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Metal-catalysed cross-couplings are a mainstay of organic synthesis and are widely used for the formation of C-C bonds, particularly in the production of unsaturated scaffolds.sup.1. However, alkyl cross-couplings using native sp.sup.3-hybridized functional groups such as alcohols remain relatively underdeveloped.sup.2. In particular, a robust and general method for the direct deoxygenative coupling of alcohols would have major implications for the field of organic synthesis. A general method for the direct deoxygenative cross-coupling of free alcohols must overcome several challenges, most notably the in situ cleavage of strong C-O bonds.sup.3, but would allow access to the vast collection of commercially available, structurally diverse alcohols as coupling partners.sup.4. We report herein a metallaphotoredox-based cross-coupling platform in which free alcohols are activated in situ by N-heterocyclic carbene salts for carbon-carbon bond formation with aryl halide coupling partners. This method is mild, robust, selective and most importantly, capable of accommodating a wide range of primary, secondary and tertiary alcohols as well as pharmaceutically relevant aryl and heteroaryl bromides and chlorides. The power of the transformation has been demonstrated in a number of complex settings, including the late-stage functionalization of Taxol and a modular synthesis of Januvia, an antidiabetic medication. This technology represents a general strategy for the merger of in situ alcohol activation with transition metal catalysis. A metallaphotoredox-based cross-coupling platform is capable of activating a wide range of free alcohols using N-heterocyclic carbene salts, cleaving C-O bonds to form free carbon radicals that are then used to form new C-C bonds., Author(s): Zhe Dong [sup.1] , David W. C. MacMillan [sup.1] Author Affiliations: (1) Merck Center for Catalysis at Princeton University, Princeton, USA Main Over the past half century, advances in [...]

Despite the widespread success of transition-metal-catalysed cross-coupling methodologies, considerable limitations still exist in reactions at sp.sup.3-hybridized carbon atoms, with most approaches relying on prefunctionalized alkylmetal or bromide coupling partners.sup.1,2. Although the use of native functional groups (for example, carboxylic acids, alkenes and alcohols) has improved the overall efficiency of such transformations by expanding the range of potential feedstocks.sup.3-5, the direct functionalization of carbon-hydrogen (C-H) bonds--the most abundant moiety in organic molecules--represents a more ideal approach to molecular construction. In recent years, an impressive range of reactions that form C(sp.sup.3)-heteroatom bonds from strong C-H bonds has been reported.sup.6,7. Additionally, valuable technologies have been developed for the formation of carbon-carbon bonds from the corresponding C(sp.sup.3)-H bonds via substrate-directed transition-metal C-H insertion.sup.8, undirected C-H insertion by captodative rhodium carbenoid complexes.sup.9, or hydrogen atom transfer from weak, hydridic C-H bonds by electrophilic open-shell species.sup.10-14. Despite these advances, a mild and general platform for the coupling of strong, neutral C(sp.sup.3)-H bonds with aryl electrophiles has not been realized. Here we describe a protocol for the direct C(sp.sup.3) arylation of a diverse set of aliphatic, C-H bond-containing organic frameworks through the combination of light-driven, polyoxometalate-facilitated hydrogen atom transfer and nickel catalysis. This dual-catalytic manifold enables the generation of carbon-centred radicals from strong, neutral C-H bonds, which thereafter act as nucleophiles in nickel-mediated cross-coupling with aryl bromides to afford C(sp.sup.3)-C(sp.sup.2) cross-coupled products. This technology enables unprecedented, single-step access to a broad array of complex, medicinally relevant molecules directly from natural products and chemical feedstocks through functionalization at sites that are unreactive under traditional methods.Direct coupling of aliphatic C-H nucleophiles to aryl electrophiles is described, through the combination of light-driven polyoxometalate hydrogen atom transfer and nickel catalysis., Author(s): Ian B. Perry [sup.1] , Thomas F. Brewer [sup.1] , Patrick J. Sarver [sup.1] , Danielle M. Schultz [sup.2] , Daniel A. DiRocco [sup.2] , David W. C. MacMillan [...]

