Imine Formation Reaction Research Articles

Synthesis and In vitro Efficacy of Tetracyclic Benzothiazepines Against Blood-Stage Plasmodium falciparum and Liver-Stage P. berghei.

A series of novel, substituted tetracyclic benzothiazepines were designed and prepared in an effort to optimize the potency of this chemical class against drug-resistant strains of the malaria parasite. Tetracyclic benzothiazepines bearing structural modification at seven distinct positions within the structure were synthesized in Knoevenagel condensation reactions followed by sequential intermolecular thio-Michael and then intramolecular imine formation reactions. Following purification and chemical characterization, the novel compounds were tested for in vitro efficacy against blood-stage P. falciparum and liver-stage P. berghei and also for in vivo efficacy against P. berghei. Benzothiazepines bearing structural modification at the sulfur atom and at the three carbocycles within the molecule were successfully synthesized. The majority of analogs inhibited bloodstage P. falciparum with submicromolar IC50 values. The potency of an 8-methoxy-substituted analog 12 exceeded that of chloroquine in all three P. falciparum strains tested. The parent benzothiazepine 1 possessed liver-stage activity, inhibiting P. berghei sporozoites infecting HepG2 cells with an IC50 of 106.4 nM and an IC90 of 408.9 nM, but failed to enhance the longevity of P. berghei infected mice compared to the controls. Compounds displayed modest toxicity toward HepG2 cells and were tolerated by mice at the highest dose tested, 640 mg/kg/dose once daily for three days. The tetracyclic benzothiazepine described, which inhibits P. berghei infected hepatic cells with an IC50 of 106.4 nM, would appear to warrant further investigation. Optimization of ADME properties may be required since the most active analogs are probably excessively lipophilic.

High‐Throughput Diversification of Complex Bioactive Molecules by Accelerated Synthesis in Microdroplets

AbstractLate‐stage diversification of drug molecules is an important strategy in drug discovery that can be facilitated by reaction screening using high‐throughput experimentation. Here we present a rapid method for functionalizing bioactive molecules based on accelerated reactions in microdroplets. Reaction mixtures are nebulized at throughputs better than 1 reaction/second and the accelerated reactions occurring in the microdroplets are followed by desorption electrospray ionization mass spectrometry (DESI‐MS). Because the accelerated reactions occur on the millisecond timescale, they allow an overall screening throughput of 1 Hz working at the low nanogram scale. Using this approach, an opioid agonist (PZM21) and an antagonist (naloxone) were diversified using three reactions important in medicinal chemistry: sulfur fluoride exchange (SuFEx) click reactions, imine formation reactions, and ene‐type click reactions. Some 269 functionalized analogs of naloxone and PZM21 were generated and characterized by tandem mass spectrometry (MS/MS) after screening over 500 reactions.

High-Throughput Diversification of Complex Bioactive Molecules by Accelerated Synthesis in Microdroplets.

Late-stage diversification of drug molecules is an important strategy in drug discovery that can be facilitated by reaction screening using high-throughput experimentation. Here we present a rapid method for functionalizing bioactive molecules based on accelerated reactions in microdroplets. Reaction mixtures are nebulized at throughputs better than 1 reaction/second and the accelerated reactions occurring in the microdroplets are followed by desorption electrospray ionization mass spectrometry (DESI-MS). Because the accelerated reactions occur on the millisecond timescale, they allow an overall screening throughput of 1 Hz working at the low nanogram scale. Using this approach, an opioid agonist (PZM21) and an antagonist (naloxone) were diversified using three reactions important in medicinal chemistry: sulfur fluoride exchange (SuFEx) click reactions, imine formation reactions, and ene-type click reactions. Some 269 functionalized analogs of naloxone and PZM21 were generated and characterized by tandem mass spectrometry (MS/MS) after screening over 500 reactions.

