Cycloaddition reactions of heterocyclic azides with 2-cyanoacetamidines as a new route to C,N-diheteroarylcarbamidines.

A novel and efficient base-catalyzed, transition-metal-free method for the synthesis of diheterocyclic compounds connected by an amidine linker, including apart from the common 1,2,3-triazole ring, either an additional pyrimidinedione, 4-nitroimidazole, isoxazole, 1,3,4-triazole, 2-oxochromone or thiazole ring, has been developed. The process was facilitated by a strong base and includes the cycloaddition reaction of 3,3-diaminoacrylonitriles (2-cyanoacetamidines) to heterocyclic azides followed by a Cornforth-type rearrangement to the final products. The reaction is tolerant to various N-monosubstituted 3,3-diaminoacrylonitriles and to different heterocyclic azides. The developed method has a broad scope and can be applied to obtain a variety of N-heteroaryl-1,2,3-triazole-4-carbimidamides with alkyl, allyl, propargyl, benzyl, cycloalkyl, and indolyl substituents at the N1 position .

Cyanothioacetamides as a synthetic platform for the synthesis of aminopyrazole derivatives.

It was shown that the reaction of 2-cyanothioacetamides with hydrazine involves both cyano- and thioamide groups, and 3,5-diaminopyrazoles are formed. In the reaction of 2-cyano-3-(dimethylamino)-N,N-dimethylprop-2-enethioamides with hydrazine and its derivatives, the interaction proceeds with the participation of cyano- and enamine groups, not affecting the thiocarbamoyl group, and leads to the formation of 4-thiocarbamoylpyrazoles. A synthesis method has been developed and a series of 1-substituted-4-thiocarbamoyl pyrazoles has been thus synthesized. The structure of the reaction products was studied using NMR spectroscopy and mass spectrometry and confirmed by X-ray diffraction analysis.

Tandem Cycloaddition of Azides to 3,3-Diaminoacrylonitriles (2-Cyanoacetamidines) and Cornforth-Type Rearrangement as an Approach to 5-Amino-1,2,3-triazole-4-N-substituted Imidamides.

An efficient base-catalyzed, metal-free method for the synthesis of 5-amino-1,2,3-triazole-4-N-sulfonyl- and arylimidamides, directed by the structure of the amidine group, has been developed. It is based on a previously unknown tandem process involving cycloaddition reaction to 3,3-diaminoacrylonitriles (2-cyanoacetamidines) with aryl(alkyl)sulfonyl or aryl azides and Cornforth-type rearrangement. During the reaction optimization, different factors were found to facilitate the title reaction, which include the use of a strong base and N-mono- or N,N'-disubstituted 3,3-diaminoacrylonitriles. The reaction is tolerant to variously N-monosubstituted and N,N'-disubstituted 3,3-diaminoacrylonitriles and to various aryl- and aryl/alkyl sulfonyl azides. The developed method has a broad scope and can be applied to obtain a variety of 5-amino-1,2,3-triazole-4-carbimidamides bearing at the N1 position alkyl, allyl, propargyl, benzyl, cycloalkyl, and heteroaryl substituents and sulfonyl and aryl substituents at the amidine group. Post-cyclization reactions of prepared 5-amino-1,2,3-triazoles with DMF-DMA DMA-DMF leads to 1,2,3-triazolo[4,5-d]pyrimidines, 8-aza purine analogues demonstrating the applicability of the prepared compounds in organic synthesis.

Synthesis of Non-Aromatic Pyrroles Based on the Reaction of Carbonyl Derivatives of Acetylene with 3,3-Diaminoacrylonitriles.

The reaction of 3,3-diaminoacrylonitriles with DMAD and 1,2-dibenzoylacetylene was studied. It is shown that the direction of the reaction depends on the structure both of acetylene and of diaminoacrylonitrile. In the reaction of DMAD with acrylonitriles bearing a monosubstituted amidine group, 1-substituted 5-amino-2-oxo-pyrrole-3(2H)ylidenes are formed. On the other hand, a similar reaction of acrylonitriles containing the N,N-dialkylamidine group affords 1-NH-5-aminopyrroles. In both cases, pyrroles containing two exocyclic double bonds are formed in high yields. A radically different type of pyrroles containing one exocyclic C=C bond and sp3 hybrid carbon in the cycle is formed in reactions of 3,3-diaminoacrylonitriles with 1,2-diaroylacetylenes. As in reactions with DMAD, the interaction of 3,3-diaminoacrylonitriles with 1,2-dibenzoylacetylene can lead, depending on the structure of the amidine fragment, both to NH- and 1-substituted pyrroles. The formation of the obtained pyrrole derivatives is explained by the proposed mechanisms of the studied reactions.

