Synthesis of multisubstituted halo-olefins via Pd-catalyzed cross-coupling reactions : applications in nucleoside chemistry

The enzyme S-adenosyl-L-homocysteine (AdoHey) hydrolase effects hydrolytic cleavage of AdoHcy to adenosine (Ado) and L-homocysteine (Hcy). The cellular levels of AdoHcy and Hcy are critical because AdoHcy is a potent feedback inhibitor of crucial transmethylation enzymes. Also, elevated plasma levels of Hcy in humans have been shown to be a risk factor in coronary artery disease. On the basis of the previous finding that AdoHcy hydrolase is able to add the enzyme-sequestered water molecule across the 5',6'-double bond of (halo or dihalohomovinyl)-adenosines causing covalent binding inhibition, we designed and synthesized AdoHcy analogues with the 5',6'-olefin motif incorporated in place of the carbon-5' and sulfur atoms. From the available synthetic methods we chose two independent approaches: the first approach was based on the construction of a new C5'- C6' double bond via metathesis reactions, and the second approach was based on the formation of a new C6'-C7' single bond via Pd-catalyzed cross-couplings. Cross-metathesis of the suitably protected 5'-deoxy-5'-methyleneadenosine with racemic 2-amino-5-hexenoate in the presence of Hoveyda-Grubb's catalyst followed by standard deprotection afforded the desired analogue as 5'E isomer of the inseparable mixture of 9'RIS diastereomers. Metathesis of chiral homoallylglycine [(2S)-amino-5-hexenoate] produced AdoHcy analogue with established stereochemistry E at C5'atom and S at C9' atom. The 5'-bromovinyl analogue was synthesized using the brominationdehydrobromination strategy with pyridinium tribromide and DBU. Since literature reports on the Pd-catalyzed monoalkylation of dihaloalkenes (Csp2-Csp3 coupling) were scarce, we were prompted to undertake model studies on Pdcatalyzed coupling between vinyl dihalides and alkyl organometallics. The 1-fluoro-1- haloalkenes were found to undergo Negishi couplings with alkylzinc bromides to give multisubstituted fluoroalkenes. The alkylation was trans-selective affording pure Zfluoroalkenes. The highest yields were obtained with PdCl 2(dppb) catalyst, but the best stereochemical outcome was obtained with less reactive Pd(PPh3)4 . Couplings of 1,1- dichloro-and 1,1-dibromoalkenes with organozinc reagents resulted in the formation of monocoupled 1-halovinyl product.

The syntheses and characterization of nickel complexes; investigation of Ni(dppp)2 and [NiX(dppp)n]x, potentially catalytically active nickel(0)/(I) species for cross-coupling reactions

This thesis describes an investigation in which we compare Ni(0), Ni(I) and Ni(II) complexes containing 1,3-bis(diphenylphosphino)propane (dppp) as a phosphine ligand for their abilities to effect three types of cross-coupling reactions: Buchwald-Hartwig Amination, Heck-Mizoroki, and Suzuki-Miyaura cross-coupling reactions with different types of substrates. The Ni(0) complex Ni(dppp)2 is known and we have synthesized it via a new procedure involving zinc reduction of the known NiCl2(dppp) in the presence of an excess of dppp. The Ni(0) complex was characterized by NMR spectroscopy and X-ray crystallography. Since Ni(I) complexes of dppp seem unknown, we have synthesized what at this stage appear to be NiXdpppn/[NiX(dppp)n]x (X = Cl, Br, I; n = 1,2, x = 1, 2) by comproportionation of molar equivalents of Ni(dppp)2 and NiX2dppp, X= Cl, Br, I.

Rapid, selective, and reversible Nitroxide Radical Coupling (NRC) reactions at amibient temperature

High activation of polystyrene with bromine end groups (PSTY-Br) to their incipient radicals occurred in the presence of Cu(I)Br, Me6TREN, and DMSO solvent. These radicals were then trapped by nitroxide species leading to coupling reactions between PSTY-Br and nitroxides that were ultrafast and selective in the presence of a diverse range of functional groups. The nitroxide radical coupling (NRC) reactions have the attributes of a “click” reaction with near quantitative yields of product formed, but through the reversibility of this reaction, it has the added advantage of permitting the exchange of chemical functionality on macromolecules. Conditions were chosen to facilitate the disproportionation of Cu(I)Br to the highly activating nascent Cu(0) and deactivating Cu(II)Br2 in the presence of DMSO solvent and Me6TREN ligand. NRC at room temperature gave near quantitative yields of macromolecular coupling of low molecular weight polystyrene with bromine chain-ends (PSTY-Br) and nitroxides in under 7 min even in the presence of functional groups (e.g., −≡, −OH, −COOH, −NH2, =O). Utilization of the reversibility of the NRC reaction at elevated temperatures allowed the exchange of chain-end groups with a variety of functional nitroxide derivatives. The robustness and orthogonality of this NRC reaction were further demonstrated using the Cu-catalyzed azide/alkyne “click” (CuAAC) reactions, in which yields greater than 95% were observed for coupling between PSTY-N3 and a PSTY chain first trapped with an alkyne functional TEMPO (PSTY-TEMPO-≡).

