Vicinal, Double C-H Functionalization of Alcohols via an Imidate Radical-Polar Crossover Cascade.

A double functionalization of vicinal sp3 C-H bonds has been developed, wherein a ß amine and γ iodide are incorporated onto an aliphatic alcohol in a single operation. This approach is enabled by an imidate radical chaperone, which selectively affords a transient ß alkene that is amino-iodinated in situ. Overall, the radical-polar-crossover cascade entails the following key steps: (i) ß C-H iodination via 1,5-hydrogen atom transfer (HAT), (ii) desaturation via I2 complexation, and (iii) vicinal amino-iodination of an in situ generated allyl imidate. The synthetic utility of this double C-H functionalization is illustrated by conversion of aliphatic alcohols to a diverse collection of α,ß,γ substituted products bearing heteroatoms on three adjacent carbons. The radical-polar crossover mechanism is supported by various experimental probes, including isotopic labeling, intermediate validation, and kinetic studies.

Rational Design, Synthesis, Characterization and Evaluation of Iodinated 4,4'-Bipyridines as New Transthyretin Fibrillogenesis Inhibitors.

The 3,3',5,5'-tetrachloro-2-iodo-4,4'-bipyridine structure is proposed as a novel chemical scaffold for the design of new transthyretin (TTR) fibrillogenesis inhibitors. In the frame of a proof-of-principle exploration, four chiral 3,3',5,5'-tetrachloro-2-iodo-2'-substituted-4,4'- bipyridines were rationally designed and prepared from a simple trihalopyridine in three steps, including a Cu-catalysed Finkelstein reaction to introduce iodine atoms on the heteroaromatic scaffold, and a Pd-catalysed coupling reaction to install the 2'-substituent. The corresponding racemates, along with other five chiral 4,4'-bipyridines containing halogens as substituents, were enantioseparated by high-performance liquid chromatography in order to obtain pure enantiomer pairs. All stereoisomers were tested against the amyloid fibril formation (FF) of wild type (WT)-TTR and two mutant variants, V30M and Y78F, in acid mediated aggregation experiments. Among the 4,4'-bipyridine derivatives, interesting inhibition activity was obtained for both enantiomers of the 3,3',5,5'-tetrachloro-2'-(4-hydroxyphenyl)-2-iodo-4,4'-bipyridine. In silico docking studies were carried out in order to explore possible binding modes of the 4,4'-bipyridine derivatives into the TTR. The gained results point out the importance of the right combination of H-bond sites and the presence of iodine as halogen-bond donor. Both experimental and theoretical evidences pave the way for the utilization of the iodinated 4,4'-bipyridine core as template to design new promising inhibitors of TTR amyloidogenesis.

Synthesis, Photochemical and In Vitro Cytotoxic Evaluation of New Iodinated Aminosquaraines as Potential Sensitizers for Photodynamic Therapy.

In this work, several benzothiazole-based aminosquaraine dyes, displaying strong absorption within the so-called phototherapeutic window (650⁻800 nm), were synthesized. The ability, of all the new dyes, to generate singlet oxygen was assessed by determining the correspondent phosphorescence emission and through the comparison with a standard. The quantum yields of singlet oxygen generation were determined and exhibited to be strongly dependent on the nature of the amino substituents introduced in the squaric ring. The photodynamic activity of the synthesized dyes was tested against four human tumor cell lines: breast (MCF-7), lung (NCI-H460), cervical (HeLa) and hepatocellular (HepG2) carcinomas; and a non-tumor porcine liver primary cell culture (PLP2). All the compounds synthesized were found to be able to inhibit tumor cells growth upon irradiation more than in the dark, in most of the cases, very significantly. Considering the photodynamic activity exhibited and the low toxicity displayed for the non-tumor cells, some of the synthetized dyes can be regarded as potential candidates as photosensitizers for PDT.

Ligand-Enabled Pd(II)-Catalyzed Bromination and Iodination of C(sp3)-H Bonds.

