Convenient synthesis and X-ray determination of 2-amino-6H-1,3,4-thiadiazin-3-ium bromides endowed with antiproliferative activity.

A new series of 1,3,4-thiadiazin-3-ium bromide derivatives 9a-g were prepared as a six-member ring by interactions between 4-substituted thiosemicarbazides 8a-e and α-halo ketones 2a,b. The reaction was conducted using hydrazine-NH2 and yielded a hexagonal shape. The structures of all obtained compounds have been verified using IR, NMR spectra, mass spectrometry, elemental analysis, and X-ray crystallography. The X-ray crystallographic analysis of compounds 9a and 9b has revealed that the salt is formed with the nitrogen atom N3 when the aromatic substituents 9a and 9d are present, but in the case of compounds 9b, 9c, 9e, 9f, and 9g with the aliphatic substituent, the salt is formed outside the ring. Compounds 9a-g were evaluated for antiproliferative activity as multitargeted inhibitors. Results revealed that targets 9a-g displayed good antiproliferative activity, with GI50 ranging from 38 nM to 66 nM against a panel of four cancer cell lines compared to the reference Erlotinib (GI50 = 33 nM). Compounds 9a, 9c, and 9d were the most potent antiproliferative derivatives, with GI50 values of 43, 38, and 47 nM, respectively. Compounds 9a, 9c, and 9d were evaluated for their inhibitory activity against EGFR, BRAFV600E, and VEGFR-2. The in vitro experiments demonstrated that the compounds being examined exhibit potent antiproliferative properties and have the potential to function as multitargeted inhibitors. In addition, the western blotting investigation demonstrated the inhibitory effects of 9c on EGFR, BRAFV600E, and VEGFR-2.

Chromium Complexes with Benzanellated N-heterocyclic Phosphenium Ligands - Synthesis, Reactivity and Application in Catalytic CO2 Reduction.

A chromium complex carrying two benzanellated N-heterocyclic phosphenium (bzNHP) ligands was prepared by a salt metathesis approach. Spectroscopic studies suggest that the anellation enhances the π-acceptor ability of the NHP-units, which is confirmed by the facile electrochemical reduction of the complex to a spectroscopically characterized radical anion. Co-photolysis with H2 allowed extensive conversion into a σ-H2-complex, which shows a diverse reactivity towards donors and isomerizes under H-H bond fission and shift of a hydride to a P-ligand. The product carrying phosphenium, phosphine and hydride ligands was also synthesized independently and reacts reversibly with CO and MeCN to yield bis-phosphine complexes under concomitant Cr-to-P-shift of a hydride. In contrast, CO2 was not only bound but reduced to give an isolable formato complex, which reacted with ammonia borane under partial recovery of the metal hydride and production of formate. Further elaboration of the reactions of the chromium complexes with CO2 and NH3BH3 allowed to demonstrate the feasibility of a Cr-catalyzed transfer hydrogenation of CO2 to methanol. The various complexes described were characterized spectroscopically and in several cases by XRD studies. Further insights in reactivity patterns were provided through (spectro)electrochemical studies and DFT calculations.

Synthesis of substituted triazole-pyrazole hybrids using triazenylpyrazole precursors.

A synthesis route to access triazole-pyrazole hybrids via triazenylpyrazoles was developed. Contrary to existing methods, this route allows the facile N-functionalization of the pyrazole before the attachment of the triazole unit via a copper-catalyzed azide-alkyne cycloaddition. The developed methodology was used to synthesize a library of over fifty new multi-substituted pyrazole-triazole hybrids. We also demonstrate a one-pot strategy that renders the isolation of potentially hazardous azides obsolete. In addition, the compatibility of the method with solid-phase synthesis is shown exemplarily.

On the mechanism of sp2 C-H borylation using ortho-N-substituted pyridinium cations.

ortho-N-Substituted pyridinium cations with the weakly coordinating anion [B(C6F5)4]- have been studied and crucial structural features in the sp2 C-H borylation catalysis of 3-methylthiophene have been identified. The electron-deficiency of the aromatic core of the cation is essential for activity together with accessible protons. The spectroscopic yield of the borylation of 3-methylthiophene with catecholborane (CatBH) was optimized up to 86% and the method was further applied to other substrates such as N-alkylbenzenes. A mechanistic DFT study revealed the rate-limiting step in the catalysis to be the liberation of molecular H2 (ΔG‡ = 27.5 kcal mol-1), whereas the overall reaction was found to be exergonic by 5.1 kcal mol-1.

