Intermolecular Hydroarylation Research Articles

Different reactivity of phosphorylallenes under the action of Brønsted or Lewis acids: a crucial role of involvement of the P=O group in intra- or intermolecular interactions at the formation of cationic intermediates.

3-Methylbuta-1,2-dien-1-ylphosphonic acid derivatives (phosphorylallenes) [X2(O=)P–CR=C=CMe2, X = Cl, OMe, NR2, or SAr] undergo intramolecular cyclization into the corresponding 1,2-oxaphospholium ions in the Brønsted superacid TfOH. These cations have been thoroughly studied by means of NMR spectroscopy. The hydrolysis of superacidic solutions of these species afforded cyclic phosphonic acids and other phosphorus-containing compounds. Contrary to Brønsted acids, 3-methylbuta-1,2-dien-1-ylphosphonic dichloride [Cl2(O=)P–HC=C=CMe2] reacted with the Lewis acid AlCl3 in an intermolecular way forming noncyclic intermediates, which were investigated by NMR spectroscopy and DFT calculations. Hydrolysis of these species resulted in the formation of phosphoryl-substituted allyl alcohols and 1,3-butadienes. A strong coordination of the oxygen of the P=O group with AlCl3 prevented the formation of cyclic 1,2-oxaphospholium ions and played a crucial role in the different reactivity of such phosphorylallenes under the action of Brønsted or Lewis acids. Apart from that, the reaction of dichlorophosphorylallenes with arenes and AlCl3 led to products of hydroarylation of the allene system, phosphoryl-substituted alkenes and/or indanes. This is the first example of a Lewis acid-promoted intermolecular hydroarylation of allenes bearing electron-withdrawing substituents. Plausible reaction mechanisms have been proposed on the basis of the investigated reactions, and NMR analysis and DFT studies of the intermediate cationic species.

Total Synthesis of the Tetrasubstituted Furan Fatty Acid Metabolite CeDFP via Au-Catalyzed Intermolecular Alkyne Hydroarylation.

The first total synthesis of the tetrasubstituted furan fatty acid (FFA) metabolite 5-[(1 E)-2-carboxyethenyl]-3,4-dimethyl-2-furanpentanoic acid (CeDFP) is reported. CeDFP is a FFA metabolite isolated from shark livers and is related to the known FFA metabolites CMPF and CMPentylF. Key elements of the synthetic route to CeDFP include an iodine-promoted 5- endo- dig cyclization of a 1,2-alkyne diol, a methyllithium-mediated insertion of the C3-methyl group, and a Au(I)-catalyzed intermolecular hydroarylation to introduce the unsaturated ester.

(P,C) Cyclometalated Gold(III) Complexes: Highly Active Catalysts for the Hydroarylation of Alkynes.

The first catalytic application of well-defined (P,C) cyclometalated gold(III) complexes is reported. The bench-stable bis(trifluoroacetyl) complexes 2 a,b perform very well in the intermolecular hydroarylation of alkynes. The reaction is broad in scope, it proceeds within few hours at 25 °C at catalytic loadings of 0.1-5 mol %. The electron-rich arene adds across the C≡C bond with complete regio- and stereo-selectivity. The significance of well-defined gold(III) complexes and ligand design are highlighted in a powerful but challenging catalytic transformation.

(P,C) Cyclometalated Gold(III) Complexes: Highly Active Catalysts for the Hydroarylation of Alkynes

AbstractThe first catalytic application of well‐defined (P,C) cyclometalated gold(III) complexes is reported. The bench‐stable bis(trifluoroacetyl) complexes 2 a,b perform very well in the intermolecular hydroarylation of alkynes. The reaction is broad in scope, it proceeds within few hours at 25 °C at catalytic loadings of 0.1–5 mol %. The electron‐rich arene adds across the C≡C bond with complete regio‐ and stereo‐selectivity. The significance of well‐defined gold(III) complexes and ligand design are highlighted in a powerful but challenging catalytic transformation.

