Subsequent Cyclization Reaction Research Articles

A coumarin chalcone ratiometric fluorescent probe for hydrazine based on deprotection, addition and subsequent cyclization mechanism.

A ratiometric fluorescent probe for hydrazine based on a coumarin chalcone framework and a levulinic acid terminal group with a low detection limit (0.1 ppb, 0.003 μM), a large ratiometric fluorescence change (I465/I575, 1265-fold enhancement) and a wide pH work range (3.0-12.0) was developed. The mechanism analysis of the isolated hydrazine product characterized by NMR, HRMS and the crystal structure indicates that the levulinic acid group is firstly removed by deprotection and then the dihydropyrazole ring is formed due to the addition and subsequent cyclization reaction in the presence of hydrazine.

Development of an Efficient Synthesis of rac‐3‐Demethoxyerythratidinone via a Titanium(III) Catalyzed Imine‐Nitrile Coupling

We herein describe the evolution of a rapid, high‐yielding synthesis of the erythrina alkaloid 3‐demethoxyerythratidinone. The natural product is assembled in six steps from commercial precursors in 30–35 % overall yield and with only two chromatographical purification operations. The key step is a titanium(III) catalyzed umpolung reaction in form of a reductive imine–nitrile coupling that can be combined with a subsequent cyclization reaction on a 50 mmol scale. Furthermore, optimized Wacker oxidation conditions enable the selective alkene oxidation in the presence of a tertiary amine functionality, which has been a problem in previous syntheses of erythrina alkaloids. The racemic route can be used to prepare the natural product on gram scale and the results may be useful for the synthesis of related alkaloids.

Chemical Degradation Pathways in Siloxane Polymers Following Phenyl Excitations.

We use ensembles of quantum-based molecular dynamics simulations to predict the chemical reactions that follow radiation-induced excitations of phenyl groups in a model copolymer of polydimethylsiloxane and polydiphenylsiloxane. Our simulations span a wide range of highly porous and condensed phase densities and include both wet and dry conditions. We observe that in the absence of water, excited phenyl groups tend to abstract hydrogen from other methyl or phenyl side groups to produce benzene, with the under-hydrogenated group initiating subsequent intrachain cyclization reactions. These systems also yield minor products of diphenyl moieties formed by the complete abstraction of both phenyl groups from a single polydiphenylsiloxane subunit. In contrast, we find that the presence of water promotes the formation of free benzene and silanol side groups, reduces the likelihood for intrachain cyclization reactions, and completely suppresses the formation of diphenyl species. In addition, we predict that water plays a critical role in chain scission reactions, which indicates a possible synergistic effect between environmental moisture and radiation that could promote alterations of a larger polymer network. These results could have impact in interpreting accelerated aging experiments, where polymer decomposition reactions and network rearrangements are thought to have a significant effect on the ensuing mechanical properties.

A Diindole-fused Corannulene Imide Derivative: Synthesis and Properties

A diindole-fused corannulene imide derivative was synthesized through two steps, Suzuki coupling and subsequent reductive cyclization reaction. Fusing indole rings to corannulene imide led to significantly red-shifted absorption, a lower HOMO–LUMO band gap, and a lower bowl-to-bowl inversion barrier than those of corannulene imide. The heterocycles also decreased the aromaticity of the rings of corannulene moiety adjacent to heterocycles.

Detection and differentiation of Cys, Hcy and GSH mixtures by 19F NMR probe

Simultaneous detection and differentiation of biomolecules is of significance in biological research. Biothiols such as cysteine (Cys), homocysteine (Hcy), and glutathione (GSH) play an important role in regulating the vital functions of living organisms. However, existing methods for simultaneous detection and differentiation of Cys, Hcy, and GSH are still challenging because of their similarity in structure and chemical properties. Herein we report a probe that simultaneously detects and discriminates between mixtures of Cys, Hcy and GSH using 19F nuclear magnetic resonance (NMR). This 19F NMR probe responds rapidly to biothiols through the Michael addition reaction and subsequent intramolecular cyclization reaction allowing differentiation between Cys, Hcy and GSH through 19F NMR chemical shift. We demonstrate that this 19F NMR probe is a powerful method for analysis of complex mixtures.

