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A series of zingerone–thiohydantoin hybrids were synthesized from O-alkyl zingerone derivatives by cyclocondensation with thiosemicarbazide in a two-step reaction. The obtained new potentially bioactive compounds were structurally characterized by IR and NMR spectroscopy, as well as by elemental and HRMS analysis. In addition, their antimicrobial and in vitro anticancer activities were tested. The tested compounds showed low to moderate antimicrobial activity. Zingerone–thiohydantoin hybrid with an O-butyl substituent exerted the significant cytotoxic activity on colon HCT-116 cancer cells, without toxicity on healthy MRC-5 cells.

Several 2-thiohydаntоin–Shiff base derivatives were prepared as ecofriendly corrosion inhibitors for mild steel in acid environment. Their anticorrosion properties were studied on mild steel in 0.5 M HCl solution as corrosion electrolyte by using usuаl grаvimеtriс and different elесtrосhemicаl techniques (wеight lоss mеаsurеmеnt, pоtеntiоdynаmiс pоlаrizаtiоn and pоtеntiоstаtiс еlесtrосhеmicаl impеdаnсе sресtrоscору). Mild steel surface was characterized using two analytical techniques, scanning electron microscopy for surface morphology and elemental composition and atomic force microscopy. The study has shown that the inhibiting action of these environmentally benign inhibitors synthesized from inexpensive commercially available starting materials could be attributed to adsorption on the metal surface.

A series of twenty two different imidazolidine-2,4-dione derivatives, divided according to their structure into five groups, including alkyl, alkenyl or aryl 5,5disubstituted hydantoins, spirohydantoins, and fused bicyclic and tricyclic hydantoins, was synthesized and examined for in vitro antimicrobial activity against 15 strains of bacteria and 4 strains of yeast. The antimicrobial activity was evaluated by the determination of the minimal inhibitory concentration (MIC) and the minimal microbicidal concentration (MMC) using the microdilution method. The assayed compounds exerted moderate antibacterial and weak antifungal activity. The antimicrobial activities were influenced by the structure and concentration of the tested compounds as well as the type of test microorganisms. The fused bicyclic hydantoin derivatives obtained by organoselenium induced intramolecular cyclization exhibited the highest inhibitory activity. The examined hydantoin derivatives seem as drug-like candidate for further evaluation of biological activities.

5-Alkenyl hydantoins and alkenyl spirohydantoins are converted into bicyclic and tricyclic hydantoins, under indirect electrochemical conditions, generating the phenylselenyl cation in situ. The reactions proceeded in good to exelent yields. The influence of electrochemical conditions on regio- and diastereoselectivity of the selenocyclization reactions is investigated.

The 3-arylidene-2-thiohydantoin derivative, 3-[(2-hydroxybenzylidene) amino]-2-thioxoimidazolidin-4-one, was synthesized in a two-step condensation reaction of 2-hydroxybenzaldehyde, thiosemicarbazide and ethyl chloroacetate. The ligand was structurally characterized by NMR and IR spectroscopy, as well as by elemental analysis. In the reaction of the well-known polymeric trans-[CuCl2(DMSO)2]n complex with the polydentate thiohydantoin type ligand, instead of the corresponding copper thiohydantoin complex, unexpectedly, the dinuclear cis-[{CuCl(DMSO)2}(μ-Cl)]2 complex (1) was formed predominantly as the final stable product. The structure of the complex 1 was confirmed by single crystal X-ray diffraction analysis. The cis-complex is obtained through assisted isomerization of the trans-form, in which the thiohydantoin derivative has a crucial role.

