Propargyl Bromide Research Articles

Chitosan-grafted Cyclodextrin via Click Chemistry as an Encapsulating Agent to Enhance the Antibacterial Activity of Thymol

Introduction: This paper aimed to investigate, for the first time, the possibility of increasing the antibacterial activities of thymol (TH) by developing an encapsulating agent based on chitosan-grafted cyclodextrin. For this purpose, β-cyclodextrin was monosubstituted at position 6 via propargyl bromide, and chitosan’s amine groups were converted to azide functions. After alkylation and diazotization reactions, the grafting of β-cyclodextrin onto the chitosan (CSβCD) was realized via click chemistry alkyne–azide cycloaddition. Methods: The incorporation of TH into chitosan-grafted β-cyclodextrin (TH/CS-βCD) was performed by the freeze-drying method, and the encapsulation efficiency was investigated based on various mass ratios (TH:CS-βCD). The optimized inclusion complex was then thoroughly examined by scanning electron microscopy (SEM), X-ray diffraction (XRD), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC). Results: The antibacterial activity was assessed against Escherichia coli, Staphylococcus aureus, and Bacillus subtilis using broth-microdilution assay. Fourier transform infrared spectroscopy analysis demonstrated the successful grafting of β-cyclodextrin onto chitosan since the optimum mass ratio between TH and CS-βCD was 1:8 (w:w), corresponding to 78 ± 3.42% of encapsulation efficiency, while SEM, XRD, TGA and DSC confirmed the establishment of TH/CS-βCD inclusion complexes. Conclusion: The in vitro investigation showed that TH/CS-βCD exhibited higher antibacterial properties compared to TH in free form.

Highly efficient synthesis of di-substituted allenes via copper-catalyzed SN2′- substitution reaction of organotitanium reagents with propargyl bromides

A simple and mild catalytic SN2′-type displacement of propargyl halides with organotitanium reagents is reported. The SN2′-type displacement of propargyl bromides with organotitanium reagents mediated by CuI (2 mol%)/MePPh2(4 mol%) in dichloro methane afforded multi-substituted allenes in good yields (up to 95 %) at 40 °C for 5 h. The aryls bearing electron-donating or electron-withdrawing groups in aryltitanium reagents gave multi-substituted allenes in good yields. In addition, the di-substituted allenes bearing a naphthyl group was obtained in 54–99 % selectivities with isolated yields of 43–83 %. The process was simple and easily performed, and it provides an efficient method for the synthesis of di-substituted allene derivatives. On the basis of the experimental results, a possible catalytic cycle has been proposed.

Dual Photoredox and Titanium Catalyzed Regioselective Allenylation of Aldehydes via Reductive Radical‐Polar Crossover

Comprehensive SummaryThe direct reductive coupling of carbonyl compounds with propargyl halides is a powerful and reliable tool in the synthesis of α‐allenols. However, stoichiometric metal reductants, harsh reaction conditions and a variety of additional additives are required in the traditional strategies. Additionally, the reactivity and regioselectivity control remains an elusive challenge. Herein, we developed the Ti‐catalyzed regioselective reductive coupling of readily available aldehydes and racemic propargyl bromides to rapidly access a wide range of α‐allenols. This method proceed efficiently in a reductive radical‐polar crossover manner featuring mild conditions, excellent regioselectivity control, broad substrate scope, and eco‐friendliness. Preliminary mechanistic studies support the radical‐involved catalytic cycle. And the DFT calculations demonstrate that the regioselectivity is determined by the Zimmerman‐Traxler‐type transition states.

Synthesis of New Pyrazolo[3,4-d]pyrimidine Derivatives: NMR Spectroscopic Characterization, X-Ray, Hirshfeld Surface Analysis, DFT, Molecular Docking, and Antiproliferative Activity Investigations.

Four new pyrazolo[3,4-d]pyrimidines (P1-P4) were successfully synthesized in good relative yields by reacting 3-methyl-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-ol with various alkylating agents (methyl iodide, propargyl bromide, and phenacyl bromide) at room temperature in DMF solvent, employing liquid-solid phase transfer catalysis. The P1-P4 structures were elucidated using NMR spectroscopy and X-ray diffraction. Intermolecular interactions in P1-P4 were analyzed via Hirshfeld surface analysis and 2D fingerprint plots. Geometrical parameters were accurately modeled by DFT calculations using the B3LYP hybrid functional combined with a 6-311++G(d,p) basis set. The antiproliferative activity of P1-P4 towards colorectal carcinoma (HCT 116), human hepatocellular carcinoma (HepG2), and human breast cancer (MCF-7) cell lines, along with one normal cell line (WI38) was investigated using the MTT assay and sunitinib as a reference. Compounds P1 and P2 exhibited antiproliferative activities comparable to the reference drug towards all tested cells, with an IC50 range of 22.7-40.75 µM. Both compounds also showed high selectivity indices and minimal cytotoxic effects on the normal cell line. Molecular docking revealed that the significant antiproliferative activity may attributed to the number and type of intermolecular hydrogen bonding established between pyrazolo[3,4-d]pyrimidines and DNA topoisomerase, a common target for various anticancer agents.