We herein report the palladium(II)-catalyzed bromination and iodination of a variety of α-hydrogen-containing carboxylic acid and amino acid-derived amides. These reactions are exclusively enabled by quinoline-type ligands. The halogenated products obtained in this reaction are highly versatile and rapidly undergo further diversification. Further, we report the first example of a free carboxylic acid-directed Pd(II)-catalyzed C(sp3)-H bromination, enabled by quinoline ligands.

Bifunctional aryliodonium salts for highly efficient radioiodination and astatination of antibodies.

In this report we describe the development of an alternative approach to arylstannane chemistry for radiolabeling antibodies with radioiodine or astatine based on aryliodonium salts precursors. Bifunctional aryliodonium salts were designed and tested for the synthesis of 125I and 211At labeled prosthetic groups for bioconjugation. The nature of the electron rich aryl group was varied and its impact on the regioselectivity of radiohalogenation was evaluated. Unexpectedly, whereas the 2-thienyl group provided the best regioselectivity towards the radioiodination of the aryl moiety of interest (98:2), it was less selective for astatination (87:13); the anisyl group providing the best regioselectivity of astatination (94:6). Under optimized conditions, both radioiodination and astatination could be performed very efficiently in mild conditions (radiochemical yields>85%). The ionic nature of the precursors was exploited to develop an efficient purification approach: the HPLC step that is usually necessary in conventionnal approaches to optimize removal of organotin toxic precursors and side products was replaced by a filtration through a silica cartridge with a significantly reduced loss of radiolabeled product. The purified radioiodinated and astatinated prosthetic groups were then conjugated efficiently to an anti-CD138 monoclonal antibody (75-80% conjugation yield). By using this novel and simple radiohalogenation procedure, higher overall radiochemical yields of astatination were obtained in comparison with the use of an arylstannane precursor and procedures of the litterature for labeling the same antibody. Overall, due to their simplicity of use and high robustness, these new precursors should simplify the labeling of proteins of interest with iodine and astatine radioisotopes for imaging and therapeutic applications.

Oxidative Dearomatization of 4,5,6,7-Tetrahydro-1H-indoles Obtained by Metal- and Solvent-Free Thermal 5-endo-dig Cyclization: The Route to Erythrina and Lycorine Alkaloids.

A facile one-pot approach based on a thermally induced metal- and solvent-free 5-endo-dig cyclization reaction of the amino propargylic alcohols in combination with Dess-Martin periodinane-promoted oxidative dearomatization of 4,5,6,7-tetrahydroindole intermediates provides an efficient and robust access to 5,6-dihydro-1H-indol-2(4H)ones. Green, relatively mild and operationally simple characteristics of the synthetic sequence are the major advantages, which greatly amplify the developed methodology. The utility of obtained indolones as unified key precursors is demonstrated by the application of these products to the formal total syntheses of a whole pleiad of Erythrina- and Lycorine-type alkaloids, namely (±)-erysotramidine, (±)-erysotrine, (±)-erythravine, (±)-γ-lycorane, and abnormal erythrinanes (±)-coccoline and (±)-coccuvinine.

Pharmacophore elucidation of phosphoiodyn A - Potent and selective peroxisome proliferator-activated receptor ß/δ agonists with neuroprotective activity.

We report the pharmacophore of the peroxisome proliferator-activated receptor δ (PPARδ) agonist natural product phosphoiodyn A is the phosphonate core. Synthesis of simplified phosphonate esters 13 and 15 provide structurally novel, highly selective and potent PPARδ agonists (EC50=78 and 112 nM, respectively). Further, both compounds demonstrate significant neuroprotective activity in an in vitro cellular model indicating that phosphonates may be an effective novel scaffold for the design of therapeutics for the treatment of neurodegenerative disorders.

An alternative to the Sandmeyer approach to aryl iodides.