The advent of transition-metal catalysed strategies for forming new carbon-carbon bonds has revolutionized the field of organic chemistry, enabling the efficient synthesis of ligands, materials, and biologically active molecules (1,3). In cases where a single metal fails to promote a selective or efficient transformation, the synergistic cooperation (4) of two distinct catalysts--multimetallic catalysis--can be used instead. Many important reactions rely on multimetallic catalysis (5,10), such as the Wacker oxidation of olefins (6,8) and the Sonogashira coupling of alkynes with aryl halides (9,10), but this approach has largely been limited to the use of metals with distinct reactivities, with only one metal catalyst undergoing oxidative addition (11,12). Here, we demonstrate that cooperativity between two group 10 metal catalysts--(bipyridine)nickel and (1,3-bis(diphenylphosphino)propane)palladium-enables a general cross-Ullmann reaction (the cross-coupling of two different aryl electrophiles)13-15. Our method couples aryl bromides with aryl triflates directly, eliminating the use of arylmetal reagents and avoiding the challenge of differentiating between multiple carbon-hydrogen bonds that is required for direct arylation methods (16,17). Selectivity can be achieved without an excess of either substrate and originates from the orthogonal reactivity of the two catalysts and the relative stability of the two arylmetal intermediates. While (1,3-bis(diphenylphosphino)propane)palladium reacts preferentially with aryl triflates to afford a persistent intermediate, (bipyridine)nickel reacts preferentially with aryl bromides to form a transient, reactive intermediate. Although each catalyst forms less than 5 per cent cross-coupled product in isolation, together they are able to achieve a yield of up to 94 per cent. Our results reveal a new method for the synthesis of biaryls, heteroaryls, and dienes, as well as a general mechanism for the selective transfer of ligands between two metal catalysts. We anticipate that this reaction will simplify the synthesis of pharmaceuticals, many of which are currently made with pre-formed organometallic reagents (1,3), and lead to the discovery of new multimetallic reactions., We envisaged that a general solution to the cross-Ullmann reaction could be realized through multimetallic catalysis if, first, each of the two catalysts activated only one of the two substrates [...]

Under an oxygen atmosphere, the cross-coupling of tris(fluorinated phenyl)boroxins and disulfides catalyzed by CuI/1,10-phenanthroline were smoothly achieved to produce the corresponding asymmetric fluorinated arylsulfides in good-to-excellent yields. Key words: disulfide, tris(fluorinated phenyl)boroxin, fluorinated arylsulfide, cross-coupling, cuprous iodide. On a effectue sans difficulte le couplage croisee de tris(flurophenyl)boroxines et de disulfures, sous atmosphere d'oxygene et catalyse par du CuI/phenanthroline; on a pu isoler les arylsulfures fluores asymetriques correspondants avec des rendements allant de bons a excellents. Mots-cles: disulfure, tris(flurophenyl)boroxine, arylsulfure fluore, couplage croise, iodure cuivreux. [Traduit par la Redaction], Introduction Transition-metal-catalyzed aryl carbon-sulfur formation reaction is an indispensable tool in synthetic organic chemistry. Aryl sulfides and their derivatives are a common functional group in numerous pharmaceutical and biological active [...]

Abstract: An efficient addition of arenes to allenes is developed by using a combination of gold and silver catalysts. The arene addition takes place exclusively at the terminal allenic carbon [...]

Aryl triflates are used for describing the first [alpha]-arylations of ketones. Palladium and nickel catalysts ligated by difluorphos for reactions of two classes of aryl triflate electrophiles have given rise to a broad range of [alpha]-arylations of ketones that has occurred with high enantioselectivity.

Tertiary aryl squaramides are synthesized by using copper-catalyzed C-N bond-formation with L-proline as the ligand. Symmetrical diaryl squaramides are prepared by using excess aryl bromide and unsymmetrical derivatives are prepared by sequential arylation, where the diarylated products are highly sensitive to steric effects.

The synthesis of enantiopure epoxides featuring a 4-biphenyl or terphenyl moiety by the Suzuki cross-coupling of enantiopure haloaryl glycidols obtained through Sharpless epoxidation and their derivatization into new optically pure [beta]-amino alcohols and bis-oxazolines is described. It is found that both the electron-deficient and the electron-rich boronic acids and the monosubstituted and the disubstituted aryl groups participate well in the reaction and that the conversion of the amino alcohols into second generation ligands is easier to obtain than by other synthetic methods.