Synthesis of MnS/MnO Decorated N, S‐Doped Carbon Derived from a Mn(II)‐Coordinated Polymer for the Catalytic Oxidation of H2O2 and Bisphenol A

AbstractA way to synthesize a Mn2+‐ coordinated polymer precursor ligated by sulfur atoms with acetate counter ions (Mn‐DTOGA) is proposed, which is achieved by an imine formation reaction between dithiooxamide and glutaraldehyde in the presence of manganese (II) acetate. MnS/MnO decorated N, S‐doped carbon nanoparticles (MnS/O‐SNC) are then prepared by calcination of the Mn ion‐coordinated polymer for the practical applications of catalytic reactions. The Mn‐DTOGA and MnS/O‐SNC structures prepared at different temperatures (700, 800, and 900 °C) are characterized using various physical and electrochemical and chemical analyses. The nanoparticles prepared at 900 °C reveal the best performance for the catalytic oxidation of Hydrogen peroxide (H2O2) and bisphenol A. The decomposition potentials of H2O2 (1.0 mm) and bisphenol A (100.0 µm) on the catalyst modified electrode are observed to be +0.40 and +0.15 V (versus Ag/AgCl), respectively. It is observed that the catalytic performances to the oxidation reactions are mainly related to MnO decorated outside the SNC particles compared to MnS formed inside the particles. The electrode reveals a wide dynamic range with the low detection limits for H2O2 (0.08 (±0.02) µm) and bisphenol A (0.17 (±0.04) µm). This study will provide essential clues for the future catalyst design.

Facile Synthesis of the Shape‐Persistent 4‐Hydroxybenzaldehyde Based Macrocycles and Exploration of their Key Electronic Properties: An Experimental and DFT Approach

AbstractIn the current study, a series of stabilized bis‐acetylene incorporated 4‐hydroxybenzaldehyde based macrocycles using the alkyne‐homocoupling approach were synthesized in moderate yields. A total of six newly stiff macrocycles were synthesized in a stepwise manner starting from 4‐hydroxybenzaldehyde. In the first step, base mediated propargylation was performed followed by copper mediated terminal alkyne homocoupling. The alkyne homocoupled substrate having carbonyl at both the terminals is cyclized in the final step via double imine formation reactions using substituted diamines as linker. All the newly synthesized rigid framework of the macrocycles were optimized at B3LYP/6‐31G (d,p) level of theory. Nonlinear optical behaviors of the synthesized macrocycles were explored by the DFT calculations where high values of first‐order hyperpolarizability and dipole moment were examined. In the reported study, a good agreement between experimental and theoretical parameters was observed that may play a significant contribution for the NLO applications.

Preparation of novel imidazo[1,2-a]pyrimidine derived schiff bases at conventional and microwave heating conditions

In this study, novel imidazo[1,2-a]pyrimidine derived schiff bases were synthesized via imine formation reaction and characterized with various spectral analysis such as FT-IR, 1H NMR, 13C NMR and MS. In addition to conventional heating reactions, microwave-assisted synthesis was applied to the C=N bond formation step. The reactions were carried out at reflux temperature in toluene and magnesium sulfate as drying agent. While final products were obtained at 10-36 h reaction times with moderate to good yields at conventional heating conditions, synthesized at 45-120 min reaction times with good yields at microwave heating conditions. Results showed that microwave-assisted synthesis which is a well-known green process for the synthesizing organic molecules provides to obtain shorter reaction times and higher yields in our study.

Asymmetric photocatalysis over robust covalent organic frameworks with tetrahydroquinoline linkage

