Nucleophilic Cyclization Research Articles

Regioselective Synthesis of Thiazole‐5‐thione Based on [2+3] Annulation Trapping of α‐Keto Sulfine with Thioamide

AbstractAiming to develop novel annulation reactions using sulfine intermediates, we have established a regioselective formal [2+3] cyclization reaction of α‐keto sulfines generated from the elimination of arylacyl sulfoxides and thioamides. This new strategy allows for the synthesis of thiazole‐5‐thiones directly without catalysts or additives. The approach features a step‐economic, one‐pot characteristics via a tandem sequence of in situ α‐keto sulfines generation, regiospecifically nucleophilic attack or [3+2] cyclizatoin, dithioate (S=C−S−) skeletons formation, and subsequent intramolecular nucleophilic cyclization. This reaction also represents a novel method for constructing dithioate (S=C−S−) skeletons.

Synthesis of (2,3-dihydrobenzofuran-3-yl)acetic acids from salicylic aldehydes: Trimethylsilyl as traceless activating group

Salicylic aldehydes were readily alkylated with (chloromethyl)trimethylsilane to give the silylated ortho-methoxy benzaldehydes in 85–96 % yields. These aldehydes were converted into arylidenemalonates in excellent yields. O-(Trimethylsilyl)methyl group was applied as the synthetic equivalent of aryloxymethyl anion in the nucleophilic cyclization at the alkene moiety promoted by cesium fluoride in DMF at 140 °C. In this way, (2,3-dihydrobenzofuran-3-yl)acetic acids and the corresponding esters were synthesized from salicylic aldehydes in 41–70 % overall yields.

A Multicomponent [2+2+1] Cascade Cyclization to Synthesize Thiazol-2(3H)-one.

A multicomponent [2+2+1] tandem cyclization of alkynones with amines and water using potassium thiocyanate as electrolyte and raw material to access thiazol-2(3H)-ones has been developed. This transformation proceeded smoothly via electrocatalytic oxidative C-H bond thiolation, and nucleophilic cascade cyclization to build the (C-S/C-N) bonds to construct the C-O bond. The reaction avoided using transition metal catalysts or oxidation reagents, making it more sustainable and renewable.

Phosphine-Catalyzed [4 + 1] Annulation of β'-Acetoxy Allenoate with α-Alkylidene Succinimides: Access to Functionalized Spirosuccinimide Derivatives.

A phosphine-catalyzed [4 + 1] annulation of β'-acetoxy allenoate with α-alkylidene succinimides is described. This method demonstrates the nucleophilic dialkylation and cyclization of α-alkylidene succinimides, resulting in the formation of functionalized spirosuccinimide derivatives. The reaction exhibits a wide substrate scope and yields ranging from moderate to excellent under the optimized conditions. In addition, the biological evaluation indicates that the cycloadduct 3u presents satisfied inhibitory activities for three human cancer cell lines (HCT116, A549, and HepG2).

Copper-Catalyzed 1,3-Aminocyclization of Cyclopropanes as a Rapid Entry to γ-Amino Heterocycles.

We herein report a copper-catalyzed 1,3-aminocyclization of cyclopropanes as a direct and versatile entry into important heterocycles. This reaction was initiated by a copper-catalyzed, NFSI-promoted ring opening of cyclopropanes, followed by nucleophilic cyclization. A variety of nucleophiles successfully participate in this transformation, including alcohols, carboxylic acids, sulfonamides, and amides, for the construction of diverse cyclic ethers, pyrrolidines, lactones, and iminolactones.

Expanding the π -conjugate structures: Synthesis of high-energy and insensitive Tricyclic fused energetic material

In order to meet the growing demand for different applications, great efforts have been made to develop new energetic materials with high energy and good safety. Fused cyclic energetic material, a special category of π-conjugate structures containing two or more rings, typically exhibits excellent performance and is currently a key focus of research. In this paper, we have designed and synthesized a new tricyclic, fused energetic material: 5-amino-[1,2,5]oxadiazolo[3,4-e]tetrazolo[1,5-c]pyrimidine 1-oxide (3). The reaction mechanism of the one-step reaction, including nucleophilic substitution and cyclization, has been theoretically investigated. Notably, compound 3 has a high density (1.864 g cm−3) at room temperature and good detonation properties (Dv: 8391 m s−1 and P: 28.2 GPa). Compound 3 has a relatively low impact and friction sensitivity (IS > 40 J, FS > 300 N), and acceptable thermal stability (Td: 175 °C), demonstrating the great potential of compound 3 as a high-energy, insensitive tricyclic fused energy-containing material.

Recent synthetic strategies for N-arylation of pyrrolidines: a potential template for biologically active molecules.

