N-alkyl Derivatives Research Articles

Brookhart's Acid-Catalyzed Switchable Regioselective N-Alkylation of Arylamines/Heterocyclic Amines with Cyclopropylcarbinols by Temperature Regulation.

An unprecedented, Brookhart's acid-catalyzed temperature-switchable regioselective divergent approach for N-alkylation of arylamines and heterocyclic amines by utilising cyclopropylcarbinols is presented herein. The reaction offers N-alkylated cyclopropyl derivatives and homoallyl amines by employing 2.5 mol% catalyst loading at different temperatures in excellent regioselectivity and yields. This method has shown to be relevant with a wide range of cyclopropylcarbinols, including aliphatic ones. Several control experiments and spectroscopic studies have been performed to gain insight into the reaction mechanism. Further, the synthetic utility of the protocol has also been described.

Elucidating cell surface glycan imbalance through SERS guided metabolic glycan labelling: An appraisal of metastatic potential in cancer cells.

The intrinsic complexities of cell-surface glycans impede tracking the metabolic changes in cells. By coupling metabolic glycan labelling (MGL) and surface-enhanced Raman scattering (SERS), we employed the MGL-SERS strategy to elucidate the differential glycosylation pattern in cancer cell lines. Herein, for the first time, we are reporting an N-alkyl derivative of glucosamine (GlcNPhAlk) as a glycan labelling precursor. The extent of labelling was assessed by utilizing Raman imaging and verified by complementary fluorescence and Western blot analysis. MGL-SERS technique was implemented for a comparative evaluation of cell surface glycan imbalance in different cancer cells wherein a linear relationship between glycan expression and metastatic potential was established. Further, the effect of sialyltransferase inhibitor, P-3Fax-Neu5Ac, on metabolic labelling of GlcNPhAlk proved the incorporation of GlcNPhAlk to the terminal glycans through the sialic acid biosynthetic pathway. Hence, this methodology unveils the phenomenon of metastatic progression in cancer cells with inherent glycosylation-related dysplasia.

An Exploration of the Effect of the Kleier Model and Carrier-Mediated Theory to Design Phloem-Mobile Pesticides Based on Researching the N-Alkylated Derivatives of Phenazine-1-Carboxylic Acid-Glycine.

The Kleier model and Carrier-mediated theory are effective for molecularly designing pesticides with phloem mobility. However, the single Kleier model or Carrier-mediated theory cannot achieve a reliable explanation of the phloem mobility of all exogenous substances. A detailed investigation of the two models and the scope of their applications can provide a more accurate and highly efficient basis for the guidance of the design and development of phloem-mobile pesticides. In the present paper, a strategy using active ingredient-amino acid conjugates as mode compounds is developed based on Carrier-mediated theory. An N-alkylated amino acid is used to improve the pesticide’s physicochemical properties following the Kleier model, thus allowing the conjugates to fall on the predicted and more accessible transportation region of phloem. Moreover, the influence of this movement on phloem is inspected by the Kleier model and Carrier-mediated theory. To verify this strategy, a series of N-alkylated phenazine-1-carboxylic acid-glycine compounds (PCA-Gly) were designed and synthesized. The results related to the castor bean seeds (R. communis L.) indicated that all the target compounds (4a–4f) had phloem mobility. The capacity for phloem mobility shows that N-alkylated glycine containing small substituents can significantly improve PCA phloem mobility, such as 4c(i-C3H7-N) > 4a(CH3-N) ≈ 4b(C2H5-N) > 4d (t-C4H9-N) > PCA-Gly > 4e(C6H5-N) > 4f(CH2COOH-N), with an oil–water partition coefficient between 1.2~2.5. In particular, compounds 4a(CH3-N), 4b(C2H5-N), and 4c(i-C3H7-N) present better phloem mobility, with the average concentrations in phloem sap of 14.62 μΜ, 13.98 μΜ, and 17.63 μΜ in the first 5 h, which are 8 to 10 times higher than PCA-Gly (1.71 μΜ). The results reveal that the Kleier model and Carrier-mediated theory play a guiding role in the design of phloem-mobile pesticides. However, the single Kleier model or Carrier-mediated theory are not entirely accurate. Still, there is a synergism between Carrier-mediated theory and the Kleier model for promoting the phloem transport of exogenous compounds. Therefore, we suggest the introduction of endogenous plant compounds as a promoiety to improve the phloem mobility of pesticides through Carrier-mediated theory. It is necessary to consider the improvement of physicochemical properties according to the Kleier model, which can contribute to a scientific theory for developing phloem-mobile pesticides.