The asymmetric photocatalytic organic synthesis (APOS) process is a sustainable and environmentally benign method for the production of optically active chemicals with sunlight as an energy source. However, it still lacks efficient semiconductors with tunable band structures and has a low recycling stability. Herein, we report the synthesis of tetrahydroquinoline-linked covalent organic frameworks (QH-COFs) with irreversible tetrahydroquinoline linkage as efficient semiconductors for the visible-light-driven asymmetric α-alkylation of aldehydes by merging with a chiral secondary amine. Up to 94% ee was obtained over QH-COFs, and the activity of QH-COFs was significantly higher than those of inorganic semiconductors (e.g., TiO2, BiVO4, and WO3) under similar conditions, which is mainly attributed to their narrow band gap and suitable band edge. As far as we know, QH-COFs are the most active semiconductors for asymmetric α-alkylation of aldehydes ever reported. The QH-COFs were prepared via a one-pot Povarov cascade imine formation and cycloaddition reaction using Sc(OTf)3/Yb(OTf)3 as Lewis acid catalysts. Attributed to the tetrahydroquinoline linkage, QH-COFs showed extremely high recycling stability, which made practicals application possible. This work not only opens up a new avenue for asymmetric photocatalysis but also provides an efficient and general method for the construction of robust COFs.

Dehydrogenation of amines in aryl-amine functionalized pincer-like nitrogen-donor redox non-innocent ligands via ligand reduction on a Ni(ii) template.

We have synthesized a series of new redox non-innocent azo aromatic pincer-like ligands: 2-(phenylazo)-6-(arylaminomethyl)pyridine (HLa-c: HLa = 2-(phenylazo)-6-(2,6-diisopropylphenylaminomethyl)pyridine, HLb = 2-(phenylazo)-6-(2,6-dimethylphenylaminomethyl)pyridine, and HLc = 2-(phenylazo)-6-(phenylaminomethyl)pyridine), in which one side arm is an arylaminomethyl moiety and the other arm is a 2-phenylazo moiety. Nickel(ii) complexes, 1-3, of these ligands HLa-c were synthesized in good yield (approximately 70%) by the reaction of ligands : (NiCl2·6H2O) in a 1 : 1 molar ratio in methanol. The amine donor in each of the ligands HLa-c binds to the Ni(ii) centre without deprotonation. In the solid state, complex 3 is a dimer; in solution it exists as monomer 3a. The reduction of acetonitrile solutions of each of the complexes 1, 2 and 3a, separately, with cobaltocene (1 equivalent), followed by exposure of the solution to air, resulted in the formation of new complexes 7, 8 and 9, respectively. Novel free ligands Lx and Ly have also been isolated, in addition to complexes 7 and 8, from the reaction of complexes 1 and 2, respectively. Complexes 7-9 and free ligands Lx and Ly have been formed via a dehydrogenation reaction of the arylaminomethyl side arm. The mechanism of the reaction was thoroughly investigated using a series of studies, including cyclic voltammetry, EPR, and UV-Vis spectral studies and density functional theory (DFT) calculations. The results of these studies suggest a mechanism initiated by ligand reduction followed by dioxygen activation. A Cl-/I- scrambling experiment revealed that the dissociation of the chloride ligand(s) was associated with the one-electron reduction of the ligand (azo moiety) in each of the complexes 1, 2 and 3a. The dissociated chloride ligand(s) were reassociated with the metal following the dehydrogenation reaction to yield the final products. All of the newly synthesized compounds were fully characterized using a variety of physicochemical techniques. Single-crystal X-ray structures of the representative compounds were determined to confirm the identities of the synthesized molecules.

Iron(III) catalyzed direct C–H functionalization at the C-3 position of chromone for the synthesis of fused chromeno-quinoline scaffolds

This communication describes an iron-catalyzed route for the synthesis of 6-substituted chromeno[3,2-c]quinolin-7-one. The method developed does not require any pre-functionalization to execute the pivotal coupling reaction at the C-3 position of flavones. The final step involves the consecutive application of imine formation, Csp2-Csp2 coupling and oxidation reaction, with aromatic aldehydes and 2-(2-aminophenyl)-4H-chromen-4-one as the reactants. Presence of electron donating/withdrawing groups was well tolerated in the aldehydes and the method developed could also be extended to other substituted 2-(2-aminophenyl)-4H-chromen-4-one’s. This is the first report of synthesis of 6-substituted chromeno[3,2-c]quinolin-7-one’s via direct functionalization of the C-3 site of flavones.

