Imine-enamine Tautomerism Research Articles

Refrachor (F) – seventy-year-old tool and a contemporary observation: estimation of equilibrium compositions of 1H- and 2H-tautomers of tetrazole and 1,2,3-triazole and imine–amine composition of acetaldimine–vinylamine tautomerism

Abstract Refrachor with a symbol F a new physical constant proposed for the first time in 1951 by Joshi and Tuli defined by the equation F = –P log( n D 20 ${n}_{\mathrm{D}}^{20}$ –1) where P is the parachor and n D 20 ${n}_{\mathrm{D}}^{20}$ is the refractive index, is now used in our present work to calculate the percentage composition of 1H- and 2H-tautomers of tetrazole, 1,2,3-triazole, and imine-enamine tautomerism of acetaldimine in their equilibrium mixtures.

Kinetic Study on the Base-Catalyzed Imine-Enamine Tautomerism of a Chiral Biologically Active Isoxazoline Derivative by HPLC on Amylose Tris(3,5-dimethylphenylcarbamate) Chiral Stationary Phase.

Isoxazoline is a nitrogen- and oxygen-containing five-membered heterocyclic scaffold with diverse biological profiles such as antimicrobial, fungicidal, anticancer, antiviral, analgesic and anti-inflammatory activity. Accordingly, the use of this peculiar structural framework in drug discovery is a successful strategy for the development of new drug candidates. Here, a chiral saccharin/isoxazoline hybrid was considered to investigate the tendency of the imine moiety of the heterocyclic ring to tautomerize to the enamine form in the presence of a basic catalyst. The pseudo-first-order rate constants for the base-catalyzed tautomerization process were measured in different solvents and at different temperatures by off-column kinetic experiments based on the amylose (3,5-dimethylphenylcarbamate)-type chiral stationary phase. The kinetic results obtained in this study may be a useful aid in the perspective of designing experimental conditions to control the stereointegrity of these types of pharmacologically active compounds and drive their synthesis toward the preferred, imine or enamine, tautomer.

Study on the degradation and pyrolysis of 2-fluoromethcathinone

Gas chromatography-mass spectrometry (GC-MS) is the first choice for law enforcement agencies in various countries to analyze new psychoactive substances (NPS) because of its advantages and complete databases. For synthetic cathinone-type NPS (SCat), alkalization and extraction processes before GC-MS analysis are essential. However, the base form of SCat is unstable, causing it to quickly degrade in solution and cause pyrolysis at the GC-MS injection inlet. In this study, we investigated the degradation of ethyl acetate and pyrolysis at the GC-MS injection inlet of 2-fluoromethcathinone (2-FMC), the most unstable SCat. Using gas chromatography-quadruple/time-of-flight mass spectrometry (GC-Q/TOF-MS) combined with the predicted data from theoretical calculations and the analysis of mass spectrometry (MS) fragmentation, the structures of 15 2-FMC degradation and pyrolysis products were identified. Among them, 11 products were produced during degradation, and six products were obtained from pyrolysis (two of which were the same as the degradation products). At the same time, the degradation and pyrolysis pathways of 2-FMC were provided. The balance between keto-enol and enamine-imine tautomerism triggered the primary degradation pathway of 2-FMC. The subsequent degradation started from the tautomer with a hydroxyimine structure, including imine hydrolysis, oxidation, imine-enamine tautomerism, intramolecular ammonolysis of halobenzene, and hydration to generate a series of degradation products. The secondary degradation reaction was the ammonolysis of ethyl acetate to yield N-[1-(2’-fluorophenyl)-1-oxopropan-2-yl]-N-methylacetamide and the byproduct, N-[1-(2’-fluorophenyl)-1-oxopropan-2-yl]-N-methylformamide. In the pyrolysis of 2-FMC, the major reactions were dehydrogenation, intramolecular ammonolysis of halobenzene, and defluoromethane. The achievements of this manuscript not only study 2-FMC degradation and pyrolysis but also lay the foundation for the study of SCat stability and their accurate analysis by GC-MS.

PEG-200: A versatile green solvent assisted catalyst-free one-pot three-component synthesis of functionalised N-amino-3-cyano-2-pyridone

PEG-200, a biodegradable, non-toxic, economical, easily available, robust and recyclable solvent mediated one-pot three-component reaction for synthesis of diverse array of functionalised N-amino-3-cyano-2-pyridone by the reaction of aldehydes, cyanoacetohydrazide and malononitrile or ethyl cyanoacetate has been demonstrated. This protocol is a cascade type reaction that includes the series of Knoevenagel condensation, Michael addition, intramolecular cyclisation, imine-enamine tautomerization and oxidative aromatization. Utilization of biodegradable greener solvent without any supplementary catalyst, shorter reaction time than previously reported protocols, easily accessible synthons, mild reaction condition and easy purification of desired products are the foremost advantages of these protocols.