Azophosphines: Synthesis, Structure and Coordination Chemistry.

The conceptual replacement of nitrogen with phosphorus in common organic functional groups unlocks new properties and reactivity. The phosphorus-containing analogues of triazenes are underexplored but offer great potential as flexible and small bite-angle ligands. This manuscript explores the synthesis and characterisation of a family of air-stable azophosphine-borane complexes, and their subsequent deprotection to the free azophosphines. These compounds are structurally characterised, both experimentally and computationally, and highlight the availability of the phosphorus lone pair for coordination. This is confirmed by demonstrating that neutral azophosphines can act as ligands in Ru complexes, and can coordinate as monodentate or bidentate ligands in a controlled manner, in contrast to their nitrogen analogues.

Synthesis of Mono-, Di-, Tri-, and Tetra-cationic Pyridinium and Vinylpyridinium Modified [2.2]Paracyclophanes: Modular Receptors for Supramolecular Systems.

In this report, a new series of mono-, di-, tri-, and tetra-cationic pyridinium and vinyl pyridinium-modified [2.2]paracyclophanes as useful molecular tectons for supramolecular systems are described. Regioselective functionalization at specific positions, followed by resolution step and successive transformations through Pd-catalyzed Suzuki-Miyaura and Mizoroki-Heck cross-coupling chemistry furnish a series of modular PCP scaffolds. In our proof-of-concept study, on N-methylation, the PCPs bearing (cationic) pyridyl functionalities were demonstrated as useful molecular receptors in host-guest supramolecular assays. The PCPs on grafting with light-responsive azobenzene (-N=N-) functional core as side-groups impart photosensitivity that can be remotely transformed on irradiation, offering photo-controlled smart molecular functions. Furthermore, the symmetrical PCPs bearing bi-, and tetra-pyridyl functionalities at the peripheries have enormous potential to serve as ditopic and tetratopic 3D molecular tectons for engineering non-covalent supramolecular assemblies with new structural and functional attributes.

Lithium aluminate flotation by pH- and light-switchable collectors based on the natural product punicine.

Derivatives of the natural product punicine [1-(2',5'-dihydroxyphenyl)pyridinium chloride] were developed as switchable collectors for the flotation of lithium-containing engineered artifical minerals (EnAMs). These EnAMs are e.g. formed by pyrometallurgical processing of end-of-life lithium-ion batteries. Depending on the pH value and the lighting conditions, punicines exist in water as cations, two different electrostatically neutral mesomeric betaines, anionic tripoles, radical cations or radical anions. The radical species form by photochemically induced disproportionation reactions. We prepared punicine derivatives introducing alkyl chains in the pyridinium moiety (4-methyl, 4-ethyl, 4-octyl and 4-undecanyl) to install hydrophobic groups and examined the recovery rates of the flotation of lithium aluminate (LiAlO2). We varied the lighting conditions (darkness, daylight, LED irradiation at λ = 390-400 nm) and the pH value, the collector's and frother's concentration, and the flotation time. With our collectors, recovery rates of lithium aluminate up to 90% were accomplished when the flotation was conducted in Hallimond tubes exposed to daylight at pH 11 in water.

The Noble Addendum of a Phosphenium Ligand to a Base Metal: Coordination, Activation, and Hydrogenation of Alkenes and Alkynes on a Chromium Complex.

The synthesis of a new bis-NHP complex (NHP=N-heterocyclic phosphenium) of chromium via salt metathesis and studies of its reactivity are reported. Photochemical reactions with H2 and selected olefins give rise to non-isolable H2- and π-alkene complexes identified spectroscopically, while internal alkynes react via activation of the triple bond to yield isolable metalla-phospha-cyclobutenes characterized by spectroscopic and XRD data. DFT studies give a preliminary account of the bonding in H2- and alkene-complexes and explain the different reactivity towards alkenes and alkynes as the consequence of kinetic effects. Photolysis of the bis-NHP-complex in the presence of H2 and olefins or alkenes enables the catalytic hydrogenation of the organic substrates, while the π-ethene complex mediates the catalytic hydrogenation of ethene in a dark reaction. The similarities and differences between both catalytic processes are shortly discussed.

