Regioselective [3 + 2] cycloaddition of di/trifluoromethylated hydrazonoyl chlorides with fluorinated nitroalkenes: a facile access to 3-di/trifluoroalkyl-5-fluoropyrazoles.

Herein we describe the base-mediated [3 + 2] cycloaddition reaction of di/trifluoromethylated hydrazonoyl chlorides with fluorinated nitroalkenes. The reaction protocol provides a direct and facile strategy for the dual incorporation of a fluorine atom and fluoroalkyl group into pyrazole cores, thus allowing rapid access to a wide variety of densely functionalized 3-di/trifluoroalkyl-5-fluoropyrazoles in generally high yields with excellent regioselectivities. Furthermore, several drug-like 3-di/trifluoroalkyl-5-fluoropyrazoles have been synthesized, demonstrating potent inhibitory activities against cyclooxygenase 2 (COX-2).

The Concept of Creating Digital Twins of Bridges Using Load Tests.

The paper sheds light on the process of creating and validating the digital twin of bridges, emphasizing the crucial role of load testing, BIM models, and FEM models. At first, the paper presents a comprehensive definition of the digital twin concept, outlining its core principles and features. Then, the framework for implementing the digital twin concept in bridge facilities is discussed, highlighting its potential applications and benefits. One of the crucial components highlighted is the role of load testing in the validation and updating of the FEM model for further use in the digital twin framework. Load testing is emphasized as a key step in ensuring the accuracy and reliability of the digital twin, as it allows the validation and refinement of its models. To illustrate the practical application and issues during tuning and validating the FEM model, the paper provides an example of a real bridge. It shows how a BIM model is utilized to generate a computational FEM model. The results of the load tests carried out on the bridge are discussed, demonstrating the importance of the data obtained from these tests in calibrating the FEM model, which forms a critical part of the digital twin framework.

Fluorinated and Non-Fluorinated 1,4-Diarylpyrazoles via MnO2-Mediated Mechanochemical Deacylative Oxidation of 5-Acylpyrazolines.

A solvent-free two-step synthesis of polyfunctionalized pyrazoles under ball-milling mechanochemical conditions was developed. The protocol comprises (3 + 2)-cycloaddition of in situ generated nitrile imines and chalcones, followed by oxidation of the initially formed 5-acylpyrazolines with activated MnO2. The second step proceeds via an exclusive deacylative pathway, to give a series of 1,4-diarylpyrazoles functionalized with a fluorinated (CF3) or non-fluorinated (Ph, COOEt, Ac) substituent at C(3) of the heterocyclic ring. In contrast, MnO2-mediated oxidation of a model isomeric 4-acylpyrazoline proceeded with low chemoselectivity, leading to fully substituted pyrazole as a major product formed via dehydrogenative aromatization. The presented approach extends the scope of the known methods carried out in organic solvents and enables the preparation of polyfunctionalized pyrazoles, which are of general interest in medicine and material sciences.

Fluorinated Analogues of Lepidilines A and C: Synthesis and Screening of Their Anticancer and Antiviral Activity.

Starting with fluorinated benzylamines, a series of 2-unsubstituted imidazole N-oxides was prepared and subsequently deoxygenated in order to prepare the corresponding imidazoles. The latter were treated with benzyl halides yielding imidazolium salts, which are considered fluorinated analogues of naturally occurring imidazolium alkaloids known as lepidilines A and C. A second series of oxa-lepidiline analogues was obtained by O-benzylation of the initially synthetized imidazole N-oxides. Both series of imidazolium salts were tested as anticancer and antiviral agents. The obtained results demonstrated that the introduction of a fluorine atom, fluoroalkyl or fluoroalkoxy substituents (F, CF3 or OCF3) amplifies cytotoxic properties, whereas the cytotoxicity of some fluorinated lepidilines is promising in the context of drug discovery. All studied compounds revealed a lack of antiviral activity against the investigated viruses in the nontoxic concentrations.