Iodoarenes are important synthons for a wide range of organic transformations. Here we report a general strategy to prepare singly iodinated electron-rich aromatic compounds through the intermediacy of diaryliodonium salts. This process, which incorporates a phase separation that greatly simplifies product purification, is an attractive replacement for the Sandmeyer approach to iodoarenes that are otherwise difficult to access.

Regio- and stereoselective iodoacyloxylations of alkynes.

A new method for the regioselective and stereoselective iodoacyloxylation of alkynes has been developed. This protocol utilizes a combination of an iodobenzene dicarboxylate and iodine to functionalize a series of activated and unactivated alkynes in an entirely selective and predictable fashion. The resultant iodo-enol esters were subsequently coupled with boronic acids to afford tetrasubstituted alkene derivatives, which could be further converted to the corresponding 1,1-disubstituted acetophenone.

Synthesis of Dibenzofurans via C-H Activation of o-Iodo Diaryl Ethers.

An efficient method for the synthesis of dibenzofuran from o-iododiaryl ether using reusable Pd/C under ligand-free conditions has been developed. Synthesis of o-iododiaryl ether was achieved in one pot through sequential iodination and O-arylation of phenol under mild reaction conditions.

Improved synthesis and application of [(11) C]benzyl iodide in positron emission tomography radiotracer production.

Positron emission tomography has increased the demand for new carbon-11 radiolabeled tracers and building blocks. A promising radiolabeling synthon is [(11) C]benzyl iodide ([(11) C]BnI), because the benzyl group is a widely present functionality in biologically active compounds. Unfortunately, synthesis of [(11) C]BnI has received little attention, resulting in limited application. Therefore, we investigated the synthesis in order to significantly improve, automate, and apply it for labeling of the dopamine D2 antagonist [(11) C]clebopride as a proof of concept. [(11) C]BnI was synthesized from [(11) C]CO2 via a Grignard reaction and purified prior the reaction with desbenzyl clebopride. According to a one-pot procedure, [(11) C]BnI was synthesized in 11 min from [(11) C]CO2 with high yield, purity, and specific activity, 52 ± 3% (end of the cyclotron bombardment), 95 ± 3%, and 123 ± 17 GBq/µmol (end of the synthesis), respectively. Changes in the [(11) C]BnI synthesis are reduced amounts of reagents, a lower temperature in the Grignard reaction, and the introduction of a solid-phase intermediate purification. [(11) C]Clebopride was synthesized within 28 min from [(11) C]CO2 in an isolated decay-corrected yield of 11 ± 3% (end of the cyclotron bombardment) with a purity of >98% and specific activity (SA) of 54 ± 4 GBq/µmol (n = 3) at the end of the synthesis. Conversion of [(11) C]BnI to product was 82 ± 11%. The reliable synthesis of [(11) C]BnI allows the broad application of this synthon in positron emission tomography radiopharmaceutical development.

Synthesis and Photophysical Properties of Polycarbo-Substituted Quinazolines Derived from the 2-Aryl-4-chloro-6-iodoquinazolines.

The reactivity of the 2-aryl-4-chloro-6-iodoquinazolines towards palladium catalyzed sequential (Sonogashira/Suzuki-Miyaura) and one-pot two-step cross-coupling (bis-Sonogashira, and successive Sonogashira/Stille) reactions to afford novel unsymmetrical polycarbo-substituted quinazolines has been evaluated. In contrast to the chloro-bromo substituted quinazolines in which selectivity has been previously found to generally favor substitution at the more activated C(4)-Cl bond over the weaker Csp(2)-Br bond, substitution in the case of the chloro-iodo derivatives favors cross-coupling through the intrinsically more reactive Csp(2)-I bond. The electronic absorption and emission properties of the prepared 2,3-diaryl-6-(phenylethynyl)quinazolines were studied in solvents of different polarity (dichloromethane, toluene, DMF, methanol) and CH2Cl2-TFA mixture using UV-Vis and emission spectroscopic techniques complemented with density functional theory method to establish the effect of substituents on intramolecular charge transfer properties.

