THE SYNTHESIS OF BRIDGED-RING CARBOCYCLES AND HETEROCYCLES VIA PALLADIUM CATALYZED REGIOSPECIFIC CYCLIZATION REACTIONS

A catalyst system comprising 10 mol % (Pd(OAc) and 20 mol % PPh3 effects the cyclisation of aryl halides onto proximate alkenes via 5-, 6-, and 7-exo-trig, and 7-endo-trig processes giving a variety of bridged-ring carbo- and hetero-cycles in excellent yield. Double bond isomerisation in the product is rarely encountered and may be suppressed by the addition of Tl(1) salts. One example of diastereospecific bis-cyclisation is given and the crystal structure of 1-aza-2-sulphonyl-3,4-benzobicyclo[3.2.1]nona-6-ene is reported.

Dioxygenase-catalysed Oxidation of Disubstituted Benzene Substrates: Benzylic Monohydroxylation versus Aryl cis-Dihydroxylation and the Meta Effect

Biotransformations of a series of ortho-, meta- and para-substituted ethylbenzene and propylbenzene substrates have been carried out, using Pseudomonas putida UV4, a source of toluene dioxygenase (TDO). The ortho- and para-substituted alkylbenzene substrates yielded, exclusively, the corresponding enantiopure cis-dihydrodiols of the same absolute configuration. However, the meta isomers, generally, gave benzylic alcohol bioproducts, in addition to the cis-dihydrodiols (the meta effect). The benzylic alcohols were of identical (R) absolute configuration but enantiomeric excess values were variable. The similar (2R) absolute configurations of the cis-dihydrodiols are consistent with both the ethyl and propyl groups having dominant stereodirecting effects over the other substituents. The model used earlier, to predict the regio- and stereo-chemistry of cis-dihydrodiol bioproducts derived from substituted benzene substrates has been refined, to take account of non-symmetric subsituents like ethyl or propyl groups. The formation of benzylic hydroxylation products, from meta-substituted benzene substrates, without further cis-dihydroxylation to yield triols provides a further example of the meta effect during toluene dioxygenase-catalysed oxidations.

Large carbon isotope fractionation associated with oxidation of methyl halides by methylotrophic bacteria

The largest biological fractionations of stable carbon isotopes observed in nature occur during production of methane by methanogenic archaea. These fractionations result in substantial (as much as 70) shifts in 13C relative to the initial substrate. We now report that a stable carbon isotopic fractionation of comparable magnitude (up to 70) occurs during oxidation of methyl halides by methylotrophic bacteria. We have demonstrated biological fractionation with whole cells of three methylotrophs (strain IMB-1, strain CC495, and strain MB2) and, to a lesser extent, with the purified cobalamin-dependent methyltransferase enzyme obtained from strain CC495. Thus, the genetic similarities recently reported between methylotrophs, and methanogens with respect to their pathways for C1-unit metabolism are also reflected in the carbon isotopic fractionations achieved by these organisms. We found that only part of the observed fractionation of carbon isotopes could be accounted for by the activity of the corrinoid methyltransferase enzyme, suggesting fractionation by enzymes further along the degradation pathway. These observations are of potential biogeochemical significance in the application of stable carbon isotope ratios to constrain the tropospheric budgets for the ozone-depleting halocarbons, methyl bromide and methyl chloride.

A method for carbon stable isotope analysis of methyl halides and chlorofluorocarbons at pptv concentrations

A pre-concentration system has been validated for use with a gas chromatography/mass spectrometry/isotope ratio mass spectrometer (GC/MS/IRMS) to determine ambient air 13C/12C ratios for methyl halides (MeCl and MeBr) and chlorofluorocarbons (CFCs). The isotopic composition of specific compounds can provide useful information on their atmospheric budgets and biogeochemistry that cannot be ascertained from abundance measurements alone. Although pre-concentration systems have been previously used with a GC/MS/IRMS for atmospheric trace gas analysis, this is the first study also to report system validation tests. Validation results indicate that the pre-concentration system and subsequent separation technologies do not significantly alter the stable isotopic ratios of the target methyl halides, CFC-12 (CCl2F2) and CFC-113 (C2Cl3F3). Significant, but consistent, isotopic shifts of -27.5 to -25.6 do occur within the system for CFC-11 (CCl3F), although the shift is correctible. The method presented has the capacity to separate these target halocarbons from more than 50 other compounds in ambient air samples. Separation allows for the determination of stable carbon isotope ratios of five of these six target trace atmospheric constituents within ambient air for large volume samples (10 L). Representative urban air analyses from Belfast City are also presented which give carbon isotope results similar to published values for 13C/12C analysis of MeCl (-39.1) and CFC-113 (-28.1). However, this is the first paper reporting stable carbon isotope signatures for CFC-11 (-29.4) and CFC-12 (-37.0).

