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16 alpha-Fluoro-17 beta-, 16 alpha-fluoro-17 alpha-, and 16 beta-fluoro-17 beta-[6,7-3H]estradiol were prepared from [6,7-3H]estrone via fluorination of 3,17-bis(tert-butyldimethylsilyloxy)-[6,7-3H]estratetraene with N-fluoropyridinium triflate and reduction of 16 alpha/beta-fluoro[6,7-3H]estrone with NaBH4. The three isomers were separated by silica-phase high-performance liquid chromatography. They were administered intravenously (4 mumol/kg to anaesthetized male rats. Their biliary metabolites (90-97% of dose over 6 h) were characterized by high performance liquid chromatography-mass spectrometry and compared with those of [6,7-3H]17 beta-estradiol. The four estrogens and their hydroxylated and methoxylated metabolites were excreted as glucuronides. C-16 fluorination blocked C-16 hydroxylated and also the dehydrogenation of the C-17 hydroxyl group. The 16 alpha-17 beta isomer was extensively glucuronylated at C(O)3 but also underwent aromatic hydroxylation and methoxylation before conjugation. Its C-17 epimer was subject to much greater aromatic hydroxylation but the catecholestrogen was O-methylated to a greater relative extent. The 16 beta-17 beta derivative underwent alicyclic as well as substantial aromatic hydroxylation and yielded numerous isomeric glucuronides of O-methylated catechols. Thus, the fluorine exerted complex effects (inhibitory and enhancing) on both localized (D-ring) and distal (A-ring) biotransformations of the estradiol molecule; the direction and magnitude of the effects being dependent upon the stereochemistry at C-16 and C-17. These findings provide structural guidelines for restricting the metabolism of tumor-imaging fluoroestrogens and thereby enhancing their delivery to the target tissue.

Science of Synthesis: Houben-Weyl Methods of Molecular Transformations is the entirely new edition of the acclaimed reference series, Houben-Weyl, the standard synthetic chemistry resource since 1909. This new edition is published in English and will comprise of 48 volumes published between the years 2000 and 2008. Science of Synthesis is a quality reference work developed by a highly esteemed editorial board to provide a comprehensive and critical selection of reliable organic and organometallic synthetic methods. Science of Synthesis is designed to be the first point of reference when searching for a synthesis strategy. This volume covers the synthesis of five-membered heterocyclic compounds with an oxygen-, sulfur-, nitrogen-, selenium-, tellurium-, or phosphorus-containing heterocycle fused to one or two benzenoid rings. Volume 10 presents selected procedures for the synthesis of benzoannulated five-membered hetarenes. It covers the synthesis of heterocyclic compounds with widely differing stabilities and chemical and physical properties ranging from unstable hetarenes, such as benzo[c]furans, to very stable dibenzohetarenes, such as dibenzothiophene. For full information on the Science of Synthesis series, visit the Science of Synthesis Homepage. Series Editors: D. Bellus, S. V. Ley, R. Noyori, M. Regitz, E. Schaumann, I. Shinkai, E. J. Thomas, B. M. Trost, P. J. Reider.

Attempts to prepare and to isolate a benzyne–platinum complex (II), analogous to the known acetylene–platinum complexes (I), by use of three precursors of benzyne are described. A benzyne complex has not been isolated, but evidence is presented for a drastic alteration in the reactions of the benzyne precursors in the presence of platinum(O), in particular the catalysed trimerisation of benzyne to triphenylene.

The synthesis of α-pyrones related to isodehydracetic acid (2,4-dimethyl-6-oxopyran-3-carboxylic acid), their bromination, and the reaction of the bromo-compounds with bases have been reinvestigated and extended. The sodium-catalysed condensation of β-keto-esters and related compounds with acetyenic esters provides a satisfactory general method for synthesis of the α-pyrones. The reactions of the bromo-pyrones with alkali depend markedly on the structure of the pyrone, the nature of the alkali, and the reaction conditions, and give, variously, acyclic, cyclopropane, cyclopentane, and furan acids or their decarboxylation products. The formation of alkylidenecyclopropanes like Feist's acid is not a very general reaction.

1-Phthalimido-1,2,3-triazoles (1) thermally fragment in the vapour phase; the products isolated are 2H-azirines (2) and compounds derived from these azirines by further fragmentation or rearrangement.

The dehydrobromination of 5,7-dibromodibenzo[a,c]cycloheptadien-6-one (II) has been investigated as a possible route to phenanthrocyclopropenone (I). The products of the reactions are derivatives of 9-phenanthroic acid, but the cyclopropenone is probably not an intermediate in their formation.