Copper nanoparticles on graphene support: An efficient photocatalyst for coupling of nitroaromatics in visible light

Copper is a low-cost plasmonic metal. Efficient photocatalysts of copper nanoparticles on graphene support are successfully developed for controllably catalyzing the coupling reactions of aromatic nitro compounds to the corresponding azoxy or azo compounds under visible-light irradiation. The coupling of nitrobenzene produces azoxybenzene with a yield of 90 % at 60 °C, but azobenzene with a yield of 96 % at 90 °C. When irradiated with natural sunlight (mean light intensity of 0.044 W cm−2) at about 35 °C, 70 % of the nitrobenzene is converted and 57 % of the product is azobenzene. The electrons of the copper nanoparticles gain the energy of the incident light through a localized surface plasmon resonance effect and photoexcitation of the bound electrons. The excited energetic electrons at the surface of the copper nanoparticles facilitate the cleavage of the NO bonds in the aromatic nitro compounds. Hence, the catalyzed coupling reaction can proceed under light irradiation and moderate conditions. This study provides a green photocatalytic route for the production of azo compounds and highlights a potential application for graphene.

Palladium Catalyzed Coupling of Tosylhydrazones with Aryl and Heteroaryl Halides in the Absence of External Ligands: Synthesis of Substituted Olefins

Palladium catalyzed cross-coupling reaction of hydrazones with aryl halides in the absence of external ligand is reported. The versatility of this coupling reaction is demonstrated in showcasing the selectivity of coupling reaction in the presence of hydroxyl and amine functional groups. This method allows synthesizing a variety of heterocyclic compounds, which are difficult to access from other traditional methods and are not synthesized by employing similar coupling reactions. Application of the present methodology is validated in tandem reaction of ketones to the corresponding substituted olefins in a single pot experiment.

A chemoselective alpha-aminoxylation of aryl ketones: a cross dehydrogenative coupling reaction catalysed by Bu4NI

Tetrabutyl ammonium iodide (TBAI) catalyzed alpha-aminoxylation of ketones using aq. TBHP as an oxidant has been accomplished. We have shown that the CDC (cross dehydrogenative coupling) reactions of ketones with N-hydroxyimidates such as N-hydroxysuccinimide (NHSI), N-hydroxyphthalimide (NHPI), N-hydroxybenzotriazole (HOBt) and 1-hydroxy-7-azabenzotriazole (HOAt) lead to the corresponding oxygenated products in good to moderate yields. The application of this method has been demonstrated by transforming a few coupled products into synthetically useful intermediates and products.

Impact of carbon dioxide pressurization on liquid phase organic reactions: A case study on Heck and Diels-Alder reactions

Heck coupling reactions of methyl acrylate with various aryl bromides have been investigated using a Pd/TPP catalyst in toluene under pressurized CO2 conditions up to 13 MPa. Although CO2 is not a reactant, the pressurization of the reaction liquid phase with CO2 has positive and negative impacts on the rate of Heck coupling depending on the structures of the substrates examined. In the case of either 2-bromoacetophenone or 2-bromocinnamate, the conversion has a maximum at a CO2 pressure of about 3 MPa; for the former, it is much larger by a factor of 3 compared with that under ambient pressure. For 2-bromobenzene, in contrast, the conversion is minimized at a similar CO2 pressure, being half compared with that at ambient pressure

Impact of Carbon Dioxide Pressurization on Liquid Phase Organic Reactions: A Case Study on Heck and Diels–Alder Reactions

Heck coupling reactions of methyl acrylate with various aryl bromides have been investigated using a Pd/TPP catalyst in toluene under pressurized CO2 conditions up to 13 MPa. Although CO2 is not a reactant, the pressurization of the reaction liquid phase with CO2 has positive and negative impacts on the rate of Heck coupling depending on the structures of the substrates examined. In the case of either 2-bromoacetophenone or 2-bromocinnamate, the conversion has a maximum at a CO2 pressure of about 3 MPa;

Vilsmeier-Haack reactions of 2-arylamino-3-acetyl-5,6-dihydro-4H-pyrans toward the synthesis of highly substituted pyridin-2(1H)-ones

A facile and efficient one-pot synthesis of highly substituted pyridin-2(IH)-ones was developed via Vilsmeier-Haack reactions of readily available enaminones, 2-arylamino-3-acetyl-5,6-dihydro-4H-pyrans, and a mechanism involving sequential ring-opening, haloformylation, and intramolecular nucleophilic cyclization reactions is proposed.