Synthesis and Cytotoxic Activity of Lepidilines A-D: Comparison with Some 4,5-Diphenyl Analogues and Related Imidazole-2-thiones.

A straightforward access to 2-unsubstituted imidazole N-oxides with subsequent deoxygenation by treatment with Raney-nickel followed by N-benzylation opens up a convenient route to lepidilines A and C. Both imidazolium salts were used to generate in situ the corresponding imidazol-2-ylidenes, which smoothly reacted with elemental sulfur, yielding imidazole-2-thiones. These reactions were performed either under classical conditions in pyridine solutions or mechanochemically using solid Cs2CO3 as a base. The structure of lepidiline C was unambiguously confirmed by X-ray analysis of its hexafluorophosphate. An analogous protocol toward lepidilines B and D and their 4,5-diphenyl analogues is less efficient due to observed instability of the key precursors, i.e., the respective 2-methylimidazole N-oxides. Comparison of cytotoxic activity against HL-60 and MCF-7 cell lines of all lepidilines, as well as their selected structural analogues (e.g., 4,5-diphenyl derivatives and PF6 salts), revealed slightly more potent activity of the 2-methylated series, irrespectively of the type of counterion present in the imidazolium salt. Remarkably, the well-known 1,3-diadamantylimidazolium bromide (the "Arduengo salt"), known as the precursor of the first, shelf-stable NHC representative, and its adamantyloxy analogue displayed the most significant cytotoxic activity in the studied series.

A straightforward conversion of 1,4-quinones into polycyclic pyrazoles via [3 + 2]-cycloaddition with fluorinated nitrile imines.

In-situ-generated N-aryl nitrile imines derived from trifluoroacetonitrile efficiently react with polycyclic 1,4-quinones, yielding fused pyrazole derivatives as the exclusive products. The reactions proceed via the initially formed [3 + 2]-cycloadducts, which undergo spontaneous aerial oxidation to give aromatized heterocyclic products. Only for 2,3,5,6-tetramethyl-1,4-benzoquinone, the expected [3 + 2]-cycloadduct exhibited fair stability and could be isolated in moderate yield (53%). The presented method offers a straightforward access to hitherto little known trifluoromethylated polycyclic pyrazoles. All products were isolated as pale colored solids with medium-intensity absorption maxima in the range of 310-340 nm for naphthoquinone-derived products and low-intensity bands in the visible region (≈400 nm) for the anthraquinone series.

The [4+2]-Cycloaddition of α-Nitrosoalkenes with Thiochalcones as a Prototype of Periselective Hetero-Diels-Alder Reactions-Experimental and Computational Studies.

The [4+2]-cycloadditions of α-nitrosoalkenes with thiochalcones occur with high selectivity at the thioketone moiety of the dienophile providing styryl-substituted 4H-1,5,2-oxathiazines in moderate to good yields. Of the eight conceivable hetero-Diels-Alder adducts only this isomer was observed, thus a prototype of a highly periselective and regioselective cycloaddition has been identified. Analysis of crude product mixtures revealed that the α-nitrosoalkene also adds competitively to the thioketone moiety of the thiochalcone dimer affording bis-heterocyclic [4+2]-cycloadducts. The experiments are supported by high-level DFT calculations that were also extended to related hetero-Diels-Alder reactions of other nitroso compounds and thioketones. These calculations reveal that the title cycloadditions are kinetically controlled processes confirming the role of thioketones as superdienophiles. The computational study was also applied to the experimentally studied thiochalcone dimerization, and showed that the 1,2-dithiin and 2H-thiopyran isomers are in equilibrium with the monomer. Again, the DFT calculations indicate kinetic control of this process.

Tuning the Magnetic Properties of Columnar Benzo[e][1,2,4]triazin-4-yls with the Molecular Shape.

