Catalytic Three‐Component Domino Reaction for the Preparation of Trisubstituted Oxazoles

Multicomponent reactions are attractive for assembling functionalized heterocyclic compounds. To this end, an efficient gold‐catalyzed three‐component domino reaction to form oxazoles directly from imines, alkynes, and acid chlorides is presented. The reaction proceeds in a single synthetic step by using a gold(III)–N,N′‐ethylenebis(salicylimine) (salen) catalyst to give trisubstituted oxazoles in up to 96 % yield. The substrate scope, a mechanistic study exploring the role of the gold catalyst, and the synthetic applications of the oxazole products are discussed.     

In Situ Generation of Oxazole Ylide and Interception with Sulfonamide: Construction of Amidines Using Two Diazo Molecules

A novel generation of oxazole ylide and interception with sulfonamide have been well developed to construct fully substituted amidines. This copper‐catalyzed four‐component reaction incorporates two diazo molecules to target amidines and shows broad substrate scope, excellent functional groups tolerance and good to excellent yields.     

Formation of Oxazoles from Elusive Gold(I) α‐Oxocarbenes: A Mechanistic Study

The gold(I) catalyzed reaction between phenylacetylene, pyridine N‐oxide and acetonitrile leading, via a putative gold‐α‐oxocarbene intermediate, towards an oxazole product has been investigated. A novel mass spectrometric method called “delayed reactant labeling” is used to track consecutive and parallel reactions. It clearly shows that the intramolecular formation of a pyridine adduct of gold‐α‐oxocarbene is in competition with the formation of the oxazole product. The reaction mechanism most probably corresponds to competition between acetonitrile and pyridine in an almost barrierless reaction with putative gold‐α‐oxocarbene within the solvent cage. The detected ionic species have been characterized by helium tagging infrared photodissociation spectroscopy.     

Combining Gold and Palladium Catalysis: One‐Pot Access to Pentasubstituted Arenes from Furan–Yne and En–Diyne Substrates

A series of furan–yne systems was transformed into the corresponding tetrasubstituted annelated phenol derivatives that bear one bromo group. The two‐step procedure consisted of a phenol synthesis and a subsequent electrophilic bromination with N‐bromosuccinimide (NBS). The reactions can be performed in a one‐pot procedure with the same precatalyst. The halogenation reaction is highly selective only in the presence of the gold catalyst. En–diyne substrates were also suitable starting materials; then the pentasubstituted aromatic core showed a completely different substitution pattern for the phenolic products. Furthermore, a one‐pot protocol that consisted of a gold‐catalyzed phenol synthesis, a gold‐catalyzed halogenation reaction, and a palladium‐catalyzed Suzuki coupling was established. The overall efficiency of this procedure was excellent and the substrate scope of the reaction was broad.     

Gold‐Catalyzed Direct Oxidative Arylation with Boron Coupling Partners

An efficient synthesis of biaryls through a gold‐catalyzed oxidative cross‐coupling of arenes with strong electron‐deprived aryl boronates is presented herein. Regio‐ and chemocontrol are achieved by the selective activation of these coupling partners by gold at different oxidation states. Under reaction conditions devoid of basic additives or directing groups, the role of acetato ligand as an internal base has been revealed as a key parameter for expanding the reaction scope in these transformations.     

Mechanistic Insights into the One‐Pot Synthesis of Propargylamines from Terminal Alkynes and Amines in Chlorinated Solvents Catalyzed by Gold Compounds and Nanoparticles

Propargylamines can be obtained from secondary amines and terminal alkynes in chlorinated solvents by a three‐ and two‐component synthesis catalyzed by gold compounds and nanoparticles (Au‐NP) under mild conditions. The use of dichloromethane allows for the activation of two C? Cl bonds and a clean transfer of the methylene fragment to the final product. The scope of the reaction as well as the influence of different gold(III) cycloaurated complexes and salts has been investigated. The involvement of gold nanoparticles generated in situ in the process is discussed and a plausible reaction mechanism is proposed on the basis of the data obtained.     

Enantioselective synthesis of methyl 2-[1-[(tert-butoxycarbonyl)amino]ethyl]-4-methyloxazole-5-carboxylate by a one–pot enamide cyclization

Methyl 2-[1-[(tert-butoxycarbonyl)amino]ethyl]-4-methyloxazole-5-carboxylate (1) was synthesized with high optical purity via a Pd–catalyzed amide coupling with vinyl triflate with subsequent oxazole formation. The latter reaction proceeds via bromination of an enamide with NBS and DBU-promoted cyclization. The oxazole subunit positional isomer in a macrocyclic azole peptide was obtained in a good yield without racemization. The scope and limitations of this reaction were also investigated.     

