Synthesis of [211At]4-astato-L-phenylalanine by dihydroxyboryl-astatine substitution reaction in aqueous solution

Astatine-211 (211At)-labeled phenylalanine is expected to be a promising agent for targeted alpha-particle therapy for the treatment of patients with glioma. The existing reactions to prepare the labeled compound usually require organic solvents and metals that are toxic and hazardous to the environment. In this study, we developed a novel method wherein astatination was realized via the substitution of 211At for a dihydroxyboryl group coupled to phenylalanine. [211At]4-astato-L-phenylalanine was obtained as the carrier-free product in aqueous medium in high radiochemical yields (98.1 ± 1.9%, n = 5). The crude reaction mixture was purified by solid-phase extraction, and the radiochemical purity of the product was 99.3 ± 0.7% (n = 5). The high yield and purity were attributed to the formation of [211At]AtI and AtI2− as the reactive intermediates in the astatination reaction. The reaction did not require any organic solvents or toxic reagents, suggesting that this method is suitable for clinical applications.

Four Different Crystalline Products from One Reaction: Unexpected Diversity of Products of the CuCl2 Reaction with N-(2-Pyridyl)thiourea

The reaction of N-(2-pyridyl)thiourea with CuCl2 in methanol yields four different crystalline products: yellow dimeric complex, [Cu2Cl2(μ-Cl)2(L)2] (1), red polymeric complex, [Cu3Cl8L2]n (2), orange crystalline product with ionic structure, L2[CuCl4] (3), and colourless ionic compound LCl (4), where L = 2-amino-[1,2,4]thiadiazolo[2,3-a]pyridin-4-ium cation as a result of oxidative cyclization of N-(2-pyridyl)thiourea. The crystal structures of all these crystalline products have been determined by single-crystal X-ray diffraction analysis. Compound 1 involves a copper(I) ion while in 2 and 3 the copper centre is in the divalent state. 1H NMR spectra for compounds 1–3 are identical and confirm deprotonated thioamide groups of N-(2-pyridyl)thiourea and the formation of a thiadiazolopyridinium cation in solution. The hydrogen bonding and π–π stacking interactions were investigated in the solid state. In addition, all crystalline products 1–4 exhibit also S···Cl bonding interactions which consolidate the complexes into networks. The X-ray diffraction analyses indicate the absence of other crystalline phases in the crude reaction mixture.

Fast and efficient copper-mediated 18F-fluorination of arylstannanes, aryl boronic acids, and aryl boronic esters without azeotropic drying

Background Copper-mediated radiofluorination is a straightforward method to produce a variety of [18F]fluoroarenes and [18F]fluoroheteroarenes. To minimize the number of steps in the production of 18F-labelled radiopharmaceuticals, we have developed a short and efficient azeotropic drying-free 18F-labelling method using copper-mediated fluorination. Our goal was to improve the copper-mediated method to achieve wide substrate scope with good radiochemical yields with short synthesis time. Results Solid phase extraction with Cu (OTf)2 in dimethylacetamide is a suitable activation method for [18F]fluoride. Elution efficiency with Cu (OTf)2 is up to 79% and radiochemical yield (RCY) of a variety of model molecules in the crude reaction mixture has reached over 90%. Clinically relevant molecules, norepinephrine transporter tracer [18F]NS12137 and monoamine transporter tracer [18F]CFT were produced with 16.5% RCY in 98 min and 5.3% RCY in 64 min, respectively. Conclusions Cu (OTf)2 is a suitable elution agent for releasing [18F]fluoride from an anion exchange cartridge. The method is fast and efficient and the Cu-complex is customizable after the release of [18F]fluoride. Alterations in the [18F]fluoride elution techniques did not have a negative effect on the subsequent labelling reactions. We anticipate this improved [18F]fluoride elution technique to supplant the traditional azeotropic drying of [18F]fluoride in the long run and to concurrently enable the variations of the copper-complex.

Separation of Unprecedented Degradants of Domperidone by Ultra-Performance Convergence Chromatography and Their Structure Elucidation

Domperidone, a gastroprokinetic agent, is a common drug to treat emesis. It was subjected to acid, base-mediated hydrolysis, peroxide-mediated oxidation, photolysis and thermal degradation according to ICH guidelines to observe stability of the selected drug under the stress conditions. Although the drug is resistant to base hydrolysis, photolysis and thermal stressors, two degradants (DP-ISO1 and DP-ISO2) were formed in acid mediated hydrolysis. Oxidation with hydrogen peroxide also resulted in one product (DP-OX). All three degradants were isolated from the crude reaction mixture by preparative high-performance liquid chromatography and supercritical fluid chromatography. Structures of isolated compounds were unambiguously characterized as 5-chloro-1-(1-(3-(6-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (DP-ISO1), 5-chloro-1-(3-(4-(5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)propyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (DP-ISO2), 4-(5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)piperidine 1-oxide (DP-OX) by analysis of mass spectrometry, 1D and 2D nuclear magnetic resonance spectra. To the best of our knowledge, DP-ISO1 and DP-ISO2 are new and DP-OX was previously reported as domperidone impurity.

