Palladium-catalyzed asymmetric hydrogenation of functionalized ketones

A novel catalytic system for asymmetric hydrogenation of functionalized ketones has been developed using a Pd/bisphosphine complex as the catalyst in 2,2,2-trifluoroethanol. The reaction exhibits high enantioselectivity, and up to 92.2% ee was obtained.

Synthesis and reactivity of α-diazo-β-keto sulfoxides: scope and synthetic potential

The research described in this thesis focuses on the design and synthesis of stable α-diazosulfoxides and investigation of their reactivity under a variety of conditions (transition-metal catalysis, thermal, photochemical and microwave) with a particular emphasis on the synthesis of novel heterocyclic compounds with potential biological activity. The exclusive reaction pathway for these α-diazosulfoxides was found to be hetero-Wolff rearrangement to give α-oxosulfine intermediates. In the first chapter, a literature review of sulfines is presented, including a discussion of naturally occurring sulfines, and an overview of the synthesis and reactivity of sulfines. The potential of sulfines in organic synthesis and recent developments in particular are highlighted. The second chapter discusses the synthesis and reactivity of α-diazosulfoxides, building on earlier results in this research group. The synthesis of lactone-based α-diazosulfoxides and, for the first time, ketone-based benzofused and monocyclic α-diazosulfoxides is described. The reactivity of these α-diazosulfoxides is then explored under a variety of conditions, such as transition-metal catalysis, photochemical and microwave, generating labile α-oxosulfine intermediates, which are trapped using amines and dienes, in addition to the spontaneous reaction pathways which occur with α-oxosulfines in the absence of a trap. A new reaction pathway was explored with the lactone based α-oxosulfines, involving reaction with amines to generate novel 3-aminofuran-2(5H)-ones via carbophilic attack, in very good yields. The reactivity of ketone-based α-diazosulfoxides was explored for the first time, and once again, pseudo-Wolff rearrangement to the α-oxosulfines was the exclusive reaction pathway observed. The intermediacy of the α-oxosulfines was confirmed by trapping as cycloadducts, with the stereochemical features dependant on the reaction conditions. In the absence of a diene trap, a number of reaction fates from the α-oxosulfines were observed, including complete sulfinyl extrusion to give indanones, sulfur extrusion to give indanediones, and, to a lesser extent, dimerisation. The indanediones were characterised by trapping as quinoxalines, to enable full characterisation. One of the overriding outcomes of this thesis was the provision of new insights into the behaviour of α-oxosulfines with different transition metal catalysts, and under thermal, microwave and photolysis conditions. A series of 3-aminofuran-2(5H)-ones and benzofused dihydro-2H-thiopyran S-oxides were submitted for anticancer screening at the U.S. National Cancer Institute. A number of these derivatives were identified as hit compounds, with excellent cell growth inhibition. One 3-aminofuran-2(5H)-one derivative has been chosen for further screening. The third chapter details the full experimental procedures, including spectroscopic and analytical data for the compounds prepared during this research. The data for the crystal structures are contained in the attached CD.

Taming hazardous chemistry in flow: The continuous processing of diazo and diazonium compounds

The synthetic utilities of the diazo and diazonium groups are matched only by their reputation for explosive decomposition. Continuous processing technology offers new opportunities to make and use these versatile intermediates at a range of scales with improved safety over traditional batch processes. In this minireview, the state of the art in the continuous flow processing of reactive diazo and diazonium species is discussed.

Catalytic Hydrogenolysis of Aromatic Ketones in Mixed Choline-Betainium Ionic Liquids

The palladium-catalyzed hydrogenolysis of aromatic ketones to alkylbenzenes was studied in mixtures of ionic liquids to explore the promotional effect of these reaction media. Choline-based ionic liquids displayed complete miscibility with the aromatic ketone substrate at reaction temperature and a clear phase separation of the derived alkylbenzene product at room temperature. Selected ionic liquids were then assessed as reaction media in the hydrogenolysis of aromatic ketones over palladium catalysts. A binary mixture of choline and betainium bis(trifluoromethylsulfonyl)imide ionic liquids resulted in the highest conversion and selectivity values in the hydrogenolysis of acetophenone. At the end of the reaction, the immiscible alkylbenzene separates from the ionic liquid mixture and the pure product phase can be isolated by simple decantation. After optimization of the reaction conditions, high yields (>90%) of alkylbenzene were obtained in all cases. The catalyst and the ionic liquid could be used at least three times without any loss of activity or selectivity.