Rhodium-Catalyzed Transannulation of 4,5-Fused 1-Sulfonyl-1,2,3-triazoles with Nitriles. The Selective Formation of 1-Sulfonyl-4,5-fused Imidazoles versus Secondary C-H Bond Migration.

The reactivity of readily available 4,5-fused-1-sulfonyl-1,2,3-triazoles was examined in the Rh(II)-catalyzed transannulation reaction with nitriles. We have come across the interesting observation that 1-sulfonyl cycloalkeno[d][1,2,3]triazoles that possess ß-hydrogens resist intramolecular ß-hydride migration and could serve as a new source of Rh-iminocarbenoids for intermolecular Rh(II)-catalyzed transannulation reactions. As a result, 1-sulfonyl cyclohexeno-, cyclohepteno-, dihydropyrano-, 5-phenyltetrahydrobenzo-, and 4,5-dihydronaphtho[d]imidazoles were synthesized from various nitriles in good yields. A one-pot methodology has also been executed for the synthesis of NH-imidazoles.

Thioisomünchnones versus Acrylamides via Copper-Catalyzed Reaction of Thioamides with Diazocarbonyl Compounds.

A novel carbenoid-mediated approach to thioisomünchnones was developed by intermolecular copper-catalyzed reactions of diazoacetamides with aromatic and heteroaromatic thioamides bearing a pyrrolidine moiety. The direction of the reaction can be switched toward 2-amino-2-heteroarylacrylamides by replacing the pyrrolidine with an aniline group or by the use of 2-cyano-2-diazoacetamides. The proposed mechanism and DFT calculations allowed us to rationalize the effect of substituents on the reaction direction. Effective methods were found for the synthesis of previously unknown both 2-heteroarylthioisomünchones and 2-heteroarylacrylamides, based on a wide scope of available reagents with a similar structure. Some of the synthesized thioisomünchnones exhibited multicolor fluorescence in the solid state and solutions.

Selective Synthesis of Azoloyl NH-1,2,3-Triazoles and Azolyl Diazoketones: Experimental and Computational Insights.

Here, we report that the reaction of enaminones, from a class of azole series, with sulfonyl azides leads to a difficult-to-separate mixture of two pairs of compounds: (1) 4-azoloyl-NH-1,2,3-triazoles with sulfonamides and (2) azolyl diazoketones with N-sulfonamidines, as a result of the implementation of two competing reactions. On one hand, the electron-donating methyl or methoxy group in the aryl para-position of arylsulfonyl azides favors the production of NH-1,2,3-triazoles together with sulfonamides. On the other hand, the use of highly electrophilic 4-nitrophenylsulfonyl azide promotes the formation of diazoketones and sulfonamidines. It is shown that the direction of each reaction is not only controlled by the nature of the initial enaminones and sulfonyl azides but also depends on the tested solvent. The problem of removing sulfonamides and amidines from the desired products was solved for the first time using new water-soluble enaminones. Based on the experimental and computational studies, the factors contributing to the selective course of alternative reactions were identified, and methods for the synthesis of azoloyl-NH-1,2,3-triazoles and azolyl diazoketones were developed. Density functional theory (DFT) results have shown that the 1,3-dipolar cycloaddition is totally driven toward one single regioisomer with a high asynchronous bond formation, and the introduction of an electron-deficient group in sulfonyl azides induces faster cycloaddition. Additionally, DFT calculations were used to gain further mechanistic insights on the reaction studied here.

Synthesis, Fungicidal Activity, and Molecular Docking of 2-Acylamino and 2-Thioacylamino Derivatives of 1H-benzo[d]imidazoles as Anti-Tubulin Agents.