New Quinazolin-4(3H)-One Derivatives Incorporating Isoxazole Moiety as Antioxidant Agents: Synthesis, Structural Characterization, and Theoretical DFT Mechanistic Study.

Background: This research centers on the development and spectroscopic characterization of new quinazolin-4(3H)-one-isoxazole derivatives (5a-e). The aim was to investigate the regioselectivity of the 1,3-dipolar cycloaddition involving arylnitriloxides and N-propargylquinazolin-4(3H)-one, and to assess the antioxidant properties of the synthesized compounds. The synthetic approach started with the alkylation of quinazolin-4(3H)-one using propargyl bromide, followed by a 1,3-dipolar cycloaddition reaction. Methods: The structural identification of the products was performed using various spectroscopic methods, such as IR, 1H, 13C, and HMBC NMR, HRMS, and single-crystal X-ray diffraction. To further examine the regioselectivity of the cycloaddition, Density Functional Theory (DFT) calculations at the B3LYP/6-31G(d) level were employed. Additionally, the antioxidant potential of the compounds was tested in vitro using DPPH (2,2-Diphenyl-1-picrylhydrazyl)radical scavenging assays. The reaction selectively produced 3,5-disubstituted isoxazoles, with the regiochemical outcome being independent of the substituents on the phenyl ring. Results: Theoretical calculations using DFT were in agreement with the experimental results, revealing activation energies of -81.15 kcal/mol for P-1 and -77.32 kcal/mol for P-2, favoring the formation of P-1. An analysis of the Intrinsic Reaction Coordinate (IRC) confirmed that the reaction proceeded via a concerted but asynchronous mechanism. The antioxidant tests demonstrated that the synthesized compounds exhibited significant radical scavenging activity, as shown in the DPPH assay. The 1,3-dipolar cycloaddition of arylnitriloxides with N-propargylquinazolin-4(3H)-one successfully resulted in novel 3,5-disubstituted isoxazoles. Conclusions: The experimental findings were well-supported by theoretical predictions, and the antioxidant assays revealed strong activity, indicating the potential for future biological applications of these compounds.

Practical Synthesis of Macrobicyclic Thiolincosamines.

Scalable syntheses of the northern macrobicyclic thiolincosamine fragments of two structurally complex antibiotic candidates, BT-33 and cresomycin, are presented. A key transformation in each route is the highly diastereoselective addition of a putative allenylzinc nucleophile to a common Ellman sulfinimine intermediate using a zinc-promoted Barbier-type propargylation protocol that is detailed herein. These transformations proceed with dynamic kinetic resolution and use just 1.2 equiv of each respective propargyl bromide precursor.

Design and synthesis of new coumarin-1,2,3-triazole hybrids as new antidiabetic agents: In vitro α-amylase, α-glucosidase inhibition, anti-inflammatory, and docking study

The current study focuses on the synthesis of coumarin-triazole hybrids (7i-t) starting from 4-hydroxy benzaldehyde or 4-hydroxyacetophenone (1a-b) and propargyl bromide. On the other hand, coumarin derivatives (5c-h) were prepared by Pechmann cyclization and treated with sodium azide to give the corresponding 3-azido methyl coumarins (6c-h). Finally, 1,3-dipolar cycloaddition between compounds 6c-h and terminal alkyne 2a-b produces coumarin-triazole hybrids (7i-t) utilizing click chemistry approaches that are high yielding, wide in scope and simple to perform. The structural proofs of the newly synthesized coumarin-triazole hybrids (7i-t) are proved by various spectroscopic techniques, including IR, 1H NMR, 13C NMR, and LC-MS. The synthesized new coumarin triazole hybrids (7i-t) were explored for their antihyperglycemic potential and therefore evaluated for α-glucosidase and α-amylase inhibitory activities along with anti-inflammatory. The results suggest that among the series, compound 7l showed excellent activity with an IC50 value of 0.67±0.014 mg/mL and 0.72±0.012 mg/mL for α-amylase, and α-glucosidase inhibitory potential while compound 7o showed promising anti-inflammatory activity with IC50 value of 0.54±0.003 mg/mL. To support the above findings, molecular docking studies were performed, which confirmed the interaction of the synthesized molecules 7i-t with an effective binding energy of -9.0 to -10.6 kcal/mol at the active site of the enzyme human pancreatic α-amylase (PDB ID: 1B2Y). Therefore, these scaffolds have the potential to function as lead candidates for antidiabetic and anti-inflammatory activities.