Palladium-mediated reaction of heterocyclic diamines and its chemoselectivity was studied. Results found that the heterocyclic diamines were important substrates for governing the chemoselectivity of the arylamination reactions.

A phosphine-free palladium-catalyzed method is described for direct C-arylation of free (N-H)-indoles and pyrroles with iodo- and bromoarene donors. This procedure has provided a rapid entry to a wide range of C-arylated (N-H)-indoles including derivatives of tryptamine.

Endogenous activation of the aryl hydrocarbon receptor (AHR) is required for normal vascular development. This biology led us to investigate the interplay between the AHR and vascular physiology by using an in vitro model of fluid shear stress. Using this system, we show that fluid flow induces a robust AHR-mediated increase in CYP1 expression. Furthermore, we demonstrate that incubation with sheared bovine or human sera is sufficient for AHR activation, indicating that direct cellular exposure to shear stress is not required for this response. Fractionation of sera by size and density revealed the AHR-activating factor to be low-density lipoprotein (LDL). Purified LDL (0.1 mg/ml) from sheared sera induces a 6-fold increase in AHR-mediated signaling as compared with LDL purified from static sera. Similar results were obtained by exposing a purified fraction of LDL to fluid flow, suggesting that shear stress is capable of directly modifying LDL structure and/or function. In addition, we show that LDL can be converted to an AHR-activating species by conventional methods of lipoprotein modification, such as NaOCl oxidation. Finally, we demonstrate that an increased level of AHR-activating LDL is present in the sera of AHR null mice as compared with heterozygous littermates, suggesting a role for the Ahr locus in the physiological response to modified LDL in vivo. Overall, these data demonstrate a previously undescribed relationship between LDL modification and AHR biology and provide a potential explanation for the vascular abnormalities observed in AHR null mice. AHR | cyp1a1 | cyp1b1 | shear stress

Microwave-assisted, palladium-catalyzed C-N bond-forming reactions with aryl/heteroaryl nonaflates and amines. This is done by using the soluble amine bases DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) or MTBD (7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene) and ligands resulted in good to excellent yields (71-99%) of arylamines in short reaction times (1-45 min).

Palladium-catalyzed procedures for the selective monoarylation of acetonitrile and primary nitriles are achieved using alpha-silyl nitriles in the presence of ZnF2. This procedure is compatible with a variety of functional groups, including cyano, keto, nitro and ester groups, on the aryl bromide.

The palladium hydroxide on carbon efficiently catalyzes intra and intermolecular direct arylation reaction of aryl iodides and bromides, providing excellent arylation-to-hydrodehalogentation ratios with broad scope for both intra- and intermolecular arylation processes. Studies aimed at determining the nature of active catalyst indicate that an active homogenous palladium species is produced under the reaction conditions.

Four types of structurally well-defined triarylethene-based extended pi-systems are prepared rapidly on the basis of an efficient Pd-catalyzed triarylation to a vinylsilane platform. From a compound library constructed by the method, a number of fluorescent materials are found, along with fluorescent properties such as aggregation-induced enhanced emission.

1-Arylimidazol-2(H)-ones are shown to be readily lithiated, using 2 mol equiv, of n-butyllithium, on the benzene ring, ortho to the heterocycle. 1-Aryl-4,5-dihydroimidazol-2(1H)-ones also undergo metalation on the aromatic substitutuent ortho to the heterocycle, but less efficiently. 1-Aryl-3-methylimidazol-2(1H)-ones are lithiated on the heterocyclic ring and then on the benzene ring ortho to the heterocycle. No ortho-directing effect was found for 1-aryl-4,5-dihydro-3-methylimidazol-2(1H)-ones. Key words: ortho-lithation, ureas for directed ortho metalation, 1-arylimidazol-2-ones, 1-arylimidazolidin-2-ones.

