Intramolecular Nucleophilic Cyclization Research Articles

The base-promoted cyclization of N-Boc arylimidrazone toward 1,2-dihydro 3H-1,2,4-triazol-3-ones

We reported the base-promoted cyclization of N-Boc arylimidrazone toward 1,2-dihydro 3H-1,2,4-triazol-3-one. This procedure tolerated methyl, methoxy, chloro, bromo, fluoro, cyano, methylcarbonyl groups well. Thus, it represents a facile and high efficient pathway leading to 1,2-dihydro 3H-1,2,4-triazol-3-one. Mechanism study revealed this procedure proceeded with the intramolecular nucleophilic cyclization rather than N-isocyanate intermediate.

Visible-light-enabled cascade cross-dehydrogenative-coupling/cyclization to construct α-chromone substituted α-amino acid derivatives.

Organophotocatalytic cascade cross-dehydrogenative-coupling/cyclization reaction of o-hydroxyarylenaminones with α-amino acid derivatives for the construction of α-chromone substituted α-amino acid derivatives was developed. Various N-arylglycine esters, amides and dipeptides underwent the cascade cyclization reaction well with o-hydroxyarylenaminones to afford the corresponding 3-aminoalkyl chromones in good to excellent yields. This approach consists of visible-light-promoted oxidation of α-amino acid derivatives, the Mannich reaction, and intramolecular nucleophilic cyclization under acidic conditions, and features a wide reaction scope, a simple operation and mild reaction conditions, which may have the potential to be used for the synthesis of bioactive molecules.

Rh(iii)-catalyzed sp3/sp2-C-H heteroarylations via cascade C-H activation and cyclization.

The development of an efficient strategy for facile access to quinoline-based bis-heterocycles holds paramount importance in medicinal chemistry. Herein, we describe a unified approach for accessing 8-(indol-3-yl)methyl-quinolines by integrating Cp*Rh(iii)-catalyzed C(sp3)-H bond activation of 8-methylquinolines followed by nucleophilic cyclization with o-ethynylaniline derivatives. Remarkably, methoxybiaryl ynones under similar catalytic conditions delivered quinoline tethered spiro[5.5]enone scaffolds via a dearomative 6-endo-dig C-cyclization. Moreover, leveraging this method for C8(sp2)-H bond activation of quinoline-N-oxide furnished biologically relevant oxindolyl-quinolines. This reaction proceeds via C(sp2)-H bond activation, regioselective alkyne insertion, oxygen-atom-transfer (OAT) and intramolecular nucleophilic cyclization in a cascade manner. One C-C, one C-N and one C[double bond, length as m-dash]O bond were created with concomitant formation of a quaternary center.

Intracerebral Fluorescence-Photoacoustic Dual-Mode Imaging for Precise Diagnosis and Drug Intervention Tracing in Depression.

Unravelling the pathophysiology of depression is a unique challenge. Depression is closely associated with reduced norepinephrine (NE) levels; therefore, developing bioimaging probes to visualize NE levels in the brain is a key to elucidating the pathophysiological process of depression. However, because NE is similar in structure and chemical properties to two other catecholamine neurotransmitters, epinephrine and dopamine, designing an NE-specific multimodal bioimaging probe is a difficult task. In this work, we designed and synthesized the first near-infrared fluorescent-photoacoustic (PA) dual-modality imaging probe for NE (FPNE). The β-hydroxyethylamine of NE was shown to react via nucleophilic substitution and intramolecular nucleophilic cyclization, resulting in the cleavage of a carbonic ester bond in the probe molecule and release of a merocyanine molecule (IR-720). This process changed the color of the reaction solution from blue-purple to green, and the absorption peak was red-shifted from 585 to 720 nm. Under light excitation at 720 nm, linear relationships between the concentration of NE and both the PA response and the fluorescence signal intensity were observed. Thus, the use of intracerebral in situ visualization for diagnosis of depression and monitoring of drug interventions was achieved in a mouse model by fluorescence and PA imaging of brain regions after administration of FPNE by tail-vein injection.