Stereoselective synthesis and X-ray structure determination of novel 1,2-dihydroquinolinehydrazonopropanoate derivatives.

A novel series of 1,2-dihydroquinolinhydrazonopropanoate have been synthesized via a convenient aza-Michael addition reaction between hydrazinylquinolinones and ethyl propiolate in ethanol under refluxing temperature. The structures for all obtained products were confirmed with FTIR, NMR spectrums, as well as mass spectrometry. In addition, the monoclinic structure for compounds 8a, 8c, and 8d was also confirmed via X-ray crystallography analyses. The E-configuration for the obtained products was confirmed form the X-ray analysis. On the other hand, the crystal packing shows that the intermolecular and hydrogen bonds between atoms are parallel to the bc plan.

From Mono- to Polynuclear 2-(Diphenylphosphino)pyridine-Based Cu(I) and Ag(I) Complexes: Synthesis, Structural Characterization, and DFT Calculations.

A series of monometallic Ag(I) and Cu(I) halide complexes bearing 2-(diphenylphosphino)pyridine (PyrPhos, L) as a ligand were synthesized and spectroscopically characterized. The structure of most of the derivatives was unambiguously established by X-ray diffraction analysis, revealing the formation of mono-, di-, and tetranuclear complexes having general formulas MXL3 (M = Cu, X = Cl, Br; M = Ag, X = Cl, Br, I), Ag2X2L3 (X = Cl, Br), and Ag4X4L4 (X = Cl, Br, I). The Ag(I) species were compared to the corresponding Cu(I) analogues from a structural point of view. The formation of Cu(I)/Ag(I) heterobimetallic complexes MM'X2L3 (M/M' = Cu, Ag; X = Cl, Br, I) was also investigated. The X-ray structure of the bromo-derivatives revealed the formation of two possible MM'Br2L3 complexes with Cu/Ag ratios, respectively, of 7:1 and 1:7. The ratio between Cu and Ag was studied by scanning electron microscopy-energy-dispersive X-ray analysis (SEM-EDX) measurements. The structure of the binuclear homo- and heterometallic derivatives was investigated using density functional theory (DFT) calculations, revealing the tendency of the PyrPhos ligands not to maintain the bridging motif in the presence of Ag(I) as the metal center.

Homolytic C-H Bond Activation by Phosphine-Quinone-Based Radical Ion Pairs.

Herein, we present the formation of transient radical ion pairs (RIPs) by single-electron transfer (SET) in phosphine-quinone systems and explore their potential for the activation of C-H bonds. PMes3 (Mes=2,4,6-Me3 C6 H2 ) reacts with DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) with formation of the P-O bonded zwitterionic adduct Mes3 P-DDQ (1), while the reaction with the sterically more crowded PTip3 (Tip=2,4,6-iPr3 C6 H2 ) afforded C-H bond activation product Tip2 P(H)(2-[CMe2 (DDQ)]-4,6-iPr2 -C6 H2 ) (2). UV/Vis and EPR spectroscopic studies showed that the latter reaction proceeds via initial SET, forming RIP [PTip3 ]⋅+ [DDQ]⋅- , and subsequent homolytic C-H bond activation, which was supported by DFT calculations. The isolation of analogous products, Tip2 P(H)(2-[CMe2 {TCQ-B(C6 F5 )3 }]-4,6-iPr2 -C6 H2 ) (4, TCQ=tetrachloro-1,4-benzoquinone) and Tip2 P(H)(2-[CMe2 {oQtBu -B(C6 F5 )3 }]-4,6-iPr2 -C6 H2 ) (8, oQtBu =3,5-di-tert-butyl-1,2-benzoquinone), from reactions of PTip3 with Lewis-acid activated quinones, TCQ-B(C6 F5 )3 and oQtBu -B(C6 F5 )3 , respectively, further supports the proposed radical mechanism. As such, this study presents key mechanistic insights into the homolytic C-H bond activation by the synergistic action of radical ion pairs.

Stereospecific Synthesis of Cyclohexenone Acids by [3,3]-Sigmatropic Rearrangement Route.