Synthesis of benzo[b][1,5]diazocin-6(5H)-one derivatives via the Cu-catalysed oxidative cyclization of 2-aryl-1H-indoles with 1,1-enediamines.

A novel protocol for the synthesis of highly functionalized benzo[b][1,5]diazocin-6(5H)-one derivatives (BDCOs, 4 and 5) from 2-aryl-1H-indoles and 1,1-enediamines was developed via a complex cascade of reactions including regioselective free radical oxidation, the 1,2-addition of imine, imine-enamine tautomerization, intramolecular cyclization, and ring expansion. The cascade reaction was enabled by refluxing a mixture of two substrates in the presence of di-tert-butyl peroxide (DTBP) as an oxidant and anhydrous CuI as a catalyst in toluene under argon protection. Consequently, a series of BDCOs (4 and 5) were synthesized with high regioselectivity in good yield. This protocol can be used for the synthesis of functionalized BDCOs via a one-pot oxidative annulation reaction rather than a multi-step reaction, which is suitable for both combinatorial and parallel syntheses of BDCOs.

Highly selective synthesis of functionalized morphan derivatives through a multi-component cascade reaction of 3-formylchromones, 2-naphthols, and enaminones

A novel protocol for the preparation of highly functionalized 2-azabicyclo[3.3.1]nonane (morphan) derivatives via a multicomponent cascade reaction, involving 3-formylchromones, 2-naphthols, and enaminones in the ionic liquid [BMIM]PF6 as the solvent and promoted by 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU), was developed, which involved the cleavage of one C–O bond and formation of four bonds (1 ​C–O, 1 ​C–N, and 2 ​C–C bonds). As a result, a series of morphan derivatives were produced through a cascade reaction, including a sequence of 1,2-addition, enol-keto tautomerization, Michael addition, dehydration, another Michael addition, imine-enamine tautomerization, and N-alkylation reactions, which were accompanied by a ring-opening reaction. This protocol was suitable for combinatorial and parallel syntheses of natural product-like morphan compounds in a one-pot reaction rather than through tedious multi-step reactions.

One-pot three-component synthesis of a new series of tetrahydrobenzofuran-chromone conjugates

An efficient one-pot three-component protocol for the synthesis of novel tetrahydrobenzofuran-chromone conjugates using 3-formylchromones and 1,3-cyclohexandiones in the presence of a variety of alkyl or aryl isocyanides was developed. The reaction sequence consists of an initial Knoevenagel condensation of aromatic aldehydes with 1,3-cyclohexandione derivatives, followed by a [4 + 1] cycloaddition of with isocyanides, and then imine-enamine tautomerization to afford the products.

A simple method for the rapid synthesis of 2-amino-7,7-dimethyl-5-oxo-1,4-diaryl-hexahydroquinoline-3-carboxamide derivatives

Simple synthesis of oxoquinoline carboxamide derivatives via one-pot, multi-component reaction of enaminones derived from the addition of dimedone to various anilines with aromatic aldehydes and cyanoacetamide is described. Optimal reaction conditions for the synthesis of products were obtained, when EtOH/H2O (1:1) was used as the solvent at 80 °C, in the presence of piperidine as the catalyst. The reactions are completed within 5–25 min, in good to high yields (74–85%). This protocol involves Michael reaction, imine-enamine tautomerization, and cyclization sequences. The structures of products were deduced from their IR, mass, 1H NMR, and 13C NMR spectra. This method includes some important aspects including simple operation under mild conditions, easy accessibility of reactants, workup procedure, high atom economy, and the use of ethanol/water as a green media.

Bismuth(III)-Catalyzed Sequential Enamine-Imine Tautomerism/2-Aza-Cope Rearrangement of Stable β-Enaminophosphonates: One-Pot Synthesis of β-Aminophosphonates.

A novel catalytic tautomeric transformation of a β-enaminophosphoryl and 2-aza-Cope rearrangement sequence has been successfully applied to the one-pot synthesis of β-aminophosphonates with high efficiency and good tolerance. In this tandem reaction, Bi(OTf)3 exhibits unique activities and promotes both of enamine-imine tautomerism and 2-aza-Cope rearrangement.