7-(Biphenyl-4-yl)-6-hydroxyindan-1-one

The title compound, C21H16O2, was isolated from the reaction of 1-(2-methoxyethoxy)-1-vinylcyclopropane, 4-ethynylbiphenyl, and CO in a [5 + 1 + 2 + 1] cycloaddition reaction catalysed by [Rh(CO)2Cl]2. The crystals precipitated directly from the crude reaction mixture. A hydrogen-bonding framework between the hydroxy and carbonyl groups of a symmetry-related neighbour connects the molecules into chains running parallel to the crystallographic c axis. A minor non-merohedral twin component was included in the refinement.

Substituted Benzenes: The Li Synthesis of Rubriflordilactone A

Cheol-Hong Cheon of Korea University (J. Org. Chem. 2014, 79, 7277) and Toshiyuki Kamei and Toyoshi Shimada of the Nara National College of Technology (Tetrahedron Lett. 2014, 55, 4245) described the ring bromination of arene boronates. The boronate can then be removed, enabling the conversion of 1 to 2. Yu Rao of Tsinghua University constructed (Chem. Commun. 2014, 50, 15037) the sulfone 5 by coupling the arenes 3 and 4 with K2S2O8. Igor Larrosa of Queen Mary University of London assembled (Chem. Sci. 2014, 5, 3509) the biphenyl 8 by arylating 6 with the iodide 7. Guy Bertrand of the University of California, San Diego showed (J. Am. Chem. Soc. 2014, 136, 13594) that under Au catalysis, the aniline 9 was sufficiently nucleophilic to add in a conjugate sense to the enone 10 to give 11. Hideo Togo of Chiba University optimized (Eur. J. Org. Chem. 2014, 6077) condi­tions for the selective ortho formylation of a phenol 12. The crude reaction mixture could also be directly oxidized with I2/ NH3 to give the nitrile 13. Silas P. Cook of Indiana University ortho metalated (J. Am. Chem. Soc. 2014, 136, 13130; Angew. Chem. Int. Ed. 2014, 53, 11065) the benzamide 14, then used an iron catalyst to couple that intermediate with a halide 15, leading to the alkylated product 16. As with the phenol 12 and the benzamide 14, aromatic functionalization has usu­ally been directed by a functional group directly attached to the ring. Daqin Shi and Yingsheng Zhao of Soochow University showed (Chem. Sci. 2014, 5, 4962) that a longer tether can be effective, as illustrated by the conversion of 17 to 19. Debabrata Maiti of the Indian Institute of Technology Bombay also used (Org. Lett. 2014, 16, 5760) a longer tether for the selective meta functionalization of 20 to 22. Motohiro Sonoda of Osaka Prefecture University constructed (Tetrahedron Lett. 2014, 55, 5302) the phenol 25 by acid-mediated rearrangement of the Diels–Alder adduct of 24 with the furan 23. Anthony G. M. Barrett of Imperial College London devised (J. Org. Chem. 2014, 79, 8706) conditions for the iodinative cyclization of 26 to 27.

Advantages of polymer-supported multivalent organocatalysts for the Baylis-Hillman reaction over their soluble analogues

Immobilization of well-defined catalytic units onto insoluble support promises significant benefits, but frequently results in a reduced activity and selectivity of the heterogenized catalysts. Recently, we showed that introduction of a dendritic spacer between the support and the units could remedy the compromised activity and/or selectivity of heterogenized catalysts and, in particular, of the systems based on N-alkylated imidazoles. These catalysts exhibit an outstanding multivalency effect on the activity in the Baylis-Hillman reaction, while preserving very high chemoselectivity. In order to better understand this remarkable effect, we decided to synthesize and examine soluble analogues of the supported systems. These soluble catalysts display poor chemoselectivity, although it improves with the increase of the dendritic generation. Though the consumption of the limiting aldehyde reactant (conversion) displays the opposite trend, experiments demonstrated that the chemoselectivity is generation-dependent rather than conversion-dependent. A hydrophobic “pocket” effect was implicated as responsible for the differences between the polystyrene-bound and the soluble catalysts. An MS analysis of the crude reaction mixture revealed that the formation of multiple adducts, which incorporate several enone and several nitrobenzaldehyde fragments into a single molecular structure (as opposed to one-to-one stoichiometry of the Baylis-Hillman reaction), is responsible for the decline in the chemoselectivity.

Notizen: Preparation of Dimeric [(η5-tBu3Cp)CoBr]2 and Convenient Synthesis of the Homodinuclear Cobalt Complex [(η5-tBu3Cp)Co]2H3 therefrom.

The title compound [(η5-tBu3Cp)CoBr]2 1 is prepared in a one pot reaction starting from 1,2,4- tBu3-cyclopentadiene followed by metallation and by reaction of the resulting tBu3Cp-K+ anion salt with anhydrous CoBr2 in THF. 1 was isolated from this reaction in 78% yield as black crystals. 1 reacts with LiAlH4 in THF at 0 °C. Subsequent alcoholysis of the crude reaction mixture with ethanol at -78 °C gives the novel trihydride cluster [(η5-tBu3Cp)Co]2H3 2 in 58% isolated yield as black crystals. 2 has been characterized by 1H NMR, ESR, MS, and IR spectroscopy, as well as by elemental analysis.