The chemistry of nitrogen-containing heterocyclic compounds has been a multifaceted area of research for an extended period due to their varied therapeutic and biological significance. N-Aryl pyrrolidine formed by condensation of aryl group with nitrogen atom of pyrrolidine is present in a wide array of compounds. Various significant activities shown by N-arylated pyrrolidine include anti-Alzheimer, antihypoxic, anticancer, plant activator, analgesic effect, and hepatitis C inhibitor. This review summarizes different synthetic approaches, e.g., transition-metal catalyzed and transition-metal-free synthesis, decarboxylation reaction, reductive amination, nucleophilic cyclization, Ullmann-Goldberg amidation, Buchwald-Hartwig reaction, Chan-Evans-Lam coupling, addition to benzyne, multistep reaction, green synthesis, rearrangement reaction, and multicomponent reaction, to afford the derivatives of N-aryl pyrrolidine. It encompasses synthetic strategies documented from 2015 to 2023.

Construction of 5-Amino-1,2-Selenazole Scaffolds through N-Selenocyanation/Cyclization of Enaminones Using KSeCN.

A metal-free and mild approach for constructing 5-amino-1,2-selenazole skeletons by NBS/KSeCN-mediated N-selenocyanation and nucleophilic cyclization of β-enaminones has been developed. Various isoselenazole compounds and the isoselenazolyl derivatives of anti-inflammatory medicines, including isosepac, oxaprozin, and ibuprofen, have been obtained with good yields. This efficient, "one-pot", and atomic economy strategy may represent an alternative route for the construction of a 1,2-selenazole framework via the "+SeCN" pathway and provide new access to heterocycles containing a Se-N bond.

Activatable NIR Fluorescence Probe for Epinephrine Detection and Bioimaging Based on Anionic Heptamethine Cyanine.

Epinephrine (EP) is an essential catecholamine in the human body. Currently, most EP detection methods are not suitable for in vivo detection due to material limitations. An organic small molecule fluorescent probe based on a chemical cascade reaction for the detection of EP was designed. Anionic heptamethine cyanine dye was selected as a fluorescent dye because of its NIR fluorescence emission with excellent biocompatibility. The secondary amine of EP nucleophilically attacks the carbonate of the probe with its stronger nucleophilicity and further undergoes intramolecular nucleophilic cyclization to release the fluorophore. Other substances containing only primary amines or no β-OH lack reaction competitiveness due to their weaker nucleophilicity or inability to undergo further cyclization. The fluorescence recovery of the probe was linearly related to the EP concentration of 2-75 μmol/L. The detection limit was 0.4 μmol/L. The recovery rate was 94.78-111.32%. Finally, we successfully achieved bioimaging of EP in living cells and EP analogue in nematodes.

One-Pot Three-Component Reaction for the Synthesis of 3,4-Dihydroquinazolines and Quinazolin-4(3H)-ones.

A highly efficient and straightforward one-pot synthesis of diversely substituted 3,4-dihydroquinazolines and quinazolin-4(3H)-ones has been achieved through a domino three-component assembly reaction of arenediazonium salts, nitriles, and bifunctional aniline derivatives. This new protocol involves three C-N bond formations through the initial formation of N-arylnitrilium intermediates from arenediazonium salts and nitriles, followed by the sequential nucleophilic addition and cyclization reactions with bifunctional anilines, leading to such N-heterocyclic compounds of biological and pharmacological importance. This method offers a simple, expedient, and robust approach with the use of amenable and easily accessible reactants/reagents under metal-free mild conditions, good functional group tolerance, and high efficiency. The synthetic applications were also demonstrated by derivatization of the products obtained from these processes and syntheses of a diverse range of valuable polycyclic N-heterocycles.

A Simple and Efficient Approach for the Synthesis of Aryl-3-(trifluoromethyl)-1H-1,2,4-triazol-5(4H)-one Derivatives

AbstractIn this work, a series of 4-aryl-3-(trifluoromethyl)-1H-1,2,4-triazol-5(4H)-one derivatives is synthesized through nucleophilic intramolecular cyclization reactions of ethyl 2-(2,2,2-trifluoro-1-(arylimino)ethyl)hydrazine-1-carboxylate intermediates, which are themselves prepared in high yields via reactions of ethyl chloroformate and N-aryl-2,2,2-trifluoroacetimidoyl chloride derivatives. Some of the merits of the reported procedure are an operationally simple and concise method, the ready availability of starting materials, excellent product yields, no formation of harmful by-products and easy purification of the products.

Adventures in Coumarin Chemistry

AbstractThe cyclization of various nucleophiles, such as 1,3-dicarbonyl compounds, 1,3-bis(silyloxy)-1,3-butadienes, hydrazones, hydroxylamine, amidines, thioglycolic esters, heterocyclic enamines and others, with 4-chlorocoumarins, containing an electron-withdrawing group at position 3, allows for a convenient synthesis of a great variety of benzo[c]coumarins and related fused coumarins. Suzuki–Miyaura reactions of coumarin-derived bis(triflates) result in formation of arylated coumarins with excellent regioselectivity that is controlled by electronic and steric features of the substrate. The combination of Suzuki–Miyaura with lactonization reactions of carba- and heterocyclic substrates allows for the synthesis of benzo[c]coumarins and of other fused coumarins. Domino Michael–retro-Michael–lactonization reactions of 1,3-bis(silyloxy)-1,3-butadienes with chromones provide a convenient access to hydroxylated benzo[c]coumarins. In a related approach, fused coumarins were prepared by domino reactions of heterocyclic enamines with chromone-3-carboxylic acids.1 Introduction2 Reactions of 3-Acceptor-4-chlorocoumarins3 Reactions of Coumarin Triflates4 Synthesis of Fused Coumarins5 Conclusions

Crystal, Solution, and Computational Study of the Structure of Ortho-Lithium N,N-Diisopropyl-P,P-Diphenylphosphinothioic Amide.