Synthesis, In Vitro and in Cell Study of a New Spirooxindoles-Based N-Alkylated Maleimides Targeting HER2/3 Signaling Pathway

A series of spirooxindoles-based N-alkylated maleimide derivatives (AMIs) were synthesized and their inhibition profile also reported. Three component, one-pot [3 + 2] cycloaddition (32CA) reactions of isatin, amino acids and AMIs were found to proceed via syn-anti-azomethine ylides (AYs) to endo-addition of AMIs. These 32CA reactions present a very low activation enthalpy, 5.1 kcal·mol−1, as a consequence of the supernucleophilic character of AYs and the strong nucleophilic character of AMIs. The favorable electrostatic interactions taking place at the zwitterionic endo transition state structure are responsible for the endo stereoselectivity found in these polar 32CA reactions. The new hits of spirooxindoles-based AMIs were screened for their anticancer activity. Compounds 4e and 4f revealed the best anti-cancer activity against breast cancer cell line (MCF-7) that highly expressed human epidermal growth factor receptor (HER)-3 with the lowest IC50 < 6 µM. 4e and 4f were able to induce apoptosis by 47.26% and 55.36% with suppression of serine/threonine kinase (Akt). The latter is crucial mediator in the enhancement HER-3 which has essential function in HER-2-mediated tumor progression. Moreover, 4e and 4f were able to repress Akt-downstream genes (NF-kB and Bcl-2) expression and upregulating the expression of p21 in treated MCF-7 cells. Further, the newly synthesized spirooxindoles-based AMIs (4e and 4f) exhibited inhibitory potency for Akt and HER-2 that was supported by good binding affinity and docking interaction. Thus, 4e and 4f represent promising proapoptotic agents for breast cancer treatment.

Selective Iron Catalyzed Synthesis of N-Alkylated Indolines and Indoles.

Whereas iron catalysts usually promote catalyzed C3-alkylation of indole derivatives via a borrowing-hydrogen methodology using alcohols as the electrophilic partners, this contribution shows how to switch the selectivity towards N-alkylation. Thus, starting from indoline derivatives, N-alkylation was efficiently performed using a tricarbonyl(cyclopentadienone) iron complex as the catalyst in trifluoroethanol in the presence of alcohols leading to the corresponding N-alkylated indoline derivatives in 31-99 % yields (28 examples). The one-pot, two-step strategy for the selective N-alkylation of indolines is completed by an oxidation to give the corresponding N-alkylated indoles in 31-90 % yields (15 examples). This unprecedented oxidation methodology involves an iron salt catalyst associated with (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) and a stoichiometric amount of t-BuOOH at room temperature.

Effects of N-acylation on the immune adjuvanticity of analogs of the Quillaja saponins derivative GPI-0100

Modification of the 3-glucuronic acid (GlcA) residue from the Quillaja saponin (QS) adjuvants by N-acylation, yields derivatives with linear alkylamides that show structural and functional changes. Structural, since the relatively unreactive added hydrophobic alkyl chains may modify these glycosides’ conformation and micellar structure. Functional, because altering the availability of proposed pharmacophores, like fucose (Fucp) and aldehyde groups, to interact with their cellular receptors, may change these glycosides’ adjuvanticity. While deacylated QS (DS-QS) adjuvants bias the response toward a sole anti-inflammatory Th2 immunity against an antigen, their N-alkylated derivatives carrying octyl to dodecylamide residues, modify that response to a pro-inflammatory Th1 immunity. As shown by their IgG2a/IgG1 titer ratios, which are higher than those for Th2 immunity. A result of the fact that in mice, the IgG2a levels are dependent on the direct influence of secreted interferon-γ (IFN-γ), a crucial Th1 cytokine. But addition of the longer and more lipophilic tetradecylamide group, yields derivatives that like DS-QS induce Th2 immunity, as shown by their low IgG2a/IgG1 ratio. Results that imply that changes in these analogs’ conformation and micellar structure, would affect the immunomodulatory properties or adjuvanticity of N-acylated DS-QS. Physical changes that may alter the availability of groups like Fucp, to bind to its presumed dendritic cells’ lectin receptor DC-SIGN; an essential step in the stimulation of Th2 immunity. Structural properties that in an aqueous environment, would depend on these glycosides’ balance of their hydrophilic and lipophilic moieties (HLB), and the interactions of the newly introduced alkyl chain with the native QS’ lipophilic triterpene aglycone and hydrophilic oligosaccharide chains. A situation that would explain these new derivatives’ qualitative and quantitative changes in adjuvanticity.

