Palladium‐Catalyzed Cross‐Coupling Reaction Using Arylgermanium Sesquioxide

Powdery reagents obtained by complete alkaline hydrolysis of arylgermanium trichlorides were found to undergo the palladium‐catalyzed cross‐coupling reaction with aryl bromides and iodides in good yields. The reaction is performed in an aqueous medium taking sodium hydroxide as an activator. Some base‐sensitive functionalities such as acetyl and trifluoromethyl groups survived the reaction.     

Facile Palladium‐Catalyzed Synthesis of 3‐Arylpyrazolo[1,5‐a]pyrimidines

An efficient palladium‐catalyzed synthesis of 3‐arylpyrazolo[1,5‐a]pyrimidines has been investigated. The key step in the synthesis is a Suzuki biaryl coupling of 3‐bromo‐2,5‐dimethyl‐7‐aminopyrazolo[1,5‐a]pyrimidines with arylboronic acids to provide 3‐arylpyrazolo[1,5‐a]pyrimidines in moderate to good yield. The synthetic utility of this methodology has been demonstrated by a concise and convergent synthesis of R121920, a potent CRHR₁ antagonist recently undergoing clinical evaluations.     

High-Pressure Diels-Alder Reaction: Preparation of [2.2]Paracyclophane Derivatives

High-pressure Diels-Alder cycloaddition reactions of 5-ethenyl[2.2]indeno-paracyclophane (1) with 1,4-benzoquinone (2), N-phenylmaleimide (3), and 2-inden-1-one (4) have been studied. Attempts to convert the cycloadducts into the corresponding aromatic helicenophanes failed. All new compounds were characterized by extensive nuclear magnetic resonance (NMR) investigations.     

Scope and Limitations of Palladium‐Catalyzed Cross‐Coupling Reactions with Organogold Compounds

Five different alkenylgold(I) phosphane complexes were prepared and then investigated in [1,1′‐bis(diphenylphosphino)ferrocene]palladium(II) dichloride‐catalyzed cross‐coupling reactions with different aryl halides, heterocyclic halides, an alkenyl halide, an alkynyl halide, allylic substrates, benzyl bromide and an acid chloride. With regard to the halides, the iodides were highly reactive, bromides or chlorides gave significantly reduced yields or failed, allylic acetates failed, too. The cross‐coupling partners contained a number of different functional groups, while free carboxylic acids did not deliver cross‐coupling products and o,o‐disubstituted arenes failed as well, a broad range of other functional groups like nitro groups, nitrile groups, ester groups, α,β‐unsaturated ester groups and lactones, aldehydes, alkoxy groups, pyridyl groups, thienyl groups, unprotected phenols and anilines, even aryl azides were tolerated. The structures of one alkenylgold(I) species and of four of the cross‐coupling products were proved by crystal structure analyses.     

2,3‐Disubstituted Benzo[b]thiophenes from Diarylalkynes via Electrophilic Addition‐Cyclization and Palladium‐Catalyzed Cross‐Coupling

Diarylalkynes are readily transformed in 3‐chlorobenzo[b]thiophenes in a two‐step electrophilic addition‐cyclization procedure that runs highly efficiently in solution or in the solid phase. The heteroaromatic carbon‐chlorine bond participates in palladium‐catalyzed Suzuki–Miyaura or Buchwald–Hartwig cross‐couplings to give, in a single step, 2,3‐disubstituted derivatives of pharmacological relevance .     

Calixarene‐Derived Mono‐Iminophosphoranes: Highly Efficient Ligands for Palladium‐ and Nickel‐Catalysed Cross‐Coupling

The first mono‐iminophosphoranes based on a calix[4]arene skeleton have been synthesised and tested in the arylation of aryl bromides and aryl chlorides. Combining these ligands with [Pd(OAc)₂] or [Ni(cod)₂] resulted in highly active Suzuki–Miyaura and Kumada–Tamao–Corriu cross‐coupling catalysts, respectively. TOFs up to ca. 4×10⁵ mol(ArBr)⋅mol(M)⁻¹⋅h⁻¹ were obtained in each case. The remarkable activities observed probably arise from the ligands’ ability to form complexes with cavity‐entrapped “MArX” moieties (endo‐complexes), their highly crowded metal environment favouring formation of mono‐ligated intermediates over that of less reactive bis‐ligated ones. Possible supramolecular interactions within the cavity involving the receptor wall and the aromatic substrate may also significantly influence the reaction rates, notably by increasing the proportion of endo‐complexes.     