New mustard-linked 2-aryl-bis-benzimidazoles with anti-proliferative activity

We describe new methodology for the synthesis of symmetric bis-benzimidazole carrying 2-aryl moieties, including 2-[4-3'-aminopropoxy)phenyl] and 2-[4-(3'-aminopropanamido)pheny] substituents, together with the synthesis of novel hybrid molecules comprising bis-benzimidazoles in ester and amide combination with the N-mustard chlorambucil. The in vitro activities of these compounds against five cancer cell lines are also provided.

Radical 1,4-aryl transfer in arylcarboxamides leading to phthalimides, biaryls and enantiomerically enriched beta-arylethylamines

5-exo Cyclisation of vinyl-, aryl- and alkyl-radicals onto the aryl group of arylcarboxamides is followed by beta-scission of the resulting spirocyclohexadienyl radicals with ejection of a carbamoyl radical. The fate of this radical depends on the substrate but, in the cases studied, either 5-endo cyclisation or direct reduction follows to give phthalimides, biaryls or beta-arylethylamines.

Crystal polymorphism in 1-butyl-3-methylimidazolium halides: supporting ionic liquid formation by inhibition of crystallization

Crystallization of 1-butyl-3-methylimidazolium chloride from mixed ionic liquid or ionic liquid-aromatic solution, and from the melt yields different crystalline polymorphs, the first direct evidence for inhibition of crystallization in ionic liquids by polymorphism.

5-aryl-pyrazolo[3,4-b]pyridazines: Potent inhibitors of glycogen synthase kinase-3 (GSK-3)

Introduction of a nitrogen atom into the 6-position of a series of pyrazolo[3,4-b]pyridines led to a dramatic improvement in the potency of GSK-3 inhibition. Rationalisation of the binding mode suggested participation of a putative structural water molecule, which was subsequently confirmed by X-ray crystallography. (C) 2003 Elsevier Science Ltd. All rights reserved.

Anomalous fluorinations of 3-aryl-2-hydroxypropanoic esters by diethylaminosulfur trifluoride (DAST).

Anomalous fluorinations of 3-aryl-2-hydroxypropanoic esters by diethylaminosulfur trifluoride (DAST). Haigh, David; Jefcott, Lee J.; Magee, Katherkine; McNab, Hamish. Dep. Med. chem., SmithKline Beecham Pharmaceuticals, Epsom, UK. Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1996), (24), 2895-2900. Publisher: Royal Society of Chemistry, CODEN: JCPRB4 ISSN: 0300-922X. Journal written in English. CAN 126:143928 AN 1997:56534 CAPLUS (Copyright (C) 2009 ACS on SciFinder (R)) Abstract Treatment of 3-aryl-2-hydroxypropanoic esters with diethylaminosulfur trifluoride (DAST) gives considerable amts. of rearranged 2-aryl-3-fluoropropanoic esters, together with the expected products. The extent of rearrangement is dependent on solvent and on the substitution pattern of the aryl ring; the mechanism of rearrangement probably involves anchimeric assistance by the aryl group in the SN1 component of the reaction pathway. Reaction of the isomeric 3-hydroxy-2-phenylpropanoic ester shows much less rearrangement under similar conditions, and an elimination product is also obtained.

Synthesis and SAR of centrally active mGlu(5) positive allosteric modulators based on an aryl acetylenic bicyclic lactam scaffold

This Letter describes the hit-to-lead progression and SAR of a series of biphenyl acetylene compounds derived from an HTS screening campaign targeting the mGlu(5) receptor. 'Molecular switches' were identified that modulated modes of pharmacology, and several compounds within this series were shown to be efficacious in reversal of amphetamine induced hyperlocomotion in rats after ip dosing, a preclinical model that shows similar positive effects with known antipsychotic agents. Published by Elsevier Ltd.

