Lyndsay Main

Ortho-manganated arenes in synthesis: IV.Ortho-manganation of substituted acetophenones and of heteroaromatic methyl ketones. The crystal structures of two cyclometallated acetylthiophene derivatives

Abstract A range of acetophenones containing methoxy, methyl and bromo substituents on the ring have been ortho-manganated with PhCH2 Mn(CO)5 in refluxing heptane to give substituted complexes of the type MeC(O)C6H4Mn(CO)4 in good yields. Similarly prepared were the ortho-manganated complexes derived from 2-acetylthiophene, 3-acetyl-2,5-dimethylthiophene, 2-acetyl-N-methylpyrrole, 2-acetylfuran and 3-acetylindole. All new complexes were fully characterised by normal methods, including 13C NMR spectra, the first reported for ortho-manganated ketones, and X-ray crystal structures are described for the two derivatives, η2-(2-acetyl-3-thienyl)tetracarbonylmanganese and η2-(3-acetyl-2,5-di- methyl-4-thienyl)tetracarbonylmanganese.

Evaluation of progesterone-ovalbumin conjugates with different length linkers in enzyme-linked immunosorbant assay and surface plasmon resonance-based immunoassay

A series of progesterone-4-ovalbumin (OVA) conjugates with different length linkers (4-, 11-, and 18-atoms long) were synthesized by successive aminocaproic acid homologation of 3-(pregn-4-ene-3,20-dione-4-yl)thiopropanoic acid (1) before conjugation to ovalbumin. The performance studies of these progesterone-4-ovalbumin conjugates showed that the effects of the length of linker on the antibody binding are dependent upon different immunoassay formats. In a rapid flow biosensor surface, on a BIAcore Surface Plasmon Resonance (SPR) instrument, antibody-binding capacities and response rate were dramatically increased for progesterone-4-ovalbumin conjugates when the length of the linker was incremented from 4 atoms to 11 or 18 atoms. Thus, highly sensitive SPR-based immunoassays for progesterone over a range of 0.1-50 ng ml(-1) were developed using biosensor surfaces immobilized with progesterone-ovalbumin conjugates having extended linkers. The SPR-based assays were fully competitive with conventional enzyme-linked immunosorbant assay (ELISA) but much more rapid and simple. However, there were little changes in antibody-binding performance using a conventional ELISA for the same conjugates. The progesterone-4-ovalbumin conjugate (1-OVA) had better antibody binding than its progesterone-7alpha-ovalbumin analog (2-OVA) in the SPR-based assay, but with a conventional ELISA there was no significant difference between these two isomeric conjugates.

Ortho-manganated arenes in synthesis: V. Ortho-manganation of N-acyl heteroaromatics, benzamides and substituted benzaldehydes. Crystal structure of (μ2-O,C-1-acetyi-2-indolyl)tetracarbonylmanganese☆

Abstract 1-Benzoylpyrrole has been shown to react with PhCH 2 Mn(CO) 5 in refiuxing heptane to ortho -manganate the heterocyclic ring to give (μ 2 -O,C-1-benzoyl-2-pyrrolyl)tetracarbonylmanganese in good yield. Similarly prepared were the corresponding derivatives of N -acetylpyrrole and of N -acetyl- and N-benzoyl-indole. N,N -Dialkylbenzamides could also be ortho -manganated in good yields, but not the parent benzamide. Benzaldehydes also react provided that they contain p -MeO or p -Me 2 N substituents. The structure of (μ 2 - O,C -1-acetyl-2-indolyl)tetracarbonyl-manganese has been determined by X-ray diffraction.

Reactions of ortho-manganated aryl-ketones, aldehydes and amides with alkynes; a new synthesis of inden-1-ols and indenones

Abstract η 2 -(2-Acetylphenyl)tetracarbonylmanganese reacts directly in benzene with diphenylacetylene to give 2,3-diphenyl-1-methylinden-1-ol in 97% yield, while ortho -manganated N,N -dimethylbenzamide or p -dimethylaminobenzaldehyde react similarly to give the corresponding indenones. Other alkynes give analogous products.

Preparation of η5-pyranyltricarbonylmanganese complexes and pyrylium triiodide salts from cyclomanganated chalcones and alkynes

Derivatives of [[1-phenyl-2-phenylcarbonyl-kO]ethenyl-kC1]tetracarbonylmanganese, i.e. chalcone (1, 3-diphenylprop-2-en-1-one) cyclomanganated at the β-position, undergo insertion reactions with alkynes under reflux in carbon tetrachloride to give [2,4-diphenylpyranyl-η5]Mn(CO)3 derivatives, the reaction being highly regioselective in the case of unsymmetrical alkynes. Reaction of the pyranyl-Mn(CO)3 complexes with iodine in carbon tetrachloride gives pyrylium triiodide salts in excellent yield. The reaction of one pyranyl complex, [2-(4-chlorophenyl)-6-phenyl-4(4-trifluoromethylpheny)pyranyl-η5]tricarbonylmanganese (2d), with Na[Fe(CO)2Cp], gave the demetallated ring-opened isomers E,E-1-phenyl-3-(4-trifluoromethylphenyl)-5-(4-chlorophenyl)penta-2, 4-dien-1-one (10a) and E, E-1-(4-chlorophenyl)-3-(4-trifluoromethylphenyl)-5-phenylpenta-2,4-dien-1-one (10b). X-ray crystal structure determinations of [2-methyl-4,6-diphenylpyranyl-η5]tricarbonylmanganese (5) and 2,6-diphenyl-4-(4-trifluoromethylphenyl)pyrylium triiodide (3b) are described, the former being the first reported for a pyranyl-η5 metal complex.

