Simple electrochemical synthesis of cyclic hydroxamic acids by reduction of nitroarenes.

The electrochemical reduction of nitroarenes allows direct access to manifold nitrogen containing heterocycles. This work reports the simple and direct electro-organic synthesis of 18 different examples of 2H,4H-4-hydroxy-1,4-benzoxazin-3-ones in up to 81% yield. The scalability of the method was demonstrated on a gram-scale.

Intramolecularly O,N,O-Coordinated Tin(II) Salts: Syntheses, Structures, Cyclization, and Transition Metal Complexation.

We report the syntheses of tin(II) salts of the types [L1SnX]SnX3 [L1 = 2,6-{(i-PrO)2(O)P}2C5H3N: 1, X = Cl; 2, X = Br], [L2SnCl]SnCl3 [L2 = 2-{(i-PrO)Ph(O)P}-6-{(i-PrO)2(O)P}C5H3N: 3], [L3SnX]SnX3 [L3 = 2,6-{MeO(O)C}2C5H3N: 4, X = Cl; 5, X = Br], [L4SnX]SnX3[L4 = 2,6-{Et2N(O)C}2C5H3N: 6, X = Cl; 7, X = Br]. These compounds were obtained by addition of SnX2 to the corresponding ligand inducing autoionization of the respective tin(II) halide. The thermal stability of 1, 3, and 4 was elucidated, giving, under ester cleavage and cyclisation, the tin(II) derivatives 8-12. The reaction of [L1SnCl]SnCl3 (1) with W(CO)4(thf)2 afforded the tungsten tetracarbonyl complex [{L1SnCl}{SnCl3}W(CO)4] (13), representing the first example in which a tin(II) stannate anion and a tin(II) stannylium cation simultaneously coordinate to a transition metal centre. The compounds were characterized by single crystal X-ray diffraction analyses and in part by elemental analyses, IR and NMR spectroscopy, electrospray ionization mass spectrometry. DFT calculations accompany the experimental work.

Efficient and Sustainable Electrosynthesis of N-Sulfonyl Iminophosphoranes by the Dehydrogenative P-N Coupling Reaction.

Iminophosphoranes are commonly used reagents in organic synthesis and are, therefore, of great interest. An efficient and sustainable iodide-mediated electrochemical synthesis of N-sulfonyl iminophosphoranes from readily available phosphines and sulfonamides is reported. This method features low amounts of supporting electrolytes, inexpensive electrode materials, a simple galvanostatic setup, and high conversion rates. The broad applicability could be demonstrated by synthesizing 20 examples in yields up to 90%, having diverse functional groups including chiral moieties and biologically relevant species. Furthermore, electrolysis was performed on a 20 g scale and could be run in repetitive mode by recycling the electrolyte, which illustrates the suitability for large-scale production. A reaction mechanism involving electrochemical mediation by the iodide-based supporting electrolyte is proposed, completely agreeing with all of the results.

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.

Peri-Alkylated Terrylenes and Ternaphthalenes Building-Blocks Towards Multi-Edge Nanographenes.

Since its first synthesis by Clar in 1948, terrylene - a fully connected ternaphthalene oligomer via naphthalene's peri-positions - has gained special focus within the rylene family, drawing interest for its unique chemical, structural, optoelectronic and single photon emission properties. In this study, we introduce a novel synthetic pathway that enhances the solubility of terrylene derivatives through complete peri-alkylation, while also facilitating extensions at the bay-positions. This approach not only broadens the scope of terrylene's chemical versatility but also opens new avenues for developing solution processable novel multi-edge nanographenes and tailoring electronic energy levels through topological edge structures. Our findings include a comprehensive structural and spectroscopic characterization along with transient absorption spectroscopy and photophysics of both the synthesized peri-alkylated terrylene and its phenylene-fused derivative.

Stable π-Extended Thio[7]helicene-Based Diradical with Predominant Through-Space Spin-Spin Coupling.

