One-pot sequential four-component coupling via Cp*RuCl-catalyzed cyclotrimerization and Suzuki-Miyaura coupling

The catalytic intermolecular cyclotrimerization of alkynylboronates, propargyl alcohols, and terminal alkynes was accomplished by means of the ruthenium catalysis and the temporary tethering approach with the C-B-O linkage to give rise to highly substituted arylboronates with excellent selectivity. The resultant arylboronates were further converted to highly substituted biaryls via the Suzuki-Miyaura coupling with various aryl iodides using Pd₂(dba)₃/PCy₃ as a catalyst precursor in aqueous toluene. As a consequence, the four-component coupling approach to highly substituted biaryls was successfully established by combining these two operations into a sequential one-pot process.     

Ring‐Opening Lithiation–Borylation of 2‐Trifluoromethyl Oxirane: A Route to Versatile Tertiary Trifluoromethyl Boronic Esters

Stereogenic trifluoromethyl‐substituted carbon centers are highly sought‐after moieties in pharmaceutical and agrochemical discovery. Here, we show that lithiation–borylation reactions of 2‐trifluoromethyl oxirane give densely functionalized and highly versatile trifluoromethyl‐substituted α‐tertiary boronic esters. The intermediate boronate complexes undergo the desired 1,2‐rearrangement of the carbon‐based group with complete retentive stereospecificity, a process that was only observed in non‐polar solvents in the presence of TESOTf. Although the trifluoromethyl group adversely affects subsequent transformations of the α‐boryl group, Zweifel olefinations provide trifluoromethyl‐bearing quaternary stereocenters substituted with alkenes, alkynes and ketones.     

A New General Synthesis of 2,2-Dialkyl-2,3-dihydro-4H-pyran-4-ones and Their Application for the in situ Preparation of Electron-Rich Dienes in Carbonyl-Alkyne Exchange Reactions with Acetylenes

The substituted 2,2-dialkyl-2,3-dihydro-4H-pyran-4-ones of type II and III have been prepared by acid-catalyzed cyclization of the corresponding substituted acetylenic ketones I in good to excellent yields (Scheme 1). These 2,2-dialkyl-2,3-dihydro-4H-pyran-4-ones II and III have been used for the in situ preparation of highly reactive dienes of type IV – VI (Scheme 2) in carbonyl-alkyne exchange reactions with electron-poor alkynes VII to yield the highly substituted aromatic compounds VIII and IX. These reactions proceed in good yields and with excellent degree of regioselectivity. Aryl-substituted 2,2-dialkyl-2,3-dihydro-4H-pyran-4-ones III (R¹ = Ar) subsequently yield highly substituted biaryls. Reaction mechanisms are presented for the formation of the 2,2-dialkyl-2,3-dihydro-4H-pyran-4-ones as well as for the carbonyl-alkyne exchange reactions with electron-poor acetylenes.     

Synthesis of 2(3H)-furanones via electrophilic cyclization

A variety of highly substituted 2(3H)-furanones are readily prepared from 3-alkynoate esters and the corresponding acids via electrophilic cyclization. Successful electrophiles in this process include I2, ICl, and PhSeCl. This highly efficient process proceeds under mild conditions, tolerates various functional groups, and generally provides substituted 2(3H)-furanones in good to excellent yields.     

Observation of neighboring ortho-hydroxyl group participation in organocatalytic asymmetric sequential Michael-lactonization reactions: synthesis of highly substituted chiral spirodihydrocoumarins

A general approach to asymmetric synthesis of highly substituted spirodihydrocoumarins with a quaternary stereocenter was achieved through neighboring ortho-hydroxyl group induced sequential Michael-lactonization reactions on 2-(2-nitrovinyl)phenols with alkyl cyclopentanone-2-carboxylates in the presence of a catalytic amount of quinine-NH-thiourea followed by p-TSA.     

