RESUMEN
Parallel Minisci reactions of nonfluorinated and gem-difluorinated C4-C7 cycloalkyl building blocks (trifluoroborates and carboxylic acids) with a series of electron-deficient heterocycles were studied. A comparison of the reaction's outcome revealed better product yields in the case of carboxylic acids as the radical precursors in most cases, albeit these reagents were used with three-fold excess under optimized conditions. The nature of the heterocyclic core was found to be important for successful incorporation of the cycloalkyl fragment. The impact of the CF2 moiety on the oxidation potential of fluorinated cycloalkyl trifluoroborates and the reaction outcome, in general, was also evaluated.
RESUMEN
A novel two-step method for formylation of fluoropyridines with silylformamidine Me3 SiC(=NMe)NMe2 (1) under catalyst-free conditions was developed. A series of all possible 18â fluoropyridines featuring one to four fluorine atoms were subjected to the reaction with 1 existing in equilibrium with its carbenic form Me2 NC(:)N(Me)SiMe3 (1'). Among them, 12â fluoropyridines were shown to react via C-H insertion. The reaction proceeded either at ß- or γ-positions affording the corresponding aminals. The more fluorine atoms in pyridines, the easier the reaction proceeded. We also hypothesized that the pyridines in which the fluorine was substituted by other halogens would react in a similar manner. To test the hypothesis, a set of 3,5-disubstituted pyridines with various combination of halogen atoms was prepared. 3,5-Difluoropyridine was taken as a compound for comparison. All the pyridines in the series also reacted likewise. In most cases, hydrolysis of the aminals afforded the corresponding aldehydes. As DFT calculations indicate, the reaction mechanism includes deprotonation of pyridine by 1' as a strong base and the following rearrangement of the formed tight ionic pair to the final product. An alternative reaction pathway involving addition of 1' to the pyridine carbon with the following hydrogen transfer via a three-membered transition state structure required much higher activation energy.
RESUMEN
The discovery and development of effective novel compounds is paramount in oncology for improving cancer therapy. In this study, we developed a new derivative of spiroindolone (7',8'-Dimethoxy-1',3'-dimethyl-1,2,3',4'-tetrahydrospiro[indole-3,5'- pyrazolo[3,4-c]isoquinolin]-2-one) and evaluated its anticancer- and immunomodulatory potential in a vitro model of chronic leukemia. We utilized the chronic leukemia cell line K562, as well as non-cancerous peripheral blood mononuclear cells (PBMC) and Vero cells (kidney epithelium of Cercopithecus aethiops). We assessed the cytotoxicity of the compound using the MTT assay, and performed cell cycle assays to determine its impact on different stages of the cell cycle. To evaluate its antineoplastic activity, we conducted a colony formation test to measure the effect of the compound on the clonal growth of cancer cells. Furthermore, we evaluated the immunomodulatory activity of the compound by measuring the levels of pro and anti-inflammatory cytokines. The study findings demonstrate that the spiroindolone-derived compound exerted noteworthy cytotoxic effects against K562 cells, with an IC50 value of 25.27 µg/mL. Additionally, it was observed that the compound inhibited the clonal proliferation of K562 cells while displaying minimal toxicity to normal cells. The compound exhibited its antiproliferative activity by inducing G2/M cell cycle arrest, preventing the entry of K562 cells into mitosis. Notably, the compound demonstrated an immunomodulatory effect by upregulating the production of cytokines IL-6 and IL-12/23p40. In conclusion, the spiroindolone-derived compound evaluated in this study has demonstrated significant potential as a therapeutic agent for the treatment of chronic myeloid leukemia. Further investigations are warranted to explore its clinical applications.
Asunto(s)
Antineoplásicos , Leucemia Mielógena Crónica BCR-ABL Positiva , Humanos , Animales , Chlorocebus aethiops , Leucocitos Mononucleares , Células Vero , Proliferación Celular , Apoptosis , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Células K562 , Citocinas/farmacología , Indoles/farmacologíaRESUMEN
Silylformamidine 1 exists in equilibrium with its carbenic form 1' due to an easy migration of the silyl group. The reaction of 1 with variously substituted fluorobenzenes proceeds as an insertion of the nucleophilic carbene 1' into the most acidic C-H bond upon mixing the reagents and does not require any catalyst. According to DFT calculations, the classical interpretation of the insertion reaction proceeding via a three-membered transition state structure requires high activation energy. Instead, low activation barriers are predicted for a transfer of the most acidic proton in the aromatic substrate to the carbene carbon. As the next step, a barrierless rearrangement of the formed ion pair toward the product completes the process. The reactivity of substituted benzenes in the reaction with silylformamidine can be roughly assessed by calculated pKa (DMSO) values for the C-H hydrogens. Benzene derivatives having pKa approx. less than 31 can undergo C-H insertion. The reaction provides aminals as the first products, which can easily be transformed into the corresponding aldehydes via acidic hydrolysis. As silylformamidine 1 is tolerant to many functional groups, the reaction can be applied to numerous benzene derivatives, making it a reliable strategy for application in organic synthesis.