PEG-supported dipyridyl ligand for palladium-catalyzed Suzuki and Suzuki-type reactions in PEG and aqueous media

An air- and water-stable PEG-supported bidentate nitrogen ligand is prepared and its applications in the palladium-catalyzed Suzuki reaction of aryl halides with arylboronic acids in PEG and Suzuki-type reaction of aryl halides with sodium tetraphenylborate in aqueous media are reported. The homogeneous catalyst system is environmentally friendly and offers the advantages of high activity, reusability and easy separation.

Application of ionic liquids in organic reactions

Room-temperature ionic liquids are good solvents for a wide of organic, inorganic and organometallic compounds. Typically consisting of nitrogen-containing organic cations and inorganic anions, they are easy to recycle, nonflammable, and have no detectable vapor pressure. More recently, ionic liquids have been found to be excellent solvents for a number of chemical reactions, e. g. hydrogenation, alkylation, epoxidation, Heck-vinylation, Suzuki cross-coupling reactions and enzyme catalyzed organic reactions. This paper focuses on the recent development of using ionic liquids as solvents for transition metal and enzyme catalyzed reactions.

Chain growth mechanism in Fischer-Tropsch synthesis: A DFT study of C-C coupling over Ru, Fe, Rh, and Re surfaces

A quantitative approach is used to understand the chain growth mechanism in FT synthesis on the Ru, Fe, Rh, and Re surfaces. The C-C coupling reactions are extensively calculated on the stepped metal surfaces. Combining the coupling barriers and reactant stabilities, we investigate the reaction rates of all possible C, + C-1 coupling pathways on the metal surfaces. It is found that (i) all the transition-state structures are similar on these surfaces, while some coupling barriers are very different; (ii) the dominant chain growth pathways on these surfaces are different: C + CH and CH + CH on Rh and Ru surfaces, C + CH3 on Fe surface, and C + CH on Re surface. The common features of the major coupling reactions together with those on the Co surface are also discussed.

Preparation of nanoparticulate metal catalysts in porous supports using an ionic liquid route; hydrogenation and C-C coupling

Aerogels containing palladium metal nanoparticles were prepared using an ionic liquid route and tested for activity towards hydrogenation and Heck C-C coupling reactions. (C) 2003 Elsevier B.V. All rights reserved.

Structure-reactivity Correlations in the catalytic coupling of ethyne over novel bimetallic Pd/Sn catalysts

The structure, thermal stability, and catalytic behavior of a novel highly dispersed silica-supported Pd/Sn catalyst prepared by an organometallic route have been examined by X-ray photoelectron, X-ray diffraction, and X-ray absorption, fine structure spectroscopies, the latter two measurements being carried outwith an in situ reaction cell. Additional reactor measurements were performed on a more Sn-rich catalyst and on a pure Pd catalyst. Varying the temperature of reduction induced large variations in catalytic performance toward ethyne-coupling reactions. These changes are understandable in terms of the destruction of SnO2-like structures surrounding the Pd core, yielding a skin of metallic Sn which subsequently undergoes intermixing with Pd. The overall thermal and catalytic behavior of these highly dispersed materials accords well with the analogous single-crystal model system.

Convergence of products from Povarov and von Miller reactions: approaches to helquinoline

Yttrium triflate or triflic acid catalysed Povarov reaction of methyl anthranilate with ethyl vinyl ether, both as aldehyde surrogate and as alkene, gave the desired 2-methyl-4-ethoxytetrahydroquinoline diastereoisomers as the major products along with four component coupling von Miller adducts. A proton NMR-study, using yttrium triflate as catalyst, revealed that the cis-diastereoisomers were the initial major products in both the Povarov and von Miller reactions but that these isomerised to the trans-diastereoisomers under the reaction conditions. Two distinct pathways for forming von Miller adducts were uncovered with the initial Povarov products being converted to von Miller adducts under the reaction conditions. Replacement of the 4-ethoxy with a 4-methoxy group under acidic conditions gave predominantly the trans-diastereoisomer, which was subsequently converted to a cis/trans mixture of the tetrahydroquinoline antibiotic helquinoline. It was also possible to convert the von Miller products to Povarov products under acidic conditions