A homologous series of disc-like 1,3,6-trisubstituted benzo[e][1,2,4]triazin-4-yls 1[n] was synthesized and their structural, thermal, optical, magnetic, and electric properties were investigated. The results demonstrate that all members of the series display a Colh phase with clearing temperatures depending on the length of the alkoxy chains at the N(1) position, hence the shape of the disc. Powder XRD and magnetic data indicate a gradual change in the column diameter and magnetic behavior in the series in transition from half-disc in 1[0] (antiferromagnetic interactions) to full-disc geometry in the 1[12] homologue (ferromagnetic interactions with J/kB =+7.5 K). Studies of binary systems revealed that a 1 : 1 mixture of 1[0] and 1[12] exhibits modest stabilization of the Colh phase with an expanded range, and magnetic behavior typical for 1[0] in the rigid phase obtained from the melt. Electric measurements demonstrated hole mobility of ∼10-3  cm2  V-1 s-1 and dark conductivity of ∼10-11  Scm-1 in the mixture and individual compounds. The latter is enhanced up to 4 times by simultaneous illumination with UV light.

2-Unsubstituted Imidazole N-Oxides as Novel Precursors of Chiral 3-Alkoxyimidazol-2-ylidenes Derived from trans-1,2-Diaminocyclohexane and Other Chiral Amino Compounds.

'Desymmetrization' of trans-1,2-diaminocyclohexane by treatment with α,ω-dihalogenated alkylation reagents leads to mono-NH2 derivatives ('primary-tertiary diamines'). Upon reaction with formaldehyde, these products formed monomeric formaldimines. Subsequently, reactions of the formaldimines with α-hydroxyiminoketones led to the corresponding 2-unsubstituted imidazole N-oxide derivatives, which were used here as new substrates for the in situ generation of chiral imidazol-2-ylidenes. Upon O-selective benzylation, new chiral imidazolium salts were obtained, which were deprotonated by treatment with triethylamine in the presence of elemental sulfur. Under these conditions, the intermediate imidazol-2-ylidenes were trapped by elemental sulfur, yielding the corresponding chiral non-enolizable imidazole-2-thiones in good yields. Analogous reaction sequences, starting with imidazole N-oxides derived from enantiopure primary amines, amino alcohols, and amino acids, leading to the corresponding 3-alkoxyimidazole-2-thiones were also studied.

Synthesis and selected transformations of 2-unsubstituted 1-(adamantyloxy)imidazole 3-oxides: straightforward access to non-symmetric 1,3-dialkoxyimidazolium salts.

Adamantyloxyamine reacts with formaldehyde to give N-(adamantyloxy)formaldimine as a room-temperature-stable compound that exists in solution in monomeric form. This product was used for reactions with α-hydroxyiminoketones leading to a new class of 2-unsubstituted imidazole 3-oxides bearing the adamantyloxy substituent at N(1). Their reactions with 2,2,4,4-tetramethylcyclobutane-1,3-dithione or with acetic acid anhydride occurred analogously to those of 1-alkylimidazole 3-oxides to give imidazol-2-thiones and imidazol-2-ones, respectively. Treatment of 1-(adamantyloxy)imidazole 3-oxides with Raney-Ni afforded the corresponding imidazole derivatives without cleavage of the N(1)-O bond. Finally, the O-alkylation reactions of the new imidazole N-oxides with 1-bromopentane or 1-bromododecane open access to diversely substituted, non-symmetric 1,3-dialkoxyimidazolium salts. Adamantyloxyamine reacts with glyoxal and formaldehyde in the presence of hydrobromic acid yielding symmetric 1,3-di(adamantyloxy)-1H-imidazolium bromide in good yield. Deprotonation of the latter with triethylamine in the presence of elemental sulfur allows the in situ generation of the corresponding imidazol-2-ylidene, which traps elemental sulfur yielding a 1,3-dihydro-2H-imidazole-2-thione as the final product.