The first crystal structure of an ortho-lithium phosphinothioic amide complexed with tetramethylethylenediamine 12 is reported. The complex consists of a spirane in which the spiro-lithium is N,N- and C,S-chelated by the diamine and organophosphorus ligands, respectively. The analogous ortho anion 14 obtained by Sn(IV)/Li transmetallation in THF has also been synthesized. Nuclear magnetic resonance study of both anions showed that they exist as monomers in solution and are involved in dynamic processes including the restricted rotation around the P-N bond. 14 is converted at room temperature by nucleophilic cyclization to the dearomatized anion 15, which evolves after a few hours to the benzophosphindole sulfide 16. Density functional theory calculations supported the aggregation state in solution and were used to explore the conformational space of anion 12, the mechanism of ortho-lithiation directed by P(X)-N (X=O, S) groups, and the mechanism of formation of 15.

Rhodium-catalyzed enantioselective in situ C(sp3)−H heteroarylation by a desymmetrization approach

A rhodium-catalyzed desymmetrization reaction for enantioselective methyl C−H arylation is achieved by utilizing an in situ arylating reagent via nucleophilic cyclization of o-aminoaryl alkyne. The reaction results in chiral indoles containing all-carbon quaternary stereocenters under atmospheric conditions, with a wide range of substrates exhibiting good enantioselectivity (44 examples). Mechnism and DFT studies show that the stereocontrol is reasonably achieved through the collaborative control of a large silicon substituted chiral ligand and C−H···π, LP···π interactions between aryl rings of the carboxylate group and the substrate. Control experiments demonstrate that Rh-aryl bond formation via in situ nucleophilic cyclization is more critical for reaction efficiency than via C−H activation of the nucleophilic cyclization byproduct.

Total Synthesis of Tetracyclic Spirooxindole Alkaloids via a Double Oxidative Rearrangement/Cyclization Cascade.

Skeleton rearrangement could rapidly transfer simple molecules to complex structures and has significant potential in the total synthesis of natural products. We developed a one-pot reaction cascade of double oxidative rearrangement of furan and indole followed by a nucleophilic cyclization that was successfully applied for the formal synthesis of rhynchophylline/isorhynchophylline and the first total synthesis of (±)-7(R)-geissoschizol oxindole/(±)-7(S)-geissoschizol oxindole. In addition, the geissoschizol oxindoles were revised to their C3 epimers, and the mechanism for the reversed stereochemistry through the retro-Mannich/Mannich cascade was proposed and supported by density functional theory calculations.

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.

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.

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.

(Invited) Electrocatalytic Radical-Polar Crossover Hydrofunctionalization of Alkenes

Due to the unique reactivity of open-shell intermediates, the development of catalytic transformations driven by single-electron transfer (SET) has been an area of intense research in organic chemistry. In particular, the employment of unconventional means of activation, including photoredox catalysis and electrocatalysis, has provided unique entry to single-electron reactivities and led to new solutions to challenging synthetic problems that are not readily addressed using existing tools.We disclose a general electrocatalytic hydrofunctionalization by utilizing a wide range of alkenes. The integration of the two involves an electrochemically instigated cobalt-hydride-catalyzed radical-polar crossover of alkenes that enable the generation of key cationic intermediates, which could readily be entrapped by challenging nucleophiles. We highlight the importance of precise control of the reaction potential by electrochemistry in conjunction with the decisive role of 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) as the co-solvent to obtain optimal and exclusive chemoselectivity.In addition, we develope an electrocatalytic method for intramolecular hydroamination of allylic sulfonamides to access azetidines. The merger of cobalt catalysis and electricity enables regioselective generation of key carbocationic intermediates, which could directly undergo intramolecular C-N bond formation. The mechanistic investigations including electrochemical kinetic analysis suggest that the catalyst regeneration by nucleophilic cyclization is involved in the rate-determining step (RDS) of our electrochemical protocol and highlight the ability of electrochemistry in providing ideal means to mediate catalyst oxidation.

Rhodium-Catalyzed Enantioselective Addition of Heteroarenium Salts Enabled by Nucleophilic Cyclization of 2-Alkynylanilines.

Transition-metal-catalyzed cyclative coupling of 2-alkynylanilines provides a feasible routine for accessing functionalized indoles. Herein, a rhodium-catalyzed highly enantioselective addition of heteroarenium salts is presented, which is enabled by the nucleophilic cyclization of 2-alkynylanilines. It offers feasible protocols to access enantioenriched functionalized indoles tethered to 1,2-dihydropyridine and 1,2-dihydroquinoline motifs with excellent enantioselectivities.