Click approach for the synthesis of 1,4-disubstituted-1,2, 3-triazoles of porphyrin-isatin/sulfa drug conjugates based on m-THPP

New porphyrin-isatin/sulfa drugs conjugates based on symmetrical 5,10,15,20-tetrakis(3-hydroxyphenyl)porphyrin ([Formula: see text]-THPP) with 1,4-regioisomers of 1,2,3-triazole linker were successfully synthesized. The constructed porphyrin-conjugates 15-19 and 22-24 contained mono-, tri- (unsymmetrical), or tetrafunctionalized units of isatin, sulfanilamide and sulfapyridine with 1,2,3-triazole linker. The synthesis of these conjugates was achieved by nucleophilic functionalization of [Formula: see text]-THPP by propargyl bromide followed by zinc metalation to achieve the mono-/tri-/tetrafunctionalized propargyl[Formula: see text]-THPP zinc-complex derivatives 3-5 (alkyne partners). The formed alkyne partners underwent cycloaddition reaction with isatin azide 8, azidosulfanilamide 13 and azidosulfapyridine 14 (azide partners) using click conditions via applying copper (I) catalyzed azide-alkyne cycloaddition (CuAAC). The utilized protocol succeeded in generating amphiphilic conjugates based on [Formula: see text]-THPP in an easy, simple, and quick manner, with high regioselectivity and high yields for potential medicinal and biological applications. The Zn-porphyrin derivatives’ photonic properties were investigated via photoabsorption and fluorescence. The optical properties were also studied and it is obvious that the Zn-porphyrin complex derivatives are different from those of the free-base porphyrin and could be relied on the number of triazole units and bioconjugate type.

Electroreductive Cross‐Electrophile Coupling of Aromatic Carbonyl Compounds and Alkyl Bromides

AbstractClassical methods for the synthesis of tertiary alcohols mainly rely on the nucleophilic addition of organometallic reagents to carbonyl compounds. Here, we disclose a strategy for synthesizing tertiary alcohols via electroreductive cross‐electrophile coupling of aromatic carbonyl compounds and alkyl bromides (allyl, propargyl, benzyl and cyclohexyl bromides). This procedure features good substrate tolerance and friendly conditions (undivided cell, cheap and reusable carbon electrodes, reaction in open air, room temperature, without any external transition metal/activating reagent). Using this method, 32 desired products can be obtained with moderate to good yields, and gram‐scale synthesis is feasible, demonstrating the practicality of this approach.

CuBr-Catalyzed Coupling of Propargyl Bromides with Terminal Alkynes: Syntheses of 1,4-Diynes and Alkynyl Shift Access to Unsymmetrical 1, n-Diynes.

A CuBr-catalyzed cross-coupling reaction of propargyl bromides with terminal alkynes for the synthesis of 1, n-diynes was investigated. In N,N-dimethylacetamide (DMAc), the cross-coupling reactions of 3-bromo-1-arylpropynes, 3-bromo-1-phenyl-butyne/pentyne with aromatic terminal alkynes in the presence of CuBr and K3PO4 under nitrogen at 40 °C occur to give 1, 5-diaryl-1, 4-diynes having 3-CH2/3-CHMe/3-CHEt/3-CHiPr moieties with high chemoselectivity. Under similar reaction conditions, either the reactions of 3-bromo-1-arylpropynes with aliphatic terminal alkynes or the reactions of 3-bromo-1-alkylpropynes with aromatic terminal alkynes afforded the unexpected unsymmetric 1, 4-disubstituted 1, 3-diynes through one of the alkynyl group shifts to the side conjugating with the aryl group; in these cases, 1, 5-disubstituted 1, 4-diynes could not be obtained at all. In addition, when 3-bromo-1-phenyl-butynes react with aliphatic terminal alkynes bearing a distal phenyl group, the formed 1, 4-diynes are expected not to undergo the alkynyl group shift due to the methyl group at 3-position to form 1, 3-diynes; however, 1, 4-diynes could not be obtained either, and the 1, 5-, 1, 6-, and 1, 7-diynes, by an unprecedented remote alkynyl shift to the side conjugating with the aryl group, were isolated from the reaction mixtures in good yields.