Herein we report a modular synthetic method for the preparation of diaryl-substituted cyclohexenone acids starting from phenyl pyruvate and suitable enones. When the reaction is carried out in alkaline tert-butanol or toluene solutions in microwave-assisted conditions mainly anti configuration products are obtained with up to 86% isolated yield. However, when the reaction is carried out in alkaline water, a mixture of products with anti and syn conformations is obtained with up to 98% overall isolated yield. Mechanistically the product with anti conformation forms by a hemiketal-oxy-Cope type [3,3]-sigmatropic rearrangement-intramolecular aldol condensation route and syn product by an intermolecular aldol condensation-electrocyclization (disrotatory type) route.

Synthesis of bis-thiohydantoin derivatives as an antiproliferative agents targeting EGFR inhibitory pathway.

(R)/(S)-the two enantiomers of 3-substituted-1-[2-(5)-3-substituted-4-benzyl-5-oxo-4-phenyl-2-thioxoimid-azolidin-1-yl]ethyl/propyl-5-benzyl-5-phenyl-2-thioxoimidazolidin-4-ones were formed during the diastereoselective reaction between N,N″-1,ω-alkanediylbis[N'-organylthiourea] derivatives and 2,3-diphenylcyclopropenone in refluxing ethanol. The structures of the isolated compounds were confirmed by NMR, IR, mass spectra and elemental analyses. Moreover, single-crystal X-ray structure analysis was also used to elucidate the structure of the isolated compounds. The mechanism describes the reaction was also discussed. The tested compounds showed EGFR inhibitory activity with IC50 values ranging from 90 to 178 nM in comparison to the erlotinib as a reference with IC50 value of 70 nM. Compound 4c (R = allyl, n = 3) was found as the most potent antiproliferative, had the highest inhibitory effect on EGFR with an IC50 value of 90 nM, compared to erlotinib's IC50 value of 70 nM. The second and third-most active compounds were 4e (R = phenyl, n = 3) and 4d (R = ethyl, n = 3) and with IC50 values of 107 nM and 128 nM. These findings imply that the compounds tested had a significant antiproliferative effect as well as the ability to act as an EGFR inhibitor. Docking studies showed that compound 4c showed high affinity to EGFR based on its docking score (S; kcal/mol) within five test compounds.

Tris(4-azidophenyl)methanol - a novel and multifunctional thiol protecting group.

The novel tris(4-azidophenyl)methanol, a multifunctionalisable aryl azide, is reported. The aryl azide can be used as a protecting group for thiols in peptoid synthesis and can be cleaved under mild reaction conditions via a Staudinger reduction. Moreover, the easily accessible aryl azide can be functionalised via copper-catalysed cycloaddition reactions, providing additional opportunities for materials chemistry applications.

Hemipiperazines as peptide-derived molecular photoswitches with low-nanomolar cytotoxicity.

Molecular photoswitches transform light energy into reversible structural changes. Their combination with known pharmacophores often allows for photomodulation of the biological activity. The effort to apply such compounds in photopharmacology as light-activated pro-drugs is, however, hampered by serious activity reduction upon pharmacophore modifications, or limited biostability. Here we report that a potent antimitotic agent plinabulin and its derivatives demonstrate up to 56-fold reversible activity photomodulation. Alternatively, irreversible photoactivation with cyan light can enhance the cytotoxicity up to three orders of magnitude-all without compromising the original activity level, as the original pharmacophore structure is unchanged. This occurs due to the presence of a peptide-derived photoswitchable motif hemipiperazine inside the plinabulin scaffold. Furthermore, we systematically describe photochromism of these thermally stable and biocompatible hemipiperazines, as well as a photoswitchable fluorophore derived from plinabulin. The latter may further expand the applicability of hemipiperazine photochromism towards super-resolution microscopy.

Copper Complexes of 1,4-Naphthoquinone Containing Thiosemicarbazide and Triphenylphosphine Oxide Moieties; Synthesis and Identification by NMR, IR, Mass, UV Spectra, and DFT Calculations.