One-Step Synthesis of N-Heterocyclic Compounds from Carbohydrates over Tungsten-Based Catalysts

A one-step reaction system has been developed to convert glucose and other renewable carbohydrates into important N-heterocyclic compounds in ammonia solution. Under optimal conditions, 2-methyl pyrazine (MP) and 4(5)-methyl imidazole (MI) were produced within 15 min with combined yields of around 40%. While the formation of 4(5)-MI was identified as a non-catalytic process, the yield of 2-MP was highly influenced by the presence of catalysts. In particular, nearly three-fold yield enhancement of 2-MP was achieved over several tungsten-based catalysts. Control experiments, isotope-labelling tests, ESI-MS, and NMR analysis revealed that the formation of 2-MP follows a fragmentation mechanism, while small tungsten clusters such as [HW2O7]- and [W4O13]2- were the catalytically active species facilitating both glucose fragmentation and the subsequent cyclization reaction to generate pyrazine rings. The work exemplifies the possibility of sustainable production of important N-containing, heterocyclic chemicals...

Indium(III) Chloride Promoted One‐Pot Multicomponent Synthesis of 1,2,4‐Triazole Carrying 1,2,4‐Triazin‐6‐ones from Nitrile Imines and N,N′‐Bis(trimethylsilyl)carbodiimine

AbstractAn indium(III) chloride/silica gel promoted one‐pot multicomponent reaction for the synthesis of 5‐[2‐(1,2,4‐triazol‐3‐yl)hydrazinyl]‐1,2,4‐triazin‐6‐ones was developed by treating hydrazonoyl hydrochlorides with N,N′‐bis(trimethylsilyl)carbodiimine. The first step of the reaction mechanism involves the promotion of the 1,3‐dipolar cycloaddition by indium(III) chloride/silica gel. The subsequent cyclization and substitution reaction sequence employs 2 equiv of the nitrile imine and the silylamide intermediate, which may be the key species, to lead to the product.

Fluorescent coumarin-based probe for cysteine and homocysteine with live cell application

Cysteine (Cys) and homocysteine (Hcy) are two of important biological thiols and function as important roles in several biological processes. The development of Cys and Hcy probes will help to explore the functions of biothiols in biological systems. In this work, a new coumarin-based probe AC, containing an acryloyl moiety, was developed for Cys and Hcy detection in cells. Cys and Hcy undergo a nucleophilic addition and subsequent cyclization reaction to remove to the acryloyl group and yield a fluorescent product, 7-hydroxylcomuarin. The probe AC showed good selectivity for cysteine and homocysteine over glutathione and other amino acids and had low detection limits of 65nM for Cys and 79nM for Hcy, respectively. Additionally, confocal imaging experiments demonstrated that the probe AC can be applied to visualize Cys and Hcy in living cells.

Iron (III) Chloride Catalyzed Claisen Rearrangement Reaction of Allyloxyarenes under Microwave Conditions

The Claisen rearrangement is a [3,3]-sigmatropic rearrangement which is an important method for new C-C bond formation in organic synthesis. This reaction is a typical thermal reaction that requires a high temperature and long reaction time. In this paper, the acceleration effects of the iron (III) chloride (FeCl3) catalyst and microwave irradiation during the Claisen rearrangement reaction of allyloxyarene derivatives are reported. The FeCl3 catalyst was able to initiate the reaction at low temperature and induced the subsequent cyclization reaction. The moderation of excellent yields was obtained in a short reaction time. The formation of complex ferric-arenes under microwave irradiation conditions to efficiently absorb the microwaves was expected and confirmed.

Synthesis, functionalization and biological activity of arylated derivatives of (+)-estrone

Various novel arylated estrone derivatives, such as 2-aryl-, 4-aryl- and 2,4-diaryl-estrones, by Suzuki-Miyaura reactions. While the synthesis of 4-arylestrones could be carried out under standard conditions, the synthesis of 2-arylestrones and 2,4-diarylestrones required a thorough optimization of the conditions and it proved to be important to use sterically encumbered biaryl ligands. The best results were obtained by the use of RuPhos. Combination of developed Suzuki coupling reactions with subsequent cyclization reactions afforded more complex hybrid structures, containing dibenzofuran, benzocoumarin and steroid moieties. These derivatives were tested as pancreatic lipase inhibitors and it was found that most of the compounds exhibited inhibition of pancreatic lipase but the maximum inhibitory potential was shown by 4-arylestrones. All of the synthesized derivatives showed inhibitory values in the range of 0.82±0.01–59.7±3.12μM. The biological activity was also rationalized on the bases of docking studies.