Nanocrystalline Magnesium Oxide‐Stabilized Palladium(0): An Efficient and Reusable Catalyst for Suzuki and Stille Cross‐Coupling of Aryl Halides

A nanocrystalline magnesium oxide‐stabilized palladium(0) catalyst is prepared by counterion stabilization of PdCl₄²⁻ with nanocrystalline MgO followed by reduction. This ligand‐free heterogeneous nanocrystalline MgO‐stabilized nanopalladium [NAP Mg Pd(0)] catalyst using the basic MgO in place of basic ligands exhibits excellent activity in Suzuki and Stille cross‐coupling of haloarenes (chloro, bromo and iodo) to afford the unsymmetrical biaryls. The catalyst is quantitatively recovered by simple filtration and reused for four cycles with almost consistent activity.     

Highly Efficient Suzuki Cross‐Coupling Catalyzed by Palladium/Phosphine‐Imidazolium Carbene System

Novel phosphine‐imidazolium salts 2 have been synthesized and successfully used in palladium‐catalyzed Suzuki cross‐coupling. A combination of 0.05 mol % of [Pd(η‐C₃H₅)Cl]₂ and 0.1 mol % of 2b in the presence of 2 equivs. of K₃PO₄ as base provided coupling products in excellent yields in the reaction of aryl bromides and chlorides with aryl boronic acids.     

Chemoenzymatic Synthesis of Sterically Hindered Biaryls by Suzuki Coupling and Vanadium Chloroperoxidase Catalyzed Halogenations

Halogenated biaryls are vital structural skeletons in bioactive products. In this study, an effective chemoenzymatic halogenation by vanadium-dependent chloroperoxidase from Camponotus inaequalis (CiVCPO) enabled the transformation of freely rotating biaryl bonds to sterically hindered axis. The yields were up to 84 % for the tribrominated biaryl products and up to 65 % when isolated. Furthermore, a one-pot, two-step chemoenzymatic strategy by incorporating transition metal catalyzed Suzuki coupling and the chemoenzymatic halogenation in aqueous phase were described. This strategy demonstrates a simplified one-pot reaction sequence with organometallic and biocatalytic procedures under economical and environmentally beneficial conditions that may inspire further research on synthesis of sterically hindered biaryls.     

The Synthesis of Pseudo‐Geminal,Pseudo‐Ortho and Ortho Hydroxy‐oxazolinyl[2.2]paracyclophanes for Use as Ligands in Asymmetric Catalysis

Synthetic routes to pseudo‐geminal, pseudo‐ortho and ortho hydroxy‐oxazolinyl[2.2]paracyclophanes (and the diastereoisomers of each) for use as N,O ligands in asymmetric catalysis have been devised. The substitution pattern was found to have a strong effect on the rate and enantioselectivity of the formed catalyst in the addition of diethylzinc to benzaldehyde.     

Resorcin[4]arene‐Derived Mono‐ and Diphosphines in Suzuki Cross‐Coupling

Three resorcin[4]arene cavitands ( 1 – 3 ) having either one or two resorcinolic C‐2 atoms substituted by a  CH₂PPh₂ podand arm were assessed in the Suzuki arylation of aryl bromides with phenylboronic acid. Using P:Pd ratios of 2:1 and operating in dioxane at 100 °C with a catalyst loading of 0.001 mol% resulted in highly efficient catalytic systems. For example, TOFs up to 34570 mol(converted ArBr)⋅mol(Pd)⁻¹⋅h⁻¹ were obtained with the proximally‐disubstituted cavitand 3 when using 4‐bromotoluene as substrate. The performance was shown to vary in the following order: monophosphine 1 <diphosphine 2 <diphosphine 3 (where 2 is the distally disubstituted cavitand). A comparison of the catalytic properties of monophosphine‐cavitand 1 with those of benzyldiphenylphosphine and o‐anisylmethyldiphenyl phosphine suggests that 1 functions as a hemilabile phosphine, the oxygen atoms close to the phosphorus atom behaving as donors able to temporarily increase the electron density on the metal and/or favour the formation of mono‐ligand Pd(0) species.     

Efficient Synthesis of Fine Chemicals and Organic Building Blocks Applying Palladium‐Catalyzed Coupling Reactions

The importance of selected palladium‐catalyzed coupling reactions for fine chemical synthesis is shown. Special focus is made on the refinement of aryl halides. Apart from known industrial processes the potential use of recently developed palladium catalysts from our group is demonstrated.     