In this work, a novel π-extended thio[7]helicene scaffold was synthesized, where the α-position of the thiophene unit could be functionalized with bulky phenoxy radicals after considerable synthetic attempts. This open-shell helical diradical, ET7H-R, possesses high stability in the air, nontrivial π conjugation, persistent chirality, and a high diradical character (y0 of 0.998). The key feature is a predominant through-space spin-spin coupling (TSC) between two radicals at the helical terminals. Variable-temperature continuous-wave electron spin resonance (cw-ESR) and superconducting quantum interference device (SQUID) magnetometry in the solid state reveal a singlet ground state with a nearly degenerate triplet state of ET7H-R. These results highlight the significance of a stable helical diradicaloid as a promising platform for investigating intramolecular TSCs.

Electrochemical Multicomponent Synthesis of Alkyl Alkenesulfonates using Styrenes, SO2 and Alcohols.

A novel electrochemical approach to access alkyl alkenesulfonates via a multicomponent reaction was developed. The metal-free method features easy-to-use SO2 stock solution forming monoalkylsulfites from alcohols with an auxiliary base in-situ. These intermediates serve a dual role as starting materials and as supporting electrolyte enabling conductivity. Anodic oxidation of the substrate styrene, radical addition of these monoalkylsulfites and consecutive second oxidation and deprotonation preserve the double bond and form alkyl ß-styrenesulfonates in a highly regio- and stereoselective fashion. The feasibility of this electrosynthetic method is demonstrated in 44 examples with yields up to 81 %, employing various styrenes and related substrates as well as a diverse set of alcohols. A gram-scale experiment underlines the applicability of this process, which uses inexpensive and readily available electrode materials.

Synthesis and photoinduced behavior of DPP-anchored nitronyl nitroxides: a multifaceted approach.

Understanding and controlling spin dynamics in organic dyes is of significant scientific and technological interest. The investigation of 2,5-dihydropyrrolo[4,3-c]pyrrolo-1,4-dione derivatives (DPPs), one of the most widely used dyes in many fields, has so far been limited to closed-shell molecules. We present a comprehensive joint experimental and computational study of DPP derivatives covalently linked to two nitronyl nitroxide radicals (DPPTh-NN2). Synthesis, single crystal X-ray diffraction study, photophysical properties, magnetic properties established using steady-state and pulse EPR, fast spin dynamics, and computational modelling using density functional theory and ab initio methods of electronic structure and spectroscopic properties of DPPTh-NN2 are presented. The single-crystal X-ray diffraction analysis of DPPTh-NN2 and computational modeling of its electronic structure suggest that effective conjugation along the backbone leads to noticeable spin-polarization transfer. Calculations using ab initio methods predict a weak exchange interaction of radical centers through a singlet ground state of DPPTh with a small singlet-triplet splitting (ΔEST) of about 25 cm-1 (∼0.07 kcal mol-1). In turn, a strong ferromagnetic exchange interaction between the triplet state of DPPTh chromophore and nitronyl nitroxides (with J ∼ 250 cm-1) was predicted.

Dehydrogenative Electrochemical Synthesis of N-Aryl-3,4-Dihydroquinolin-2-ones by Iodine(III)-Mediated Coupling Reaction.

Electrochemically generated hypervalent iodine(III) species are powerful reagents for oxidative C-N coupling reactions, providing access to valuable N-heterocycles. A new electrocatalytic hypervalent iodine(III)-mediated in-cell synthesis of 1H-N-aryl-3,4-dihydroquinolin-2-ones by dehydrogenative C-N bond formation is presented. Catalytic amounts of the redox mediator, a low supporting electrolyte concentration and recycling of the solvent used make this method a sustainable alternative to electrochemical ex-cell or conventional approaches. Furthermore, inexpensive, readily available electrode materials and a simple galvanostatic set-up are applied. The broad functional group tolerance could be demonstrated by synthesizing 23 examples in yields up to 96 %, with one reaction being performed on a 10-fold higher scale. Based on the obtained results a sound reaction mechanism could be proposed.

Inherent Fluorescence Demonstrates Immunotropic Properties for Novel Janus Kinase 3 Inhibitors.

