23:16–26, 2012; View this article online at wileyonlinelibrary.com . DOI 10.1002/hc.20747     

Novel Benzyl‐ or 4‐Cyanobenzyl‐Substituted N‐Heterocyclic (Bromo)(carbene)silver(I) and (Carbene)(chloro)gold(I) Complexes: Synthesis and Preliminary Cytotoxicity Studies

N‐Heterocyclic carbene (NHC) complexes bromo(1,3‐dibenzyl‐1,3‐dihydro‐2H‐imidazol‐2‐ylidene)silver(I) ( 2a ), bromo[1‐(4‐cyanobenzyl)‐3‐methyl‐1,3‐dihydro‐2H‐imidazol‐2‐ylidene]silver(I) ( 2b ), and bromo[1‐(4‐cyanobenzyl)‐3‐methyl‐1,3‐dihydro‐2H‐benzimidazol‐2‐ylidene]silver(I) ( 2c ) were prepared by the reaction of 1,3‐dibenzyl‐1H‐imidazol‐3‐ium bromide ( 1a ), 3‐(4‐cyanobenzyl)‐1‐methyl‐1H‐imidazol‐3‐ium bromide ( 1b ), and 3‐(4‐cyanobenzyl)‐1‐methyl‐1H‐benzimidazol‐3‐ium bromide ( 1c ), respectively, with silver(I) oxide. NHC Complexes chloro(1,3‐dibenzyl‐1,3‐dihydro‐2H‐imidazol‐2‐ylidene)gold(I) ( 3a ), chloro[1‐(4‐cyanobenzyl)‐3‐methyl‐1,3‐dihydro‐2H‐imidazol‐2‐ylidene]gold(I) ( 3b ), and chloro[1‐(4‐cyanobenzyl)‐3‐methyl‐1,3‐dihydro‐2H‐benzimidazol‐2‐ylidene]gold(I) ( 3c ) were prepared via transmetallation of corresponding (bromo)(NHC)silver(I) complexes with chloro(dimethylsulfido)gold(I). The complex 3a was characterized in two polymorphic forms by single‐crystal X‐ray diffraction showing two rotamers in the solid state. The cytotoxicities of all three bromo(NHC)silver(I) complexes and three (chloro)(NHC)gold(I) complexes were investigated through 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl‐2H‐tetrazolium bormide (MTT)‐based preliminary in vitro testing on the Caki‐1 cell line in order to determine their IC₅₀ values. (Bromo)(NHC)silver(I) complexes 2a – 2c and (chloro)(NHC)gold(I) complexes 3a – 3c were found to have IC₅₀ values of 27±2, 28±2, 34±6, 10±1, 12±5, and 12±3 μM , respectively, on the Caki‐1 cell line.     

The More Gold—The More Enantioselective: Cyclohydroaminations of γ‐Allenyl Sulfonamides with Mono‐, Bis‐, and Trisphospholane Gold(I) Catalysts

A series of chiral mono‐, di‐, and trinuclear gold(I) complexes have been prepared and used as precatalysts in the asymmetric cyclohydroamination of N‐protected γ‐allenyl sulfonamides. The stereodirecting ligands were mono‐, di‐, and tridentate 2,5‐diphenylphospholanes, which possessed C₁, C₂, and C₃ symmetry, respectively, thereby rendering the catalytic sites in the di‐ and trinuclear complexes symmetry equivalent. The C₃‐symmetric trinuclear complex displayed the highest activity and enantioselectivity (up to 95 % ee), whilst its mono‐ and dinuclear counterparts exhibited considerably lower enantioselectivities and activities. A similar trend was observed in a series of mono‐, di‐, and trinuclear 2,5‐dimethylphospholane gold(I) complexes. Aurophilic interactions were established from the solid‐state structures of the trinuclear gold(I) complexes, thereby raising the question as to whether these secondary forces were responsible for the different catalytic behavior observed.     

Coordination Behavior of Sterically Protected Phosphaalkenes on the AuCl Moiety Leading to Catalytic 1,6‐Enyne Cycloisomerization

Mes*‐substituted 2,3‐dimethyl‐1,4‐diphosphabuta‐1,3‐diene, 1,2‐diphenyl‐3,4‐diphosphinidenecyclobutene, 2,2‐bis(methylsulfanyl)‐1‐phosphaethene, and 3,3‐diphenyl‐1,3‐diphosphapropenes (Mes*=2,4,6‐tri‐tert‐butylphenyl) were employed as P ligands of gold(I) complexes. The (E,E)‐2,3‐dimethyl‐1,4‐diphosphabuta‐1,3‐diene functioned as a P2 ligand for digold(I) complex formation with or without intramolecular Au–Au contact, which depends on the conformation of the 1,3‐diphosphabuta‐1,3‐diene. The 1,2‐diphenyl‐3,4‐diphosphinidenecyclobutene, which has a rigid s‐cis P?C? C?P skeleton, afforded the corresponding digold(I) complexes with a slight distortion of the planar diphosphinidenecyclobutene framework and intramolecular Au–Au contact. In the case of the 2,2‐bis(methylsulfanyl)‐1‐phosphaethene, only the phosphorus atom coordinated to gold, and the sulfur atom showed almost no intra‐ or intermolecular coordination to gold. On the other hand, the 1,3‐diphosphapropenes behaved as nonequivalent P2 ligands to afford the corresponding mono‐ and digold(I) complexes. Some phosphaalkene–gold(I) complexes showed catalytic activity for 1,6‐enyne cycloisomerization without cocatalysts such as silver hexafluoroantimonate.     