Halogen Substitution Effects on the Molecular Packing and Thin Film Transistor Performances of Carbazoledioxazine Derivatives

Solution-processable carbazoledioxazine derivatives with different halogen substituents (F, Cl, and Br) were newly synthesized by condensation and subsequent cyclization reactions. The chemical structures were confirmed by 1H NMR and IR spectroscopies as well as MALDI-TOF mass spectrometry. All three carbazoledioxazines possessed a high thermal stability with decomposition temperatures exceeding 270 °C and exhibited thermal transitions upon heating. The phases were characterized by their wide-angle X-ray diffraction patterns at various temperatures. In addition, the energy levels of the carbazoledioxazines were estimated from the optical absorption spectra and electrochemical redox potentials of the thin films. All three derivatives displayed more or less the same energy levels: highest occupied molecular orbitals (HOMOs) of −5.3 eV and lowest unoccupied molecular orbitals (LUMOs) of −3.5 ∼ −3.6 eV. Despite this fact, the Br derivative showed higher hole mobilities with the maximum mobility of 4.9 × 10–3 ...

An Energetic Triazolo‐1,2,4‐Triazine and its N‐Oxide

AbstractThe reaction of 3‐amino‐5‐nitro‐1,2,4‐triazole with nitrous acid produces the corresponding diazonium salt. When the diazonium salt is treated with nitroacetonitrile, a subsequent condensation and cyclization reaction occurres to produced 4‐amino‐3,7‐dinitrotriazolo‐[5,1‐c][1,2,4] triazine (DPX‐26). X‐ray crystallographic analysis shows that the DPX‐26 has a density of 1.86 g cm−3, while it is calculated to have a heat of formation of 398.3 kJ mol−1. DPX‐26 is predicted to approach the explosive performance of RDX but displays significantly better safety properties. Oxidation of DPX‐26 using hypofluorous acid produces 4‐amino‐3,7‐dinitrotriazolo‐[5,1‐c][1,2,4] triazine 4‐oxide (DPX‐27), which is also predicted to be a high‐performance material with enhanced safety properties.

An Energetic Triazolo-1,2,4-Triazine and its N-Oxide.

The reaction of 3-amino-5-nitro-1,2,4-triazole with nitrous acid produces the corresponding diazonium salt. When the diazonium salt is treated with nitroacetonitrile, a subsequent condensation and cyclization reaction occurres to produced 4-amino-3,7-dinitrotriazolo-[5,1-c][1,2,4] triazine (DPX-26). X-ray crystallographic analysis shows that the DPX-26 has a density of 1.86 g cm-3 , while it is calculated to have a heat of formation of 398.3 kJ mol-1 . DPX-26 is predicted to approach the explosive performance of RDX but displays significantly better safety properties. Oxidation of DPX-26 using hypofluorous acid produces 4-amino-3,7-dinitrotriazolo-[5,1-c][1,2,4] triazine 4-oxide (DPX-27), which is also predicted to be a high-performance material with enhanced safety properties.

Amine-Mediated Transimination and Aromatization-Triggered Domino Reaction in the Synthesis of Polyfunctionalized 4-Aminoquinolines.

Dearomatization provides numerous possibilities for the development of new transformative modes of aromatic compounds. A conceptually novel metal-free multicomponent domino reaction of the dearomatized products of 2-alkynylanilines is developed. The reaction involves the secondary amine-mediated transimination with α-amino nitriles and subsequent aromatization-triggered cascade rearrangement, nucleophilic cyclization, and retro-Strecker reaction. This process provided a new practical method for the rapid synthesis of polyfunctionalized 4-aminoquinolines from readily available starting materials.

ChemInform Abstract: Formation of C(sp2)—N Bond under Metal‐Catalyst‐Free Conditions for the Synthesis of Pyridopyrazoloquinazoline Derivatives.

AbstractThe title compounds are prepared by reaction of aminobenzohydrazides with chloropyridinecarbaldehyde involving a subsequent condensation, cyclization, and nucleophilic substitution reaction of the pyridine ring.

Mitochondria-Targeting Chromogenic and Fluorescence Turn-On Probe for the Selective Detection of Cysteine by Caged Oxazolidinoindocyanine.