Prediction of the tautomer stability and acidity of phenacylpyridines in aqueous solution

In this work, the aqueous acidity and tautomeric equilibrium constants are predicted in a systematic manner for the family of 2-, 3- and 4-phenacylpyridines which exhibit simultaneous keto–enol and imine–enamine tautomerism. The computational approach is based on electronic structure methods rooted in density functional theory, on an implicit SMD solvation model, and on thermodynamic cycles. In some instances, the high-quality hybrid CBS-QB3 method is used to obtain accurate gas-phase Gibbs free energies. The cationic, neutral, anionic and zwitterionic states of phenacylpyridines are considered, subject to a careful conformational analysis. Provided that a flexible enough basis set is used, estimated aqueous $${\text{p}}K_{{\mathrm{a}}}$$ and $${\text{p}}K_{{\mathrm{t}}}$$ values based on direct thermodynamic cycle correlate well with experimental data and show a reasonable quantitative agreement. On the other hand, it is found that the proton exchange scheme does not improve the accuracy of the predictions and different reference compounds are needed for each different type of the acidic site. Therefore, the errors herein are beyond systematic control. We use our results to present a brief discussion of the factors influencing the accuracy for the prediction of $${\text{p}}K_{{\mathrm{a}}}$$ and $${\text{p}}K_{{\mathrm{t}}}$$ for phenacylpyridines and presumably for other tautomeric compounds with multiple acidic centers.

Reactivity of 5-alkynyl-3,4-dihydro-2H-pyrroles with Au(III): Route to vinylgold(III) complexes, aurocycles by cyclisation of these complexes and ML complexes

The reaction of 5-alkynyl-3,4-dihydro-2H-pyrroles (imine) with AuCl3 led to the synthesis of the vinyl gold (III) complexes 3 that could give the aurocycles 4 with an excess of AuCl3. In the base presence the dimerization of 4 was observed leading to 5. If NaAuCl4 was used as gold (III) source a ligand exchange was observed leading to the complexes 6. Nucleophilicity of both nitrogen atom and alkyne function as well as imine-enamine tautomerism were involved to explain the formation of 3.

Catalytic formal [4 + 1] isocyanide-based cycloaddition: an efficient strategy for the synthesis of 1H-cyclopenta[b]quinolin-1-one derivatives.

An unprecedented catalytic isocyanide-based cycloaddition of alkyl and aryl isocyanides with (Z)-2-(2-hydroxy-2-alkylvinyl)quinoline-3-carbaldehydes was developed for the direct and efficient synthesis of 1H-cyclopenta[b]quinolin-1-one derivatives. On the basis of DFT calculations, a mechanism is proposed involving formal [4 + 1] cycloaddition of isocyanides, followed by imine-enamine tautomerization and air oxidation.

Cobalt(II), copper(II), and zinc(II) isostructural, pseudotetrahedral, racemic complexes of pyrrolo[2,3-b]quinoxaline with bis(2-thienylmethyl)propylenediamine chain: Synthesis, crystal structure, spectroscopy

Cobalt(II), copper(II), and zinc(II) cations all have similar effective ionic radii so they form with (E)-1-phenyl-3-{N-[N′,N′-bis(thiophen-2-ylmethyl)-3-aminopropyl]aminophenylmethylidene}-1,3-dihydro-2H-pyrrolo[2,3-b]quinoxalin-2-one (1) isostructural, pseudotetrahedral complexes 2a, 2b, and 2c, respectively. Single crystal X-ray analysis of the synthesized complexes reveals that they are chiral (Λ-M-pS, pS; Δ-M-pR, pR) and crystalize as racemates in P 21/c space group. There is axial chirality connected with tetrahedrally substituted metal center and crystallization induced planar chirality of two symmetry independent ligand molecules (different conformers). In solution only metal center chirality is maintained due to the conformational lability of the 3-[N,N-bis(thien-2-ylmethyl)amino]propyl group. Chirality of zinc complex 2c in solution was confirmed by the analysis of 1D and 2D NMR spectra. NMR data show diastereotopic protons of aliphatic chain and the restriction of phenyl ring rotation at C(30) carbon atom. Complex 2c is fluorescent in solid state as well as in solution (fluorescence quantum yield in acetonitrile, ϕ = 0.1). The NMR titration at room temperature shows that the major product of zinc coordination is not 2c but the complex with a tautomeric form of the ligand having proton located at N(4) nitrogen atom (enamine-imine tautomerism). UV–Vis data for 2a, 2b, and 2c both in solid and in solution are discussed.