There is a general question in small molecule pharmacology about how apparent compound concentrations in blood, plasma, and organs actually relate to actual amounts at the target site of a compound. In this study, we used inherently fluorescent JAK3 ligands and their macrolide conjugates to investigate the relationship between physical properties, apparent bulk concentration, and organ and subcellular distribution. In vitro uptake into immune cells suggested that much of the substance was associated with granules or organelles. Samples from murine pharmacokinetic studies were analyzed by both conventional mass spectrometry and cryofluorescence microscopy methods to show the distribution of a compound within organs and cells without artifacts of fixation. These observations confirm the uptake of granules observed in vitro. Data from macrolides carrying either a coumarin fluorophore or a JAK3 inhibitor were similar, suggesting that the distribution is directed by the properties of the larger macrolide. These data show a propensity for azalide macrolides to concentrate in the lung and gut epithelia and suggest that the plasma- or whole-blood-derived estimates of drug levels almost certainly underestimate concentrations of macrolides in the mucous membranes. Thus, their apparent efficacy at sub-bacteriostatic doses may reflect their higher levels in barrier layers.

Principles and Applications of CF2X Moieties as Unconventional Halogen Bond Donors in Medicinal Chemistry, Chemical Biology, and Drug Discovery.

As an orthogonal principle to the established (hetero)aryl halides, we herein highlight the usefulness of CF2X (X = Cl, Br, or I) moieties. Using tool compounds bearing CF2X moieties, we study their chemical/metabolic stability and their logP/solubility, as well as the role of XB in their small molecular crystal structures. Employing QM techniques, we analyze the observed interactions, provide insights into the conformational flexibilities and preferences in the potential interaction space. For their application in molecular design, we characterize their XB donor capacities and its interaction strength dependent on geometric parameters. Implementation of CF2X acetamides into our HEFLibs and biophysical evaluation (STD-NMR/ITC), followed by X-ray analysis, reveals a highly interesting binding mode for fragment 23 in JNK3, featuring an XB of CF2Br toward the P-loop, as well as chalcogen bonds. We suggest that underexplored chemical space combined with unconventional binding modes provides excellent opportunities for patentable chemotypes for therapeutic intervention.

5-[(4-Methyl-phen-yl)sulfon-yl]-1-phenyl-thio-pyrano[4,3-b]indole-3(5H)-thione di-chloro-methane monosolvate.

Rhodium-catalyzed [2+2+2] cyclo-addition of carbon di-sulfide to o,N-dialkynyl-tosyl-anilines gives two isomeric indolo-thio-pyran-thio-nes, a violet and a red isomer. This is the first crystal structure of a red isomer, which crystallizes with one solvent mol-ecule of di-chloro-methane in the asymmetric unit, C24H17NO2S3·CH2Cl2. In the extended structure, centrosymmetric pairs of the planar annulated system are arranged in strands and solvent mol-ecules fill the space between the strands.

Twisted Diindeno-Fused Dibenzo[a,h]anthracene Derivatives and their Dianions.

We report a facile synthesis of diindeno-fused dibenzo[a,h]anthracene derivatives (DIDBA-2Cl, DIDBA-2Ph, and DIDBA-2H) with different degrees of non-planarity using three substituents (chloro, phenyl, and hydrogen) of various sizes. The planarization of their cores, as evidenced by the decreased end-to-end torsional angles, was confirmed by X-ray crystallography. Their enhanced energy gaps with twisting were investigated by a combination of spectroscopic and electrochemical methods with density functional theory, which showed a transition from singlet open-shell to closed-shell configuration. Moreover, their doubly reduced states, DIDBA-2Ph2- and DIDBA-2H2- , were achieved by chemical reduction. The structures of dianions were identified by X-ray crystallographic analysis, which elucidated that the electron charging further distorted the backbones. The electronic structure of the dianions was demonstrated by experimental and theoretical approaches, suggesting decreased energy gaps with larger non-planarity, different from the neutral species.

Design and Optimization of Novel Benzimidazole- and Imidazo[4,5-b]pyridine-Based ATM Kinase Inhibitors with Subnanomolar Activities.