RESUMEN
The reaction of trimethyl(trifluoromethyl)silane-tetrabutylammonium difluorotriphenylsilicate (CF3SiMe3-TBAT) with a series of imidazoles gives products of the formal difluorocarbene insertion into the C-H bond at the C-2 position (i.e., C-difluoromethylation). According to NMR spectra, the corresponding 2-(trimethylsilyl)difluoromethyl-substituted derivatives are likely formed as the intermediates in the reaction, and then, they slowly convert to 2-difluoromethyl-substituted imidazoles. Quantum chemical calculations of two plausible reaction mechanisms indicate that it proceeds through the intermediate imidazolide anion stabilized through the interaction with solvent molecules and counterions. In the first proposed mechanism, the anion reacts with difluorocarbene without an activation barrier, and then, the CF2 moiety of the adduct attacks the CF3SiMe3 molecule. After the elimination of the CF3 anion, 2-(trimethylsilyl)difluromethyl-substituted imidazole is formed. Another possible reaction pathway includes silylation of imidazolide anion at the N-3 atom, followed by the barrierless addition of difluorocarbene at the C-2 atom and then by 1,3-shift of the SiMe3 group from N-3 to the carbon atom of the CF2 moiety. Both proposed mechanisms do not include steps with high activation barriers.
RESUMEN
Recently, an unusual elongation of the C-S bond was observed experimentally for some sulfur-containing heterocycles. Using a superior ab initio (SCS-MP2/cc-pVTZ) level of theory, we showed that the phenomenon can be explained by a contribution of a donor-acceptor adduct of a carbene with an unsaturated ligand. One may achieve further elongation of the C-S bond, eventually turning it to a coordinate one, by increasing the stability of each part of the system as, e.g., in the utmost case of spiro adducts with Arduengo carbenes. The effect of carbene stability was quantified by employing the isodesmic reactions of carbene exchange.
RESUMEN
Physico-chemical properties important to drug discovery (pKa , LogP, and aqueous solubility), as well as metabolic stability, were studied for a series of functionalized gem-difluorinated cycloalkanes and compared to those of non-fluorinated and acyclic counterparts to evaluate the impact of the fluorination. It was found that the influence of the CF2 moiety on the acidity/basicity of the corresponding carboxylic acids and amines was defined by inductive the effect of the fluorine atoms and was nearly the same for acyclic and cyclic aliphatic compounds. Lipophilicity and aqueous solubility followed more complex trends and were affected by the position of the fluorine atoms, ring size, and even the nature of the functional group present; also, significant differences were found for the acyclic and cyclic series. Also, gem-difluorination either did not affect or slightly improved the metabolic stability of the corresponding model derivatives. The presented results can be used as a guide for rational drug design employing fluorine and establish the first chapter in a catalog of the key in vitro properties of fluorinated cycloalkanes.
Asunto(s)
Química Farmacéutica , Cicloparafinas , Flúor/química , Halogenación , SolubilidadRESUMEN
Using DFT and ab initio calculations, we demonstrate that noncyclic formamidines can undergo thermal rearrangement into their isomeric aminocarbenes under rather mild conditions. We synthesized the silylformamidine, for which the lowest activation energy in this process was predicted. Experimental studies proved it to serve as a very reactive nucleophilic carbene. The reactions with acetylenes, benzenes, and trifluoromethane proceeded via insertion into sp, sp2, and sp3 CH bonds. The carbene also reacted with the functional groups, such as CHO, COR, and CN at double or triple bonds, displaying high mobility of the trimethylsilyl group. The obtained silylformamidine can be considered as a latent nucleophilic carbene. It can be prepared in bulk quantities, stored, and used when the need arises. Calculation results predict similar behavior for some other silylated formamidines and related compounds.