Adamantylated Calix[4]arenes Bearing CuAAC-Ready 2-Azidoethyl or Propargyl Functionalities

1,3-Alternate calix[4]arenes were prepared, having bulky adamantyl groups in the p-positions of all four aromatic units of the macrocycles and pairs of propargyl or 2-azidoethyl groups alternating with n-propyl groups at the phenol oxygen atoms. The step-wise syntheses were carried out through a selective distal alkylation of the parent p-adamantylcalix[4]arene with propargyl bromide or 1,2-dibromoethane, resulting in calix[4]arenes bearing pairs of propargyl or 2-bromoethyl groups at their narrow rims. The bromine atoms were replaced by azide groups, and then both calix[4]arene diethers were exhaustively alkylated at the remaining OH-groups with 1-iodopropane under stereoselective conditions to fix the macrocycles in an 1,3-alternate shape. The structures of the prepared p-adamantylcalix[4]arenes were confirmed by NMR and HRMS data, and, for the 1,3-alternate dipropargyl ether, the X-ray diffraction data were also collected. Preliminary data on the reactivity of the prepared calixarenes under the CuAAC conditions suggested a strong steric hampering created by the adamantane units nearby the reacting alkyne or azide groups that affected the outcome of the two-fold cycloaddition involving the calixarene bis(azides) or bis(alkynes) as complementary partners.

Regioselective Propargylic Suzuki-Miyaura Coupling by SciPROP-Iron Catalyst.

The iron-catalyzed Suzuki-Miyaura cross-coupling of secondary propargyl electrophiles with lithium organoborates has been established. A propyl-bridged bulky bisphosphine ligand, SciPROP-TB, cooperated with the bulky TIPS substituent at the alkyne terminal position to achieve the cross-coupling reaction with exclusive propargylic selectivity. The reaction features high functional group compatibility, regioselectivity, and yield with a broad substrate scope. The reaction of an optically active chiral propargyl bromide proceeds with complete racemization, supporting a mechanism involving propargyl radical formation.

Network pharmacology and experimental insights into STAT3 inhibition by novel isoxazole derivatives of piperic acid in triple negative breast cancer

STAT3 is a crucial member within a family of seven essential transcription factors. Elevated STAT3 levels have been identified in various cancer types, notably in breast cancer (BC). Consequently, inhibiting STAT3 is recognized as a promising and effective strategy for therapeutic intervention against breast cancer. We herein synthesize a library of isoxazole (PAIs) from piperic acid [2E, 4E)-5-(2H-1,3-Benzodioxol-5-yl) penta-2,4-dienoic acid] on treatment with propargyl bromide followed by oxime under prescribed reaction conditions. Piperic acid was obtained by hydrolysis of piperine extracted from Piper nigrum. First, we checked the binding potential of isoxazole derivatives with breast cancer target proteins by network pharmacology, molecular docking, molecular dynamic (MD) simulation and cytotoxicity analysis as potential anti-breast cancer (BC) agents. The multi-source databases were used to identify possible targets for isoxazole derivatives. A network of protein-protein interactions (PPIs) was generated by obtaining 877 target genes that overlapped gene symbols associated with isoxazole derivatives and BC. Molecular docking and MD modelling demonstrated a strong affinity between isoxazole derivatives and essential target genes. Further, the cell viability studies of isoxazole derivatives on the human breast carcinoma cell lines showed toxicity in all breast cancer cell lines. In summary, our study indicated that the isoxazole derivative showed the significant anticancer activity. The results highlight the prospective utility of isoxazole derivatives as new drug candidates for anticancer chemotherapy, suggesting route for the continued exploration and development of drugs suitable for clinical applications.

SYNTHESIS OF 1,2,3-TRIAZOLES BASED ON PHENACYL AZIDE DERIVATIVES VIA CLICK CHEMISTRY

Etherification of n-hexanol, n-heptanol and n-octanol with propargyl bromide in the presence of sodium hydroxide in DMF afforded the terminal alkynes (2) a, b and c. Phenacyl bromide, p-bromophenacyl bromide and p-phenylphenacyl bromide were converted to corresponding azides (4) a, b and c respectively by traditional SN2 reaction of the mentioned bromides and sodium azide in DMF. The cycloaddition of the propargyl ethers (2) with the prepared organic azides (4) using click conditions gave the target 1,4-disubstituted 1,2,3- triazoles (5)-(7) in good yields. All the synthesized triazoles were characterized by FT-IR while the compounds (5) a,b and c were characterized by 1H NMR and 13C NMR in addition to FT-IR technique.

