Nucleophilic Cyclization Research Articles

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.

TBAF-Catalyzed O-Nucleophilic Cyclization of Enaminones: A Process for the Synthesis of Dihydroisobenzofuran Derivatives.

A novel methodology for the stereoselective synthesis of dihydroisobenzofuran derivatives is described in this paper. The procedure was realized by the bifunctional TBAF catalyzed selective O-nucleophilic cyclization of enaminone with intramolecular alkyne under mild and non-metal-mediated conditions. The results of control experiments suggested that the cation-π interaction and basicity, offered by TBAF, might be indispensable for the isomerization of enaminone and the formation of carbon-oxygen bond.

Gold(i)-catalyzed nucleophilic cyclization of β-monosubstituted o-(alkynyl)styrenes: a combined experimental and computational study.

The stereospecific gold(i)-catalyzed nucleophilic cyclization of β-monosubstituted o-(alkynyl)styrenes to produce C-1 functionalized 1H-indenes including challenging substrates and nucleophiles, such as β-(cyclo)alkyl-substituted o-(alkynyl)styrenes and a variety of alcohols as well as selected electron-rich aromatics, is reported. DFT calculations support the stereochemical outcome of the process that involves the formation of a key cyclopropyl gold carbene intermediate through a regiospecific 5-endo cyclization.

Visible-light-mediated difluoromethylphosphonation of alkenes for the synthesis of CF2P-containing heterocycles

Novel synthesis of CF2P-containing heterocycles has been developed via visible-light-mediated nucleophilic cyclization of unsaturated carboxylic acids, alcohol and sulfonamides.

Nickel Catalyzed syn-Selective Aryl Nickelation and Cyclization of Aldehyde/Enone-Tethered Terminal Alkynes with Arylboronic Acids.

A syn-arylative nickelation followed by nucleophilic syn-selective cyclization of o-propargyloxy benzaldehydes is achieved toward the synthesis of chromanol skeletons with alkenyl substitution at C3. The capture of the intermediate vinyl nickel in its cis geometry is done also with a Michael acceptor to synthesize 4-alkylated derivatives. This protocol is equally applicable to o-propargylamino benzaldehydes to access 3,4-disubstituted tetrahydro-hydroquinolines.

Ionic Liquids Catalysis for Carbon Dioxide Conversion With Nucleophiles.

Carbon dioxide, as a promising C1 synthon, has attracted great interest in organic synthesis. Due to the thermodynamic stability and kinetic inertness of CO2, developing efficient strategies for CO2 activation and subsequent conversion is very crucial. In this context, Ionic liquids (ILs) show great potential for capturing and activating CO2 owing to their unique structures and properties, making them become ideal alternatives to volatile organic solvents and/or catalysts for CO2 transformation. This minireview aims at summarizing ILs-promoted reactions of CO2 with N-nucleophiles (primary amines)/O-nucleophiles (primary alcohols, water). Two catalytic systems i.e., metal/ILs binary systems such as Cu/ILs systems and Ag/ILs systems as well as single ILs systems including anion-functionalized ILs and bifunctionalized ILs have been developed for CO2 catalytic conversion, for instance, carboxylative cyclization of nucleophiles e.g., propargylic alcohols, amines, 2-aminobenzonitriles and o-aminobenzenethiol, and formylation of amines or 2-aminothiophenols with hydrosilanes to afford various value-added chemicals e.g., cyclic carbamates, unsymmetrical organic carbonates, α-hydroxyl ketones, and benzimidazolones. In a word, IL could provide a powerful tool for efficient CO2 utilization.

Synthetic Approaches to Tetracyclic Indolines as Versatile Building Blocks of Diverse Indole Alkaloids.

Indole alkaloids bearing the tetracyclic indoline scaffolds of 1H-pyrrolo[2,3-d]carbazole have shown fascinating chemical diversity and significant biological activities. The development of efficient synthetic methodologies for such a tetracyclic scaffold remains highly desirable in both synthetic chemistry and medicinal chemistry. This review outlines key strategies for the construction of the tetracyclic indoline scaffolds in total syntheses of many indole alkaloids. The key strategies include nucleophilic additions, Diels-Alder reactions, radical cyclizations, and palladium-catalyzed coupling reactions. The representative examples and their applications in the total syntheses are described here and discussed in depth.