N-Alkylated Analogues of Indolylthio Glycosides as Glycosyl Donors with Enhanced Activation Profile.

While studying indolylthio glycosides, previously we determined their activation profile that required large excess of activators. This drawback was partially addressed in the present study of N-alkylated SInR derivatives. The activation process was studied by NMR and the increased understanding of the mechanism led to a discovery of different activation pathways taking place with SIn versus SInR derivatives. Also investigated was orthogonality of the SInR leaving groups versus thioglycosides and selective activation of thioimidates over SInR glycosides.

Powder X-ray diffraction as a powerful tool to exploit in organic electronics: shedding light on the first N,N',N''-trialkyldiindolocarbazole.

The first crystal structure of a fully N-alkylated diindolocarbazole derivative, namely, 5,8,14-tributyldiindolo[3,2-b;2',3'-h]carbazole (1, C36H39N3), has been determined from laboratory powder X-ray diffraction (PXRD) data. A complex trigonal structure with a high-volume unit cell of 12987 Å3 was found, with a very long a(=b) [52.8790 (14) Å] and a very short c [5.36308 (13) Å] unit-cell parameter (hexagonal setting). The detailed analysis of the intermolecular interactions observed in the crystal structure of 1 highlights its potential towards the implementation of this core as a semiconductor in organic thin-film transistor (OTFT) devices. Since the molecule has a flat configuration reflecting its π-conjugated system, neighbouring molecules are found to stack atop each other in a slipped parallel fashion via π-π stacking interactions between planes of ca 3.30 Å, with a centroid-centroid distance between the aromatic rings corresponding to the shortest axis of the unit cell (i.e. c). The alkylation of the three N atoms proves to be a decisive feature since it favours the presence of C-H...π interactions in all directions, which strengthens the crystal packing. As a whole, PXRD proves to be a valuable option for the resolution of otherwise inaccessible organic crystal structures of interest in different areas.

Synthesis of Fluorescent, DNA-Binding Benzo[b]indolonaphthyridinium Derivatives by a Misguided Westphal Condensation.

A novel type of azoniahetarene, namely, benzo[b]indolonaphthyridinium, was unexpectedly formed by the reaction of N-alkylated β-carbolinium derivatives and the enolizable 1,2-cyclohexadione under typical conditions of a Westphal reaction. The products exhibit high fluorescence intensities in polar solvents (Φfl = 0.52-0.67) and bind to DNA by intercalation with high affinity (Kb = 1.5 × 106 M-1). Furthermore, under the same conditions, DNA-binding sempervirine derivatives were synthesized in a Westphal reaction from 1,2-diketones that have at least one non-enolizable α-carbon atom, which shows that the reaction pathway is determined by the substrate structure.

Rare-Earth-Metal-Complex-Catalyzed Hydroalkoxylation and Tandem Hydroalkoxylation/Cyclohydroamination of Isocyanates: Synthesis of Carbamates and Oxazolidinones.