A new thermoresponsive polymer with reactive aldehyde groups for postmodification to tune the solubility and phase transition temperature

We first report a new thermoresponsive homopolymer with reactive functional groups in the backbone. A well-defined thermoresponsive polymer poly(2-(2-(diethylamino)ethoxy)-5-vinylbenzaldehyde) (PDEVB) with diethylamino groups and reactive aldehyde groups in each repeating unit was synthesized via reversible addition-fragmentation chain transfer polymerization. PDEVB shows lower critical solution temperature (LCST) in ethanol/water mixture. The influences of solvent composition, molecular weight, concentration on the LCST were also investigated. Thanks to the reactive aldehyde groups, the solubility and LCST behavior can be conveniently tuned by postmodification with 2-aminoethanol and 3-(aminooxy)propan-1-amine via imine formation reaction or oxime formation reaction, respectively. The obtained polymer exhibits LCST at a relatively higher water content after modification with 2-aminoethanol and becomes water soluble and shows a pH-responsive LCST after modification with 3-(aminooxy)propan-1-amine. Moreover, the PDEVB can serve as a scaffold for preparation of UCST-type polyelectrolyte via the combination of quaternization of diethylamino groups and anion exchanged with NaBF4, and the UCST of the polyelectrolyte can be tuned by postmodification of the reactive aldehydes as well. PDEVB is anticipated to be a useful novel thermoresponsive polymer and may have promising new applications.

Spectroscopic studies of a ring opening process between epoxy- and aminosilanes and imine formation reactions in aqueous solutions

NMR and Raman spectroscopy studies were performed for different 3-aminopropyl(trimethoxy)- and 3-glycidoxypropyl(trimethoxy)silane based sol-gel systems containing different ketones. Exceptionally stable imine products were obtained depending on a reaction system at alkaline pH conditions and in the presence of water. These imine formation reactions were carried out without further catalyst. In addition, effect of water for the epoxy ring opening process was demonstrated, as well as the effect of solvents for the reaction path was confirmed.

Modification on the Surface of Gold Nanoparticles with Imine Formation and Cycloaddition Reaction

Modification on the Surface of Gold Nanoparticles with Imine Formation and Cycloaddition Reaction

One-pot synthesis of novel 1-(1H-tetrazol-5-yl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine derivatives via an Ugi-azide 4CR process.

A facile one-pot method has been developed for the synthesis of novel pyrrolo[2,1-a]pyrazine scaffolds. A variety of 1-(1H-tetrazol-5-yl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine derivatives were obtained in moderate to high yields in methanol using a one-pot four-component condensation of 1-(2-bromoethyl)-1H-pyrrole-2-carbaldehyde, amine, isocyanide and sodium azide at room temperature. These reactions presumably proceed via a domino imine formation, intramolecular annulation and Ugi-azide reaction. Unambiguous assignment of the molecular structures was carried out by single-crystal X-ray diffraction.

An improved and scalable synthesis of zolpidem via a CuI/BINOL-mediated tandem reaction of imine and alkyne

Abstract An improved and scalable method for the synthesis of zolpidem (1), a hypnotic drug, was developed. A two-step sequence involving imine formation and subsequent tandem reaction between an imine and propiolamide in the presence of CuI/BINOL, an efficient promoter for the tandem reaction, is described. Zolpidem was efficiently prepared in a 54% isolated yield and the hemitartrate salt of zolpidem was produced in 37% yield by simple crystallization, without tedious column chromatography. The procedure can be scaled up to >10 g. The yield of 1 increased to 83% following isolation of the intermediate imine 5.