Synthesis of a Novel Tetracyclic Isoxazole by Intramolecular Nitrile Oxide Cycloaddition

Intramolecular cycloadditions have the great advantage of forming two rings simultaneously. We report the use of intramolecular [3 + 2] cycloaddition of the nitrile oxide derived from an N-propargylbenzimidazole oxime in the synthesis of a hitherto unreported tetracyclic isoxazole-containing ring system bearing “6-5-5-5”-membered ring fusions. The initial condensation was achieved through reaction of o-phenylenediamine with ethyl diethoxyacetate, followed by alkylation with propargyl bromide, deprotection of the acetal to the aldehyde, formation of an aldoxime, and intramolecular nitrile oxide cycloaddition (INOC). Characterization of the aldoxime and tetracyclic isoxazole is included herein.

Formation of five-membered ring structures via reactions of o-benzyne

The formation of five-membered ring structures is important for the generation of curved and bowl-shaped polycyclic aromatic hydrocarbons (PAHs) under combustion conditions. Here, we report the identification of the indenyl (C9H7) radical – the simplest aromatic hydrocarbon radical carrying an adjacent five- and six-membered ring, as the major product of the o-benzyne (o-C6H4) reaction with propargyl (C3H3). Because real flames exhibit a complex chemistry, elucidation of a specific reaction is very challenging. Instead, we studied the o-C6H4 + C3H3 reaction in a resistively heated microtubular SiC reactor at controlled conditions of 1150 K and a pressure near 10–20 Torr. To this end, the reactants o-benzyne and propargyl were pyrolytically generated from benzoyl chloride and propargyl bromide. We identified the reactants and the indenyl radical isomer-selectively utilizing photoion mass-selected threshold photoelectron spectroscopy (ms-TPES). The experimentally observed predominant formation of indenyl radicals finally confirms the theoretical predictions of Matsugi and Miyoshi [Phys. Chem. Chem. Phys. 14 (2012), 9722–9728] and highlights a versatile route for the formation of five-membered rings and curved PAHs via reactions of o-benzyne that favor the formation of multiring species over aliphatically substituted aromatic species.

Modular access to multi-substituted allenones via environmentally friendly organocatalytic C–H allenylation of aldehydes

Organocatalytic direct C–H allenylation of aldehydes with propargyl bromides has provided a straightforward and step-economical strategy for allenone modular synthesis.

Reactivity Study of 4-Hydroxythiocoumarin: A Novel Synthetic Route to Fused Chromono-thiophene and -thiopyran Derivatives through Solvent-dependent Thio-Claisen Rearrangement

The alkylation of 4-hydroxythiocoumarins (1a-f) was carried out with various allyl bromides as well as propargyl bromides using K2CO3 (2 equiv.) in anhydrous acetone at room temperature, and the corresponding...

Synthesis of triazole-fused tetracyclic spirooxindole derivatives via metal-free Huisgen cycloaddition.

We report an efficient, metal free method for synthesizing tetracyclic spirooxindole derivatives from N-protected isatins and propargyl bromide via Huisgen cycloaddition. This simple and practicle method provides access to spirooxindoles containing five-, six-, or seven-membered rings fused to a triazole ring.

A Click-Chemistry Approach to New, Potentially Substituted Chemical Structure, Synthesis, And In Vitro Antimicrobial, Cytotoxic, And Antifungal Activity of Novel Chromene Derivatives

A group of chromene derivatives, labeled as 4a-c, were produced by a three-step process using sodium carbonate as a catalyst. The experiment used a solvent mixture consisting of 96% ethanol and water, with a volume ratio of 1:5. A successful reaction between the corresponding hydroxyl chromenes derivatives and propargyl bromide resulted in the propargyl ether compounds 5a-c, which are derived from chromene-3-carbonitriles. 4H-chromene-chlorophenyl conjugates 7a-c were produced by 1H-1,2,3-triazole-tethered click chemistry with propargyl ethers 5a-c and 1-azido-2-chlorobenzene. Copper ions were the most effective catalysts for these chemical reactions. The yields of 1H-1,2,3-triazole varied between 75% and 80%. The antimicrobial activity of all three triazoles (a-c) was studied in vitro. In the study conducted by MCC in 2010, four compounds were found to be effective against B. subtilis, four against S. aureus, four against P. aeruginosa, and five against E. coli.