This work deals with the synthesis and evaluation of fungicidal activity of benzimidazole derivatives, which are structural analogues of commercial anti-tubulin fungicides. A number of N-acyl and N-thioacyl derivatives of 2-amino-1H-benzo[d]imidazole were prepared, and their fungicidal activity against 13 strains of phytopathogenic fungi was studied. The most active compounds against the majority of the studied strains were 3a, 4l, and 4o, and the EC50 values of these compounds were in the range 2.5-20 µg/mL. Compound 3a showed the highest activity against the P. infestans strain, the growth of which is not suppressed by carbendazim. The formation of ligand-receptor complexes of various tautomeric forms of the studied benzimidazoles with homologous models of ß-tubulins of B. cinerea, F. oxysporum, and P. infestans was modeled. Induced fit docking has been used for the simulation. The obtained data suggest the possibility of binding of benzimidazole fungicides to ß-tubulin in the ″nocodazole cavity″ in the tautomeric form bearing a double exocyclic C═N bond. The importance of the formation of hydrogen bonds of benzimidazoles with the amino acid residue Val236 along with the Glu198 residue is also revealed in the present study.

Regioselective synthesis of heterocyclic N-sulfonyl amidines from heteroaromatic thioamides and sulfonyl azides.

N-Sulfonyl amidines bearing 1,2,3-triazole, isoxazole, thiazole and pyridine substituents were successfully prepared for the first time by reactions of primary, secondary and tertiary heterocyclic thioamides with alkyl- and arylsulfonyl azides. For each type of thioamides a reliable procedure to prepare N-sulfonyl amidines in good yields was found. Reactions of 1-aryl-1,2,3-triazole-4-carbothioamides with azides were shown to be accompanied with a Dimroth rearrangement to form 1-unsubstituted 5-arylamino-1,2,3-triazole-4-N-sulfonylcarbimidamides. 2,5-Dithiocarbamoylpyridine reacts with sulfonyl azides to form a pyridine bearing two sulfonyl amidine groups.

Structure-Activity Relationships of Novel Thiazole-Based Modafinil Analogues Acting at Monoamine Transporters.

Atypical dopamine reuptake inhibitors, such as modafinil, are used for the treatment of sleeping disorders and investigated as potential therapeutics against cocaine addiction and for cognitive enhancement. Our continuous effort to find modafinil analogues with higher inhibitory activity on and selectivity toward the dopamine transporter (DAT) has previously led to the promising thiazole-containing derivatives CE-103, CE-111, CE-123, and CE-125. Here, we describe the synthesis and activity of a series of compounds based on these scaffolds, which resulted in several new selective DAT inhibitors and gave valuable insights into the structure-activity relationships. Introduction of the second chiral center and subsequent chiral separations provided all four stereoisomers, whereby the S-configuration on both generally exerted the highest activity and selectivity on DAT. The representative compound of this series was further characterized by in silico, in vitro, and in vivo studies that have demonstrated both safety and efficacy profile of this compound class.

Water/Alkali-Catalyzed Reactions of Azides with 2-Cyanothioacetamides. Eco-Friendly Synthesis of Monocyclic and Bicyclic 1,2,3-Thiadiazole-4-carbimidamides and 5-Amino-1,2,3-triazole-4-carbothioamides.

The reactions of thioamides with azides in water were studied. It was reliably shown that the reaction of 2-cyanothioacetamides 1 with various types of azides 2 in water in the presence of alkali presents an efficient, general, one-step, atom-economic, and eco-friendly method for the synthesis of 1,2,3-thiadiazol-4-carbimidamides 5 and 1,2,3-triazole-4-carbothioamides 4. This method can be extended to the one-pot reaction of sulfonyl chlorides and 6-chloropyrimidines 2'o with sodium azide, leading to final products in higher yields, that is, avoiding the isolation of unsafe sulfonyl azides. The method was furthermore applied to the reaction of N,N'-bis-(2-cyanothiocarbonyl)pyrazine 1h with sulfonyl azides to afford bicyclic 1,2,3-thiadiazoles 8 and 1,2,3-triazoles 9 connected via a 1,1'-piperazinyl linker. 2-Cyanothioacetamides 1 were also shown to react with aromatic azides in water in the presence of alkali to afford 1-aryl-5-amino-1,2,3-triazole-4-carbothioamides 11. In contrast to aromatic azides and similarly to sulfonyl azides, 6-azidopyrimidine-2,4-diones 2o-q react with cyanothioacetamides to form N-pyrimidin-6-yl-5-dialkylamino-1,2,3-thiadiazole-4-N-l-carbimidamides 12. A mechanism was proposed to rationalize the role of water in changing the reactivity of azides toward 2-cyanothioacetamides.