Computational Study on Gold-Catalyzed Cascade Reactions of 1,4-Diynes and Pyrroles: Mechanism, Regioselectivity, Role of Catalyst, and Effects of Substituent and Solvent

This study is devoted to a theoretical investigation of the mechanism, regioselectivity, role of catalyst, and effect of substituent and solvent in the Au-catalyzed cascade reaction between 1,4-diynes and pyrroles. Density functional theory (DFT) calculations indicate that this reaction comprises four principal stages: (1) formation of different intermediates through the first intermolecular hydroarylation, (2) 1,3-H transfer to give the enyne intermediates, (3) a second intermolecular hydroarylation, and (4) a second proton transfer along with Au(I) catalyst regeneration and final product formation. In addition, the computational results suggest that the first regioselectivity is determined by the electronic effects of the reagents. However, the torsional strains within the transition structures (intramolecular cyclization) and electronic effects of enyne intermediates would account for the second regioselectivity. A global reactivity index (GRI) analysis for different gold catalysts (namely, IPrAu+, PPh...

Regioselective Domino Synthesis of 2-Alkylflavans via Hidden Brønsted Acid Catalysis

A range of alkyl-substituted flavans, which are important structural elements in natural products and pharmaceutical molecules, were prepared by successive hidden Brønsted acid catalyzed domino reaction, intermolecular hydroarylation, and intramolecular hydroalkoxylation. 1,1-Disubstituted allenes were activated under mild acidic AgOTf/t-BuCl condition to initiate the regioselective Friedel–Crafts reaction with phenol derivatives, and the consecutive reaction triggered by the 6-endocyclization led to the formation of a new type of 2-alkylflavan. Mechanistic study of the reaction intermediates and control experiments support the catalytic pathway and advantage of hidden Brønsted acid catalysis.

Advances in Transition-Metal-Catalysed Alkyne Hydroarylations.

We present herein a personal account of our achievements in the development of novel catalytic systems based on late-transition-metal complexes for the hydroarylation of alkynes. In particular, our targets were intermolecular hydroarylation reactions with arene or heteroarene substrates devoid of directing groups. We have shown that complexes of palladium, platinum or gold with N-heterocyclic carbene (NHC) ligands can be particularly useful catalysts for this reaction; the NHC ligand imparts greater stability to the complex and renders the catalytic system more productive. Furthermore, we have identified promoters and reaction media that allow to significantly improve the catalytic activity under mild conditions, to control the reaction chemoselectivity and to steer it towards more complex products; thus making this reaction considerably more attractive for the synthetic chemist.

ChemInform Abstract: Synthesis of Multiple‐Substituted Pyrroles via Gold(I)‐Catalyzed Hydroamination/Cyclization Cascade.

A gold-catalyzed cascade hydroamination/cyclization reaction of α-amino ketones with alkynes to form substituted pyrroles has been developed. The method offers several advantages such as high regioselectivity with the tested cases, wide functional group tolerance, and easily accessible starting materials. The synthetic utility of the obtained pyrrole products was demonstrated by their efficient transformations to 2-vinylated pyrroles via gold-catalyzed intermolecular hydroarylation.

Synthesis of Multiple-Substituted Pyrroles via Gold(I)-Catalyzed Hydroamination/Cyclization Cascade.

A gold-catalyzed cascade hydroamination/cyclization reaction of α-amino ketones with alkynes to form substituted pyrroles has been developed. The method offers several advantages such as high regioselectivity with the tested cases, wide functional group tolerance, and easily accessible starting materials. The synthetic utility of the obtained pyrrole products was demonstrated by their efficient transformations to 2-vinylated pyrroles via gold-catalyzed intermolecular hydroarylation.

ChemInform Abstract: Hydroarylation of Arynes Catalyzed by Silver for Biaryl Synthesis.

AbstractA new biaryl synthesis via silver‐catalyzed intra‐ and intermolecular hydroarylation of acyclic arynes with unactivated arenes is developed.

ChemInform Abstract: Rhodium‐Catalyzed Intermolecular Hydroarylation of Internal Alkynes with N‐1‐Phenylbenzotriazoles.

AbstractAttempts towards performing the reaction using 1‐phenyl‐indole or 1‐phenyl‐1,3‐benzodiazole instead of the 1‐phenyl‐1,2,3‐benzotriazole derivatives fail.

Rhodium-catalyzed intermolecular hydroarylation of internal alkynes with N-1-phenylbenzotriazoles

A rhodium-catalyzed intermolecular hydroarylation of internal alkynes with N-1-phenylbenzotriazoles via C-H bond activation is described. This transformation offers an alternative method for the hydroarylation of internal alkynes with high stereoselectivity. The reaction mechanism was discussed according to the deuterium-labeling experiments.

Alkyne hydroarylation with Au N-heterocyclic carbene catalysts.