Regioselective Copper‐Catalyzed Oxidative Cross‐Coupling of Imidazo[1,2‐a]pyridines with Methyl Ketones: An Efficient Route for Synthesis of 1,2‐Diketones

An efficient copper‐catalyzed oxidative coupling of imidazo[1,2‐a]pyridines with methyl ketones to directly generate structurally sophisticated 1,2‐dicarbonyl imidazo[1,2‐a]pyridine derivatives under oxidative conditions is described. The reaction proceeds in good yields using the environmental friendly molecular oxygen as the oxidant. ¹⁸O‐Labelling experiments unambiguously established that the oxygen of the dicarbonyl products originated from oxygen rather than from water.

     

Efficient Synthesis of Chiral Isoquinoline and Pyrido[1,2‐b]‐isoquinoline Derivatives via Intramolecular Heck Reactions

The palladium(0)‐catalyzed reaction of derivatives of γ‐amino‐α,β‐unsaturated esters bearing an N‐(2‐iodobenzoyl) substituent results in an intramolecular Heck reaction, the outcome of which depends on the structure of the substrate as well as on the experimental conditions. The methodology developed has been applied to the efficient syntheses of chiral isoquinoline and pyrido[1,2‐b]–isoquinoline derivatives.     

Efficient Synthesis of Substituted Selenophenes Based on the First Palladium(0)‐Catalyzed Cross‐Coupling Reactions of Tetrabromoselenophene

Regioselective Suzuki cross‐coupling reactions of tetrabromoselenophene allow a convenient synthesis of aryl‐substituted selenophenes. High yields were obtained using a novel biaryl‐monophosphine ligand. The first tetra(1‐alkynyl)selenophene was prepared in one step by a Sonogashira reaction of tetrabromoselenophene.     

An Electron‐Deficient Diene as Ligand for Palladium‐Catalyzed Cross‐Coupling Reactions: An Efficient Alkylation of Aryl Iodides by Primary and Secondary Alkylzinc Reagents

An electron‐deficient diene, L₁ , was found to be an effective ligand in facilitating palladium‐catalyzed Negishi couplings involving primary and secondary alkylzinc reagents. The reactions took place readily at 60 °C in THF with 5 mol% of a catalyst generated in situ from bis(acetonitrile)palladium dichloride [PdCl₂(MeCN)₂] and L₁ , and functional groups such as chloro, bromo, etc. attached to phenyl ring as well as β‐H atoms adjacent to the reaction site were well tolerated. The problematic isomerizations in secondary alkyzinc reagents involved in the reactions reported in the literature were also observed in our system when isopropylzinc chloride was employed alone as the nucleophile. However, the isomerization was significantly suppressed when i‐Pr₂Zn was utilized in the presence of L₁ .     

Samarium Powder‐Catalyzed Palladium‐Free and Ligand‐Free Sonogashira Coupling Reactions

A study of samarium powder‐catalyzed cross‐coupling reactions of aryl halides with terminal alkynes is described. The couplings performed in the polyethylene glycol PEG‐600 provided the corresponding coupling products in good yields. The first example of palladium‐free, copper‐free and amine‐free catalytic system for Sonogashira couplings is presented in the absence of ligand.     

Efficient Catalyst for Both Suzuki and Heck Cross‐Coupling Reactions: Synthesis and Catalytic Behaviour of Geometry‐ Constrained Iminopyridylpalladium Chlorides

A series of geometry‐constrained iminopyridyl‐palladium chlorides were synthesized and characterized. These phosphine‐free palladium complexes were explored for their catalytic activities in both Suzuki and Heck cross‐coupling reactions, achieving turnover numbers as high as 10⁶ towards various aryl bromides, even those containing various functionalities. In addition, the influence of substituents with steric and electronic factors was reflected by the differences observed in their activities.

     

Studies on Palladium‐Catalyzed Synthesis of Dihydrocycloocta‐ [b]indoles and their Thermal Reactivities with Maleimide or Maleic Anhydride

A palladium(0)‐catalyzed reaction of 2‐allyl‐3‐indolyl boronates/propargylic carbonates was observed to afford dihydrocycloocta[b]indoles highly efficiently via carbon‐carbon coupling, [1,5]‐hydrogen migration involving dearomatization, and electrocyclization involving rearomatization. Their thermal reactions with the addition of dienophiles involving eletrocyclization and [4+2] cycloaddition have been studied.