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.

DBU-Catalyzed Alkyne-Imidate Cyclization toward 1-Alkoxypyrazino[1,2- a]indole Synthesis.

1-(Propargyl)indol-2-carbonitriles react with alcohols to afford 1-alkoxypyrazino[1,2- a]indoles under DBU-catalyzed microwave-assisted conditions. The reaction scope includes a wide range of indoles, primary and secondary alcohols, and a thiol. The initial mechanistic study shows that the domino process presumably proceeds through an alkyne-allene rearrangement, imidate formation, and nucleophilic cyclization reaction sequence.

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.

Cascade and Effective Syntheses of Functionalized Tellurophenes.

A one-pot and transition-metal-catalyst-free synthetic strategy to construct functionalized tellurophenes has been developed. Substituted 1,1-dibromo-1-en-3-ynes are smoothly converted to tellurophenes with telluride salts in high yield via a series of cascade reactions through reductive debromination, hydrotelluration, nucleophilic cyclization, and aromatization. Close inspection of the results clearly showed that the reactivity of in situ prepared telluride salts are significantly influenced by the polarity of the solvent system and the electronic nature of the substituent on the enyne substrate. This method reports the first direct synthesis of 3-aryltellurophenes in high yields at room temperature. This novel reaction strategy is also found to be a promising synthetic method for multisubstituted tellurophenes and selenophenes.

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.

Total synthesis of akuammiline alkaloid (+)-strictamine

An asymmetric total synthesis of the akuammiline alkaloid (+)-strictamine is described. The key steps of the synthetic route involve an improved Johnson-Claisen rearrangement to facilitate the formation of the challenging C15–C20 linkage and the (E)-alkene side chain, intramolecular nucleophilic substitution cyclization to establish the E ring and diastereoselective Brown hydroboration of the terminal alkene to introduce the C16 stereocenter.

A domino reaction of 2-isocyanophenyloxyacrylate and aryne to synthesize arenes with vicinal olefin and benzoxazole.

An unusual domino reaction of 2-isocyanophenyloxyacrylate and aryne has been disclosed. The present strategy experiences nucleophilic addition, Michael addition, carbon-oxygen cleavage, and cyclization, thus enabling the quick aryne vicinal difunctionalization by the installation of a benzoxazole and an olefin.

Efficient Formation of 2,3-Dihydrofurans via Iron-Catalyzed Cycloisomerization of α-Allenols

Herein, we report a highly efficient iron-catalyzed intramolecular nucleophilic cyclization of α-allenols to furnish substituted 2,3-dihydrofurans under mild reaction conditions. A highly diastereoselective variant of the reaction was developed as well, giving diastereomeric ratios of up to 98:2. The combination of the iron-catalyzed cycloisomerization with enzymatic resolution afforded the 2,3-dihydrofuran in high ee. A detailed DFT study provides insight into the reaction mechanism and gives a rationalization for the high chemo- and diastereoselectivity.

Copper-Catalyzed Alkene Aminoazidation as a Rapid Entry to 1,2-Diamines and Installation of an Azide Reporter onto Azahetereocycles.

A copper-catalyzed aminoazidation of unactivated alkenes is achieved for the synthesis of versatile unsymmetrical 1,2-diamine derivatives. This transformation offers an effective approach to installing an amide and an azide from two diffenent amino precursors onto both terminal and internal alkenes, with remarkable regio- and stereoselectivity. Mechanistic studies show that this diamination reaction proceeds via a nucleophilic amino cyclization followed by an intermolecular C-N bond formation using electrophilic azidoiodinane. This pathway differs from previous azidoiodinane-initiated alkene functionalization, suggesting new reactivity of azidoiodinane. Furthermore, this aminoazidation reaction provides an efficient strategy to introduce azide, one of the most useful chemical reporters, onto a broad range of bioactive azaheterocycles, offering new opportunities in bioorthogonal chemistry and biological studies. Rapid syntheses of 5-HT2C agonist, (-)-enduracididine and azido-cholesterol derivatives demonstrate broad applications of this method in organic synthesis, medicinal chemistry, and chemical biology.

