Enantioselective Palladium‐Catalyzed Oxidative β,β‐Fluoroarylation of α,β‐Unsaturated Carbonyl Derivatives

The site‐selective palladium‐catalyzed three‐component coupling of deactivated alkenes, arylboronic acids, and N‐fluorobenzenesulfonimide is disclosed herein. The developed methodology establishes a general, modular, and step‐economical approach to the stereoselective β‐fluorination of α,β‐unsaturated systems.     

Catalytic Asymmetric Oxidative γ‐Coupling of α,β‐Unsaturated Aldehydes with Air as the Terminal Oxidant

A novel concept for catalytic asymmetric coupling reactions is presented. Merging organocatalysis with single‐electron oxidation by using a catalytic amount of a copper(II) salt and air as the terminal oxidant, we have developed a highly stereoselective carbon–carbon oxidative coupling reaction of α,β‐unsaturated aldehydes. The concept relies on the generation of a dienamine intermediate, which is oxidized to an open‐shell activated species that undergoes highly selective γ‐homo‐ and γ‐heterocoupling reactions. In the majority of examples presented, only a single stereoisomer was formed.     

Carbon Magnetic Resonance Spectra of α, β, γ, δ- and α, β, α′, β′- Unsaturated Ketones

Carbon-13 spectra of a series of 26 unsaturated ketones (ortho- and para-cyclo-hexadienones and corresponding open-chain analogues) have been measured by Fourier-transform. Pulse spectroscopy. A complete analysis has been achieved by means of double resonance experiments using noise-modulated and coherent off-resonance proton irradiation and with the aid of non-decoupled spectra. Chemical shifts are interpreted in terms of charge distribution in the dienone system and of methyl substituent effects. Carbon chemical shifts were also obtained for O-protonated ortho- and para-cyclohexadienones. One-bond and long-range carbon-proton and carbon-fluorine spin coupling constants are reported for several compounds.     

β‐to‐β 2,5‐Pyrrolylene‐Linked Cyclic Porphyrin Oligomers

β‐to‐β 2,5‐Pyrrolylene linked cyclic porphyrin oligomers have been synthesized by Suzuki–Miyaura coupling of 2,5‐diborylpyrrole and 3,7‐dibromoporphyrin. The cyclic porphyrin oligomers exhibit roughly coplanar structures, strong excitonic coupling, small electrochemical HOMO–LUMO gaps, and ultrafast excitation energy transfer between the neighboring porphyrins via the pyrrolylene bridge.     

Palladium‐Catalyzed Carbonylative α‐Arylation to β‐Ketonitriles

A carbonylative α‐arylation process employing unactivated nitriles for the first time is described. The reaction tolerates a range of (hetero)aryl iodides and several nitrile coupling partners. No prefunctionalization of the nitriles is necessary and the resulting β‐ketonitriles are obtained in good to excellent yields. The methodology also allows for a convenient ¹³C‐labelling of the generated carbonyl moiety.     

Catalytic Asymmetric Electrochemical α‐Arylation of Cyclic β‐Ketocarbonyls with Anodic Benzyne Intermediates

Asymmetric catalysis with benzyne remains elusive because of the highly fleeting and nonpolar nature of benzyne intermediates. Reported herein is an electrochemical approach for the oxidative generation of benzynes (cyclohexyne) and its successful merging with chiral primary aminocatalysis, formulating the first catalytic asymmetric enamine–benzyne (cyclohexyne) coupling reaction. Cobalt acetate was identified to stabilize the in situ generated arynes and facilitate its coupling with an enamine. This catalytic enamine‐benzyne protocol provides a concise method for the construction of diverse α‐aryl (α‐cyclohexenyl) quaternary carbon stereogenic centers with good stereoselectivities.     

Synthesis and Antitumor Activity Evaluation of γ-Monofluorinated and γ,γ-Difluorinated Goniothalamin Analogues

A series of novel γ,γ‐difluorinated Goniothalamin analogues 4a – 4i and 6a – 6i were synthesized. The key steps included the construction of C‐5 stereocenter adjacent to gem‐difluoromethylene group by way of lipase AK catalyzed kinetic resolution, the introduction of aryl group via Stille coupling, and lactonization by 1,5‐oxidative cyclization. These γ,γ‐difluorinated Goniothalamin analogues 4a – 4i and their enantiomers 6a – 6i , together with several corresponding γ‐monofluorinated Goniothalamin analogues were biologically evaluated against four different cancer cell lines. Compound 7h showed a nearly equivalent potency as the parent (R)‐Goniothalamin in the micromolar range. The different fluorine effects between fluoromethylene and gem‐difluoromethylene on antitumor activity were discussed through the analysis of bioassay data.     