New 1,4-naphthoquinone derived by triphenylphosphaneylidene (Ph3P) and N-substituted-hydrazine-1-carbothioamides were obtained during a one-pot reaction of 2,3-dichloro-1,4-naphthoquinone with thiosemicarbazides, Ph3P and in the presence of triethyl amine (Et3N) as a catalyst. The structure of the ligands was established by ESI, IR, and NMR spectra, in addition to elemental analyses and X-ray structure analysis. On subjecting the newly prepared ligands with CuCl2 and Ph3P, autoxidation occurs, and (E)-(2-(1,4-dioxo-3-(triphenyl phosphanylidene)-3,4-dihydronaphthalen-2(1H)-ylidene)carbamothioyl)hydrazinyl)-((triphenylphosphanyl)oxy)copper derivatives were formed in very good yields. The structure of the obtained complexes was proved by ESI, IR, NMR, and UV spectra, in addition to elemental analyses and theoretical calculations.

Functionalized C3-Symmetric Building Blocks-The Chemistry of Triaminotrimesic Acid.

A series of C3-symmetric fully substituted benzenes were prepared based on alkyl triamino-benzene-tricarboxylates. Starting with a one step-synthesis, the alkyl triamino-benzene-tricarboxylates were synthesized using the corresponding cyanoacetates. The reactivity of these electronically sophisticated compounds was investigated by the formation of azides, the click reaction of the azides and a Sandmeyer-like reaction. Caused by the low stability of triaminobenzenes, direct N-alkylation was rarely reported. The use of the stable alkyl triamino-benzene-tricarboxylates allowed us total N-alkylation under standard alkylation conditions. The molecular structures of the C3-symmetric structures have been corroborated by an X-ray analysis.

Annellated 1,3,4,2-Triazaphospholenes-Simple Modular Synthesis and a First Exploration of Ligand Properties.

The successful use of 1,3,4,2-triazaphospholenes (TAPs) as organo-catalysts stresses the need for efficient synthetic routes to these molecules. In this study, we establish the [1 + 4]-cycloaddition of PBr3 to azo-pyridines as a new approach to preparing pyrido-annellated TAPs in a single step from easily available precursors. The modular assembly of the azo-component via condensation of primary amines and nitroso compounds along with the feasibility of post-functionalization at the P-Br bond under conservation of the heterocyclic structure allows, in principle, to address a wide range of target molecules, which is illustrated by prototypical examples. The successful synthesis of a transition metal complex confirms for the first time the ability of a TAP to act as a P-donor ligand. Crystallographic studies suggest that hyperconjugation effects and intermolecular interactions induce a qualitatively similar ionic polarization of the P-Br bonds in TAPs as in better known isoelectronic diazaphospholenes.

Water Reduction and Dihydrogen Addition in Aqueous Conditions With ansa-Phosphinoborane.

Ortho-phenylene-bridged phosphinoborane (2,6-Cl2 Ph)2 B-C6 H4 -PCy2 1 was synthesized in three steps from commercially available starting materials. 1 reacts with H2 or H2 O under mild conditions to form corresponding zwitterionic phosphonium borates 1-H2 or 1-H2 O. NMR studies revealed both reactions to be remarkably reversible. Thus, when exposed to H2 , 1-H2 O partially converts to 1-H2 even in the presence of multiple equivalents of water in the solution. The addition of parahydrogen to 1 leads to nuclear spin hyperpolarization both in dry and hydrous solvents, confirming the dissociation of 1-H2 O to free 1. These observations were supported by computational studies indicating that the formation of 1-H2 and 1-H2 O from 1 are thermodynamically favored. Unexpectedly, 1-H2 O can release molecular hydrogen to form phosphine oxide 1-O. Kinetic, mechanistic, and computational (DFT) studies were used to elucidate the unique "umpolung" water reduction mechanism.

Efficient Synthesis of Various Substituted (Thio)Ureas, Semicarbazides, Thiosemicarbazides, Thiazolidones, and Oxadiazole Derived from [2.2]Paracyclophane.

The strategies of the syntheses of various (thio)ureas, semicarbazides, thiosemicarbazides, thiazolidones, and oxadiazole derived from the [2.2]paracyclophane molecule are achieved starting with 4-(2.2]paracyclophanyl)isocyanate. The structures of the obtained products were elucidated by NMR, mass spectrometry, and infrared (IR) spectroscopy in addition to high-resolution mass spectrometry (HRMS). X-ray structure analysis was also used to prove the assigned structure.