The synthesis and characterization of novel hetrometallic complexes [{cis‐PtCl(NH3)2(μ‐4,4′‐bipyridyl)ZnCl(terpy‐Cl)}](ClO4)2 (C1a), [{trans‐PtCl(NH3)2(μ‐4,4′‐bipyridyl)ZnCl(terpy)}](ClO4)2 (C2a), [{cis‐PtCl(NH3)2(μ‐pyrazine)ZnCl(terpy‐Cl)}](ClO4)2 (C3a) and [{trans‐PtCl(NH3)2(μ‐pyrazine)ZnCl(terpy‐Cl)}](ClO4)2 (C4a) (where terpy‐Cl = 4′‐chloro‐2,2′:6′,2′′‐terpyridine) was done. Acid–base titrations were performed by UV–Vis spectrophotometric method to evaluate the pKa values of corresponding aqua complexes. Interactions between complexes and important biomolecules, guanosine‐5′‐monophosphate (5′‐GMP) and glutathione (GSH) were examined by 1H NMR spectroscopy. The chloride substituent at the 4′ position on the middle pyridine ring of terpyridine ligand significantly affects the coordination of biomolecules, as well as overall stability of complexes. The complexes were evaluated in vitro for the antioxidant prevention of DNA damages. All tested novel complexes demonstrated a significant reduction in DNA damage against oxidative modifications of DNA caused by the hydroxyl and peroxyl radicals. Also, cytotoxicity evaluation showed that significant cytotoxicity occurs only after long‐term effect of C1a, C2a and C3a, complexes in HCT‐116 cells. Molecular docking studies predict results in agreement with experimental research. [ABSTRACT FROM AUTHOR]

A series of mono- and heteronuclear platinum(II) and zinc(II) complexes with 4,4′,4″-tri-tert-butyl-2,2′:6′,2″-terpyridine ligand were synthesized and characterized. The DNA and protein binding properties of [ZnCl2(terpytBu)] (C1), [{cis-PtCl(NH3)2(μ-pyrazine)ZnCl(terpytBu)}](ClO4)2 (C2), [{trans-PtCl(NH3)2(μ-pyrazine)ZnCl(terpytBu)}](ClO4)2 (C3), [{cis-PtCl(NH3)2(μ-4,4′-bipyridyl)ZnCl(terpytBu)}](CIO4)2 (C4) and [{trans-PtCl(NH3)2(μ-4,4′-bipyridyl)ZnCl(terpytBu)}](CIO4)2 (C5) (where terpytBu = 4,4′,4″-tri-tert-butyl-2,2′:6′,2″-terpyridine), were investigated by electronic absorption, fluorescence spectroscopic, and molecular docking methods. Complexes featuring transplatin exhibited lower Kb and Ksv constant values compared to cisplatin analogs. The lowest Ksv value belonged to complex C1, while C4 exhibited the highest. Molecular docking studies reveal that the binding of complex C1 to DNA is due to van der Waals forces, while that of C2–C5 is due to conventional hydrogen bonds and van der Waals forces. The tested complexes exhibited variable cytotoxicity toward mouse colorectal carcinoma (CT26), human colorectal carcinoma (HCT116 and SW480), and non-cancerous mouse mesenchymal stem cells (mMSC). Particularly, the mononuclear C1 complex showed pronounced selectivity toward cancer cells over non-cancerous mMSC. The C1 complex notably induced apoptosis in CT26 cells, effectively arrested the cell cycle in the G0/G1 phase, and selectively down-regulated Cyclin D. [ABSTRACT FROM AUTHOR]

We describe the preparation, dynamic, assembly characteristics of vase‐shaped basket 13− along with its ability to form an inclusion complex with anticancer drug mitoxantrone in abiotic and biotic systems. This novel cavitand has a deep nonpolar pocket consisting of three naphthalimide sides fused to a bicyclic platform at the bottom while carrying polar glycines at the top. The results of 1H Nuclear Magnetic Resonance (NMR), 1H NMR Chemical Exchange Saturation Transfer (CEST), Calorimetry, Hybrid Replica Exchange Molecular Dynamics (REMD), and Microcrystal Electron Diffraction (MicroED) measurements are in line with 1 forming dimer [12]6−, to be in equilibrium with monomers 1(R)3− (relaxed) and 1(S)3− (squeezed). Through simultaneous line‐shape analysis of 1H NMR data, kinetic and thermodynamic parameters characterizing these equilibria were quantified. Basket 1(R)3− includes anticancer drug mitoxantrone (MTO2+) in its pocket to give stable binary complex [MTO⊂1]− (Kd=2.1 μM) that can be precipitated in vitro with UV light or pH as stimuli. Both in vitro and in vivo studies showed that the basket is nontoxic, while at a higher proportion with respect to MTO it reduced its cytotoxicity in vitro. With well‐characterized internal dynamics and dimerization, the ability to include mitoxantrone, and biocompatibility, the stage is set to develop sequestering agents from deep‐cavity baskets. [ABSTRACT FROM AUTHOR]