Transforming Olefins into γ,δ‐Unsaturated Nitriles through Copper Catalysis

We have developed a strategy to transform olefins into homoallylic nitriles through a mechanism that combines copper catalysis with alkyl nitrile radicals. The radicals are easily generated from alkyl nitriles in the presence of the mild oxidant di‐tert ‐butyl peroxide. This cross‐dehydrogenative coupling between simple olefins and alkylnitriles bears advantages over the conventional use of halides and toxic cyanide reagents. With this method, we showcase the facile synthesis of a flavoring agent, a natural product, and a polymer precursor from simple olefins.     

Oxidative β‐Csp3−H Functionalization of tBuOH: A Selective Radical/Radical Cross‐Coupling Access to β‐Hydroxy Thioethers

An oxidative β‐Csp³?H functionalization of tert‐butanol (tBuOH) for the construction of C?S bonds through an iodine‐catalyzed Csp³?H/S?H coupling was successfully achieved. Different kinds of mercaptans were shown to be good coupling partners, affording the desired products in good yields. This protocol not only offers a novel method for the synthesis of β‐hydroxy thioethers, but also provides an effective strategy for selective radical/radical cross‐coupling.     

Palladium‐Catalyzed Insertion of α‐Diazoesters into Vinyl Halides To Generate α,β‐Unsaturated γ‐Amino Esters

As easy as 1, 2, 3 : A palladium‐catalyzed three‐component coupling generates α,β‐unsaturated γ‐amino acids in a single step (see scheme). The reaction is believed to involve migration of a vinyl substituent to a highly electrophilic palladium carbene. Unlike previous synthetic approaches, this synthesis provides access to γ‐amino acids with non‐natural side chains.

     

Palladium‐catalyzed decarboxylative coupling of α,β‐unsaturated carboxylic acids with aryl tosylates

We report a general method for selective cross‐coupling of α,β‐unsaturated carboxylic acids with aryl tosylates enabled by versatile Pd(II) complexes. This method features the general cross‐coupling of ubiquitous α,β‐unsaturated carboxylic acids by decarboxylation. The transformation is characterized by its operational simplicity, the use of inexpensive, air‐stable Pd(II) catalysts, scalability and wide substrate scope. The reaction proceeds with high trans selectivity to furnish valuable (E)‐1,2‐diarylethenes.     

Transition‐Metal‐Free Coupling of Alkynes with α‐Bromo Carbonyl Compounds: An Efficient Approach towards β,γ‐Alkynoates and Allenoates

A direct transition‐metal‐free coupling between alkynes and α‐bromo carbonyl compounds has been developed with ultraviolet (UV) light in aqueous media. This method represents a facile approach to synthetically useful β,γ‐alkynyl esters and amides stereoselectively from two readily available starting materials. As an example of the synthetic application of the products, the alkynyl esters were readily converted into allenoates.     

N‐Heterocyclic Carbene Catalyzed Oxidative Coupling of Alkenes/ α‐Bromoacetophenones with Aldehydes: A Facile Entry to α,β‐Epoxy Ketones

A novel, N‐heterocyclic carbene (NHC) catalyzed direct oxidative coupling of styrenes with aldehydes has been described for the synthesis of α,β‐epoxy ketones in good yields. This unprecedented regioselective oxidative coupling employs NBS/DBU/DMSO (DBU=1,8‐diazabicyclo [5.4. 0] undec‐7‐ene, DMSO=dimethylsulfoxide, NBS=N‐bromosuccinimide) as an oxidative system at ambient conditions. Additionally, first NHC‐catalyzed Darzens reaction of α‐bromoketones and aldehydes under mild reaction conditions has also been described. Interestingly, mechanistic studies have revealed the preferred reactivity of NHC with alkene/α‐bromoketone rather than aldehydes, thus proceeding via the ketodeoxy Breslow intermediate.     

Controlled Heterocyclization/Cross‐Coupling Domino Reaction of β,γ‐Allendiols and α‐Allenic Esters: Method and Mechanistic Insight for the Preparation of Functionalized Buta‐1,3‐dienyl Dihydropyrans

Starting from β,γ‐allendiols and α‐allenic acetates, a chemo‐ and regiocontrolled palladium‐catalyzed methodology has provided access to enantiopure 3,6‐dihydropyrans that bear a buta‐1,3‐dienyl moiety. Thus, it has been demonstrated for the first time that the preparation of six‐membered heterocycles through cross‐coupling reactions of two different allenes can be accomplished. These heterocyclization/cross‐coupling reactions have been developed experimentally and their mechanisms have additionally been investigated by a computational study.     