Polysubstituted 3-trifluoromethylpyrazoles: regioselective (3 + 2)-cycloaddition of trifluoroacetonitrile imines with enol ethers and functional group transformations.

Non-catalysed addition of trifluoroacetonitrile imines to enol ethers provided fully regioselectively (3 + 2)-cycloadducts, which either spontaneously or via Brønsted acid-induced elimination of ROH molecules led to the formation of 3-trifluoromethylated pyrazoles. In the case of 2,3-dihydrofuran, the respective bicyclic intermediate was isolated and its structure was confirmed by X-ray analysis. Using the developed protocol the synthesis of a known antitumor compound SC-560 was performed in 45% yield. Subsequent functionalisations of selected 4-(ω-hydroxyalkyl)pyrazoles at C(5) through lithiation/addition, cross-coupling reactions or via intramolecular Pd-catalysed C-H arylations opened up an access to polysubstituted pyrazoles including unusual tricyclic systems comprising 7-membered rings (oxepane, thiepane and azepane) as the central unit.

Substituent-Dependent Magnetic Behavior of Discotic Benzo[e][1,2,4]triazinyls.

Discotic mesogens containing the benzo[e][1,2,4]triazinyl radical as the central unit exhibit a Colh phase below 80 °C. Depending on the substituent at the N(1) position, they show different modes of thermal expansion and magnetic behavior, presumably due to differences in molecular organization. Thus, for 1-phenyl (1a) and 1-PhF-m (1b) derivatives, the Colh phase has positive thermal expansion coefficient κ and antiferromagnetic interactions, while for the 1-(3,4,5-(C12H25X)3C6H2) derivatives 1c (X = O) and 1d (X = S), κ is negative and weak ferromagnetic interactions in the crystalline phase are observed for 1c (J/kB = +4.76 K). Compounds 1a and 1c exhibit photoinduced hole transport (µ ≈ 1.3 × 10(-3) cm(2) V(-1) s(-1)) in the Colh phase.

[Keto acidosis and coma in 44-years old man with diabetes t1 in Internal Diseases Department in Dabrowa Tarnowska]. / Kwasica i spiaczka ketonowa u 44-letniego mezczyzny z cukrzyca t1 na Oddziale Wewnetrznym w Dabrowie Tarnowskiej.

Diabetic ketoacidosis (DKA) is an acute complication metabolic occur- ring in patients with diabetes type-1 and much less likely to type 2 diabetes. This article shows clinical manifesta- tion, biochemical criteria and algorithm for the immediate assessment and management of diabetic acidosis in a 44 years old men. This specification describes a rare case of keto acidosis and coma therapy and the challenges that these disorders carry.

Tetragonal phase of 6-oxoverdazyl bent-core derivatives with photoinduced ambipolar charge transport and electrooptical effects.

Bent-core mesogens containing 6-oxoverdazyl radical as the angular central unit exhibit rich polymorphism that includes isotropic-isotropic transition, re-entant isotropic (I(re)), and a novel 3D tetragonal (Tet) phases. Surprisingly, the paramagnetic Tet phase interacts linearly with applied electric field and exhibits photoinduced ambipolar charge transport (µ ≈ 10(-3) cm(2) V(-1) s(-1)). Magnetic analysis showed gradual increase of antiferromagnetic interactions upon cooling.

Oligoclonal gammopathy: An analysis of 253 cases.