Mono- and dinuclear gold complexes with N-heterocyclic carbene (NHC) ligands have been employed as catalysts in the intermolecular hydroarylation of alkynes with simple unfunctionalised arenes. Both mono- and dinuclear gold(III) complexes were able to catalyze the reaction; however, the best results were obtained with the mononuclear gold(I) complex IPrAuCl. This complex, activated with one equivalent of silver tetrafluoroborate, exhibited under acidic conditions at room temperature much higher catalytic activity and selectivity compared to more commonly employed palladium(II) catalysts. Moreover, the complex was active, albeit to a minor extent, even under neutral conditions, and exhibited lower activity but higher selectivity compared to the previously published complex AuCl(PPh3). Preliminary results on intramolecular hydroarylations using this catalytic system indicate, however, that alkyne hydration by traces of water may become a serious competing reaction.

Heterobimetallic Pd–Sn catalysis: highly selective intermolecular hydroarylation of α-methyl substituted aryl alkenes

The heterobimetallic catalyst [Pd(COD)Cl–SnCl3] efficiently promotes the intermolecular hydroarylation of α-methyl substituted arenes (otherwise known to be dimerized/polymerized in presence of Lewis Acids) with indoles and other O-, S-heteroarenes leading to Markovnikov adducts. The reaction takes place under air and moisture insensitive condition.

Ruthenium‐Catalyzed Hydroarylation of Methylenecyclopropanes through CH Bond Cleavage: Scope and Mechanism

Intermolecular hydroarylation reactions of highly strained methylenecyclopropanes 2-phenylmethylenecyclopropane (1), 2,2-diphenylmethylenecyclopropane (2), methylenespiropentane (3), bicyclopropylidene (4), (dicyclopropylmethylene)cyclopropane (5), and benzhydrylidenecyclopropane (6) through C-H bond functionalization of 2-phenylpyridine (7 a) and other arenes with directing groups were studied. The reaction was very sensitive to the substitution on the methylenecyclopropanes. Although these transformations involved (cyclopropylcarbinyl)-metal intermediates, substrates 1 and 4 furnished anti-Markovnikov hydroarylation products with complete conservation of all cyclopropane rings in 11-93 % yield, whereas starting materials 3 and 5 were inert toward hydroarylation. Methylenecyclopropane 6 formed the products of formal hydroarylation reactions of the longest distal C-C bond in the methylenecyclopropane moiety in high yield, and hydrocarbon 2 afforded mixtures of hydroarylated products in low yields with a predominance of compounds that retained the cyclopropane unit. As byproducts, Diels-Alder cycloadducts and self-reorganization products were obtained in several cases from substrates 1-3 and 5. The structures of the most important new products have been unambiguously determined by X-ray diffraction analyses. On the basis of the results of hydroarylation experiments with isotopically labeled 7 a-[D(5)], a plausible mechanistic rationale and a catalytic cycle for these unusual ruthenium-catalyzed hydroarylation reactions have been proposed. Arene-tethered ruthenium-phosphane complex 53, either isolated from the reaction mixture or independently prepared, did not show any catalytic activity.

Regioselective synthesis of 3,3-bis(indolyl)propanoic acid derivatives by iron(III)-catalyzed hydroarylation of propynoic acid derivatives with indoles

Intermolecular hydroarylation of propynoic acid and its esters with indoles proceeded efficiently in acetic acid under a catalytic system of FeCl 3/3AgOTf and afforded the corresponding 3,3-bis(indol-3yl)propanoic acids and their esters in high yields. In the case of 2-methylindole, 3-indolylacrylic acid and its ethyl ester were obtained in high yields. This iron-catalyzed hydroarylation showed a high regioselectivity at the 3-position of indoles and a high utility for the synthesis of bis(indol-3-yl) compounds, which are important for biological and pharmaceutical fields.

ChemInform Abstract: 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 (r(2) = 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.

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 (r(2) = 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.

Synthesis of Functionalized Chromanes via a Formal [3+3]Cycloaddition of Allene Sulfonamides to Phenols

The Bronsted acid catalyzed formal [3 + 3] cycloaddition reaction of allene sulfonamides 1 with phenols 2 provides functionalized chromanes. This formal [3 + 3] cycloaddition reaction is proposed to proceed via a stepwise process involving intermolecular hydroarylation followed by intramolecular cyclization.

ChemInform Abstract: Gold(I)‐Catalyzed Intermolecular Hydroarylation of Alkenes with Indoles under Thermal and Microwave‐Assisted Conditions.

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