RESUMEN
A Cu-catalyzed, easily scalable one-pot synthesis of fused pyridines by the reaction of cyclic ketones with propargylamine is described. The protocol was optimized based on the results of more than 30 experiments. The highest product yields were achieved in i-PrOH as a solvent in the presence of 5.0 mol % CuCl2 in air. In contrast to the well-known Au-catalyzed protocol, our procedure is "laboratory friendly", cost-effective, and suitable for preparing dozens of grams of fused pyridine-based building blocks and does not require a high-pressure autoclave technique. Decreasing the catalyst amount in the reaction to 1.25 mol % CuCl2 provided a yield comparable to that achieved with 5 mol % catalyst, though a longer reaction time was required. A plausible reaction mechanism was proposed. The scope and limitation of the reaction were studied using 24 different cyclic ketones as starting materials. The fused pyridine yield decreased among cyclic ketones in the following order: six-membered â« eight-membered > five-membered â¼ seven-membered. The elaborated reaction conditions demonstrated tolerance to a number of protective functional groups in ketone such as ester, tert-butoxycarbonyl (Boc)-protected amine, and acetal moieties.
RESUMEN
Structural restriction of the sulfonamide bond was used to design sultams with abnormal geometric parameters. Based on analysis of tertiary aliphatic sulfonamides published in the Cambridge crystallographic database, Paquette's sultams (i.e., bridged bicyclic sultams with a bridgehead nitrogen atom) were outlined, and a number of these compounds (including the novel smallest representative, 2-thia-1-azabicyclo[2.1.1]hexane 2,2-dioxide) were synthesized by cyclization of the corresponding amino sulfonyl fluorides. A series of tertiary aliphatic sulfonamides was studied by crystallographic and quantum chemical methods. It was found that the s-character of the nitrogen lone pair is the most important factor defining properties of the S-N bond. Thus, going from the sp3-hybrid lone pair in common sulfonamides to the sp-like lone pair in the smallest Paquette's sultam resulted in an increase in S-N bond length by ca. 0.06 Å. The strain energy of ca. 30 kcal/mol was predicted for the latter compound, which was higher than for any existing sulfonamides studied.
RESUMEN
Anopheles darlingi is the main vector of malaria in Brazil, characterized by a high level of anthropophilia and endophagy. Imidacloprid, thiacloprid, and acetamiprid are the most widespread insecticides of the neonicotinoid group. However, they produce adverse effects on the non-target insects. Flupyradifurone has been marketed as an alternative to non-fluorinated neonicotinoids. Neonicotinoids containing trifluoroacethyl substituent reveal increased insecticidal activity due to higher hydrophobicity and metabolic stability. We synthesized novel neonicotinoid insecticides containing fluorinated acceptor groups and their interactions were estimated with the nicotinic acetylcholine receptor (nAChR) binding site by molecular docking studies, to evaluate their larvicidal activity against A. darlingi, and to assess their outdoor photodegradation behavior. New neonicotinoid analogues were prepared and characterized by NMR and mass-spectrometry. The synthesized molecules were modelled by time-dependent density functional theory and analyzed, their interaction with nAChR was investigated by molecular docking. Their insecticide activity was tested on Anopheles larvae collected in suburban area of Manaus, Brazil. Four new fluorinated neonicotinoid analogs were prepared and tested against 3rd instars larvae of A. darlingi showing high larvicidal activity. Docking studies reveal binding modes of the synthesized compounds and suggest that their insecticidal potency is governed by specific interactions with the receptor binding site and enhanced lipophilicity. 2-Chloro-5-(2-trifluoromethyl-pyrrolidin-1-ylmethyl)pyridine 5 showed fast degradation in water maintaining high larvicidal activity. All obtained substances possessed high larvicidal activity in low concentrations in 48 hours of exposure, compared to commercial flupyradifurone. Such activity is connected to a unique binding pattern of the synthesized compounds to insect's nAChR and to their enhanced bioavailability owing to introduction of fluorinated amino-moieties. Therefore, the compounds in question have a high potential for application as control agents for insects transmitting tropical diseases, and they will be less persistent in the environment.