Sequential C-H and C-Ru bond formation and cleavage during the thermally induced rearrangement of aryl ruthenium(II) complexes with [C6H3(CH2NMe2)(2)-2,6](-) as a bidentate eta(2)-C,N coordinated ligand. The crystal structures of the isomeric pairs [RuCl{eta(6)-C10H14}{eta(2)-C,N-C6H3(CH2NMe2)(2)-2,n}] (n = 4 or 6) and [Ru(eta(5)-C5H5){(eta(2)-C,N-C6H3(CH2NMe2)(2)-2,n} (PPH3)] (n = 4 or 6)

New air-stable ruthenium(II) complexes that contain the aryldiamine ligand [C6H3(CH2-NMe2)(2)-2,6](-) (NCN) are described. These complexes are [RuCl{eta(2)-C,N-C6H3(CH2NMe2)(2)-2,6}(eta(6)-C10H14)] (2; C10H14 = p-cymene = C6H4Me-Pr-i-4), [Ru{eta(2)-C,N-C6H3(CH2NMe2)(2)-2,6}(eta(5)-C5H5)(PPh3)] (5), and their isomeric forms [RuCl{eta(2)-C,N-C6H3(CH2NMe2)(2)-2,4}(eta(6)-C10H14)] (3) and [Ru{eta(2)-C,N-C6H3(CH2NMe2)(2)-2,4}(eta(5)-C5H5)(PPh3)] (6), respectively. Complex 2 has been prepared from the reaction of [Li(NCN)](2) with [RuCl2(eta(6)-C10H14)](2), whereas complex 5 has been prepared by the treatment of [RuCl{eta(3)-N,C,N-C6H3(CH2NMe2)(2)-2,6}(PPh3)] (4) with [Na(C5H5)](n). Both 2 and 5 are formally 18-electron ruthenium(II) complexes in which the monoanionic potentially tridentate coordinating ligand NCN is eta(2)-C,N-bonded, In solution (halocarbon solvent at room temperature or in aromatic solvents at elevated temperature), the intramolecular rearrangements of 2 and 5 afford complexes 3 and 6, respectively. This is a result of a shift of the metal-C-aryl bond from position-1 to position-3 on the aromatic ring of the NCN ligand. The mechanism of the isomerization is proposed to involve a sequence of intramolecular oxidative addition and reductive elimination reactions of both aromatic and aliphatic C-H bonds. This is based on results from deuterium labeling, spectroscopic studies, and some kinetic experiments. The mechanism is proposed to contain fully reversible steps in the case of 5, but a nonreversible step involving oxidative addition of a methyl NCH2-H bond in the case of 2. The solid-state structures of complexes 2, 3, 5, and 6 have been determined by single-crystal X-ray diffraction. A new dinuclear 1,4-phenylene-bridged bisruthenium(II) complex, [1,4-{RuCl(eta(6)-C10H14)}(2){C-6(CH2NMe2)(4)-2,3,5,6-C,N,C',N'}] (9) has also been prepared from the dianionic ligand [C-6(CH2NMe2)(4)-2,3,5,6](2-) (C2N4). The C2N4 ligand is in an eta(2)-C,N-eta(2)-C',N'-bis(bidentate) bonding mode. Compound 9 does not isomerize in solution (halocarbon solvent), presumably because of the absence of an accessible C-aryl-H bond. Complex 9 could not be isolated in an analytically pure form, probably because of its high sensitivity to air and very low solubility, which precludes recrystallization.

Toluene and naphthalene dioxygenase-catalysed sulfoxidation of alkyl aryl sulfides

A series of alkyl aryl sulfides were metabolised, using selected strains of the soil bacterium Pseudomonas putida containing either toluene dioxygenase (TDO) or naphthalene dioxygenase (NDO), to give chiral sulfoxides. Alkyl aryl sulfoxides 2a-2k, 4a-4j and 4l, having enantiomeric excess (ee) values of >90%, were obtained by use of the appropriate strain of P. putida (UV4 or NCIMB 8859), Enantiocomplimentarity was observed for the formation of sulfoxides 2a, 2b, 2d, 2j, 4a, 4b and 4d, with TDO-catalysed (UV4) oxidation favouring the (R) enantiomer and NDO-catalysed oxidation (NCIMB 8859) the (S) enantiomer. Evidence of involvement of the TDO enzyme was obtained using a recombinant strain of Escherichia coli (pKST 11), The marked degree of stereoselectivity appears to be mainly due to enzyme-catalysed asymmetric sulfoxidation, however the possibility of a minor contribution from kinetic resolution, in some cases, cannot be excluded.

Cu-Based Nanoalloys in the Base-Free Ullmann Heterocyle-Aryl Ether Synthesis

We report the first liquid-liquid Ullmann etherification process mediated not only by oxidatively stable Cu but also by CuZn and CuSn nanoparticle catalysts in conjunction with microwave heating that also avoids the use of solid and expensive bases. Conditions have led to improved turnovers and excellent yields in heteroaromatic Ullmann-type coupling reactions. Further enhancement is achieved upon the addition of 18-crown-6 as a kinetic promoter.