BACKGROUND: Oligoclonal gammopathy (OG) is a rare disorder of the lymphoid system that is characterized by the presence of at least 2 distinct monoclonal proteins in a patient's serum or urine. The biological and clinical characteristics of this disease are as yet poorly understood. OBJECTIVES: The study aimed to assess whether there are significant differences between patients with OG regarding the developmental history (i.e., OG diagnosed at the first presentation compared to OG that has developed in patients with an original monoclonal gammopathy) and the number of monoclonal proteins (2 compared to 3). Moreover, we attempted to determine when secondary oligoclonality develops following the original diagnosis of monoclonal gammopathy. MATERIAL AND METHODS: Patients were analyzed with regard to their age at diagnosis, sex, serum monoclonal proteins, and underlying hematological disorders. Multiple myeloma (MM) patients were additionally evaluated for their Durie-Salmon stage and cytogenetic alterations. RESULTS: Patients with triclonal gammopathy (TG: n = 29) did not differ significantly from patients with biclonal gammopathy (BG: n = 223) (p = 0.81) in terms of age at diagnosis and the dominant diagnosis (MM was the most common diagnosis (65.0% and 64.7%, respectively)). In both cohorts, myeloma patients were mainly classified to the Durie-Salmon stage III. In the TG cohort, there was a higher proportion of males (69.0%) than among patients with BG (52.5%). Oligoclonality developed at various times after diagnosis (up to 80 months in the investigated cohort). However, the occurrence of new cases was higher during the initial 30-month period following the diagnosis of monoclonal gammopathy. CONCLUSIONS: There are only small differences between patients with primary compared to secondary OG, between BG and TG, and most patients have a combination of IgGκ+IgGλ. Oligoclonality could develop at any time after the diagnosis of monoclonal gammopathy, but it happens more frequently during the first 30 months, with advanced myeloma being the most prevalent underlying disorder.

Functional group transformations in derivatives of 6-oxoverdazyl.

Transformations of functional groups, such as OCH2Ph, OCOPh, NO2 and I, in 1,3,5-triphenyl-6-oxoverdazyls 1a-1e were investigated in order to expand the range of synthetic tools for incorporation of the verdazyl system into more complex molecular architectures and to increase spin delocalization. Thus, Pd-catalyzed debenzylation of the OCH2Ph group or basic hydrolysis of the OCOPh group gave the phenol functionality, which was acylated, but could not be alkylated. Orthogonal deprotection of diphenol functionality was also demonstrated in radical 1c. Pt-catalyzed reduction of the NO2 group led to the aniline derivative, which was acylated. Attempted C-C coupling reactions to iodophenyl derivatives 1e and 5e were unsuccessful. Selected verdazyl radicals were characterized by EPR and electronic absorption spectroscopy, and results were analyzed with the aid of DFT computational methods.

One-Pot Synthesis of 1-Aryl-3-trifluoromethylpyrazoles Using Nitrile Imines and Mercaptoacetaldehyde As a Surrogate of Acetylene.

A synthetically useful approach for one-pot preparation of 1-aryl-3-trifluoromethylpyrazoles using in situ generated nitrile imines and mercaptoacetaldehyde applied as 1 equiv of acetylene is presented. This protocol comprises (3 + 3)-annulation of the mentioned reagents to form 5,6-dihydro-5-hydroxy-4H-1,3,4-thiadiazine, followed by cascade dehydration/ring contraction reactions with p-TsCl. In addition, representative nonfluorinated analogues functionalized with Ph, Ac, and CO2Et groups at the C(3)-position of the pyrazole ring were also prepared by the devised method.

Trifluoromethylated 4,5-Dihydro-1,2,4-triazin-6(1H)-ones via (3+3)-Annulation of Nitrile Imines with α-Amino Esters.

The synthesis of two series of monocyclic and bicyclic trifluoromethylated 4,5-dihydro-1,2,4-triazin-6(1H)-one derivatives based on (3+3)-annulation of methyl esters derived from natural α-amino acids with in situ generated trifluoroacetonitrile imines has been described. The devised protocol is characterized by a wide scope, easily accessible substrates, remarkable functional group tolerance, and high chemical yield. In reactions with chiral starting materials, no racemization at the stereogenic centers was observed and the respective enantiomerically pure products were obtained. Selected functional group interconversions carried out under catalytic hydrogenation and mild PTC oxidation conditions were also demonstrated.