Highly Enantioselective Nickel‐Catalyzed Intramolecular Reductive Cyclization of Alkynones

The first asymmetric nickel‐catalyzed intramolecular reductive cyclization of alkynones is reported. A P‐chiral monophosphine and triethylsilane were used as the ligand and the reducing reagent, respectively, to form a series of tertiary allylic alcohols bearing furan/pyran rings in excellent yields and enantioselectivities. This reaction has a broad substrate scope and enabled the efficient synthesis of dehydroxycubebin and chiral dibenzocyclooctadiene skeletons.     

Total Synthesis of the Post‐translationally Modified Polyazole Peptide Antibiotic Goadsporin

The structurally unique polyazole antibiotic goadsporin contains six heteroaromatic oxazole and thiazole rings integrated into a linear array of amino acids that also contains two dehydroalanine residues. An efficient total synthesis of goadsporin is reported in which the key steps are the use of rhodium(II)‐catalyzed reactions of diazocarbonyl compounds to generate the four oxazole rings, which demonstrates the power of rhodium carbene chemistry in organic chemical synthesis.     

Gold‐Catalyzed Cadiot–Chodkiewicz‐type Cross‐Coupling of Terminal Alkynes with Alkynyl Hypervalent Iodine Reagents: Highly Selective Synthesis of Unsymmetrical 1,3‐Diynes

A new and efficient method for the synthesis of unsymmetrical 1,3‐butadiynes by gold‐catalyzed C(sp)–C(sp) cross‐coupling of terminal alkynes with alkynyl hypervalent iodine(III) reagents has been developed. The reaction features high selectivity and efficiency, mild reaction conditions, wide substrate scope, and functional‐group compatibility, and is a highly attractive complement to existing methods. Mechanistic studies reveal that formation of a phenanthrolinyl‐ligated gold(I) complex is crucial for the efficiency and selectivity of the target transformation.     

Concise Total Synthesis of Enigmazole A

An efficient entry into the phosphorylated marine macrolide enigmazole A is described. Enigmazole A interferes with c‐Kit signaling by an as yet unknown mode of action and is therefore a potential lead in the quest for novel anticancer agents. Key to success is a gold‐catalyzed cascade comprising a [3,3]‐sigmatropic rearrangement of a propargyl acetate along the periphery of a macrocyclic scaffold, followed by a transannular hydroalkoxylation of the resulting transient allenyl acetate. This transformation mandated the use of a chiral gold catalyst to ensure a matching double‐asymmetric setting. Other noteworthy steps are the preparation of the oxazole building block by a palladium‐catalyzed C?H activation, as well as the smooth ring‐closing alkyne metathesis of a diyne substrate bearing a propargylic leaving group, which has only little precedent.     

Oxidative Intramolecular 1,2‐Amino‐Oxygenation of Alkynes under AuI/AuIII Catalysis: Discovery of a Pyridinium‐Oxazole Dyad as an Ionic Fluorophore

Oxidative intramolecular 1,2‐amino‐oxygenation reactions, combining gold(I)/gold(III) catalysis, is reported. The reaction provides efficient access to a structurally unique ionic pyridinium‐oxazole dyad with tunable emission wavelengths. The application of these fluorophores as potential biomarkers has been investigated.     

Reactions of Cationic Gold(I) with Allenoates: Synthesis of Stable Organogold(I) Complexes and Mechanistic Investigations on Gold‐Catalyzed Cyclizations

The reaction of allenoates with cationic gold(I)—generated in situ from a phosphine gold chloride and a silver salt—formed unusual, room temperature stable vinyl gold(I) lactones under very mild conditions. The scope and limitations for the synthesis of this novel organogold complex was investigated. DFT calculations on the highest occupied molecular orbitals (HOMOs) of allenoates and the natural bond orbital (NBO) charge densities provided an explanation for the limitations. A plausible mechanism for its formation was proposed based on in situ ¹H and ³¹P NMR spectroscopic analyses. Controlled experiments for the cleavage of the gold–carbon bond by electrophiles indicated that this vinyl gold(I) complex is the likely intermediate in the gold‐catalyzed reaction of carbon–carbon multiple bonds.     

Cobalt‐Catalyzed Cross‐Dehydrogenative C(sp2)−C(sp3) Coupling of Oxazole/Thiazole with Ether or Cycloalkane

Direct C5‐alkylation of oxazole/thiazole with ether or cycloalkane has been achieved through a cobalt‐catalyzed cross‐dehydrogenative coupling (CDC) process in moderate to good yields. This transformation represents the first C(sp²)−C(sp³) cross‐coupling at the C5‐position of the oxazole/thiazole via double C−H bond cleavages. Various functional groups on oxazole/thiazole substrates, as well as water and air, are well‐tolerated with this concise and practical protocol, constituting straightforward access to heterocycles with great medicinal significance. A preliminary mechanism involving a radical process has also been proposed.     