High Electron Affinity Molecular Dopant CN6-CP for Efficient Organic Light-Emitting Diodes.

p-Type molecular doping of organic materials with high ionization energies (IEs) of above 5.50 eV is still a challenge, limiting the use of doping in high-performance organic light-emitting diodes (OLEDs). Here, we investigate the molecular dopant hexacyano-trimethylene-cyclopropane (CN6-CP) with a high electron affinity of 5.87 eV as p-dopant in OLEDs. We show that CN6-CP can be used not only as a dopant in the traditional hole transport material 4,4'-cyclohexylidenebis[ N, N-bis(4-methylphenyl)benzenamine] (TAPC, IE = 5.50 eV) but also effectively dopes the host material tris(4-carbazoyl-9-ylphenyl)amine (TCTA, IE = 5.85 eV), reaching a conductivity of 1.86 × 10-4 S/cm at a molar ratio of 0.25. Using CN6-CP-doped TAPC as hole injection and transport layer, we achieve a low driving voltage of 2.92 V at the practical brightness of 1000 cd/m2 and 3.18 V at a current density of 10 mA/cm2 for a green phosphorescent OLED based on bis[2-(2-pyridinyl- N)phenyl- C](acetylacetonato)iridium(III) (Ir(ppy)2(acac)), together with a maximum external quantum efficiency of 18% and a luminous efficacy of 78 lm/W. The device also exhibits a very low efficiency roll-off at high luminance. Further, by directly adopting CN6-CP-doped TCTA as the injection/transport layer, the driving voltage drops to 2.78 V at 1000 cd/m2 and 2.93 V at 10 mA/cm2. Moreover, conductivity and absorption measurements suggest that CN6-CP could also dope CBP with an IE as high as 6.05 eV. The results show that CN6-CP is an excellent p-type dopant for efficient OLEDs and possesses great potential for future application in organic optoelectronic devices.

Layer-by-Layer Assembly Enabled by the Anionic p-Dopant CN6-CP•-K+: a Route to Achieve Interfacial Doping of Organic Semiconductors.

Highly efficient 2D (interfacial) doping of organic semiconductors, poly(3-hexylthiophene) (P3HT) and TIPS-pentacene, was achieved by a polyelectrolyte-supported layer-by-layer assembly of the dual-mode functional dopant CN6-CP•-K+, having an anionic group for its fixation onto oppositely charged surfaces/molecules as well as electron-deficient groups providing its p-doping ability. Polyelectrolyte-supported dopant layers were used to generate conductive channels at the bottom or at the top of semiconducting films. Unlike to the case of sequentially processed P3HT films doped by F4TCNQ ( Moulé , J. Chem. Mater. 2015 , 27 , 5765 ; Koech , P. K. J. Mater. Chem. C 2013 , 1 , 1876 ; Schwartz , B. J. J. Phys. Chem. Lett. 2015 , 6 , 4786 ), the use of more polar CN6-CP•-K+ dopant and ultrathin polycation separation interlayer enables predominantly interfacial kind of doping placement with no or minimal intercalation of the dopant into the semiconductor bulk. The layered structure of the doped film was proved by transmission electron microscopy of the cross-section and it agrees well with other data obtained in this work. The interfacial doping enabled an impressive conductivity of 13 S/cm even for ultrathin P3HT films. We propose to explain the superior efficiency of the interfacial doping compared to the bulk doping in terms of unperturbed morphology of the semiconductor and high mobility of charge carriers, which are spatially separated from the dopant phase.

Heterocyclic Analogues of Modafinil as Novel, Atypical Dopamine Transporter Inhibitors.