We report a chromogenic and fluorescence turn-on probe based on crotonoyl ester-functionalized oxazolidinoindole for the selective detection of cysteine in neutral buffer. The probe rapidly formed indocyanophenolate through the Michael addition and a subsequent cyclization reaction of cysteine, inducing both a dramatic bathochromic shift (>130 nm) and a large fluorescence turn-on response (F/F0 12) in the UV-vis and fluorescence spectra and affording a micromolar limit of detection (LOD = 5.0 μM) of cysteine in HEPES buffer. When cysteine was added, the probe exhibited a dual optical change with strong green fluorescence and dramatic red color by the oxazolidinoindole-to-hydroxyethylindolium transformation. Further cellular application of the probe was successfully performed for the mitochondrial imaging of HeLa cells.

Potent acetylcholinesterase inhibitors: Synthesis, biological assay and docking study of nitro acridone derivatives

The reaction of o-halobenzoic acid with aniline derivatives and their subsequent cyclization reaction yielded the acridone derivatives. The series of nitro acridone derivatives were prepared by Ullmann condensation in presence of copper as catalyst and were characterized by FTIR, 1H, 13C NMR and mass spectra. The structure of 5-nitro-(2-phenyl amino) benzoic acid (4) was confirmed by X-ray crystallography and was found to crystallize in P21/c space group. The in vitro efficacy of the compounds for their acetylcholinesterase (AChE) and antimicrobial inhibitory activities have been evaluated against the standard drugs Ampicillin and Gentamicin against Gram positive and Gram negative bacteria. 1,7-Dinitroacridone was found to be the most potent AChE inhibitor (IC50=0.22μM). Moreover, the compounds have been screened for their antioxidant activity using the DPPH assay. Also, docking study results were found to be in good agreement with the results obtained through in vitro experiments. The docking study further predicted possible binding conformation.

Copper(I)-catalyzed synthesis of thienopyrazoloquinazolinone derivatives under ligand-free conditions

A series of fused tetracyclic thieno[3′,2′:3,4]pyrazolo[5,1-b]quinazolin-6(4H)-one derivatives were synthesized by reaction of 2-aminobenzohydrazide and 3-bromothiophene-2-carbaldehyde in good yields. The reaction includes subsequent condensation, cyclization, and CuBr-catalyzed Ullmann-type reaction under ligand-free conditions.

ChemInform Abstract: Divergent Synthesis of Chiral Heterocycles via Sequencing of Enantioselective Three‐Component Reactions and One‐Pot Subsequent Cyclization Reactions.

AbstractThe Zr‐catalyzed three‐component reaction of methyl phenyldiazoacetate (II) with aldimine (Ia) and alcohols (V) gives rise to chiral aminoalcohols (VI).

Elucidating the Mechanisms of Formation for Two Unusual Cytochrome P450-Mediated Fused Ring Metabolites of GDC-0623, a MAPK/ERK Kinase Inhibitor.

Two isomeric metabolites of GDC-0623 [5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)imidazo[1,5-a]pyridine-6-carboxamide], a mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) kinase inhibitor, were identified in radiolabeled mass balance studies in rats and dogs (approximately 5% in excreta) and were also observed in human circulation (nonradiolabeled). Mass spectrometric data indicated that both metabolites had formed a new ring structure fused to the imidazopyridine core. Given their unusual structures, we conducted experiments to elucidate their chemical structures and understand the mechanisms for their formation. For the first metabolite, M14, a pyrazol-3-ol ring was generated by N-N bond formation between the aniline and hydroxamate. For the second metabolite, M13, an imidazol-2-one was generated by a Hofmann-type rearrangement that involved C-C bond cleavage and C-N bond formation. Both reactions were catalyzed by CYP2C9 and CYP2C19. M14 was generated directly from GDC-0623 and we speculate that its formation was via oxidative activation of the hydroxamic ester by cytochrome P450 (P450) and intramolecular nucleophilic displacement of the ester side chain. M13 (the rearranged metabolite) formed from the N-reduced hydroxamate (amide) and not from GDC-0623 directly. We propose for M13 that a P450-mediated reaction formed a cationic amide intermediate, which enabled the molecular rearrangement of the imidazopyridine core migrating from the amide carbon to the nitrogen and subsequent cyclization reaction. Each of these metabolic pathways constitutes a novel biotransformation mediated by P450 enzymes.