The ATM kinase is a promising target in cancer treatment as an important regulator of the cellular response to DNA double-strand breaks. In this work, we present a new class of specific benzimidazole-based ATM inhibitors with picomolar potency against the isolated enzyme and favorable selectivity within relative PIKK and PI3K kinases. We could identify two promising inhibitor subgroups with significantly different physicochemical properties, which we developed simultaneously. These efforts lead to numerous highly active inhibitors with picomolar enzymatic activities. Furthermore, initial low cellular activities on A549 cells could be increased significantly in numerous examples resulting in cellular IC50 values in the subnanomolar range. Further characterization of the highly potent inhibitors 90 und 93 revealed promising pharmacokinetic properties and strong activities in organoids in combination with etoposide. Additionally, 93 showed no off-target activities within a kinome-representative mini kinase panel, with favorable selectivities within the PIKK- and PI3K-families.

Extending Chirality in Group XIV Metallatranes.

The syntheses of the racemic amino alcohol rac-N(CH2CMe2OH)(CMe2CH2OH)(CH2CHMeOH) (L22'1*H3, 2) and its representative N(CH2CMe2OH)(CMe2CH2OH)(CH2C(R)HMeOH) (L22'1RH3, 3) with the stereogenic carbon center being R-configured are reported. Also reported are the stannatranes L22'1*SnOt-Bu (4) L22'1RSnOt-Bu (6) and germatranes L22'1*GeOEt (5) and L22'1RGeOEt (7) as well as the trinuclear tin oxocluster [(µ3-O)(µ3-O-t-Bu){SnL22'1R}3] (8). NMR and IR spectroscopy, electrospray ionization mass spectrometry (ESI MS), and single crystal X-ray diffraction analysis characterize these compounds. Computational studies accompany the experimental work and help understand the diastereoselectivity observed in the course of the metallatrane syntheses.

Simple and scalable electrosynthesis of 1H-1-hydroxy-quinazolin-4-ones.

Cathodic synthesis provides sustainable access to 1-hydroxy- and 1-oxy-quinazolin-4-ones from easily accessible nitro starting materials. Mild reaction conditions, inexpensive and reusable carbon-based electrode materials, an undivided electrochemical setup, and constant current conditions characterise this method. Sulphuric acid is used as a simple supporting electrolyte as well as a catalyst for cyclisation. The broad applicability of this protocol is demonstrated in 27 differently substituted derivatives in high yields of up to 92%. Moreover, mechanistic studies based on cyclic voltammetry measurements highlight a selective reduction of the nitro substrate to hydroxylamine as a key step. The relevance for preparative applications is demonstrated by a 100-fold scale-up for gram-scale electrolysis.

2,5-Bis[5-(3,5-dido-decyl-oxyphen-yl)-1,3,4-oxa-diazol-2-yl]-3,6-di-methyl-pyrazine.

The nearly planar mol-ecule of the title compound, C70H112N6O6, is centrosymmetric with two all-s-trans chains, the other two chains have an s-cis unit starting with the oxygen atoms. The chains are inter-digitated in the packing.

(Z)-4,5-Di-bromo-3,3,6,6-tetra-methyl-2,3,6,7-tetra-hydro-thiepine-1,1-dione.

The crystal of the title compound, C10H16Br2O2S, is formed from layers built from centrosymmetric pairs of mol-ecules. The mol-ecule adopts a twist conformation with the carbon atoms next to sulfur above or below the mean plane.

Direct Electrochemical Synthesis of 2,3-Disubstituted Quinoline N-oxides by Cathodic Reduction of Nitro Arenes.

The use of electric current in synthetic organic chemistry offers a sustainable tool for the selective reductive synthesis of quinoline N-oxides starting from easily accessible nitro compounds. The reported method employs mild and reagent-free conditions, a simple undivided cell, and constant current electrolysis set-up which provides conversion with a high atom economy. The synthesis of 30 differently substituted quinoline N-oxides was successfully performed in up to 90 % yield. Using CV studies, the mechanism of the selective formation of the quinoline N-oxides was elucidated. The technical relevance of the described reaction could be shown in a 50-fold scale-up reaction.

13,13'-Bi(dibenzo[a,i]fluorenyl-idene).

The asymmetric unit of the title compound, C42H24, contains two almost identical mol-ecules. The mol-ecules have approximate D 2 symmetry. They show a largely twisted double bond, the mol-ecular halves enclosing dihedral angles of 62.86 (4) and 61.22 (3)°. The crystal studied was twinned by non-merohedry.