Gold(I) Complexes Stabilized by Nine- and Ten-Membered N-Heterocyclic Carbene Ligands

Nine- and ten-membered N-heterocyclic carbene (NHC) ligands have been developed and for the first time their gold(I) complexes were synthesized. The protonated NHC pro-ligands 2 a – h were prepared by the reaction of readily available N,N′-diarylformamidines with bis-electrophilic building blocks, followed by anion exchange. In situ deprotonation of the tetrafluoroborates 2 a – h with tBuOK in the presence of AuCl(SMe₂) provided fast access to NHC-gold(I) complexes 3 – 10 . These new NHC-gold(I) complexes show very good catalytic activity in a cycloisomerization reaction (0.1 mol % catalyst loading, up to 100 % conversion) and their solid-state structures reveal high steric hindrance around the metal atom (%V_bur up to 53.0) which is caused by their expanded-ring architecture.     

Inclusion Complexes of Gold(I)-Dithiocarbamates with β-Cyclodextrin: A Journey from Drug Repurposing towards Drug Discovery

The gold(I)-dithiocarbamate (dtc) complex [Au(N,N-diethyl)dtc]₂ was identified as the active cytotoxic agent in the combination treatment of sodium aurothiomalate and disulfiram on a panel of cancer cell lines. In addition to demonstrating pronounced differential cytotoxicity to these cell lines, the gold complex showed no cross-resistance in therapy-surviving cancer cells. In the course of a medicinal chemistry campaign on this class of poorly soluble gold(I)-dtc complexes, >35 derivatives were synthesized and X-ray crystallography was used to examine structural aspects of the dtc moiety. A group of hydroxy-substituted complexes has an improved solubility profile, and it was found that these complexes form 2 : 1 host–guest inclusion complexes with β-cyclodextrin (CD), exhibiting a rarely observed “tail-to-tail” arrangement of the CD cones. Formulation of a hydroxy-substituted gold(I)-dtc complex with excess sulfobutylether-β-CD prevents the induction of mitochondrial reactive oxygen species, which is a major burden in the development of metallodrugs.     

Tunable Gold-catalyzed Reactions of Propargyl Alcohols and Aryl Nucleophiles

Gold-catalyzed transformations of 1,3-diarylpropargyl alcohols and various aryl nucleophiles were studied. Selective tunable synthetic methods were developed for 1,1,3-triarylallenes, diaryl-indenes and tetraaryl-allyl target products by C3 nucleophilic substitution and subsequent intra- or intermolecular hydroarylation, respectively. The reactions were scoped with regards to gold(I)/(III) catalysts, solvent, temperature, and electronic and steric effects of both the diarylpropargyl alcohol and the aryl nucleophiles. High yields of triaryl-allenes and diaryl-indenes by gold(III) catalysis were observed. Depending on the choice of aryl nucleophile and control of reaction temperature, different product ratios have been obtained. Alternatively, tetraaryl-allyl target products were formed by a sequential one-pot tandem process from appropriate propargyl substrates and two different aryl nucleophiles. Corresponding halo-arylation products (I and Br; up to 95 % 2-halo-diaryl-indenes) were obtained in a one-pot manner in the presence of the respective N-halosuccinimides (NIS, NBS).     

The Impact of Crystal Packing and Aurophilic Interactions on the Luminescence Properties in Polymorphs and Solvate of Aroylacetylide–Gold(I) Complexes

The influence of the chemical substitution, crystal packing, and aurophilic interactions of the gold(I) acetylide complexes of the type (ArCOC≡C)_nAuPEt₃ (n=1,2) on their luminescent properties were examined. All described complexes undergo ligand scrambling in solution, which results in the formation of stable, easily isolated crystals that contain [ArCO(C≡C)_n]₂Au⁻(Et₃P)₂Au⁺ homoleptic species. In particular, we observed that the (benzoylacetylide)gold(I) complex yields three crystal forms with strikingly different luminescence properties. We monitored the conversion pathway for these forms: an orange luminescent form of homoleptic complex upon drying undergoes spontaneous transformation to bright green fluorescent form and finally to the weakly blue emissive one. In addition, we report a rare example of a helical arrangement of Au⋅Au⋅Au chains that are observed for the first time in acetylide gold(I) complexes in the case of heteroleptic (benzoylacetylide)gold(I) complex. This is a very rare case in which crystal structures and ensuing electronic properties of the heteroleptic and Au^I complexes could be directly compared.     

Highly Efficient and Stereoselective Thioallylation of Alkynes: Possible Gold Redox Catalysis with No Need for a Strong Oxidant

Stereoselective thioallylation of alkynes under possible gold redox catalysis was accomplished with high efficiency (as low as 0.1 % catalyst loading, up to 99 % yield) and broad substrate scope (various alkynes, inter‐ and intramolecular fashion). The gold(I) catalyst acts as both a π‐acid for alkyne activation and a redox catalyst for Au^I/III coupling, whereas the sulfonium cation generated in situ functions as a mild oxidant. This novel methodology provides an exciting system for gold redox catalysis without the need for a strong oxidant.