Differentiation between enamines and tautomerizable imines in the oxidation reaction with TEMPO

Enamine and imine represent two of the most common reaction intermediates in syntheses, and the imine intermediates containing α-hydrogen often exhibit the similar reactivity to enamines due to their rapid tautomerization to enamine tautomers. Herein, we report that the minor structural difference between the enamine and the enamine tautomer derived from imine tautomerization results in the different chemo- and regioselectivity in the reaction of cyclohexanones, amines and TEMPO: the reaction of primary amines furnishes the formal oxygen 1,2-migration product, α-amino-enones, while the reaction of secondary amines under similar conditions generates exclusively arylamines via consecutive dehydrogenation on the cyclohexyl rings. The 18O-labeling experiment for α-amino-enone formation revealed that TEMPO served as oxygen transfer reagent. Experimental and computational studies of reaction mechanisms revealed that the difference in chemo- and regioselectivity could be ascribed to the flexible imine-enamine tautomerization of the imine intermediate containing an α-hydrogen.

Synthesis and photochromic properties of some N-phthalimide azo-azomethine dyes. A DFT quantum mechanical calculations on imine-enamine tautomerism and trans-cis photoisomerization.

This paper presents synthesis, photophysical characterization and quantum mechanical calculations of some N-phthalimide azo-azomethine dyes. The dyes were synthesized via azo coupling reaction between 2,4-substituted aromatic anilines and salicylic aldehyde followed by condensation reactions between azo dyes and N-aminophtalimide. Quantum chemical calculations to optimise the molecular geometry and to determine the electron densities of the trans (E) imine ⇌ enamine and the cis (Z) imine ⇌ enamine isomers and their vibrational frequencies have been computed by using DFT at B3LYP/6-31 + G(d,p) level of theory in vacuo. The effect of the used DMF solvent on the molecular structure and bond energies has been determined by using the IEFPCM model. Thermodynamic parameters such as total electronic energy E(RB3LYP), enthalpy H298 (sum of electronic and thermal enthalpies), free Gibbs energy G298 (sum of electronic and thermal free Gibbs energies) and dipole moment μ were computed in order to estimate the ΔE, Δμ, ΔH, ΔG and ΔS values. The NBO analysis was performed in order to understand the intramolecular charge transfer and the energy of resonance stabilization. After molecular geometry optimization, the electronic spectra were obtained by TD-DFT calculations at the above mentioned basis set using the IEFPCM model of DMF as a solvent. The solvatochromic effect of the dyes in four solvents with different polarity has been studied by UV-VIS spectroscopy and compared with the theoretically predicted. The coincidence between measured and calculated spectra is satisfactory. The dynamic photoisomerization experiments were performed in DMF under irradiation with UV light at λ = 365 nm (mostly E → Z) and with VIS light at λ = 400-800 nm (mostly Z → E). The spectra were recorded in the spectral region from 300 to 800 nm at identical sample concentrations of the three dyes and illumination times in order to investigate the photodynamical E → Z → E conversion of the NN chromophore group of the dyes as well as the imine ⇌ enamine tautomerization.

Synthesis of New 5-amino-7-(aryl)-1,2,3,7-tetrahydro-8-nitroimidazo[1,2-a]pyridine- 6-carboxamide and 6-amino-2,3,4,8-tetrahydro-9-nitro-8-(aryl)-1H-pyrido[1,2- a]pyrimidine-7-carboxamide Derivatives

Aim and Objectives: Development of simple synthetic routes for widely used organic compounds from readily available reagents is one of the major tasks in organic chemistry. Therefore, new approaches for increasing the molecular diversity of simple starting materials, are needed. Herein, an efficient synthesis of imidazo[1,2-a]pyridine, pyrido[1,2-a]pyrimidine and pyrido[1,2-a][1,3]diazepine derivatives is described. Materials and Methods: A one-pot, multi-component reaction of nitro ketene aminal derived from the addition of various 1,n-diamines to 1,1-bis(methylthio)-2-nitroethene with cyanoacetamide and aromatic aldehydes is described. The reactions are completed within 2-5 h, in ethanol at reflux, in good to high yields (70-93%). The structures of products were deduced from their IR, mass, 1H NMR, and 13C NMR spectra. Results: Optimal reaction conditions for the synthesis of products were obtained, when ethanol was used as the solvent at reflux. This protocol involves Michael reaction, imine–enamine tautomerization, and cyclization sequences. Conclusion: This work represents an efficient synthesis of imidazo[1,2-a]pyridine, pyrido[1,2-a]pyrimidine and pyrido[1,2-a][1,3]diazepine derivatives via a one-pot, multi-component reaction. The advantages of this protocol are mild conditions, easy accessibility of reactants, absence of catalyst, high atom economy, simple work-up and purification process with no chromatographic technique.