Asymmetric Conjugate Addition of Benzofuran‐2‐ones to Alkyl 2‐Phthalimidoacrylates: Modeling Structure–Stereoselectivity Relationships with Steric and Electronic Parameters

A highly predictive model to correlate the steric and electronic parameters of tertiary amine thiourea catalysts with the stereoselectivity of Michael reactions of 3‐substituted benzofuranones and alkyl 2‐phthalimidoacrylates is described. As predicted, new 3,5‐bis(trifluoromethyl)benzyl‐ and methyl‐substituted tertiary amine thioureas turned out to be highly suitable catalysts for this reaction and enabled the synthesis of enantioenriched α‐amino acid derivatives with 1,3‐nonadjacent stereogenic centers.     

Asymmetric synthesis of dihydroindanes by convergent alkoxide-directed metallacycle-mediated bond formation

A convergent synthesis of highly substituted and stereodefined dihydroindanes is described from alkoxide-directed Ti-mediated cross-coupling of internal alkynes with substituted 4-hydroxy-1,6-enynes (substrates that derive from 2-directional functionalization of readily available epoxy alcohol derivatives). In addition to describing a new and highly stereoselective approach to bimolecular [2 + 2 + 2] annulation that delivers products not available with other methods in this area of chemical reactivity, evidence is provided to support annulation by way of regioselective alkyne-alkyne coupling, followed by metal-centered [4 + 2] rather than stepwise alkene insertion and reductive elimination. Overall, the reaction proceeds with exquisite stereochemical control and defines a convenient, convergent, and enantiospecific entry to fused carbocycles of great potential value in target-oriented synthesis and medicinal chemistry.     

Benign and highly efficient synthesis of quinolines from 2-aminoarylketone or 2-aminoarylaldehyde and carbonyl compounds mediated by hydrochloric acid in water

An environmentally friendly and highly efficient procedure for the preparation of substituted quinoline derivatives was developed by a simple Friedländer reaction of 2-aminoarylketone or 2-aminoarylaldehyde with carbonyl compounds in the presence of hydrochloric acid utilizing water as the solvent.     

Metalated 2-Alkenylsulfoximides in Asymmetric Synthesis: Diastereoselective Preparation of Highly Substituted Pyrrolidine Derivatives

Thanks to a productive interaction between reagent and substrate control, 2-alkenylsulfoximides 1 react to provide highly substituted pyrrolidine derivatives 2 enantiomerically pure and with defined absolute configuration at the newly formed stereogenic centers. Tol=tolyl, BOC=tert-butoxycarbonyl.     

One-pot synthetic routes to multiply substituted indene derivatives by hydrolysis of zirconocene-mediated intermolecular coupling reactions of aromatic ketones and alkynes

Two one-pot multicomponent synthetic methods for highly substituted indenes are described. The intermolecular coupling of aromatic ketones with alkynes on low-valent zirconocene species generates oxazirconacyclopentenes, which upon hydrolysis with 20% HCl for 3 h afforded indene derivatives in good to excellent yields. Similarly, the pair-selective coupling of two identical or different alkynes bearing at least one aromatic substituent formed zirconacyclopentadienes. Quenching of the reaction mixture with concentrated H(2)SO(4) also results in the formation of highly substituted indenes in high yields.     

Ruthenium-catalyzed regioselective oxidative coupling of aromatic and heteroaromatic esters with alkenes under an open atmosphere

A ruthenium-catalyzed oxidative coupling of substituted aromatic and heteroaromatic esters with alkenes in the presence of catalytic amounts of AgSbF(6) and Cu(OAc)(2) to provide highly substituted alkene derivatives in good to excellent yields under an open atmosphere is described.     

Cu(OTf)2-catalyzed synthesis of highly substituted 1-methoxy imidazoles via (3 + 2) cycloaddition between imino carbenoids and nitriles

A Cu(OTf)₂-catalyzed simple synthetic approach for highly substituted 1-alkoxy imidazole has been described. This protocol involves (3 + 2) cycloaddition of oximino carbenoids with organo nitriles. This method has wide substrate scope and tolerates alkyl, aryl, substituted aryl, vinyl, and ester nitriles.     