Remote chiral induction in the organocatalytic hydrosilylation of aromatic ketones and ketimines

Lewis basic, metal-free pyridyloxazolines catalyze the redn. of prochiral arom. ketones and ketimines with Cl3SiH in good enantioselectivity (? 94% ee). Arene-arene interactions between the substrate and the catalyst are likely to play a role in the enantiodifferentiation process.

Study of the transamidative ring expansion of N--halogenoalkyl--lactams of alkyl chain lengths 2–12 in liquid ammonia and other liquid amines: syntheses of 7-, 8- and 9-membered 1,5-diaza cyclic ketones, including routes to (±)-dihydroperiphylline and (±)-celabenzine

N-(3-Halogenopropyl)-4-phenylazetidin-2-ones undergo amination in liquid ammonia followed by transamidative ring expansion to give the eight-membered 4-phenyl -1,5-diazacyclooctan-2-one in excellent yield. Ring expansion of the amines in liquid ammonia is found to be much more effective than in hydrocarbon solvents. Formation of 7-, 8-, and 9-membered azalactams from the requisite -halogenoalkyl--lactams is an excellent synthetic process, though it is not applicable to 10membered rings. In the cases of rings of 13-, 15- and 17-members, although amination and apparent expansion takes place, the large rings appear not to be stable to ammonia and the final products are acyclic amides. N-[4-Halogenobut-2(Z)-enyl]-4-phenylazetidin-2-one satisfactorily forms a 9-membered (Z)-olefinic azalactam, but the (E)-isomer gives an acyclic amino amide. By using alkyl-substituted -lactam side-chains, C-substituted medium rings can be obtained; the relative instability of N-acyl -lactams to ammonia, however, leads to acylamino amides rather than expanded rings.Employing ethylamine in place of ammonia, it is shown that N-ethylated azalactams are formed satisfactorily, and using allylamine, N-allyl medium rings capable of further elaboration are obtained. The chemistry of these systems is discussed. Using transamidation in liquid ammonia, a short synthesis of the 9-membered spermidine alkaloid (±)-dihydroperiphylline is reported. Synthesis of key intermediates, whose transformation into the 13-membered alkaloids of the celabenzine group has already been effected, has been carried out.X-Ray single-crystal structure determinations for 4-phenyl-1,5-diazacyclononan-2-one, trans-4-phenyl-8-methyl-1,5-diazacyclooctan-2-one and (Z)-4-phenyl-1,5-diazacyclonon-7-en-2-one are reported, and comment is made on certain conformational features.

Reaction of tetracyanoethylene with alpha,beta-unsaturated ketones

Synthesis and Chemistry of simple tetracyanoalkanes is well studied. We performed tetracyanoethylation of unsaturated ketones with an active double bond in alpha-position. The reaction of tetracyanoethylene with alpha,beta-unsaturated ketones may result in four probable products depending on the character of substituents.

Cation complexation by chemically modified calixarenes. 11. Complexation and extraction of alkali cations by calix[5]- and -[6]arene ketones. Crystal and molecular structures of calix[5]arene ketones and Na+ and Rb+ complexes

A series of four calix[5]arenes and three calix[6]arenes (R-calixarene-OCH2COR1) (R = H or Bu-t) with alkyl ketone residues (R-1 = Me or Bu-t) on the lower rim have been synthesized, and their affinity for complexation of alkali cations has been assessed through phase-transfer experiments and stability constant measurements. The conformations of these ketones have been probed by H-1 NMR and X-ray diffraction analysis, and by molecular mechanics calculations. Pentamer 3 (R R-1 = Bu-t) possesses a symmetrical cone conformation in solution and a very distorted cone conformation in the solid state. Pentamer 5 (R = H, R-1 = Bu-t) exists in a distorted 1,2-alternate conformation in the solid state, but in solution two slowly interconverting conformations, one a cone and the other presumed to be 1,2-alternate, can be detected. X-ray structure analysis of the sodium and rubidium perchlorate complexes of 3 reveal the cations deeply encapsulated by the ethereal and carbonyl oxygen atoms in distorted cone conformations which can be accurately reproduced by molecular mechanics calculations. The phase-transfer and stability constant data reveal that the extent of complexation depends on calixarene size and the nature of the alkyl residues adjacent to the ketonic carbonyls with tert-butyl much more efficacious than methyl.