The Photo‐Nazarov Reaction: Scope and Application

The reaction conditions and scope of the photo‐Nazarov reaction of aryl vinyl ketones were investigated. In contrast to the conventional acid‐catalyzed methods, this photolytic electrocyclization proceeds in the neutral or basic conditions. Irradiating substrates bearing various aromatic rings, acid‐sensitive groups, cyclohexenyl, cycloheptenyl, and unsaturated pyran with UV‐light (254 nm) smoothly yielded hexahydrofluorenones and related structures. This photo‐Nazarov reaction could also be applicable to the substrates carrying β‐alkyl groups on the enone, which gave corresponding polycyclic rings containing quaternary centers. These photo‐electrocyclized products may prove useful for synthesizing a variety of natural products and their derivatives. Further application of this mild photo‐Nazarov reaction in the synthesis of taiwaniaquinol B was achieved.     

Gold‐Catalyzed Oxidation/C−H Functionalization of Ynones: Efficient and Rapid Access to Functionalized Polycyclic Salicyl Ketones

An efficient strategy to construct salicyl ketones through gold‐catalyzed oxidation/C?H functionalization of ynones is reported. A variety of functionalized salicyl ketones are readily accessed by utilizing this non‐diazo approach, thus providing a viable alternative to synthetically useful salicyl ketones with a yield up to 98 %. The α‐oxo gold carbenes generated in situ through gold‐catalyzed oxidation of ynones can be trapped effectively by internal aryl and heteroaromatic groups. Electronic and steric effects were also investigated in this reaction. The anticancer activity of one salicyl ketone analogue was investigated and its cytotoxicity assays against the PC‐3 prostate cancer cell line and SKOV‐3 human ovarian carcinoma cell line yield IC₅₀ were 0.81±0.05 and 0.87±0.15 μm , respectively, demonstrating that salicyl ketone analogues showed good anticancer activity.     

Gold(I)‐Catalyzed Dearomative [2+2]‐Cycloaddition of Indoles with Activated Allenes: A Combined Experimental–Computational Study

The gold‐catalyzed synthesis of methylidene 2,3‐cyclobutane‐indoles is documented through a combined experimental/computational investigation. Besides optimizing the racemic synthesis of the tricyclic indole compounds, the enantioselective variant is presented to its full extent. In particular, the scope of the reaction encompasses both aryloxyallenes and allenamides as electrophilic partners providing high yields and excellent stereochemical controls in the desired cycloadducts. The computational (DFT) investigation has fully elucidated the reaction mechanism providing clear evidence for a two‐step reaction. Two parallel reaction pathways explain the regioisomeric products obtained under kinetic and thermodynamic conditions. In both cases, the dearomative C?C bond‐forming event turned out to be the rate‐determining step.     

Reductive Decarboxylative Alkynylation of N‐Hydroxyphthalimide Esters with Bromoalkynes

A new method for the synthesis of terminal and internal alkynes from the nickel‐catalyzed decarboxylative coupling of N‐hydroxyphthalimide esters and bromoalkynes is presented. This reductive cross‐electrophile coupling is the first to use a C(sp)−X electrophile, and appears to proceed via an alkynylnickel intermediate. The internal alkyne products are obtained in yields of 41–95 % without the need for a photocatalyst, light, or a strong oxidant. The reaction displays a broad scope of carboxylic acid and alkyne coupling partners, and can tolerate an array of functional groups, including carbamate NH, halogen, nitrile, olefin, ketone, and ester moieties. Mechanistic studies suggest that this process does not involve an alkynylmanganese reagent and instead proceeds through nickel‐mediated bond formation.     

Propargylsilanes as Reagents for Synergistic Gold(I)‐Catalyzed Propargylation of Carbonyl Compounds: Isolation and Characterization of σ‐Gold(I) Allenyl Intermediates

Reported herein is the isolation and characterization, for the first time, of a σ‐gold allenyl complex as an intermediate in gold catalysis. This intermediate was captured during the study of a novel gold(I)‐catalyzed propargylation of carbonyl compounds with propargylsilanes. Notably, the gold‐catalyzed propargylation reaction, which proceeds with aldehydes and ketones, can be driven to the formation of either homopropargyl silyl ethers or the in situ synthesis of corresponding 2‐silyl‐4,5‐dihydrofurans.     

Gold/Acid‐Co‐catalyzed Direct Microwave‐Assisted Synthesis of Fused Azaheterocycles from Propargylic Hydroperoxides

The gold–acid‐co‐catalyzed synthesis of nine series of fused azaheterocycles with structural diversity starting from the same synthons as readily available propargylic hydroperoxides and aromatic amines has been achieved. The overall tandem process consists in a gold‐catalyzed hydroperoxide rearrangement/Michael reaction followed by a final acid‐catalyzed cyclization.