Palladium‐Catalyzed Oxidative Intramolecular C?C Bond Formation via Double sp2 C?H Activation between the 2‐Position of Imidazoles and a Benzene Ring

Oxidative intramolecular C C bond formation via double sp² C H activation between the 2‐position of imidazoles and a benzene ring catalyzed by palladium(II) has been developed, which provides an atom‐economical, concise and efficient methodology to synthesize imidazole‐ or benzimidazole‐fused isoquinoline polyheteroaromatic compounds.     

4‐Alkylated Silver–N‐Heterocyclic Carbene (NHC) Complexes with Cytotoxic Effects in Leukemia Cells

Computational chemistry has shown that backbone‐alkylated imidazoles ought to be efficient ligands for transition metal catalysts with improved carbene‐to‐metal donation. In this work, such alkylated imidazoles were synthesized and complexed with silver(I) by means of an eight/nine‐step synthetic pathway we devised to access a new class of biologically active silver complexes. The synthesis involves selective iodination of the imidazole backbone, followed by Sonogashira coupling to replace the backbone iodine. The installed alkyne moiety is then subjected to reductive hydrogenation with Pearlman’s catalyst. The imidazole N1 atom is arylated by the palladium‐catalyzed Buchwald N‐arylation method. The imidazole N3 position was then methylated with methyl iodine, whereupon the synthesis was terminated by complexation of the imidazolium salt with silver(I) oxide. The synthetic pathway provided an overall yield of ≈20 %. The resulting complexes were tested in vitro against HL60 and MOLM‐13 leukemic cells, two human‐derived cell lines that model acute myeloid leukemia. The most active compounds exhibiting low IC₅₀ values of 14 and 27 μM , against HL60 and MOLM‐13 cells, respectively. The imidazole side chain was found to be essential for high cytotoxicity, as the imidazole complex bearing a C₇ side chain at the 4‐position was four‐ to sixfold more potent than the corresponding imidazole elaborated with a methyl group.     

Design and Synthesis of Polycyclic Imidazole‐Containing N‐ Heterocycles based on C?H Activation/Cyclization Reactions

A new strategy for the synthesis of polycyclic imidazole‐containing N‐heterocycles, based on the two general synthetic ways, namely the Pd(II)‐catalyzed intramolecular arylation via CH/C Hal and CH/CH coupling reactions, was developed. The method proposed here enables the synthesis of many fused N‐heterocycles containing purine, 1‐deazapurines and benzimidazole structural units.     

Copper‐Catalyzed Three‐Component Synthesis of 2‐Iminodihydrocoumarins and 2‐Iminocoumarins

An efficient synthesis of N‐sulfonyl‐substituted 2‐imino‐3,4‐dihydrocoumarins and 2‐iminocoumarins via a copper‐catalyzed multicomponent reaction of sulfonyl azides with terminal alkynes and β‐(ortho‐hydroxyphenyl)‐α,β‐unsaturated ketones or ortho‐hydroxyphenylpropiolates has been developed. The cascade process involves trapping the keteimine by a nucleophilic addition and an intramolecular Michael addition. This methodology could well be extended to the concise synthesis of the polysubstituted piperidine scaffold.     

A New One‐Pot Synthesis of Polysubstituted Indoles from Pyrroles and β‐Nitroacrylates

The reaction of β‐nitroacrylates with pyrroles, under solvent‐ and catalyst‐free conditions, allows the formation of Friedel–Crafts adducts which, after in situ treatment with Amberlyst 15 in isopropyl alcohol under reflux, provide polysubstituted indoles, via a benzannulation reaction, in a one‐pot process.     

Curing mechanism of epoxides by imidazoles

The courses of the reactions of the epoxides with the various derivatives of imidazole in the concentration range 0.5–25 epox. weight eq./mol imidazole and in the temperature range 80–155°C were studied. All imidazoles from adducts with epoxides very quickly, namely the 1-substituted imidazole 1 : 1 adducts, in case of the 1,3-unsubstituted imidazoles the reaction continues to the 1 : 2 adducts. The polymerization effectiveness of the imidazoles falls in order 2-ethyl-4-methylimidazole (EMI) > 1-n-butylimidazole (BI) > 2-phenylimidazole (PI) > imidazole (I) ? 1-vinylimidazole (VI) > benzimidazole (BZI). The effect of temperature, epoxide, and imidazole concentrations on the overall curing rate and the limiting conversion were investigated. In the concentration and temperature range studied the overall curing rate is directly proportional to the imidazole and epoxide concentrations and follows the Arrhenius ratio with similar values of the overall activation energy E_a = 70 to 79 kJ/mol for all active tested imidazoles in the studied concentration and temperature range.     