Novel N,N,N-tridentate β-diketiminato rare-earth-metal dialkyl complexes LRE(CH2SiMe3)2 [RE = Y (1a), Gd (1b), Yb (1c), Lu (1d); L = MeC(NDipp)CHC(Me)N(CH2)2NC4H8, where Dipp = 2,6-iPr2C6H3] have been conveniently synthesized by one step from reactions of the rare-earth-metal trialkyl complexes RE(CH2SiMe3)3(THF)2 (THF = tetrahydrofuran) with a pyrrolidine-functionalized β-diketiminate HL, and their catalytic behaviors toward hydroalkoxylation and tandem hydroalkoxylation/cyclohydroamination of isocyanates have been described. These rare-earth-metal catalysts exhibited high efficiency in the hydroalkoxylation of isocyanates, providing a variety of N-alkyl and N-aryl carbamate derivatives under mild reaction conditions with a rather low catalyst loading (0.04 mol %). More significantly, they can promote a tandem hydroalkoxylation/cyclohydroamination reaction between terminal and internal propargylic alcohols with substituted arylisocyanates, leading to the efficient synthesis of methylene and (Z)-selective arylidene oxazolidinones in good-to-high yields via consecutive C-O and C-N bond formation. The stoichiometric reaction of 1a with p-tolylisocyanate generated an unusual dinuclear yttrium complex, {[η2-(4-MePhNCO)(CH2SiMe3)]Y[μ-η2:η1:η1-(4-MePhNCO)CC(Me)(NDipp)C(Me)N(CH2)2NC4H8]}2 (7a), with two different amidate units, which underwent an sp2 C-H bond activation of the β-diketiminato backbone, followed by the insertion of isocyanate.

Synthetic Studies toward 1,2,3,3a,4,8b-Hexahydropyrrolo[3,2-b]indole Core. Unusual Fragmentation with 1,2-Aryl Shift.

Base-assisted transformations of 2-(3-oxoindolin-2-yl)acetonitriles were investigated. Unexpectedly, attempted reactions of substrates possessing nonprotected nitrogen atoms were accompanied by unusual extrusions of 2-arylacetonitriles, followed by a 1,2-aryl shift to afford 3-hydroxyindolin-2-ones. On the other hand, the reactions for N-alkyl derivatives of oxoindolines took the expected route by only providing 1,2,3,3a,4,8b-hexahydropyrrolo[3,2-b]indoles.

In-situ synthesis of mercury(II)-N-heterocyclic carbene complexes by using “oxide route”, structural characterization and their photo-catalytic degradation activity for dyes

N-alkylated imidazole derivatives (1a-1b), mono-azolium salts (SL2-SL3) and their symmetrically (SC2) and non-symmetrically (SC3) substituted mercury(II)-N-heterocyclic carbene (Hg(II)-NHC) complexes were synthesized by using “oxide route”. The characterization was done by using physical (i.e., solubility, melting point determination, compound microscopic analysis) and spectral (i.e., UV-Visible spectroscopy, FT-IR spectroscopy, 1H and 13C NMR spectroscopy) methods. Chemical equilibrium between monomeric and dimeric structures of bromide-bridging Hg(II)-NHC complexes was also observed in the presence of solvent. Photo-catalytic degradation rate of two environmentally polluting dyes i.e., methylene blue (MR) and congo red (CR), was investigated by using compound 1 (SC2) and compound 2 (SC3) which demonstrated that the compound 2 had maximum degradation rate in the range of 70–80% as compared to the compound 1 (60–70% ).

Modulation of the optical properties of soluble N-alkylated 4-pyridyl diketopyrrolopyrrole derivatives

The absorption and fluorescence properties of N-alkylated 3,6-di (pyridin-4-yl)-2,5-dihydropyrrolo [3,4-c]pyrrole-1,4-dione (PyrDPP NH) derivatives in solution and the solid state are reported, along with the modulation of these properties under varying acidity or basicity. The compounds with hexyl (PyrDPP N-Hex) and methoxy ethoxy ethyl (PyrDPP N-MEE) chains were synthesised from PyrDPP NH giving highly soluble dyes. In addition, the mono-substituted derivatives were also isolated. A range of solvents was explored to provide understanding regarding their potential use in applications ranging from organic electronics to sensors. Optically the dyes are highly fluorescent and, as a result of N-alkylation breaking the hydrogen bond network, emissive in the solid state with large Stokes shifts. The nature of the chain dictates the π interactions and packing of the materials, resulting in modulation of the solid-state absorption spectra and theoretical mobility predicted from the crystal structures. The methoxy ethoxy ethyl chain twists out of the plane and bends to allow considerable molecular overlap and small interchromophore displacement with strikingly similar π interactions to the parent PyrDPP NH, resulting in a contribution of H-type aggregation to the absorption band and an order of magnitude improvement in theoretical mobility compared with the hexyl analogue. In contrast, PyrDPP N-Hex possesses a distorted CH-π interaction between pyridyl and lactam units, with greater molecular displacement manifesting in dominant J -aggregation contribution to absorption band and moderate mobility. The results emphasise the potential for sidechain modification and show structural evidence for the potential benefits of the flexible polar chains. The nitrogen lone pair of the pyridyl ring can be protonated in acidic environment to produce a photometric response suggesting potential as a proton sensor. The mono-substituted compounds are responsive to both base and acid, making them interesting for molecular logic applications.