5-Alkenyl hydantoins and alkenyl spirohydantoins are converted into bicyclic and tricyclic hydantoins, under indirect electrochemical conditions, generating the phenylselenyl cation in situ. The reactions proceeded in good to exelent yields. The influence of electrochemical conditions on regioand diastereoselectivity of the selenocyclization reactions is investigated. [ABSTRACT FROM AUTHOR]

The polydentate ligand, 3-[(2-hydroxy-benzylidene)-amino]-2-thioxo-imidazolidin-4-one, was synthesized by intermolecular cyclocondensation reaction of 2-hydroxybenzaldehyde thiosemicarbazone and ethylchloroacetate. Novel palladium(II) complex was obtained by nucleophilic substitution of both DMSO ligands from cis-[Pd(DMSO)2Cl2] with iminic nitrogen and thiolactamic sulfur from ligand. The structure of compounds was characterized on the basis of their spectral data. The cytotoxic activity of the ligand and palladium(II) complex was studied on tumor cell lines: human colon carcinoma HCT-116 and SW-480 cells using MTT viability test. The results show that investigated palladium(II) complex has significantly greater cytotoxic effect compared to ligand. [Projekat Ministarstva nauke Republike SRbije, br. 172011 and III41010]

New heterometallic complexes [{ZnCl(terpy)(μ-pyrazine)CuCl(terpy)}] (ClO4)2 (Zn-L1-Cu) and [{ZnCl(terpy)(μ-4,4′-bipyridyl)CuCl(terpy)}] (ClO4)2 (Zn-L2-Cu) (where terpy = 2,2′:6′,2′′-terpyridine, L1 = pyrazine, L2 = 4,4′-bipyridyl) were synthesized. The substitution reactions with biologically important nucleophiles were investigated at pH 7.4 by UV-Vis spectrophotometric method. The obtained results have shown different orders of reactivity of guanosine-5′-monophosphate (5′-GMP), inosine-5′-monophosphate (5′-IMP) and glutathione (GSH) toward heterometallic Zn(II)-L-Cu(II) complexes. Spectrophotometric titration of diaqua Zn-L-Cu complexes has shown that aqua ligands coordinated to both metal centers can exhibit different pKa values depending on the distance between them. Both synthesized complexes showed moderate antimicrobial activity against most of the tested bacterial and fungal strains. The cytotoxic activity of heteronuclear Zn-L1-Cu and Zn-L2-Cu complexes was determined on human colorectal cancer (HCT-116) and human healthy lung pleura (MRC-5) cell lines. Both complexes exerted significant cytotoxic effects, especially after 72 h (IC50 < 0.01 µM) and significantly reduced cell viability. Complexes induced a significant increase in reactive radical species which consequently induced cell death and thus lower IC50 values. As the response of the cells to an increased radical level induced by treatment, glutathione level also increased in a time and dose-dependent manner. [ABSTRACT FROM AUTHOR]

The novel heteronuclear complexes [{cis‐PtCl (NH3)(μ‐pyrazine)ZnCl (terpy)}](ClO4)2 (Pt‐L1‐Zn) and [{cis‐PtCl (NH3)(μ‐4,4′‐bipyridyl)ZnCl (terpy)}](ClO4)2 (Pt‐L2‐Zn) (where terpy = 2,2′:6′,2′′‐terpyridine, L1 = pyrazine, L2 = 4,4′‐bipyridyl) were synthesized and characterized. The pKa values were determined, and based on them it was established that the π‐acceptor ability of the pyrazine bridging ligand is more affective on lower pKa values. The kinetic measurements of the substitution reactions with biologically relevant ligands, such as guanosine‐5′‐monophosphate (5′‐GMP), inosine‐5′‐monophosphate (5′‐IMP) and glutathione (GSH), were studied at pH 7.4. The reactions were followed under pseudo‐first‐order conditions by UV–Vis spectrophotometry. The order of reactivity of the investigated biomolecules for the first reaction is 5′‐GMP > 5′‐IMP > GSH, while for the second is 5′‐IMP > GSH. Pt‐L1‐Zn complex is more reactive than Pt‐L2‐Zn. The cytotoxic activity of heteronuclear Pt‐L1‐Zn and Pt‐L2‐Zn complexes was determined on human colorectal cancer cell line (HCT‐116) and human breast cancer cell line (MDA‐MB‐231). Both complexes significantly reduced cell viability on tested cell lines and exerted significant cytotoxic effects, with better effect on HCT‐116 cells than cisplatin, especially after 72 hr (IC50 < 0.52 μM). The Pt‐L2‐Zn complex showed higher activity against human breast cancer cells (MDA‐MB‐231) than cisplatin after 72 hr. The higher reactivity toward DNA constituent and significant cytotoxic activity may be attributed to the different geometry, Lewis acidity of different metal centers, as well as, to choice of bridging ligands. [ABSTRACT FROM AUTHOR]