An IR study, in the region of OH stretching, of a reference hydrogen-bond donor, 4-fluorophenol, hydrogen bonded to primary, secondary, and tertiary arylamines differently substituted on the ring and on the nitrogen, shows the formation of two kinds of 1:1 complexes in C[Cl.sub.4] solution: an OH *** [pi] and an OH *** N hydrogen-bonded complex. The IR method gives only access to a global complexation constant [K.sub.t]. A method is proposed for separating [K.sub.t] into a [K.sub.[pi]] component for hydrogen bonding to the [pi] system and a [K.sub.N] component for hydrogen bonding to the nitrogen atom. This method is validated by comparing the estimated [K.sub.[pi]] and [K.sub.N] values to theoretically calculated descriptors of basicity: the nitrogen lone pair orientation towards the aromatic ring, the molecular electrostatic potentials around the nitrogen and the [pi] cloud, and the enthalpy of hydrogen bonding of hydrogen fluoride with the [pi] system of selected arylamines. The main electronic and steric factors governing the competition between [pi] and N sites are analysed. The strongest [pi] and N bases among the arylamines are julolidine and Troger's base, respectively. Triphenylamine and diphenylamine, which are nitrogen Bronsted bases, become [pi] bases in hydrogen bonding. Moreover, there is no correlation between the p[K.sub.HB] and the [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] scales of basicity of arylamines. The use of the [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] scale is therefore not recommended in hydrogen-bonding studies. Key words: hydrogen bonding, arylamines, p[K.sub.HB] scale, competition of [pi] and N hydrogen-bonded sites.

The reactions of 2,6-difluorobenzonitrile with acetophenones and acetonaphthones shed light on its ambident behavior in nucleophilic aryl substitutions. The study shows that selectivity for either C- or O-arylation depends on the stereoelectronic character of the enolate, solvent and substrate. Anion polarity and steric hindrance at the carbon site favor nucleophilic attack from the oxygen site. More polar solvents also favor O-arylation. The electron-withdrawing character of the substrate's ortho function, which increases when the cyano group is replaced by a nitro group, is biased against O-arylation and favors CN and hydride displacement.

Benzenation of 4,6-di-O-acetyl-1,5-anhydro-2-deoxy-D-erythro-hex-1-en-ulose, its D-threo isomer and its 4-O-acetyl-2,6-dideoxy-L-erythro analogue in the presence of acetic acid and palladium acetate forms the corresponding mixes of phenyl C-glycosyl enones and ketones. The enones are probably formed by anti-elimination or by Pd-migration from the beta- to the alpha-face that leadsto epimerization of C-2, while the ketones are formed by solvolysis as evidenced by an increase in their realtive yield in the presence of water. Reduction of the enones yields phenyl 2-deoxy-beta-C-glycosides.

The compound MgBr2(dioxane)2 arylates NiBr2.2dme (dme = 1,2-dimethoxyethane) in tetrahydrofuran, and the addition of benzonitrile results in the organonitrile derivative cis-(Ni C6F5 2 PhCN 2). This cis geometry is confirmed by the infrared spectrum of the compound which shows an 'x-sensitive' mode of C6F5. The reaction of this organonitrile with aqueous QOH (Q = NBu4) in acetone produces the Q2(Ni C6F5 2 mu-OH)2 dimer. X-ray crystallography indicates that the dimer consists of centrosymmetric binuclear (Ni C6F5 2 mu-OH 2)2- anions and Q1+ cations.

Dialkyl oxalates have undergone selective diarylation on one of their carbonyl carbons after the treatment with arylboron reagents in the presence of a rhodium catalyst to produce the corresponding [alpha]-hydroxydiarylacetates. The arylation of benzoylformate and benzil has proceeded efficiently under similar conditions.

Trifluoroacetic acid mediates the hydroarylation of alkenes to afford dihydrocoumarins and dihydroquinolones in good yield. The intermolecular and intramolecular procedures for hydroarylation of cinnamic acids with phenols are compared.

High-yield and stepwise introduction of aryl groups into the 2,2-diamino derivative is established through an ortho-lithiation/iodization/Suzuki-Miyaura coupling protocol. The results have facilitated the preparation of a variety of 3,3-substituted 2,2-diamino-1,1-binaphthyl compounds, which are important intermediates for obtaining related ligands and organocatalysts.