Decarbonylative Radical Coupling of α‐Aminoacyl Tellurides: Single‐Step Preparation of γ‐Amino and α,β‐Diamino Acids and Rapid Synthesis of Gabapentin and Manzacidin A

A new radical‐based coupling method has been developed for the single‐step generation of various γ‐amino acids and α,β‐diamino acids from α‐aminoacyl tellurides. Upon activation by Et₃B and O₂ at ambient temperature, α‐aminoacyl tellurides were readily converted into α‐amino carbon radicals through facile decarbonylation, which then reacted intermolecularly with acrylates or glyoxylic oxime ethers. This mild and powerful method was effectively incorporated into expeditious synthetic routes to the pharmaceutical agent gabapentin and the natural product (?)‐manzacidin A.     

Ligand‐Controlled α‐ and β‐Arylation of Acyclic N‐Boc Amines

The palladium‐catalyzed ligand‐controlled arylation of α‐zincated acyclic amines, obtained by directed α‐lithiation and transmetalation, is described. Whereas PtBu₃ gave rise to α‐arylated Boc‐protected amines, more flexible N‐phenylazole‐based phosphine ligands induced major β‐arylation through migrative cross‐coupling.     

First Stereoselective Total Synthesis of a Dimeric Naphthoquinonopyrano‐γ‐lactone: (+)‐γ‐Actinorhodin

We have accomplished the first total synthesis of an isomerically pure naphthoquinonopyrano‐γ‐lactone dimer, γ‐actinorhodin, in eleven steps. Two steps exploit pairs of peri‐MeO groups as unusual selectivity controls. The respective MeO groups convey the steric bulk of a bromo or iodo substituent located ortho to one MeO group as steric hindrance into the vicinity of the second MeO group. This relay effect was indispensable for exerting regiocontrol in an aromatic bromination and diastereocontrol in an oxa‐Pictet–Spengler cyclization. The absolute configuration of our target compound was established in an asymmetric Sharpless dihydroxylation of a β,γ‐unsaturated ester, which was synthesized in a Heck coupling of a bromoiodonaphthalene with ethyl vinylacetate. The dihydroxylation provided the γ‐hydroxylactone moiety of the bromonaphthalene that was used as the substrate in the oxa‐Pictet–Spengler cyclization. Dimerization to the core of γ‐actinorhodin occurred by two Suzuki couplings.     

Synthesis of α‐fluoro‐β‐trifluoromethyl alka‐2,4‐dienes

The palladium/copper(I) iodide cocatalyzed coupling reaction of (Z)‐α‐fluoro‐β‐trifluoromethylstannanes ( 1 ) with vinyl iodides ( 2 ) has been explored giving substituted α‐fluoro‐β‐trifluoromethyl dienes ( 3 ) in 33–95% yields. In studies we have conducted so far, a larger number of the configurations of the products remained unchanged (cases 3a, 3e–h ), though in several cases (cases 3b–d ) two configurations of the products were obtained. © 2007 Wiley Periodicals, Inc. Heteroatom Chem 18:208–211, 2007; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20284     

Indium Tribromide Catalyzed Coupling Reaction of Enol Ethers with Silyl Ketene Imines toward the Synthesis of β,γ‐Unsaturated Nitriles

Herein, a coupling reaction of enol ethers with silyl ketene imines in the presence of catalytic amounts of InBr₃ and Me₃SiBr is described. Kinetic studies have revealed that an indium catalyst and Me₃SiBr accelerated the coupling process and the regeneration of the catalyst, respectively. Various types of enol ethers and silyl ketene imines are applicable. In addition, a formal synthesis of verapamil was achieved by using this novel coupling reaction.     

Synthesis of poly(γ-methoxypropylmethylsilylene) and poly(γ-methoxypropylmethylsilylene-co-di-n-hexylsilylene)

The synthesis of γ;-methoxypropylmethyldichlorosilane, and its subsequent polymerization and copolymerization with di;-n;-hexyldichlorosilane through the reductive coupling with sodium has been accomplished. The resulting polymers contain methyl ether side groups that allow further synthetic transformations on the polysilane backbone. For poly (γ;-methoxypropylmethylsilylene) these groups impart solubility characteristics different than typical alkyl and aryl substituted polysilanes. These new polymers and copolymers have been characterized by GPC and ¹H-, ¹³C-, and ²⁹Si-NMR. © 1994 John Wiley & Sons, Inc.