An efficient and easy synthetic route to substituted pyrrolidine derivatives has been established through [3 + 2] dipolar cycloaddition of vinyl ketones and azomethine ylides. The reactions proceed smoothly, under mild conditions, affording moderate to high isolated yields (up to 88%) of the products, within a short reaction time (15–45 min), providing a series of novel potentially bioactive compounds. Mechanistic considerations revealed that this cycloaddition exclusively proceeds following endo-pathway which enables access to the cis-derivatives. The products that contain acetyl group at C4 easily undergo isomerization, as it was confirmed by monitoring of the reaction kinetics and DFT calculations. [ABSTRACT FROM AUTHOR]

The mechanism of substitution from tetrahedral [ZnCl2(en)] and square-pyramidal [ZnCl2(terpy)] complexes (where en = 1,2-diaminoethane or ethylenediamine and terpy = 2,2′:6′,2′′-terpyridine) by guanosine-5′-monophosphate (5′-GMP) have been investigated by 1H NMR spectroscopy. The substitution reaction of [ZnCl2(terpy)] complex is faster than the reaction of [ZnCl2(en)], which was finished after 48 h. Information about the structures of the final products in solution were obtained from the DFT calculations (B3LYP/6-31G(d)) and experimental 1H NMR data acquired during the course of the reaction. The cytotoxic activity of zinc(II) complexes was tested on human breast cancer cell line MDA-MB-231, human colon cancer cell line HCT-116 and normal human lung fibroblast cell line MRC-5. Both complexes reduced cell viabilities, while [ZnCl2(terpy)] was significantly cytotoxic on MDA-MB-231 after 72 h, and HCT-116 after 24 h without dose dependence. The differences in reactivity toward 5′-GMP and cytotoxic activity of Zn(II) complexes may be attributed to the very stable square-pyramidal geometry of [ZnCl2(terpy)] in solution, while weak ligand effect of the en compared to the terpy affected slow interaction of tetrahedral [ZnCl2(en)] complex with the target bio-molecule. [ABSTRACT FROM AUTHOR]

An efficient strategy for a four-step synthesis of angularly fused tricyclic hydantoins as suitable precursors of cis-fused bicyclic a- amino acids is developed by combining a highly diastereoselective Bucherer- Bergs reaction of 2-alkenylcycloalkanones and a regiospecific selenium-induced closure of pyrrolidine ring. This methodology was applied in a five-step synthesis of bicycloproline derivatives in high overall yield. The method could be used for the multigram preparation of free conformationally constrained bicyclic a-amino acids with two points of diversity (size of cycloalkyl ring and substituent at the pyrrolidine ring). [ABSTRACT FROM AUTHOR]

Considering that induction of apoptosis is one of the main strategies in cancer therapy, the molecular mechanisms of cytotoxic effects of A llium flavum L. on colon cancer cell lines were investigated and applied in single and co-treatments with new-synthesized Pd( II) complex. The analysis of chemical composition identified caffeic acid glycosides as the most dominant phenolics in A . flavum extract. In all investigated extracts, A . flavum showed cytotoxic effects on colon cancer cells ( IC50 = 1.64-84 μg/mL) but not on healthy cells. Combinations of plant extracts with Pd(II) complex caused lower IC50 values and better proapoptotic activity. Pd( II) complex induced high percentage of necrosis in a single treatment, but in the combination with plant extracts it had better proapoptotic and lower necrotic activity. Treatments and co-treatments induced higher O2− production and influenced apoptosis biomarkers, leading to Fas protein overexpression and activation of caspases 8 and 9. Practical Applications In view of the achieved anticancer properties, insufficiently investigated Allium flavum L. is a promising candidate for developing new anticancer compounds and deserves further research and scientific validation. This study has great impact on investigation of new anticancer substances from natural source, focuses on the importance of using plants as the source of medicinal drugs, contributes to the development of the appropriate therapy and gives contribution in both scientific and practical means. Because of its synergistic actions with the newly synthesized chemical anticancer agent and ability to reduce side effects (thus reducing necrotic activity of Pd[ II] complex), A . flavum can be used as a dietary food supplement or supplement to chemotherapy perhaps in combination with currently used chemotherapeutics or in some strategies in cancer therapy. This finding is also important from a nutritional point of view because this extracts contain significant amounts of bioactive constituents, which provide health benefits. [ABSTRACT FROM AUTHOR]