An efficient Hiyama coupling reaction is developed between benzylic halide and aryltrialkoxysilane by using Pd nanoparticles. The procedure has accommodated many functional groups to produce a diverse range of diarylmethanes, which are ubiquitous units of natural products and pharmaceuticals.

The Pd-catalyzed C-N cross-coupling reactions of aryl iodides are examined and NaI is shown to have inhibitory effect on these processes. Catalyst systems based on biarylphosphine ligands are used for reacting aryl iodides with an array of primary and secondary amines in high yields.

Two different reaction pathways, the enolate arylation and the acylation of the aryl halide, is promoted by a Pd(0) catalyst starting from [beta]-(2-iodoanilino) carboxamides. The intramolecular acylation of [beta]-(2-iodoanilino) carboxamides is the first example of a nucleophilic attack of a [sigma]-arylpalladium species at the carboxamide group, a framework that is inert toward organopalladium reagents.

Sterically pressured mid- to high-valent uranium complexes with an aryloxide substituted triazacyclononane ligand scaffold are analyzed for carbon dioxide activation and transformation chemistry. The molecular structures of the synthesized uranium carbamate complexes have highlighted the different reactivities due to the steric pressure introduced by the alkyl derivatized tris(aryloxide) triazacyclononane ligand.

The first example of achieving Hiyama couplings of aryl arenesulfonates is described. The desired C-C bond formation has proceeded under mild conditions with good functional group tolerance.

Several unique features are identified for the catalytic oxidative biaryl coupling (OBC) with 1,5-diaza-cis-decalin copper complexes. The results have highlighted the opportunities to achieve selective modulation of oxidase vs oxygenase activity in aerobic oxidation reactions.

Rhodium-catalyzed aryl- and alkylthiolation reaction of fluorobenzene with disulfides is applied on the single bond metathesis of CF and SS bonds. The studies have shown that the rhodium-catalyzed method has a notable mode of CF activation by the transition metal catalyst and has offered a broad scope for the manipulation of organosulfur compounds.

The palladium-catalyzed 1,2-addition reactions of potassium aryl- and alkenyltrifluoroborates to aldehydes via use of the thioether-imidazolinium carbene ligand are described. The process tolerated a diverse range of potassium trifluoroborate salts and aldehydes to yield a variety of carbinol derivatives.

The three-component coupling reaction between phenylacetylene, carbon dioxide, and 3-bromo-1-phenyl-1-propyne was explored to develop a simple synthesis method for arylnaphthalene lignan lactones as valuable natural products. The level of regioselectivity for obtained products with promising anticancer and antiviral properties were enhanced by tuning the electronic properties.

The development of an efficient method for the synthesis of primary arylamines from aryl halides using amidine hydrochlorides as the ammonia surrogates is reported. The method provides an important motif for synthesis of natural products and pharmaceutical and medicinal compounds as well as polymers and materials.

A highly efficient DDQ-mediated oxidative cross-coupling reaction between diarylpropargylic [sp.sup.3] C-H and active methylenic [sp.sup.3] C-H is reported. The reaction provides a direct method for the propargylation of 1,3-dicarbonyl compounds to synthesize corresponding products.

The development of a novel, convenient, and efficient method for selective synthesis of spirocycle, polycycle, and di- and tetrahydronaphthalene systems is reported. The synthesis involved aryl-substitution of propargylic alcohols by Fe[Cl.sub.3]- or TsOH-catalyzed multiple activations of unsaturated C-C bonds and C-H bonds.

A new, convenient method is described for the syntheses of 2-substituted benzimidazole and benzothizole. The method has used [H.sub.2][O.sub.2]/CAN system and 1,2-phenylenediamines and 2-aminothiophenol and wide variety of aryl aldehydes as starting material.

Chiral phosphoramidite ligands and [[RhCl[(coe).sub.]].sub.2] were used to construct highly enantioselective catalytic intramolecular ortho-alkylation of aromatic imines containing alkenyl groups tethered at the meta position relative to the imine directing group. This stereoselective catalytic transformation provides access to a range of chiral indanes, dihydrobenzofurans, and dihyropyrroloindoles with different substitution patterns and could be used for asymmetric synthesis of a range of biologically active compounds.