Enantioselective Michael Addition/Cyclization/Desymmetrization Sequence of Prochiral Cyclic Hemiacetals and Nitroolefins: Synthesis of Chiral Oxygen-Bridged Bicyclic Compounds.

The organocatalytic enantioselective Michael addition of functionalized prochiral cyclic hemiacetals and nitroolefins has been developed under cooperative enamine and hydrogen bond catalysis. The obtained chiral hemiacetal intermediates could be used in the subsequent diastereocontrolled cyclization/desymmetrization divergent process to access (1) 9-oxabicyclo[3.3.1]nonane or 8-oxabicyclo[3.2.1]octane frameworks via oxocarbenium ion-mediated Friedel-Crafts cyclization, and (2) 2,9-dioxabicyclo[3.3.1]nonane frameworks via intramolecular nucleophilic cyclization. Experimental results suggest that there is neighboring group participation controlling the diastereoselectivities of the desymmetrization process.

Combining Enzyme and Photoredox Catalysis for the Construction of 3-Aminoalkyl Chromones.

Herein, we reported a practical and efficient strategy combining photoredox and enzyme catalysis for the construction of 3-aminoalkyl chromones from o-hydroxyaryl enaminones and N-arylglycine esters. A variety of 3-aminoalkyl chromones were synthesized with good yields under mild conditions in one pot. This synthetic protocol consists of sequential enzymatic hydrolysis and photoredox decarboxylation of N-arylglycine esters, oxidation of aminoalkyl radicals, Mannich reaction, and intramolecular nucleophilic cyclization, which affords a convenient pathway for the preparation of various 3-substituted chromones.

Synthesis of 4-(organoselenyl) oxazolones via cyclization of N-alkynyl ethylcarbamates promoted by organoselenium.

Organoselenyl iodide promoted the intramolecular nucleophilic cyclization of N-alkynyl ethylcarbamates in the synthesis of 4-(organoselenyl) oxazolones. The reaction was regioselective, giving the five-membered oxazolone products as the unique regioisomer via an initial activation of the carbon-carbon triple bond through a seleniranium intermediate, followed by an intramolecular 5-endo-dig cyclization mode. The generality of the methodology has been proven by applying the optimized reaction conditions to different organoselenyl iodides and N-alkynyl ethylcarbamates having different substituents directly bonded to the nitrogen atom and in the terminal position of the alkyne.

Iodine Catalyzed Oxidative Coupling of Diaminoazines and Amines for the Synthesis of 3,5-Disubstituted-1,2,4-Triazoles.

A simple, convenient, transition metal-free one pot synthesis of 3,5-disubstituted-1,2,4-triazoles has been established. The innovation in this reaction is the use of easily available 1,1-diaminoazines as substrates. This method provides the products with wider substrate scope, at an expedited rate, and with relatively better yields in comparison to the reported methods. The reaction mechanism involves an initial intermolecular nucleophilic addition (facilitated by I2) followed by intramolecular nucleophilic cyclization.

An efficient method for the stereoselective synthesis of bicyclic azasugars with glycosidic heteroatom

A mild and effective method for the stereoselective synthesis of bicyclic azasugars with glycosidic heteroatom isdescribed. An SN2 reaction of D-ribose tosylate with amino alcohol or diamine followed by iminium formation and intramolecular N,X-acetak formation. As a result, a new class of bicyclic azasugars wherein the heteroatom is present at the glycosidic position through the intramolecular nucleophilic cyclization reaction without any catalyst were obtained in good to excellent yields with excellent stereoselectivity, and the desired products can be further derivatized to obtain more structural types of azasugars which act as the potential glucosidase inhibitors.