Toxicity of chitosan derivatives to Varroa destructor (Anderson and Trueman) and their effects on immune gene expression in honey bees

Varroasisis caused by Varroa destrucor (Anderson and Trueman) is considered the most dangerous honey bee disease. V. destructor mites parasitize both brood and adults, causing considerable losses to the colony population. The control of Varroa mites is highly dependent on the application of synthetic acaricides, however, acaricide resistance can develop. To eliminate the risk of Varroa mite resistance and to reduce residues in hive products, organic-based substances for Varroa mite control are being applied. In the present study, the acaricidal activity of N-alkyl and O-acyl chitosan derivatives against Varroa mites and their side effects on honey bees have been evaluated. Chitosan has been extracted from the corpses of honey bees. The yield, degree of deacetylation, and molecular weight of chitosan from the chitin of honey bee corpses were determined as 89%, 90%, and 20 kDa, respectively. Varroa mite mortalities were observed between 6.28-84.38% and 0.00-90.47% by N-alkyl and O-acyl chitosan derivatives, respectively. The best derivatives against Varroa mite were N-(3-phenylbutyl)chitosan (NAC-5) and O-(heptanoyl)chitosan (OAC-4). The results showed that different lethal concentrations of NAC-5 and OAC-4 had side effects against honey bees less than 26%. No significant difference was found between honey bee mortalities at 24, 48, and 72 hours post-treatment, while mortalities significantly differed between 4, and 24 h post-treatment. Immune gene expression in honey bees exposed to a lethal concentration of NAC-5and OAC-4 showed that the expressions of AmHym, AmBask, and AmSpz were significantly lower compared with those of control honey bees.

Regioselectivity evaluation of the (Z)-5-(4-hydroxybenzylidene)-thiazolidine-2,4‑dione alkylation in alkaline environment

Thiazolidine-2,4‑dione represents a key heterocyclic core in medicinal chemistry because it has the ability to bind to a wide variety of protein targets and has been intensively studied for developing bioactive multitargeting agents. The N-alkylation of imides and O-alkylation of phenols are important reactions frequently used in the synthesis of biologically active compounds, like the thiazolidine-2,4‑dione derivatives. Based on literature data, by treating (Z)-5-(4-hydroxybenzylidene)-thiazolidine-2,4‑dione with alkyl halides in a 1:1 molar ratio, either O-alkylation or N-alkylation reactions can take place. Six (Z)-5-(4-hydroxybenzylidene)-thiazolidine-2,4‑dione derivatives were synthesized by alkylating (Z)-5-(4-hydroxybenzylidene)-thiazolidine-2,4‑dione with aliphatic halogenated derivatives in alkaline environment, using a 1:1 molar ratio and then were physically and spectrally analyzed. The spectral data and the results obtained from the theoretical evaluation of the parent compound's acidity support the formation of N-alkylated derivatives in the reaction conditions.

Synthesis of New Chiral N-alkyl Betti-base Ligands via One-Pot Three Component Strategy

Background: Betti base derivatives were employed as chiral ligands or as chiral auxiliaries in asymmetric transformations. In particular, N-alkyl Betti base derivatives are gaining importance as excellent ligands in asymmetric reactions. However, no appropriate method exists for regioselective N-alkylation of Betti base. Therefore, there is an urgent need to develop a new protocol for the regioselective N-alkylation of chiral Betti-base. Methods: An efficient method has been developed for one-pot synthesis of chiral N-alkyl Bettibase ligands from (S)-(+)-Betti base, arylglyoxals and cyclic 1,3-C,N-binucleophiles under catalyst- free conditions. Results: The chiral N-alkyl Betti-base ligands were obtained in good yields with excellent enantioselectivities. This method is rapid, clean and does not require a catalyst or chromatographic purification. Conclusion: We have developed an efficient one-pot three component strategy for the synthesis of new chiral N-alkyl Betti-base ligands from (S)-(+)-Betti base, arylglyoxals and cyclic 1,3-C,Nbinucleophiles in the absence of a catalyst.