Design and Applications of Metastable-State Photoacids

Proton transfer is one of the most common processes in nature, and many chemical, material, and biological processes are sensitive to proton concentration, from acid-catalyzed reactions to the activities of many enzymes. Photoacids that reversibly undergo proton dissociation upon irradiation promise remote spatial and temporal control over proton-sensitive processes and could provide a way to convert photoenergy into other types of energy. The recently discovered metastable-state photoacids can produce a large proton concentration with high efficiency and good reversibility. A reversible pH change of over 2 units has been demonstrated using an aqueous solution of a metastable-state photoacid. Additionally, moderate-intensity visible light, for example, from LEDs and sunlight, can be used to activate this type of photoacid. This photocontrolled proton release occurs in aqueous and nonaqueous solutions and in polymeric materials. Therefore, this type of photoacid can be conveniently incorporated into different systems to control various proton transfer processes. Metastable-state photoacids are generally designed by linking an electron-accepting moiety and a weakly acidic nucleophilic moiety with a double bond. Photoinduced trans-cis isomerization of the double bond allows a nucleophilic cyclization reaction to occur between the two moieties. The tandem reaction generates a highly acidic metastable form, which releases a proton. In the dark, the metastable form relaxes to the original form and takes back the proton. Several electron-accepting and nucleophilic moieties have been used to construct different types of metastable-state photoacids for different applications. The advantages and disadvantages of these photoacids in terms of their photoacidity, dark acidity, reversibility, stability, etc. will be discussed in this Account. Metastable-state photoacids have been used to catalyze bond formation and bond-breaking reactions in which the reactions can be activated and stopped by turning on and off irradiation, respectively. They have been used to reversibly protonate molecules to affect the ionic and hydrogen bonding between molecules or between different moieties of a molecule. Protonation can also alter the electronic configuration of molecules to change their electronic and optical properties. Since a proton has a positive charge, photoacids have been used to control ion exchange processes. Applying metastable-state photoacids to control Fisher esterification, volume-changing hydrogels, the killing of bacteria, odorant release, the color of materials, the formation of nanoparticles, and polymer conductivity has been reported by our group. Metastable-state photoacids have also been utilized to control supramolecular assemblies, molecular switches, microbial fuel cells, cationic sensors, nanoparticle aggregation, and ring-opening polymerizations. The future prospects of this research area will be discussed at the end of this Account.

Cycloaromatization of Enediyne Compounds under the Action of Bromide Ions: Diradical/Zwitterionic/Anionic Pathways

AbstractCycloaromatization reactions of enediynes are renowned for their widespread applications and interesting reactivity characteristics. In the presence of a lithium halide and a weak acid, the cycloaromatization of cyclodeca‐1,5‐diyn‐3‐ene can be redirected away from the usual formation of a phenyl diradical towards a zwitterionic pathway. We extended this zwitterionic reaction system to other enediyne compounds and found that it offered good applicability to all‐carbon systems. However, in the case of maleimide‐based enediynes, only diradical (phenyl‐substituted) or anionic (butyl‐substituted) cyclization pathways were observed. Notably, the nucleophilic cyclization of maleimide‐based enediynes that was initiated by bromide ions exhibited a previously unreported C2−C7 cyclization pattern.

Nucleophilic and electrophilic cyclization of N-alkyne-substituted pyrrole derivatives: Synthesis of pyrrolopyrazinone, pyrrolotriazinone, and pyrrolooxazinone moieties.

Intramolecular nucleophilic and electrophilic cyclization of N-alkyne-substituted pyrrole esters is described. Efficient routes towards the synthesis of pyrrolopyrazinone, pyrrolotriazinone and pyrrolooxazinone have been developed. First, N-alkyne-substituted pyrrole ester derivatives were synthesized. Introduction of various substituents into the alkyne functionality was accomplished by a copper-catalyzed cross-coupling reaction. Nucleophilic cyclization of N-alkyne-substituted methyl 1H-pyrrole-2-carboxylates with hydrazine afforded the 6-exo-dig/6-endo-dig cyclization products depending on the electronic nature of the substituents attached to the alkyne. On the other hand, cyclization of N-alkyne-substituted methyl 1H-pyrrole-2-carboxylates with iodine only resulted in the formation of the 6-endo-dig cyclization product regardless of the substitution of the alkyne functionality.