Specific Fluorescent Probe Based on “Protect–Deprotect” To Visualize the Norepinephrine Signaling Pathway and Drug Intervention Tracers

In recent years, increased social pressure and other factors have led to a surge in the number of people suffering from depression: studies show that quite a few people will experience major depression in their lifetime. Currently, it is widely believed that the internal cause of major depression is reduced levels of norepinephrine (NE) in brain tissue. Norepinephrine is very similar in structure and chemical properties to the other two catecholamine neurotransmitters, epinephrine (EP) and dopamine (DA). These three neurotransmitters are synthesized sequentially through enzymatic reactions in the biological system. Therefore, design of a norepinephrine-specific fluorescent probe is very challenging. In this work, we utilized a "protect-deprotect" strategy: longer emission wavelength cyanine containing water-soluble sulfonate was protected by a carbonic ester linking departing group thiophenol; the β-hydroxy ethyl amine moiety of norepinephrine may react with the carbonic ester via nucleophilic substitution and intramolecular nucleophilic cyclization to release the fluorophore. The process realized the specific red fluorescence detection of norepinephrine. Imaging of the norepinephrine nerve signal transduction stimulated by potassium ion was studied. More importantly, real-time fluorescence imaging of norepinephrine levels in the brain of rats stimulated by antidepressant drugs was studied for the first time.

Aza-Henry and aza-Knoevenagel reactions of nitriles for the synthesis of pyrido[1,2-a]indoles.

N-(Propargyl)indole-2-carbonitriles undergo DBU-catalyzed addition of CH-acids to nitriles, followed by cyclization to give 9-aminopyrido[1,2-a]indoles. The reaction proceeds through the initial formation of a push-pull enamine, alkyne-allene rearrangement and intramolecular nucleophilic cyclization. Nitromethane and malonate esters can be employed as the CH-acids. The resulting compounds were found to exhibit fluorescence properties.

Light-enabled, AlCl3-catalyzed regioselective intramolecular nucleophilic addition of non-nucleophilic alkyls to alkynes.

Light-enabled, AlCl3-catalyzed regioselective intramolecular nucleophilic cyclization of alkynes using non-nucleophilic alkyls as the nucleophile is reported. Upon photoexcitation, o-alkylphenyl alkynyl ketones can be transferred into (E)-photoenols. Thus, a nucleophilic methylene is formed from the non-nucleophilic alkyl. An AlCl3 catalyst can stabilize the (E)-photoenol intermediate and facilitate further intramolecular nucleophilic cyclization. DFT calculations indicated that the AlCl3-catalyzed cyclization is the regioselectivity determining step.

POCl3‐Mediated Reaction: A New Entry to Polysubstituted 2‐Pyridones via Self‐condensation of β‐Keto Amides

Synthesis of polysubstituted 2‐pyridones and their analogues from β‐keto amides via self‐condensation cyclization is described. Notable advantages include mild reaction conditions, reduced synthetic steps, high yields, and a readily available starting materials. Further mechanistic studies suggest that the transformation proceeds through self‐condensation, intramolecular nucleophilic cyclization, and elimination.

Comparison between Conventional and Nonconventional Methods for the Synthesis of Some 2-Oxazolidinone Derivatives and Preliminary Investigation of Their Inhibitory Activity Against Certain Protein Kinases

A series of propargyl and allyl carbamates were prepared directly from propargyl and allyl alcohols and phenyl or cyclohexyl isocyanate or indirectly by generating the isocyanates in situ from the corresponding Cbz-protected amines. The obtained carbamates underwent intramolecular nucleophilic cyclization in presence of cesium hydroxide monohydrate as a base catalyst under conventional and ultrasonic irradiation conditions to give the corresponding substituted 4-(benzylidene)methylidene-2-oxazolidinones in good to excellent yields. The use of ultrasonic irradiation provided remarkably improved yield of the cyclization products and significant shortening of the reaction time. In some cases the reaction was highly stereoselective, and (Z)-4-benzylideneoxazolidinones were formed as a single stereoisomer. A series of biological tests were performed to evaluate the inhibitory potential of all synthesized compounds against some protein kinases.