Solvent-Free Three Component Synthesis of N-alkylated Derivatives of N-Acylhydrazones from Hydrazides, Aldehydes and α,β-unsaturated Esters

A number of new N-alkylated derivatives of N-acylhydrazones have been prepared via one pot three-component reaction between hydrazide, aldehyde, and &amp;#945;,&amp;#946;-unsaturated ester using 1,4-diazabicyclo[ 2,2,2]octane (DABCO), as an inexpensive base and tetrabutylammonium bromide (TBAB), an ionic organic salt media, under solvent-free conditions. In case of 2-hydroxy benzaldehyde, the reaction proceeds with the exclusive formation of the N-alkyl derivative without any concurrent O-alkylation side reaction.

Antibiotic resistance and drug modification: Synthesis, characterization and bioactivity of newly modified potent ciprofloxacin derivatives

Development of new derivatives of commercial antibiotics using different organic reagents and testing these derivatives against different microorganisms are the main goals of this article. Thus, the antibiotic ciprofloxacin, CF, was acylated via reaction with ethyl cyanoacetate and ethyl acetoacetate in basic medium to give the cyanoacetylpiprazinyl dihydroquinoline derivative 3, and oxobutanoylpiprazinyl dihydroquinoline derivative 5, respectively. On the other hand, N-alkylated derivatives 8–10, were prepared through the reaction of CF with chloroacetonitrile, chloroacetyl acetone and chloroacetone in the presence of carbonate salt. In basic medium, both 3 and 10 were coupled with benzenediazonium chloride to afford hydrazono derivatives, which were then cyclized to give 4-(dihydropyridazinecarbonyl)piperazinyl-1,4-dihydroquinoline. Furthermore, compounds 3 and 10 were reacted with benylidenemalononitrile to produce 4H-pyan and pyrido[1,2-a]pyrazine derivatives, respectively. Both 3 and 10 were reacted with DMFDMA to give enaminone derivatives. These enaminones were cyclized to aminopyrimidine derivatives by reacting with urea or thiourea. X-ray, elemental analysis and spectral data were used to illustrate and confirm the structures of the isolated compounds. The bioactivities of the novel compounds were investigated against different gram-positive and gram-negative bacteria. In addition, these novel antibiotic derivatives were tested against ciprofloxacin-resistant bacteria isolated from patients aged 65–74 years. This study reveals that most of the modified drugs show high to moderate antibacterial activity. Additionally, these drugs show good effects against ciprofloxacin-resistant bacteria.

Ruthenium-Catalyzed Chemoselective N-H Bond Insertion Reactions of 2-Pyridones/7-Azaindoles with Sulfoxonium Ylides.

A ruthenium-catalyzed highly chemoselective N-alkylation of 2-pyridones has been developed, affording N-alkylated 2-pyridone derivatives in good yields and excellent N-selectivity. The key to achieve this unprecedented N-H rather than O-H insertion reaction is the use of CpRu(PPh3)2Cl as the catalyst and sulfoxonium ylides as the alkylation reagents. Moreover, this protocol is also amenable to 7-azaindoles by slightly varying the reaction conditions. Furthermore, sulfonium ylides are also suitable alkylation reagents, providing the N-alkylated 2-pyridones in good selectivity.

Polymer-supported synthesis of N-substituted anthranilates as the building blocks for preparation of N-arylated 3-hydroxyquinolin-4(1H)-ones.

Fast and simple access to N-arylated 3-hydroxyquinolin-4(1H)-ones starting from easily available 1-methyl-2-iodoterephthalate and variously substituted anilines is presented. N-Alkylated anthranilic acid derivatives represent important intermediates. They can be advantageously prepared by solid-phase synthesis, by Buchwald–Hartwig amination or reductive amination with wide substrate scope and with excellent crude purities.