Metal-Free Halogen(I) Catalysts for the Oxidation of Aryl(heteroaryl)methanes to Ketones or Esters: Selectivity Control by Halogen Bonding.

Metal-free halogen(I) catalysts were used for the selective oxidation of aryl(heteroaryl)methanes [C(sp3 )-H] to ketones [C(sp2 )=O] or esters [C(sp3 )-O]. The synthesis of ketones was performed with a catalytic amount of NBS in DMSO solvent. Experimental studies and density functional theory (DFT) calculations supported the formation of halogen bonding (XB) between the heteroarene and N-bromosuccinimide, which enabled imine-enamine tautomerism of the substrates. No additional activator was required for this crucial step. Isotope-labeling and other supporting experiments suggested that a Kornblum-type oxidation with DMSO and aerobic oxygenation with molecular oxygen took place simultaneously. A background XB-assisted electron transfer between the heteroarenes and halogen(I) catalysts was responsible for the formation of heterobenzylic radicals and, thus, the aerobic oxygenation. For selective acyloxylation (ester formation), a catalytic amount of iodine was employed with tert-butyl hydroperoxide in aliphatic carboxylic acid solvent. Several control reactions, spectroscopic studies, and Time-Dependent Density Functional Theory (TD-DFT) calculations established the presence of acetyl hypoiodite as an active halogen(I) species in the acetoxylation process. With the help of a selectivity study, for the first time we report that the strength of the XB interaction and the frontier orbital mixing between the substrates and acyl hypoiodites determined the extent of the background electron-transfer process and, thus, the selectivity of the reaction.

Synthesis of 5-amino-N'-(9H-fluoren-9-ylidene)-8-nitro-7-aryl-1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-6-carbohydrazide derivatives based on heterocyclic ketene aminals.

A new class of tetrahydroimidazo[1,2-a]pyridine derivatives has been successfully prepared via a five-component domino reaction using cyanoacetohydrazide, 9-fluorenone, aromatic aldehydes, 1,1-bis(methylthio)-2-nitroethene and ethylenediamine in ethanol at reflux. The new efficient cascade approach involves a sequence of N,N-acetal formation, Knoevenagel condensation, Michael addition, imine–enamine tautomerization and N-cyclization as key steps. The merit of this protocol is highlighted by its available and economical starting compounds, operational simplicity, clean reaction profile and tolerance of a wide diversity of functional groups.

An efficient and ecofriendly synthesis of highly functionalized pyridones via a one-pot three-component reaction.

A simple and convenient protocol has been developed for the synthesis of N-amino-3-cyano-2-pyridone derivatives by a one-pot reaction of cyanoacetohydrazide, activated nitrile substrates (malononitrile, ethyl cyanoacetate, cyanoacetamide) and aromatic aldehydes in the presence of piperidine in water or a mixture of water and ethanol. The sequence of cascade reactions includes Knoevenagel condensation, Michael addition, intramolecular cyclization, imine-enamine tautomerization and oxidative aromatization. The main advantages of this procedure are availability of starting compounds, simple procedure, mild conditions, easy purification of products and the use of water or water/ethanol as green solvents.

Computational investigation of the structure and antioxidant activity of some pyrazole and pyrazolone derivatives

Pyrazoles and pyrazolones constitute a group of organic compounds that have various medical applications such as antimicrobial, antipyretic, anti-inflammatory, antitumor and antioxidants. Pyrazolones can exist in different isomeric forms (CH, NH, OH) due to keto-enol, lactam-lactim and imine-enamine tautomerism. Determination of the most stable tautomeric form is thus important for understanding their biological roles at the molecular level. We performed a theoretical investigation of the structural and antioxidant properties of three synthetic pyrazolones (1–3), one synthetic pyrazole (4), one natural pyrazole (5) and two engineered hydroxyl derivatives of 1 (7, 8) and of 5 (9, 10) using the density functional theory at the B3LYP/6-311++G(d,p) level of theory in gas phase and in methanol (using the polarizable continuum model). It is found that substituents and solvents may influence the relative stability of pyrazolone isomers and that the CH tautomer is typically the least stable. Vertical ionization potentials, vertical electron affinities and X–H bond dissociation energies (X = C, N, O, S) are calculated for the global minimum structures and compared with those of the standard antioxidant flavonoid quercetin (6). Calculations predict that compounds 1 and 5 have antioxidant activity similar to 6 and that their mono and dihydroxyl derivatives (7–10) are more efficient antioxidants. Results also indicate that compounds 1–10 preferably interact with free radicals adopting the H atom transfer rather than the sequential electron transfer proton transfer mechanism. The study gives insight into the structural requirements for the design of highly efficient antioxidants.