Microwave-assisted synthesis of highly substituted aminomethylated 2-pyridones

By employing microwave-assisted organic synthesis (MAOS) efficient conditions to introduce aminomethylene substituents in highly substituted bicyclic 2-pyridones have been established. Primary amino methylene substituents were introduced via a cyanodehalogenation followed by a borane dimethyl sulfide reduction of the afforded nitrile. In both of these transformations, microwave irradiation proved to be superior to traditional conditions and the primary amines were obtained in good overall yields (55-58% over three steps). To incorporate tertiary aminomethylene substituents in the 2-pyridone framework, a microwave-assisted Mannich reaction using preformed iminium salts proved to be effective. Thus highly substituted 2-pyridones were obtained in 48-93% yields.     

Regiochemical studies of the ring expansion reactions of hydroxy azides with cyclic ketones

The regiochemistry of ring expansions of 2-substituted cyclic ketones using 1,2-azidoethanol and 1,3-azidopropanol was examined. It was determined that the reactions of ketones with an adjacent methyl or ethyl group are generally unselective, but that bulkier substituents lead to preferential migration of the more highly substituted carbon. In addition, it was found that ketones bearing inductively electron-withdrawing substituents (OMe, Ph, Br) undergo selective migration of the less highly substituted carbon. For some substrates, alternative reaction pathways were also identified.     

Asymmetric synthesis of highly substituted azapolycyclic compounds via 2-alkenyl sulfoximines: potential scaffolds for peptide mimetics

The application of metalated, enantiomerically pure acyclic and cyclic 2-alkenyl sulfoximines for the synthesis of highly substituted aza(poly)cyclic ring systems is described. The method relies on a one-pot combination of a reagent-controlled allyl transfer reaction to alpha- or beta-amino aldehydes, followed by a Michael-type cyclization of the intermediate vinyl sulfoximines generated in the first step. The sulfur-free target compounds are preferentially obtained by samarium iodide treatment of the sulfonimidoyl substituted heterocycles. In addition to this methodological work, initial results on the biological activity of selected examples are reported. Furthermore, a concept for the transformation of peptidic lead structures into non-peptide mimetics is described, and the relevance of the new approach to highly substituted azaheterocycles in this context is discussed.     

A simple, modular synthesis of substituted pyridines

A simple, modular method to prepare highly substituted pyridines is disclosed. The method employs a cascade reaction comprising (1) a novel N-iminative, Cu-catalyzed cross-coupling of alkenylboronic acids at the N-O bond of alpha,beta-unsaturated ketoxime O-pentafluorobenzoates, (2) electrocyclization of the resulting 3-azatriene, and (3) air oxidation affording highly substituted pyridines in moderate to excellent isolated yields (43-91%). Starting materials are readily available, and functional group tolerance is very good.     

Enantioselective Synthesis of Tetrahydroquinolines by Borrowing Hydrogen Methodology: Cooperative Catalysis by an Achiral Iridacycle and a Chiral Phosphoric Acid

We report herein the highly enantioselective synthesis of 2‐substituted tetrahydroquinolines through borrowing hydrogen, a process recognized for its environmentally benign and atom‐economical nature. The use of an achiral iridacycle complex in combination with a chiral phosphoric acid as catalysts was the key to the development of this highly efficient and enantioselective transformation.     

A highly regio- and chemoselective addition of carbon nucleophiles to pyrimidinones. A new route to C4 elaborated Biginelli compounds

Ethyl 6-methyl-pyrimidine-2-one-5-carboxylates react with C-nucleophiles in a diversity oriented synthetic sequence to afford C4 substituted congeners of medicinally potent Biginelli dihydropyrimidinones, in a highly regioselective manner.     

Synthesis of substituted naphthalenes by the palladium-catalyzed annulation of internal alkynes

[reaction: see text] A variety of substituted naphthalenes have been prepared by the palladium-catalyzed carboannulation of internal alkynes. This method (1) forms two new carbon-carbon bonds in a single step, (2) accommodates a variety of functional groups, and (3) affords excellent yields of highly substituted naphthalenes.     

Total syntheses of graphisin A and sydowinin B

Efficient syntheses of the highly substituted benzophenone graphisin A and the xanthone sydowinin B are described. Key steps involve aryl anion addition to substituted benzaldehyde derivatives, subsequent methyl ester installation, and dehydrative cyclization. Oxidation of graphisin A led to a spirodienone derived from a highly substituted benzoquinone intermediate.