ortho-Directed electrophilic boronation of a benzyl ketone: the preparation, X-ray crystal structure, and some reactions of 4-ethyl-1-hydroxy-3-(4-hydroxyphenyl)-2-oxa-1-boranaphthalene

Abstract 4-Ethyl-1-hydroxy-3-(4-hydroxyphenyl)-2-oxa-1-boranaphthalene ( 4 ) is formed in 78% yield from the reaction of 1-(4-methoxyphenyl)-2-phenylbutan-1-one with an of excess boron tribromide in dichloromethane followed by treatment with water. Reaction of 4 with iodine in aqueous sodium hydroxide gives a second oxaboracycle, 3-ethyl-1-hydroxy-3-(4-hydroxybenzoyl)-2,1-benzoxaborolane ( 5 ). The X-ray crystal structure determinations of both boron heterocycles are reported. Other new compounds reported are 1-(4-hydroxyphenyl)-2-(1-hydroxyphenyl)-butan-1-one ( 6 ), formed by reaction of 4 with alkaline hydrogen peroxide, and 1-(4-hydroxyphenyl)-2-(2-biphenyl)-butan-1-one ( 8 ), formed by coupling of 4 with bromobenzene in the presence of Pd(PPh 3 ) 4 .

Estrogen conjugation and antibody binding interactions in surface plasmon resonance biosensing

Thioether-linked 3-mercaptopropionic acid derivatives of 17beta-estradiol and estrone were formed at the A-ring 4-position of the steroids by substitution of their 4-bromo analogues. The carboxylic acid terminal was used to link to an oligoethylene glycol (OEG) chain of 15-atoms in length. The OEG derivative of 17beta-estradiol was then in situ immobilized on a carboxymethylated dextran-coated gold sensor surface used to detect refractive index changes upon protein binding to the surface by surface plasmon propagation in a BIAcore surface plasmon resonance (SPR) instrument. Two other estradiol-OEG derivatives with Mannich reaction linkage at the 2-position and hemisuccinate linkage at the 3-position were also immobilized on the sensor surfaces for comparison. Binding performance between these immobilized different positional conjugates and monoclonal anti-estradiol antibody, raised from a 6-position conjugate, clearly demonstrated that both 2- and 4-conjugates, not conjugated through existing functional groups, gave strong antibody bindings, whereas the 3-conjugate through an existing functional group (3-OH) gave very little binding (2% compared to the 2-conjugate). Both 2- and 4-position conjugates were then applied in a highly sensitive estradiol SPR immunoassay with secondary antibody mediated signal enhancement that gave up to a 9.5-fold signal enhancement of primary antibody binding, and a detection limit of 25 pg/mL was achieved for a rapid and convenient flow-through immunoassay of estradiol.

Preparation of cyclomanganated chalcones and their reactions with methyl acrylate and other α, β-unsaturated carbonyl compounds

Abstract Chalcones [( E )-1,3-diarylprop-2-en-1-ones] react with benzyltetracarbonylmanganese under reflux in petroleum spirit to give two types of cyclomanganation products. The first, involving metallation at the alkenyl β-carbon of the enone, are derivatives of [[1-phenyl-2-phenylcarbonyl- κO ]ethenyl- κC 1 ]tetracarbonylmanganese, while the second type, manganated at the aryl ring ortho -carbon, are derivatives of [2-[3-phenylprop-2-en-1-onyl- κO ]phenyl- κC 1 ]tetracarbonylmanganese. In general, more “alkene-manganated” than “ring-manganated” product is formed, with the ratio influenced significantly by certain substituents, e.g. a 4-CF 3 substituent on the phenyl ring at C3 of the enone strongly promotes “alkene-manganation”. In some cases there are minor by-products derived from coupling of two chalcone molecules after initial cyclomanganation. The crystal structures are reported for two such products, [2-((1 S ∗ , 2 R ∗ , 3 S ∗ )-1- hydroxy -1-((E)-2-(2- trifluoromethylphenyl)ethenyl )-3-(2- trifluoromethylphenyl )-6- methoxy -2- indanylcarbonyl -κO)-6- methoxyphenyl -κC 1 ] tetracarbonylmanganese and (1S ∗ , 4S ∗ , 5R ∗ )-5-(4-bromobenzoyl)-1-(4-bromophenyl)-3,4-di-(4-trifluoromethylphenyl)cyclopent-2-en-1-ol. In acetonitrile under reflux, alkene-manganated chalcones react with methyl acrylate (methyl propenoate) to form derivatives of methyl ( E )-4,6-diphenyl-6-oxohex-2-enoate and of 5-(2-methoxycarbonylethyl)-3,5-diphenylfuran-2(5H)-one. The latter butenolides are not formed when the reactions are carried out in carbon tetrachloride, only the former α, β-unsaturated esters. By contrast, in a few reactions studied, acrolein (propenal) and methyl vinyl ketone (but-3-en-2-one) give only the butenolide products when treated with alkene-manganated chalcones in refluxing acetonitrile. An exception is the reaction of methyl vinyl ketone with [[1-(3,4,5-trimethoxyphenyl)-2-(4-chlorophenylcarbonyl- κO )]ethenyl- κC 1 ]tetracarbonylmanganese to form the cyclized product 5-acetyl-1-(4-chlorophenyl)-3-(3,4,5-trimethoxyphenyl)cyclopent-2-en-1-ol.