Modafinil is a wake promoting compound with high potential for cognitive enhancement. It is targeting the dopamine transporter (DAT) with moderate selectivity, thereby leading to reuptake inhibition and increased dopamine levels in the synaptic cleft. A series of modafinil analogues have been reported so far, but more target-specific analogues remain to be discovered. It was the aim of this study to synthesize and characterize such analogues and, indeed, a series of compounds were showing higher activities on the DAT and a higher selectivity toward DAT versus serotonin and norepinephrine transporters than modafinil. This was achieved by substituting the amide moiety by five- and six-membered aromatic heterocycles. In vitro studies indicated binding to the cocaine pocket on DAT, although molecular dynamics revealed binding different from that of cocaine. Moreover, no release of dopamine was observed, ruling out amphetamine-like effects. The absence of neurotoxicity of a representative analogue may encourage further preclinical studies of the above-mentioned compounds.

A novel heterocyclic compound improves working memory in the radial arm maze and modulates the dopamine receptor D1R in frontal cortex of the Sprague-Dawley rat.

A series of compounds have been shown to enhance cognitive function via the dopaminergic system and indeed the search for more active and less toxic compounds is continuing. It was therefore the aim of the study to synthetise and test a novel heterocyclic compound for cognitive enhancement in a paradigm for working memory. Specific and effective dopamine re-uptake inhibition DAT (IC50=4,1±0,8µM) made us test this compound in a radial arm maze (RAM) in the rat. CE-125 (4-((benzhydrylsulfinyl)methyl)-2-cyclopropylthiazole), was tested for dopamine (DAT), serotonin and norepinephrine re-uptake inhibition by a well-established system. The working memory index (WMI) was evaluated in male Sprague Dawley rats that were intraperitoneally injected with CE-125 (1 or 10mg/kg body weight). In order to evaluate basic neurotoxicity, the open field, elevated plus maze, rota rod studies and the forced swim test were carried out. Frontal cortex was taken at the last day of the RAM test and dopamine receptors D1R and D2R, DAT and phosphorylated DAT protein levels were determined. On the 10th day both doses were increasing the WMI as compared to the vehicle-treated group. In both, trained and treated groups, D1R levels were significantly reduced while D2R levels were unchanged. DAT levels were comparable between all groups while phosphorylated DAT levels were increased in the trained group treated with 1mg/kg body weight. CE-125 as a probably non-neurotoxic compound and specific reuptake inhibitor was shown to increase performance (WMI) and modulation of the dopaminergic system is proposed as a possible mechanism of action.

Switchable Synthesis of 4,5-Functionalized 1,2,3-Thiadiazoles and 1,2,3-Triazoles from 2-Cyanothioacetamides under Diazo Group Transfer Conditions.

High yield solvent-base-controlled, transition metal-free synthesis of 4,5-functionalized 1,2,3-thiadiazoles and 1,2,3-triazoles from 2-cyanothioacetamides and sulfonyl azides is described. Under diazo transfer conditions in the presence of a base in an aprotic solvent 2-cyanothioacetamides operating as C-C-S building blocks produce 5-amino-4-cyano-1,2,3-thiadiazoles exclusively. The use of alkoxide/alcohol system completely switches the reaction course due to the change of one of the reaction centers in the 2-cyanothioacetamide (C-C-N building block) resulting in the formation of 5-sulfonamido-1,2,3-triazole-4-carbothioamide sodium salts as the only products. The latter serve as good precursors for 5-amino-1,2,3-thiadiazole-4-carboximidamides, the products of Cornforth-type rearrangement occurring in neutral protic medium or under acid conditions. According to DFT calculations (B3LYP/6-311+G(d,p)) the rearrangement proceeds via intermediate formation of a diazo compound, and can be catalyzed by acids via the protonation of oxygen atom of the sulfonamide group.

High Conductivity in Molecularly p-Doped Diketopyrrolopyrrole-Based Polymer: The Impact of a High Dopant Strength and Good Structural Order.

[3]-Radialene-based dopant CN6-CP studied herein, with its reduction potential of +0.8 versus Fc/Fc+ and the lowest unoccupied molecular orbital level of -5.87 eV, is the strongest molecular p-dopant reported in the open literature, so far. The efficient p-doping of the donor-acceptor dithienyl-diketopyrrolopyrrole-based copolymer having the highest unoccupied molecular orbital level of -5.49 eV is achieved. The doped films exhibit electrical conductivities up to 70 S cm(-1) .

A Novel Heterocyclic Compound CE-104 Enhances Spatial Working Memory in the Radial Arm Maze in Rats and Modulates the Dopaminergic System.