Functionalization of P3HT with Various Mono- and Multidentate Anchor Groups

Due to its favorable optoelectronic properties and the accessibility via Grignard metathesis (GRIM) polymerization, poly(3-hexylthiophene) (P3HT) is one of the most applied conjugated polymers. The ‘living' nature of GRIM polymerization enables the modification of the polymer and the installation of desired properties. In the present study, two versatile approaches for the synthesis of anchor group-modified P3HT have been developed, which enable the functionalization of various inorganic nanoparticles. Depending on the polymerization conditions, mono- and bifunctional ethynyl-terminated P3HT or solely monofunctionalized aldehyde-terminated P3HT was synthesized. Afterwards, the quantitative introduction of amine, mono- and multidentate disulfide and catechol anchor groups was performed by copper-catalyzed 1,3-dipolar cycloaddition or via imine formation reactions. The influence of the polymeric ligand structure on the functionalization of nanoparticles was then investigated for CdSe@ZnS quantum dots and TiO2 nanorods by transmission electron microscopy (TEM) and infrared (IR) spectroscopy.

Efficient synthesis of pyrrolo[1,2-a]quinoxalines catalyzed by a Brønsted acid through cleavage of C-C bonds.

An efficient and convenient one-pot domino reaction for the direct synthesis of pyrrolo[1,2-a]quinoxalines has been developed. This approach utilizes an imine formation reaction, SEAr reaction and cleavage of C-C bonds catalyzed by a Brønsted acid. β-Diketones and β-keto esters are both well tolerated to give the corresponding products in moderate to excellent yields.

Fast screening of analytes for chemical reactions by reactive low-temperature plasma ionization mass spectrometry.

Approaches for analyte screening have been used to aid in the fine-tuning of chemical reactions. Herein, we present a simple and straightforward analyte screening method for chemical reactions via reactive low-temperature plasma ionization mass spectrometry (reactive LTP-MS). Solution-phase reagents deposited on sample substrates were desorbed into the vapor phase by action of the LTP and by thermal desorption. Treated with LTP, both reagents reacted through a vapor phase ion/molecule reaction to generate the product. Finally, protonated reagents and products were identified by LTP-MS. Reaction products from imine formation reaction, Eschweiler-Clarke methylation and the Eberlin reaction were detected via reactive LTP-MS. Products from the imine formation reaction with reagents substituted with different functional groups (26 out of 28 trials) were successfully screened in a time of 30 s each. Besides, two short-lived reactive intermediates of Eschweiler-Clarke methylation were also detected. LTP in this study serves both as an ambient ionization source for analyte identification (including reagents, intermediates and products) and as a means to produce reagent ions to assist gas-phase ion/molecule reactions. The present reactive LTP-MS method enables fast screening for several analytes from several chemical reactions, which possesses good reagent compatibility and the potential to perform high-throughput analyte screening. In addition, with the detection of various reactive intermediates (intermediates I and II of Eschweiler-Clarke methylation), the present method would also contribute to revealing and elucidating reaction mechanisms.

Strain-Induced Reactivity in the Dynamic Covalent Chemistry of Macrocyclic Imines.

The displacement of molecular structures from their thermodynamically most stable state by imposition of various types of electronic and conformational constraints generates highly strained entities that tend to release the accumulated strain energy by undergoing either structural changes or chemical reactions. The latter case amounts to strain-induced reactivity (SIR) that may enforce specific chemical transformations. A particular case concerns dynamic covalent chemistry which may present SIR, whereby reversible reactions are activated by coupling to a high-energy state. We herewith describe such a dynamic covalent chemical (DCC) system involving the reversible imine formation reaction. It is based on the formation of strained macrocyclic bis-imine metal complexes in which the macrocyclic ligand is in a high energy form enforced by the coordination of the metal cation. Subsequent demetallation generates a highly strained free macrocycle that releases its accumulated strain energy by hydrolysis and reassembly into a resting state. Specifically, the metal-templated condensation of a dialdehyde with a linear diamine leads to a bis-imine [1+1]-macrocyclic complex in which the macrocyclic ligand is in a coordination-enforced strained conformation. Removal of the metal cation by a competing ligand yields a highly reactive [1+1]-macrocycle, which then undergoes hydrolysis to transient non-cyclic aminoaldehyde species, which then recondense to a strain-free [2+2]-macrocyclic resting state. The process can be monitored by (1) H NMR spectroscopy. Energy differences between different conformational states have been evaluated by Hartree-Fock (HF) computations. One may note that the stabilisation of high-energy molecular forms by metal ion coordination followed by removal of the latter, offers a general procedure for producing out-of-equilibrium molecular states, the fate of which may then be examined, in particular when coupled to dynamic covalent chemical processes.