Abstract: Substitution reactions of monofunctional [Ru(terpy)(bipy)(H2O)]2+ complex, where terpy=2,2′:6′,2″-terpyridine and bipy=2,2′-bipyridine, with biologically relevant sulfur-donor nucleophiles, such as thiourea, l-methionine, l-cysteine and glutathione, are studied in aqueous solutions by 1H and 13C NMR spectroscopy techniques. All reactions are studied at pH 7.4, in the presence of phosphate buffer, to mimic the physiological environment during the substitution process. The reactions are carried out at 295K under the second-order conditions. Observed results show that the rate of substitution strongly depends on the type and the structure of the entering nucleophile. The obtained order of reactivity for the entering sulfur-donor ligands is: thiourea> l-methionine> l-cysteine>glutathione. The pK a value of coordinated water ligand was determined in D2O by the 1H NMR technique. These results confirm the strong influence of inert polypyridyl ligands on the chemical behavior of Ru(II) complex as well as their influence on the lability of coordinated water molecule. [Copyright &y& Elsevier]

Studies on the phenylselenoetherification of some Δ-alkenols in the presence of pyridine and some Lewis acids are described. All alkenols underwent intramolecular cyclization yielding corresponding tetrahydrofuran or tetrahydropyran derivatives. Yield and diastereomeric ratio of the cyclic products depend on counterion of selenylating reagent used. We found that external additives, such as pyridine and some Lewis acids coordinating to the electrophilic and/or nucleophilic species are used to control the course of cyclizations with high degrees of efficiency and improve the level of stereoinduction. J. Heterocyclic Chem., (2010). [ABSTRACT FROM AUTHOR]

The 3-arylidene-2-thiohydantoin derivative, 3-[(2-hydroxybenzylidene) amino]-2-thioxoimidazolidin-4-one, was synthesized in a two-step condensation reaction of 2-hydroxybenzaldehyde, thiosemicarbazide and ethyl chloroacetate. The ligand was structurally characterized by NMR and IR spectroscopy, as well as by elemental analysis. In the reaction of the well-known polymeric trans-[CuCl2(DMSO)2]n complex with the polydentate thiohydantoin type ligand, instead of the corresponding copper thiohydantoin complex, unexpectedly, the dinuclear cis-[{CuCl(DMSO)2}(μ-Cl)]2 complex (1) was formed predominantly as the final stable product. The structure of the complex 1 was confirmed by single crystal X-ray diffraction analysis. The cis-complex is obtained through assisted isomerization of the trans-form, in which the thiohydantoin derivative has a crucial role. [ABSTRACT FROM AUTHOR]