1-(3,4-Dihydro-4-oxoquinazolin-3-yl)-2-vinylaziridines (I) undergo two competing thermal rearrangements: one to give the corresponding pyrrolines (II), and the other, a new type of rearrangement, to give the hydrazones (III). At higher temperatures a fragmentation involving cleavage of the N–N bond competes. An analogous thermal fragmentation of trans-2,3-diphenyl-1-phthalimidoaziridine (X) gives 2,3-diphenylazirine (XI), which in turn rearranges to 2-phenylindole. Reaction mechanisms are discussed.

Vapour phase pyrolysis of phthalimidodiphenyl-sulphoximide (1a) gives benzocyclobutenedione (70%), diphenyl sulphoxide (80%), and nitrogen; other sulphoximides fragment analogously.

Upon heating the sodium or silver salts of 2-chloroacrylic, 2-bromo-3,3-diphenylacrylic, and α-bromofluorenylideneacetic acid alone, in inert solvents, or in olefins, decarboxylation results and, where possible, rearrangement to acetylenes. Similarly, methyl fluorenylideneacetates are demethylated and decarboxylated on heating with sodium iodide. These decompositions do not involve carbenes.Treatment of esters of α-bromofluorenylideneacetic acid with alcoholic alkali or alkoxides causes replacement of bromine by hydrogen, to give fluorenylideneacetic acid in high yield, probably by hydride transfer from the alkoxide ion to the electrophilic double bond.

The double bond in dimethyl and diethyl 3-methylenecyclopropane-trans-1,2-dicarboxylate is reactive towards radical addition of thiophenol, bromotrichloromethane, and benzaldehyde, to give the normal adducts of terminal olefins; no evidence was found for participation of a non-classical cyclopropylmethyl radical. The double bond could not be epoxidised but reacted readily with ethyl diazoacetate to give the spiropentane esters.The bromine adducts of the unsaturated esters react with nucleophiles at the primary rather than at the tertiary bromine.

In contrast with NN′-dialkylsulphamides the oxidation of diarylsulphamides by hypochlorite is not a general route to aromatic azo-compounds; instead the major products are usually quinone anils, formed in a new aromatic rearrangement. The photolysis of the arylsulphamides and the thermolysis of their NN′-dichloro-derivatives do give azo compounds, however. The photochemical reaction appears to be intramolecular, possibly involving extrusion of sulphur dioxide as the first step.

1-Phthalimidoaziridines (III) with a conjugating substituent, when irradiated in the presence of another olefin, undergo an exchange reaction which results in the formation of a new phthalimidoaziridine incorporating the added olefin. Evidence is presented to show that the reaction involves the concerted fragmentation of the phthalimidoaziridines to give olefins and phthalimidonitrene, which is then trapped by the added olefin. The reaction has been extended to 1-(3,4-dihydro-2-methyl-4-oxoquinazolin-3-yl)aziridines (V), but it is not a general reaction for all aziridines with a heteroatom substituent at the 1-position.

Phthalimidoaziridines (I) show temperature-dependent 1H n.m.r. spectra. The coalescence temperatures for several 2- and 3-substituted phthalimidoaziridines have been found to lie in the range 75—125°. However, in the case of the 2,3-dichloro-derivatives, the coalescence temperatures are below 0°.

Oxidation of N-aminophthalimide, 3-amino-2-methyl-4-quinazolone, and 1-amino-2-quinolone with lead tetra-acetate in the presence of a wide range of electrophilic and nucleophilic olefins is a useful, stereospecific route to aziridines. The generation and cycloaddition of singlet amino-nitrenes is proposed.Several chloro- and bromo-substituted aziridines undergo an almost quantitative, uncatalysed thermal rearrangement, with opening of the aziridine ring, to give hydrazones.

Oxidation of 3-aminobenzotriazin-4-ones with lead tetra-acetate proceeds by two simultaneous independent routes, which involve (a) the loss of one mol. of nitrogen to form indazolones and (b) the loss of two mol. of nitrogen to form benzocyclopropenones. The indazolones, which can be intercepted by dienes, react with nucleophiles without rearrangement of the carbonyl group. Benzocyclopropenones react with nucleophiles with rearrangement of the carbonyl group to give isomeric pairs of benzoic acid derivatives. Concerted fragmentations of intermediate aminonitrenes are proposed to explain these results. The mechanisms suggested are supported by an 15N-labelling experiment and by extended Huckel molecular orbital calculations.