Formation of an Oxidant-Sensible Pd(II) Coordination Compound and Its 1H NMR Specific Characterization: A Preparative and Analytical Challenge in Current Coordination Chemistry

A three-part experiment that leads to the synthesis of palladium(II) complex starting from a C3-symmetric triaminoguanidinium-based ligand is presented. In the first part, the preparation of tris-benzylidenetriaminoguanidinium chloride ([H6Br3L]Cl) by an acidic catalyzed 3-fold imine formation reaction of 5-bromo-2-hydroxybenzaldehyde and triaminoguanidinium chloride is described. Starting from the second part, the reaction procedures are performed under inert gas atmosphere. The conversion of PdCl2 with acetonitrile to give [Pd(MeCN)4]Cl2 as a precursor is performed at 80 °C. The third part of the experiment is a three-step procedure that begins with deprotonation of [H6Br3L]Cl, followed by transfer of [Pd(MeCN)4]Cl2 to the reaction flask, where the chelation of Pd(II)-precursor leads to the in situ species [Pd(MeCN)H3Br3L]. Addition of PPh3 as the final reaction step yields [Pd(PPh3)H3Br3L]. This sequence of experiments provides an excellent example of ligand and transition metal preparation and its subsequent complexation to form an oxidant-sensitive organometallic species. Undergraduate students get the opportunity to learn Schlenk techniques and to investigate 1H NMR spectra of organic and organometallic compounds starting from relatively simple to more advanced spectra. The distinct result of the chemical shift of the 4JP–H-affected doublet mirrors the preparative success of the student and demonstrates the utility of 1H NMR experiments.

Fabrication of Meso/Macroporous Carbon Monolith and its Application as a Support for Adsorptive Separation of D-Amino Acid from Racemates

(S)-Alanine Racemase Chiral Analogue ((S)-ARCA) was used as an efficient adsorbent for the selective separation of D-amino acids (D-AAs), which are industrially important as chiral building blocks for the synthesis of pharmaceutical intermediates. The organic phase, containing (S)-ARCA adsorbent and phase transfer reagents, such as ionic liquid type molecules (Tetraphenylphosphonium chloride (TPPC), Octyltriphenylphosponium bromide (OTPPBr)), were coated on the surfaces of mesoporous carbon supports. For the immobilization of chiral adsorbents, meso/macroporous monolithic carbon (MMC), having bimodal pore structures with high surface areas and pore volumes, were fabricated. The separation of chiral AAs by adsorption onto the heterogeneous (S)-ARCA was performed using a continuous flow type packed bed reactor system. The effects of loading amount of ARCA on the support, the molar ratio of AA to ARCA, flow rates, and the type of phase transfer reagent (PTR) on the isolation yields and the optical purity of product D-AAs were investigated. D-AAs were selectively combined to (S)-ARCA through imine formation reaction in an aqueous basic solution of racemic D/L-AA. The (S)-ARCA coated MMC support showed a high selectivity, up to 95 ee%, for the separation of D-type phenylalanine, serine and tryptophan from racemic mixtures. The ionic liquids TPPC and OTPPBr exhibited superior properties to those of the ionic surfactant Cetyltrimethyl ammonium bromide (CTAB), as a PTR, showing constant optical purities of 95 ee%, with high isolation yields for five repeated reuses. The unique separation properties in this heterogeneous adsorption system should provide for an expansion of the applications of porous materials for commercial processes.