Selective Hydrogenation of alpha,beta-Unsaturated Aldehydes and Ketones using Novel Manganese Oxide and Platinum Supported on Manganese Oxide Octahedral Molecular Sieves as Catalysts

The selective hydrogenation of ,-unsaturated aldehydes and ketones has been studied using ketoisophorone and cinnamaldehyde as model substrates using manganese oxide octahedral molecular sieve (OMS-2) based catalysts. For the first time, OMS-2 has been shown to be an efficient and selective hydrogenation catalyst. High selectivities for either the CC or CO double bond at approximate to 100% conversion were achieved by using OMS-2 and platinum supported on OMS-2 catalysts. Density functional theory (DFT) calculations showed that the dissociation of H2 on OMS-2 was water assisted and occurred on the surface Mn of OMS-2(001) that had been modified by an adsorbed H2O molecule. The theoretically calculated activation barrier was in good agreement with the experimentally determined value for the hydrogenation reactions, indicating that H2 dissociation on OMS-2 is likely to be the rate-determining step. A significant increase in the rate of reaction was observed in the presence of Pt as a result of the enhancement of H2 dissociative adsorption and subsequent reaction on the Pt or spillover of the hydrogen to the OMS-2 support. The relative adsorption strengths of ketoisophorone and cinnamaldehyde on the OMS-2 support compared with the Pt were found to determine the product selectivity.

Cationic palladium(II) complexes as catalysts for the oxidation of terminal olefins to methyl ketones using hydrogen peroxide.

Ligated Pd(II) complexes have been studied for the catalytic oxidation of terminal olefins to their corresponding methyl ketones. The method uses aqueous hydrogen peroxide as the terminal oxidant; a sustainable and readily accessible oxidant. The choice of ligand, counterion and solvent all have a significant effect on catalytic performance and we were able to develop systems which perform well for these challenging oxidations.

Acetalization of ketones on K-10 clay and rare earth exchanged HFAU-Y zeolites: A mild and facile procedure for the synthesis of dimethylacetals

Dimethylacetals of ketones; cyclohexanone, acetophenone, and benzophenone have been prepared by reacting ketones with methanol under mild reaction conditions. Large pore zeolites (H-Y and its rare earth metal, Ce3+, La3+, and RE3+ modified forms), and mesoporous clay (K-10 montmorillonite and its cerium exchanged counterpart) with regular pore structure, silica and silica-alumina have been used as catalysts. Clay catalysts are found to be much more active than zeolites, thanks to slightly bigger pore size. The nature of the pores of the solid acid catalysts determine acetalization efficiency of a particular catalyst. As evidenced by the reaction time studies, the catalyst decay is greater over the zeolites than over the clays. Carrying out the reaction with ketones of different molecular sizes it is shown that K-10 clays and rare earth exchanged H-Y zeolites are promising environmentally friendly catalysts for their use in the production fine chemicals.

Effect of pore size on the catalytic activities of K-I 0 clay and H-zeolites for the acetalization of ketones with methanol

One-pot acetalizations of cyclohexanone. acetophenone and benzophenone were carried out using methanol over H-montmorillonite clay (a mesoporous material). silica, alumina, and different zeolites such as HFAU-Y.HBeta, H-ZSM-5, and H-mordenite. In all the cases a single product-the corresponding dimethylacetal-was obtained in high yields. Hemiacetal formation was not observed with any catalyst. A comparison of catalytic activity indicated that montmorillonite K-10 is the most active catalyst for the reaction. As evidenced by the reaction time studies, the catalyst decay is greater over the zeolite catalyst than over the clay.

Synthesis of dimethyl acetal of ketones: design of solid acid catalysts for one-pot acetalization reaction

The synthesis of dimethyl acetals of carbonyl compounds such as cyclohexanone, acetophenone, and benzophenone has successfully been carried out by the reaction between ketones and methanol using different solid acid catalysts. The strong influence of the textural properties of the catalysts such as acid amount and adsorption properties (surface area and pore volume) determine the catalytic activity. The molecular size of the reactants and products determine the acetalization ability of a particular ketone. The hydrophobicity of the various rare earth exchanged Mg–Y zeolites, K-10 montmorillonite clay, and cerium exchanged montmorillonite (which shows maximum activity) is more determinant than the number of active sites present on the catalyst. The optimum number of acidic sites as well as dehydrating ability of Ce3+-montmorillonite and K-10 montmorillonite clays and various rare earth exchanged Mg–Y zeolites seem to work well in shifting the equilibrium to the product side.

The synthesis of chiral N-heterocyclic carbene–borane and –diorganoborane complexes and their use in the asymmetric reduction of ketones

Chiral N-heterocyclic carbene–borane complexes have been synthesised, and have been shown to reduce ketones with Lewis acid promotion. Chiral N-heterocyclic carbene–borane and –diorganoborane complexes can reduce ketones with enantioselectivities up to 75% and 85% ee, respectively.