Asunto(s)
Anopheles/efectos de los fármacos , Halogenación , Insecticidas/toxicidad , Simulación del Acoplamiento Molecular , Neonicotinoides/toxicidad , 4-Butirolactona/análogos & derivados , 4-Butirolactona/química , 4-Butirolactona/toxicidad , Animales , Insecticidas/química , Larva/efectos de los fármacos , Neonicotinoides/síntesis química , Neonicotinoides/química , Piridinas/química , Piridinas/toxicidad , Espectrofotometría Ultravioleta , Electricidad EstáticaRESUMEN
A comprehensive study on the synthesis of 5-fluoroalkyl-substituted isoxazoles starting from functionalized halogenoximes is reported. One-pot metal-free [3 + 2] cycloaddition of CF3-substituted alkenes and halogenoximes bearing ester, bromo, chloromethyl, and protected amino groups was developed for the preparation of 5-trifluoromethylisoxazoles. The target 3,5-disubstituted derivatives were obtained in a regioselective manner in good to excellent yield on up to 130 g scale. 5-Fluoromethyl- and 5-difluoromethylisoxazoles were synthesized by late-stage deoxofluorination of the corresponding 5-hydroxymethyl or 5-formyl derivatives, respectively, in turn prepared via metal-free cycloaddition of halogenoximes and propargylic alcohol. An alternative approach based on nucleophilic substitution in 5-bromomethyl derivatives was found to be more convenient for the preparation of 5-fluoromethylisoxazoles. Reaction of isoxazole-5-carbaldehydes with the Ruppert-Prakash reagent was used for the preparation of (ß,ß,ß-trifluoro-α-hydroxyethyl)isoxazoles. Utility of described approaches was shown by multigram preparation of side-chain functionalized mono-, di-, and trifluoromethylisoxazoles, for example, fluorinated analogues of ABT-418 and ESI-09.
Asunto(s)
Isoxazoles/síntesis química , Oximas/química , Ciclización , Isoxazoles/química , Estructura Molecular , EstereoisomerismoRESUMEN
Several possible reaction pathways are analyzed for the recently studied experimental reaction of diaminocarbenes with aroylimines, where the carbene acted as an oxygen-abstracting agent. A number of structures corresponding to local minima and transition states are located by geometry optimization. In contrast to the more recent interpretation of the mechanism of this process, the reaction does not proceed via the direct formation of the corresponding carbonyl ylide resulted from the electrophilic addition of diaminocarbene to the carbonyl oxygen atom. Two other, more favorable pathways were predicted instead: the nucleophilic attack of the carbene lone pair on the imino nitrogen (pathway "a") or on the carbon atom in the CâN moiety of aroylimine (pathway "b"), in agreement with predictions of the frontier molecular orbital (FMO) theory. Both intermediate adducts undergo a subsequent decomposition onto nitrile ylide and urea. Which of the two pathways becomes preferential depends on the nature of the substituents: pathway "a" is more favored for the experimentally studied species, whereas pathway "b" is thermodynamically preferable for the small-sized model structures.
RESUMEN
1,2-Migration of the phosphano-group to the carbene center in N-phosphano functionalized N-heterocyclic carbenes has been studied by density functional theory (DFT) calculations. An intramolecular mechanism with a three-center transition state structure seems to be most plausible for the isolated carbenes, while an intermolecular pathway catalyzed by azolium salts may be preferable for a migration proceeding in the course of generating the carbenes in situ. Our calculations show that amino-substitution at the phosphorus atom and an enhanced nucleophilicity of the heterocycle scaffold facilitate the phosphorus shift. Calculated singlet-triplet energy gaps do not correlate with thermodynamic stability of the studied carbenes and their disposition toward the 1,2-rearrangement.
RESUMEN
A series of trifluoromethyl-substituted carbenes R-C(:)-CF3 (R = NMe2, OMe, F, PMe2, P(NMe2)2, P(N(Pr-i)2)2, SMe, Cl); (dimethylamino)(perfluoroalkyl)carbenes Me2N-C(:)-R (R = CF3, C2F5, n-C3F7, i-C3F7, and t-C4F9) and symmetrically substituted carbenes R-C(:)-R (R = NMe2, OMe, F, PMe2, SMe, Cl) have been investigated by means of quantum chemistry methods. Different levels of approximation were used, including the CCSD(T) approach also known in quantum chemistry as the "golden standard", in combination with three different basis sets (TZVP, cc-pVDZ, cc-pVTZ). Relative stabilities of carbenes have been estimated using the differences between the singlet and triplet ground state energies (ΔEST) and energies of the hydrogenation reaction for the singlet and triplet ground states of the carbenes. The latter seem to correlate better with stability of carbenes than the ΔEST values. The (13)C NMR chemical shifts of the methylidene carbon indicate the more high-field chemical shift values in the known, isolable carbenes compared to the unstable ones. This is the first report on the expected chemical shifts in the highly unstable singlet carbenes. Using these criteria, some carbene structures from the studied series (as, for instance, Me2N-C(:)-CF3, Me2N-C(:)-C3F7-i) are proposed as good candidates for the experimental preparation.
RESUMEN
Addition of anions derived from dialkyl methylphosphonates to (Ss)-N-tert-butanesulfinyl (3,3,3)-trifluoroacetaldimine afforded (Ss,R) addition adducts in moderate to good yield (53-75%) with excellent diastereoselectivity (94-95% de). After selective removal of the N-sulfinyl group, dipeptides containing enantiomerically pure diethyl 2-amino-3,3,3-trifluoropropylphosphonate were synthesized to investigate the influence of the trifluoromethyl substituent on N-terminal coupling.