We describe the preparation, dynamic, assembly characteristics of vase-shaped basket 1 3- along with its ability to form an inclusion complex with anticancer drug mitoxantrone in abiotic and biotic systems. This novel cavitand has a deep nonpolar pocket consisting of three naphthalimide sides fused to a bicyclic platform at the bottom while carrying polar glycines at the top. The results of 1 H Nuclear Magnetic Resonance (NMR), 1 H NMR Chemical Exchange Saturation Transfer (CEST), Calorimetry, Hybrid Replica Exchange Molecular Dynamics (REMD), and Microcrystal Electron Diffraction (MicroED) measurements are in line with 1 forming dimer [1 2 ] 6- , to be in equilibrium with monomers 1 (R) 3- (relaxed) and 1 (S) 3- (squeezed). Through simultaneous line-shape analysis of 1 H NMR data, kinetic and thermodynamic parameters characterizing these equilibria were quantified. Basket 1 (R) 3- includes anticancer drug mitoxantrone (MTO 2+ ) in its pocket to give stable binary complex [MTO⊂1] - (K d =2.1 μM) that can be precipitated in vitro with UV light or pH as stimuli. Both in vitro and in vivo studies showed that the basket is nontoxic, while at a higher proportion with respect to MTO it reduced its cytotoxicity in vitro. With well-characterized internal dynamics and dimerization, the ability to include mitoxantrone, and biocompatibility, the stage is set to develop sequestering agents from deep-cavity baskets., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Fluorinated piperidines find wide applications, most notably in the development of novel therapies and agrochemicals. Cyclization of alkenyl N -tosylamides promoted by BF 3 -activated aryliodine(III) carboxylates is an attractive strategy to construct 3-fluoropiperidines, but it suffers from selectivity issues arising from competitive oxoaminations and the inability to easily modulate the reactions diastereoselectivity. Herein, we report an itemized optimization of the reaction conditions carried out on both cyclic and acyclic substrates and outline the origins of substrate- and reagent-based stereo-, regio-, and chemoselectivity. Extensive mechanistic studies encompassing multinuclear NMR spectroscopy, deuterium labeling, rearrangements on stereodefined substrates, and careful structural analyses (NMR and X-ray) of the reaction products are performed. This revealed the processes and interactions crucial for achieving controlled preparation of 3-fluoropiperidines using I(III) chemistry and has provided an advanced understanding of the reaction mechanism. In brief, we propose that BF 3 -coordinated I(III) reagents attack C═C to produce the corresponding iodiranium(III) ion, which then undergoes diastereodetermining 5- exo -cyclization. Transiently formed pyrrolidines with an exocyclic σ-alkyl-I(III) moiety can further undergo aziridinium ion formation or reductive ligand coupling processes, which dictate not only the final product's ring size but also the chemoselectivity. Importantly, the selectivity of the reaction depends on the nature of the ligand bound to I(III) and the presence of electrolytes such as TBABF 4 . Reported findings will facilitate the usage of ArI(III)-dicarboxylates in the reliable construction of fluorinated azaheterocycles.

Selenium promoted-cyclization of unsaturated substrates containing internal nitrogen nucleophiles, such as different amines and amides, including the examples of its application in the synthesis of more complex polycyclic compounds is reviewed. Selenocyclization reactions of some more specific polyfunctional substrates, like Biginelli hybrids and hydantoins, are also covered., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Selenium and palladium containing compounds separately exert multifunctional effects on cells. While selenium containing compounds usually exert antioxidative properties, palladium(II) containing compounds are cytotoxic and prooxidative. Here we investigated biological effects of bicyclic seleno-hydantoin cis-7a-ethyl-5-methyl-5-phenylselanylmethyl-tetrahydro-pyrrolo[1,2-c]imidazole-1,3-dione (Hid-Se), and its palladium(II) complex, trans-bis-(cis-7a-ethyl-5-methyl-5-phenylselanylmethyl-tetrahydro-pyrrolo[1,2-c]imidazole-1,3-dionato) palladium(II) chloride ((Hid-Se)2Pd) on human colon HCT-116 and breast MDA-MB-231 cancer cell lines. Hid-Se and (Hid-Se)2Pd showed prooxidative and cytotoxic character. In all performed experiments (Hid-Se)2Pd proved to be more active, i.e. this substance exerted greater prooxidative effect, cytotoxicity and influence on cell migration potential. Even though Hid-Se and (Hid-Se)2Pd enhanced migration of HCT-116 cells, very important feature of these substances is the strong antimigratory potential on metastatic MDA-MB-231 cells.

The mechanism and selectivity of a bicyclic hydantoin formation by selenium-induced cyclization are investigated. The proposed mechanism involves the intermediates formed by an electrophilic addition of the selenium reagent on a double bond of the starting 5-alkenylhydantoin prior the cyclization. These intermediates are readily converted into the more stable cyclic seleniranium cations. A key step of the mechanism is an intramolecular cyclization which is realized through an anti-attack of the internal nucleophile, the amidic nitrogen, to the seleniranium cation yielding the intermediate imidazolinium cations. Their deprotonation is followed by the formation of the fused bicyclic reaction products. Important intermediates and key transition states are studied by using density functional theory (DFT) methods. The pathways of the reaction are investigated in detail. There are two regioselective pathways related to 5-exo and 6-endo products. Theoretical calculations and the monitoring of the cyclization reaction using (1)H NMR spectroscopy are in a good agreement with the proposed mechanism and are consistent with our experimental results. The preferred pathway for formation of 5-exo products is confirmed.