The development of a convenient and efficient method to the arylation of tertiary silanes under mild conditions is reported. The application of silylation to the total synthesis of a TAC-101 analogue, a synthetic retinobenzoic acid with selective binding affinity for retinoic acid receptor (RAR)-[alpha] is also described.

The superacid-promoted ionization reactions of [alpha]-hydroxy and [alpha]-ketoamides that leads to varied aryl-substituted oxyindole products are reported. The results provide a new route to aryl-substituted oxyindoles from reactions of [alpha]-hydroxy and [alpha]-ketoamides with an arene in superacidic C[F.sub.3]S[O.sub.3]H and mechanism for conversions of dicationic superelectrophiles.

The annulation of in situ generated arynes by 2-haloarenecarboxaldehydes in the presence of a palladium catalyst was used to prepare fluoren-9-ones and its derivatives. The method provides a route to fluoren-9-ones that avoids the use of harsh oxidizing agents and strong mineral acids and show tolerance of benzdaldehydes containing multiple halogens.

(Arylimido)vanadium(V) triisopropoxides are prepared by the reaction of VO[(O[super i]Pr).sub.3] with the aryl isocyanates without solvent. The one-dimensional linear polymer complex or the one-dimensional zigzag one through [mu]-oxo-bridging is formed in a solid state with the bimetallic (arylimido)vanadium(V) complex.

The first Pd-catalyzed direct arylation via C-OH bond activation of tautomerizable heteorcycles with aryl boronic acids is developed by using phosphonium salts. This direct arylation via C-OH bond activation using phosphonium salts is applicable to other transition-metal-catalyzed cross-coupling reactions, such as the Sonogashira and the Heck reaction.

Medicinally important 3-alkoxy-3-aryloxindoles are prepared by the rapid microwave-promoted palladium-catalyzed intramolecular enolate arylation of mandelate-derived anilides. The results have highlighted the tolerance of the arylation protocol toward heteroatom substituents upon the enolate and the convergent nature of the synthesis coupled with the potential for asymmetric variants has made them a convenient approach to this class of molecules.

Both antipodes of 2-azido-1-arylethanols are prepared with excellent optical purity via enzymatic reduction of the corresponding [alpha]-azidoacetophenone derivatives catalyzed by a recombinant carbonyl reductase from Candida magnoliae (CMCR) or an alcohol dehydrogenase from Saccharomyces cerevisiae. (S)-2-Azido-1-(p-chlorophenyl)ethanols have reacted with alkynes by using click chemistry to produce high yields of optically pure triazole-containing [beta]-adrenergic receptor blocker analogues with potential biological activity.

The nucleophilic aromatic substitution of some activated aryl or heteroaryl halides is performed in ionic liquid solution, by using the 1-butyl-3-methylimidazolium azide as a nucleophile. The studies have shown that in some cases it is possible to obtain aromatic or heteroaromatic azide derivatives in good yields by means of [S.sub.N]Ar reaction by using [bmim][[N.sub.3]] as the nucleophile.

The discovery of several eicosanoid molecules such as 5,6-dihydroxyeicosatetraenoic acid isomers (5,6-DiHETEs) as endogenous activators of the aryl hydrocarbon receptor (AHR) is reported. The results reveal the connection between AHR activation and inflammatory signaling molecules produced by the 5-lipoxygenase pathway.

The carbon-fluorine bond formation from two high-valent aryl palladium fluoride complexes is demonstrated. The data obtained on reductive elimination provide insight into carbon-fluorine bond formation from arylpalladium complexes.

The chemoenzymatic syntheses and detailed kinetic analysis of a library of phenyl [beta]-glycosides of xylogluco-oligosaccharides is reported. The newly developed chromogenic substrates might find wide range of application in the discovery, screening, and detailed kinetic analysis of new xyloglucan-active enzymes.

Organo-SOMO catalysis is used for achieving the first asymmetric [alpha]-vinylation of aldehydes by using vinyl trifluoroborate salts and a commercial amine catalyst. These mild catalytic conditions have allowed the production of [alpha]-formyl, [alpha]-vinyl, methine stereogenic centers without olefin transposition or subsequent erosion in enantiopurity.