Asunto(s)
Dipéptidos/química , Fosforamidas/química , Fosforamidas/síntesis química , Técnicas de Química Sintética , Metilación , EstereoisomerismoRESUMEN
The effect of cyclochirality of rccc-2,8,14,20-tetra-n-decyl-4,10,16,22-tetra-O-methylresorcin[4]arene (C) on the enantiodiscrimination of a number of chiral bidentate and tridentate aromatic and aliphatic biomolecules (G) has been investigated by nano-electrospray ionization (nano-ESI)-Fourier transform ion cyclotron resonance mass spectrometry. The experimental approach is based on the formation of diastereomeric proton-bound [C·H·G](+) complexes by nano-ESI of solutions containing an equimolar amount of quasi-enantiomers (C) together with the chiral guest (G) and the subsequent measurement of the rate of the G substitution by the attack of several achiral and chiral amines. In general, the heterochiral complexes react faster than the homochiral ones, except when G is an aminoalcoholic neurotransmitter whose complexes, beyond that, exhibit the highest enantioselectivity. The kinetic results were further supported by both collision-induced dissociation experiments on some of the relevant [C(2) ·H·G](+) three-body species and Density functional theory (DFT) calculations performed on the most selective systems.
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Calixarenos/química , Fenilalanina/análogos & derivados , Espectrometría de Masa por Ionización de Electrospray/métodos , Análisis de Fourier , Gases/química , Cinética , Compuestos Macrocíclicos/química , Modelos Moleculares , Fenilalanina/química , EstereoisomerismoRESUMEN
Accurate full dimensional quantum dynamics calculations studying the photodissociation of CH(3)I@resorc[4]arene on an ab initio based potential energy surface (PES) model are reported. The converged 189D quantum dynamics calculations are facilitated by the multilayer multi-configurational time-dependent Hartree (ML-MCTDH) approach combined with the correlation discrete variable representation (CDVR) for the evaluation of potential energy matrix elements. The potential employed combines an established ab initio PES describing the photodissociation of methyl iodide in the A band with a harmonic description of the resorc[4]arene host and a bilinear modeling of the host-guest interaction. All potential parameters required in the description of the vibrations of the host molecule and the host-guest interaction are derived from ab initio calculations on the host-guest complex. Absorption spectra at 0 K and 300 K are calculated and the electronic population dynamics during the bond breaking process occurring in the first 20-30 fs after the photoexcitation is investigated. Weak but significant effects resulting from the host-guest interaction on this time scale are found and interpreted. The present study demonstrates that accurate fully quantum mechanical dynamics calculations can be preformed for systems consisting of more than 50 atoms using the ML-MCTDH/CDVR approach. Utilizing an efficient statistical approach for the construction of the ensemble of initial wavepackets, these calculations are not restricted to zero temperature but can also study the dynamics at 300 K.
RESUMEN
Several resorcin[4]arenes functionalized with two anthracene units on opposite sides of the upper rim of the macrocycle were synthesized. We investigated the potentially photochromic properties of these systems, with the main focus on the intramolecular [4+4] cycloaddition of the anthracenes and its reversibility by thermal ring opening. Whereas compound 9 proved to be a switchable host system (by irradiation and temperature, T-type photochromic substances), compounds 10-12 formed intramolecular photodimers upon irradiation, which are only stable at low temperature. The reopening occurred immediately at room temperature and was followed by UV/VIS spectroscopy. Further investigations showed that the cyclodimer of 11 can be stabilized significantly by sodium cations due to crown ether-like complexation. Additionally, quantum chemical calculations were performed to evaluate the different behaviour.
RESUMEN
The displacement processes of several guests, incorporated in a calixarene host system, were investigated in the gas phase by electrospray ionization-Fourier transform-ion cyclotron resonance (ESI-FT-ICR) mass spectrometry. The complexes resulting from a resorcin[4]arene host with ammonia and sec-butylamine guests were isolated in an ICR-cell, separately using both states of the photoswitch as well as two reference systems for the open and closed forms of the photoswitchable host. The isolated complexes were forced to exchange the guest by using methylamine, ethylamine and sec-butylamine, resulting in different reaction rates for all the measured systems. Especially, the reaction rates of both states of the photoswitch are dependent on the provided guest. Potential side effects like proton exchanges were examined by an H/D-exchange experiment. The results were investigated and supported by quantum chemical calculations (DFT).