Unexpected intramolecular nucleophilic cyclization of ureidoacetamide: A novel route towards the synthesis of 2,4,5-trisubsituted oxazoles

A variety of N, 2-diaryl-2-ureidoacetamide prepared from the condensation of N-aryl-α-aminoamide with potassium cyanate (KOCN) undergo efficient Hendrickson’s reagent-mediated nucleophilic cyclization to afford 2,5-diamine-4-aryloxazoles. The two-step synthesis provides seven target products in yields of 61–78% under mild conditions. This reaction involves an unusual pathway in which the electrophilic amide carbonyl carbon is activated by Hendrickson’s reagent and attacked by a nucleophilic ureido oxygen in a 5-exo-trig O-cycloisomerization.

Diastereoselective Synthesis of N-Protected 2,3-Dihydropyrroles via Iron-Catalyzed Cycloisomerization of α-Allenic Sulfonamides

Herein, we report the synthesis of 2,3-dihydropyrroles via an iron-catalyzed intramolecular nucleophilic cyclization of α-allenic sulfonamides. A highly diastereoselective variant of the reaction w...

Cascade Strategy for Atmospheric Pressure CO2 Fixation to Cyclic Carbonates via Silver Sulfadiazine and Et4NBr Synergistic Catalysis

It is of great significance and challenge for highly efficient catalytic transformation of carbon dioxide into cyclic carbonates especially under low pressure and energy input conditions. In this regard, an efficient silver sulfadiazine/Et4NBr synergistic catalytic system was developed for the three-component cascade reaction of propargylic alcohols, CO2, and vicinal diols. The reaction was performed in the absence of any solvent under atmospheric CO2 pressure to afford splendid yields of cyclic carbonates. The excellent performance was ascribed to the simultaneous activation of hydroxyl group in propargylic alcohols/vicinal diols by silver sulfadiazine and synergistic effect between silver species and bulkier Et4N+ in the procedure of intramolecular nucleophilic cyclization confirmed by control experiments and NMR spectra.

Synthesis of polyfluorinated arylhydrazines, arylhydrazones and 3-methyl-1-aryl-1H-indazoles

Polyfluorinated arylhydrazones were synthesized starting from 1-(4-amino-tetrafluorophenyl)ethanone and polyfluorinated arylhydrazines by action of p-toluenesulfonic acid in good yields. The resulting mixtures of E- and Z-isomers were next treated with K2CO3 in MeCN at room temperature. Under these mild reaction conditions Z-isomers underwent intramolecular nucleophilic cyclization to form 3-methyl-1-aryl-1H-indazole derivatives, while E-isomers were not active and were isolated unchanged. Molecular and crystal structures of prepared polyfluorinated (E)-arylhydrazones as well as selected 3-methyl-1-aryl-1H-indazoles were solved by the X-ray diffraction analysis. Meanwhile, the polyfluorinated acetophenone reacted with hydrazine in THF in the absence of a catalyst through a condensation–nucleophilic substitution cascade process to form a 3-methyl-1H-indazole derivative in excellent yield.

Synthesis of 2-Azabicyclo[n.2.0]alkane-Derived Building Blocks

An approach to 2-azabicyclo[n.2.0]alkane derivatives (n = 1, 2), which relies on a tandem Strecker reaction–intramolecular nucleophilic cyclization (STRINC) sequence of the corresponding 2-(ω-chloroalkyl)cyclobutanones (in turn prepared by [2+2] cycloaddition of keteniminium salts and ethylene) is described. The utility of the method is demonstrated by multigram syntheses of bicyclic proline analogues, monoprotected diamines, as well as parent 2-azabicyclo[4.2.0]octane.

Efficient copper-catalyzed synthesis of 2-arylbenzimidazole derivatives by reaction of 1-fluoro-2-nitrobenzene with benzamidine hydrochlorides

Figure not available: see fulltext. A novel and efficient approach to the preparation of 2-arylbenzimidazoles is described. Heating a mixture of 1-fluoro-2-nitrobenzene and benzamidine hydrochlorides in the presence of CuBr and K2CO3 in DMSO afforded 2-arylbenzimidazoles in good to excellent yields. The reaction was initiated by nucleophilic aromatic substitution and further proceeded by intramolecular nucleophilic copper-catalyzed cyclization reaction of benzamidine. © 2018, Springer Science+Business Media, LLC, part of Springer Nature.