Various psychostimulants targeting monoamine neurotransmitter transporters (MATs) have been shown to rescue cognition in patients with neurological disorders and improve cognitive abilities in healthy subjects at low doses. Here, we examined the effects upon cognition of a chemically synthesized novel MAT inhibiting compound 2-(benzhydrylsulfinylmethyl)-4-methylthiazole (named as CE-104). The efficacy of CE-104 in blocking MAT [dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter] was determined using in vitro neurotransmitter uptake assay. The effect of the drug at low doses (1 and 10 mg/kg) on spatial memory was studied in male rats in the radial arm maze (RAM). Furthermore, the dopamine receptor and transporter complex levels of frontal cortex (FC) tissue of trained and untrained animals treated either with the drug or vehicle were quantified on blue native PAGE (BN-PAGE). The drug inhibited dopamine (IC50: 27.88 µM) and norepinephrine uptake (IC50: 160.40 µM), but had a negligible effect on SERT. In the RAM, both drug-dose groups improved spatial working memory during the performance phase of RAM as compared to vehicle. BN-PAGE Western blot quantification of dopamine receptor and transporter complexes revealed that D1, D2, D3, and DAT complexes were modulated due to training and by drug effects. The drug's ability to block DAT and its influence on DAT and receptor complex levels in the FC is proposed as a possible mechanism for the observed learning and memory enhancement in the RAM.

Combined experimental and theoretical studies of regio- and stereoselectivity in reactions of ß-isoxazolyl- and ß-imidazolyl enamines with nitrile oxides.

Reactions of ß-azolyl enamines and nitrile oxides were studied by both experimental and theoretical methods. (E)-ß-(4-Nitroimidazol-5-yl), (5-nitroimidazol-4-yl) and isoxazol-5-yl enamines smoothly react regioselectively at room temperature in dioxane solution with aryl, pyridyl, and cyclohexylhydroxamoyl chlorides without a catalyst or a base to form 4-azolylisoxazoles as the only products in good yields. The intermediate 4,5-dihydroisoxazolines were isolated as trans isomers during the reaction of (E)-ß-imidazol-4-yl enamines with aryl and cyclohexylhydroxamoyl chlorides. Stepwise and concerted pathways for the reaction of ß-azolyl enamines with hydroxamoyl chlorides were considered and studied at the B3LYP/Def2-TZVP level of theory combined with D3BJ dispersion correction. The reactions of benzonitrile oxide with both E- and Z-imidazolyl enamines have been shown to proceed stereoselectively to form trans- and cis-isoxazolines, respectively. The preference of E-isomers over Z-isomers, driven by the higher stability of the former, apparently controls the stereoselectivity of the investigated cycloaddition reaction with benzonitrilе oxide. Based on the reactivity of azolyl enamines towards hydroxamoyl chlorides, a novel, effective catalyst-free method was elaborated to prepare 4-azolyl-5-substituted isoxazoles that are otherwise difficult to obtain.

Influence of Semiconductor Thickness and Molecular Weight on the Charge Transport of a Naphthalenediimide-Based Copolymer in Thin-Film Transistors.

The N-type semiconducting polymer, P(NDI2OD-T2), with different molecular weights (MW=23, 72, and 250 kg/mol) was used for the fabrication of field-effect transistors (FETs) with different semiconductor layer thicknesses. FETs with semiconductor layer thicknesses from ∼15 to 50 nm exhibit similar electron mobilities (µ's) of 0.2-0.45 cm2 V(-1) s(-1). Reduction of the active film thickness led to decreased µ values; however, FETs with ∼2 and ∼5 nm thick P(NDI2OD-T2) films still exhibit substantial µ's of 0.01-0.02 and ∼10(-4) cm2 V(-1) s(-1), respectively. Interestingly, the lowest molecular weight sample (P-23, MW≈23 kg/mol, polydispersity index (PDI)=1.9) exhibited higher µ than the highest molecular weight sample (P-250, MW≈250 kg/mol, PDI=2.3) measured for thicker devices (15-50 nm). This is rather unusual behavior because typically charge carrier mobility increases with MW where improved grain-to-grain connectivity usually enhances transport events. We attribute this result to the high crystallinity of the lowest MW sample, as confirmed by differential scanning calorimetry and X-ray diffraction studies, which may (over)compensate for other effects.