[(18) F]CuCF3 : a [(18) F]trifluoromethylating agent for arylboronic acids and aryl iodides.

Positron emission tomography has emerged as the leading method for medical imaging with fluorine-18 as the most widely used radioactive isotope. Here we report a semi-automated method for the preparation of valuable [(18) F]trifluoromethylcopper, as well as its use for the radiosynthesis of [(18) F]trifluoromethylarenes and heteroarenes. Mild conditions of [(18) F]trifluoromethylation make this method particularly useful for the radiosynthesis of pharmacologically relevant [(18) F]trifluoromethylarenes and heteroarenes.

tert-Butyl peroxybenzoate-promoted α-methylation of 1,3-dicarbonyl compounds.

A tert-butyl peroxybenzoate (TBPB)-promoted direct α-methylation of 1,3-dicarbonyl compounds has been developed, providing α-methyl derivatives in moderate to good yields. In this procedure, TBPB plays a dual role, serving as both the methyl source and radical initiator. This work represents a key complement to the traditional α-methylation of 1,3-dicarbonyl compounds using methyl iodide.

Molecular iodine-mediated reaction of 2-(2-phenylethynyl)-Morita-Baylis-Hillman adducts: an easy route to naphthyl ketones and iodo-substituted isochromenes.

The molecular iodine-promoted reaction of 2-(2-phenylethynyl)-Morita-Baylis-Hillman adducts is reported. In the presence of I2, naphthyl ketone derivatives are produced, whereas in the presence of I2/K3PO4, iodo-substituted isochromene derivatives are produced.

Controlled trifluoromethylation reactions of alkynes through visible-light photoredox catalysis.

The control of a reaction that can form multiple products is a highly attractive and challenging concept in synthetic chemistry. A set of valuable CF3 -containing molecules, namely trifluoromethylated alkenyl iodides, alkenes, and alkynes, were selectively generated from alkynes and CF3 I by environmentally benign and efficient visible-light photoredox catalysis. Subtle differences in the combination of catalyst, base, and solvent enabled the control of reactivity and selectivity for the reaction between an alkyne and CF3 I.

Pd(II)-catalyzed C-H iodination using molecular I2 as the sole oxidant.

Pd-catalyzed ortho-C-H iodination directed by a weakly coordinating amide auxiliary using I2 as the sole oxidant was developed. This reaction is compatible with a wide range of heterocycles including pyridines, imidazoles, oxazoles, thiazoles, isoxazoles, and pyrazoles.

One-pot synthesis of hypervalent iodine reagents for electrophilic trifluoromethylation.

Simplified syntheses suited for large scale preparations of the two hypervalent iodine reagents 1 and 2 for electrophilic trifluoromethylation are reported. In both cases, the stoichiometric oxidants sodium metaperiodate and tert-butyl hypochlorite have been replaced by trichloroisocyanuric acid. Reagent 1 is accessible in a one-pot procedure from 2-iodobenzoic acid in 72% yield. Reagent 2 was prepared via fluoroiodane 11 in a considerably shorter reaction time and with no need of an accurate temperature control.

Highly efficient and chemoselective α-iodination of acrylate esters through Morita-Baylis-Hillman-type chemistry.

The chemoselective α-iodination of various simple and multi-functionalised acrylic esters is efficiently accomplished by a Morita-Baylis-Hillman protocol involving the use of N-iodophthalimide, 3-quinuclidinol and KF-Celite in acetonitrile. No degradation of the obtained compounds was observed under the optimized conditions thus, furnishing α-iodoacrylates suitable for organometallic reactions (i.e. Nozaki-Kishi-Hiyama type coupling).

Synthesis of α-iodoketals from methyl ketones via sustainable and orthogonal tandem catalysis.

A highly efficient method for the direct synthesis of α-iodoketals from methyl ketones has been developed via sustainable integration of orthogonal tandem catalytic reactions: copper(II) oxide catalyzed iodination reaction and the subsequent excess or regenerated iodine catalyzed regioselective ketalization reaction.