Kinetics and mechanism of the cyclisation of 2′,6′-dihydroxychalcone and derivatives

pH–Rate profiles are reported for the cyclisation in water to 5-hydroxyflavanones of 2′,6′-dihydroxychalcone (1) and its 4-methoxy (2), 3,4-dimethoxy (3), 3,4,5-trimethoxy (4), 2,4,6-trimethoxy (5), 4-chloro (6), and 3,4,4′-trimethoxy (8) derivatives. As for the previously studied 2′,6′-dihydroxy-4,4′-dimethoxychalcone (7), rate coefficients are established for acid-catalysed cyclisation of neutral chalcone, for unimolecular cyclisation of the neutral, monoanionic, and dianionic chalcone, and for the base-catalysed reverse ring-opening reaction. Cyclisation of the monoanion of 2′,6′-dihydroxychalcone is almost 40 times faster than that of the monoanion of the 2′-hydroxy-6′-methoxychalcone (10) and is also estimated to be about ten times faster than that of the reactive monoanion of 2′,4′-dihydroxychalcone. These are the first calculations of the enhancement of rate of monoanion cyclisation by the 6′-OH group. The effect is only small, and is suggested to arise largely from stabilisation of the transition state for ketonisation by hydrogen bonding to enolate oxygen. Other reactivity differences amongst the chalcone monoanions are also discussed. Enthalpy and entropy of activation data are reported for monoanion cyclisation of (1), (2), and (4)–(6). Rate coefficients for the cyclisation of the chalcone monoanions are almost identical for (1)–(4) and (6) in water but not in deuterium oxide: kinetic hydrogen isotope effect (KIE) values are 3.4 (1), 5.7 (2), 4.9 (3), 3.0 (4), 7.5 (5), 2.9 (6), and 5.0 (8). For chalcones (2) and (7), the KIE values of which are both 5.7, the amounts of H versus D incorporation at the flavanone 3-carbon for monoanion cyclisation in H2O/D2O mixtures were established by mass spectroscopy. This gave product (or ‘discrimination’) isotope effect (PIE) values of 7.9 for (2) and 3.8 for (7), suggesting for (2) but not (7) an inverse isotope effect contribution to KIE from sources other than rate-limiting proton transfer to carbon. Monoanion cyclisation of (1) in D2O was established by 1H n.m.r. as involving almost equal amounts of anti and syn addition of 2′-O– to the enone double bond. Reactivity differences amongst the chalcones for reactions other than monoanion cyclisation are only briefly considered.

β-Cyclomanganated 1,5-diphenylpenta-1,4-dien-3-ones and their reactions with alkynes: routes to η5-pyranyl and η5-oxocycloheptadienylMn(CO)3 complexes

Abstract 1,5-Diphenylpenta-1,4-dien-3-ones (4) are cyclometalated with benzylpentacarbonylmanganese to form [[1-phenyl-2-((E)-3-phenylprop-2-en-1-oyl-κO)]ethenyl-κC1]tetracarbonylmanganese derivatives (5). Coupling of 5 with alkynes in some cases gives [4-phenyl-2-(2-phenylethenyl)pyranyl-η5]tricarbonylmanganese complexes (6) analogous to those previously reported for β-manganated chalcones, but in other cases an alternative cyclisation pathway subsequent to insertion of alkyne into the CMn bond leads to [6-oxo-4,7-diphenylcyclohepta-1,4-dienyl-1,2,3,4,5-η]tricarbonylmanganese complexes (7). The X-ray crystal structure determination is reported for one such compound, [6-oxo-2,4,7-triphenylcyclohepta-1,4-dienyl-1,2,3,4,5-η]tricarbonylmanganese (7a), derived from 1,5-diphenylpenta-1,4-dien-3-one and phenylacetylene. The 7-phenyl group is found to occupy the endo position, and a mechanism involving Mn-mediated aryl migration is suggested to explain this stereochemistry. The reaction of 7a with ammonium cerium(IV) nitrate gives a low yield of 2-nitro-3,5,7-triphenylcyclohepta-2,4,6-trien-1-one (9), whose structure was established by X-ray crystal structure analysis. The pyranyl complexes (6) provide the corresponding pyrylium triiodide salts (8) when demetalated with iodine.