A Practical Asymmetric Synthesis of Enantiopure Spiro[4,4]nonane‐1,6‐dione

A practical asymmetric synthesis of enantiopure spiro[4,4]nonane‐1,6‐dione, a valuable precursor for chiral ligand development, is reported. This synthetic strategy includes a kinetic resolution of the readily synthesized ketone precursor with a chiral quaternary carbon center by bioreduction with baker’s yeast as the key step, followed by a hydroformylation, oxidation, esterification and Dieckmann cyclization reaction sequence to generate the spiro five‐membered ring. It was found that the masking of the β‐ketone carbonyl group of enantiopure ethyl 1‐allyl‐2‐oxocyclopentanecarboxylate via formation of a ketal with 1,3‐diol derivative is necessary during the process of Dieckmann condensation in order to prevent its racemization under basic conditions. This method allows the gram‐scale preparation of both enantiomers of spiro[4,4]nonane‐1,6‐dione ( 1 ) with excellent enantiopurities (up to >99% ee) in the overall yields of 54% [(R)‐ 1 ] and 42% [(S)‐ 1 ], respectively. The practicality of the present synthetic procedure has provided a fundamental platform for the development of spiro[4,4]nonane‐1,6‐dione‐based chiral chemistry.     

Synthesis of β‐Aminonitrones by Regioselective Oxidation of 4H‐Imidazoles

A new regioselective synthesis for aminonitrones of type 4 via oxidative modification of 4H‐imidazoles 1 has been developed. An X‐ray structural analysis revealed an unexpected tautomeric fixation of the hydrogen atom in 4 . NMR investigations of the ¹⁵N‐labelled derivative 4b showed that this fixation is also present in solution. All new synthesized aminonitrones reported here are unusually stable which can be explained by contribution of anionic as well as cationic delocalized mesomeric structures. Treatment of 4 with acetic anhydride leads to formation of the O‐acylated hydroxylamine derivatives 5 .     

A Three‐Way Switchable Process for Suzuki Cross‐Coupling,Hydrodehalogenation, or an Assisted Tandem Hydrodehalogenation and Suzuki Cross‐Coupling Sequence

A three‐way switchable Pd‐catalyzed and microwave assisted process appropriate for selective arylation or hydrodehalogenation of the imidazole backbone was discovered and entirely optimized. The “arylation switch position” was adapted and optimized for the synthesis of 4,5‐diaryl‐1H‐imidazoles, while the “hydrodehalogenation switch position” was used for the preparation of 4(5)‐iodo‐1H‐imidazole. The hydrodehalogenation and the cross‐coupling reactions were also successfully combined in “the third switch position” that performs an assisted tandem reaction sequence that produced 4(5)‐aryl‐1H‐imidazole. All of the three pathways produced their corresponding products in excellent yield.

     

Platinum(IV)‐Catalyzed Synthesis of Unsymmetrical Polysubstituted Benzenes via Intramolecular Cycloaromatization Reaction

A one‐pot synthesis of polysubstituted benzene derivatives was achieved via a platinum(IV)‐catalyzed intramolecular cycloaromatization reaction. The reaction proceeds via a tandem skeletal rearrangment, dehydration and double bond isomerization, which proved to be very useful for the syntheses of a range of interesting polyalkyl‐substituted benzenes.

     

Polymerization of p-cresyl glycidyl ether catalyzed by imidazoles I. The influence of the imidazole concentration,the reaction temperature,and the presence of isopropanol on the polymerization

The polymerization of p-cresyl glycidyl ether catalyzed by imidazoles has been investigated as a model reaction for the polymerization of technical epoxy resins. The dependence of oligomer yield on time, temperature, and imidazole concentration, the distribution of the polymerization degrees, and the influence of isopropanol have been studied. The reaction rate and the average degree of polymerization are affected by the presence or absence of a secondary nitrogen on the imidazole, i.e., different results are obtained when 2-ethyl, 4-methyl imidazole (EMI) or 1-methyl imidazole (1-MIA) are used. 1-MIA seems to be “precursor” of the catalyst rather than a catalyst by itself. The comparisons of CGE polymerizations catalyzed by 1-MIA in the absence and presence of isopropanol show only quantitative differences: The polymerization in the presence of isopropanol is faster, and the average degree of polymerization is shifted to higher values. The activation energies of CGE polymerizations catalyzed by different imidazoles have been determined.     

Microencapsulation of imidazole curing agents by spray‐drying method

An epoxy resin–imidazole system was used to form the adhesives for the anisotropic conducting film (ACF), and a latent curing system was necessary for the ACF. In this study, imidazoles were microencapsulated for the latent curing system. Polycaprolactone (PCL) was used as the wall material, and the spray‐drying method was used to form the microcapsule. The imidazoles used in this study were imidazole, 2‐methylimidazole, and 2‐phenylimidazole. The effect of the ratio of PCL to imidazoles, and the effect of PCL molecular weight were investigated during the microcapsule formation. The amount of imidazoles in the microcapsule was measured using thermogravimetric analyzer and elemental analysis. The permeability of the microcapsules was measured in ethanol, and the shelf life of the microcapsules was studied for the epoxy resin. The curing behavior of these microcapsules to epoxy resin was examined using differential scanning calorimeter. In the curing reaction, the microcapsule of imidazoles exhibited delayed kinetic behaviors compared to pure imidazoles. And the curing times were estimated at 150 and 180°C using an indentation method. These microcapsules of imidazoles exhibited a long shelf life, and the curing did not occur in some of the microcapsule–epoxy resin systems at 20°C for 15 days. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

First Copper‐Catalyzed Intramolecular Amidation in Substituted 4‐Iodopyrazoles Leading to the Synthesis of Pyrazolo[4,3‐b]‐ pyridin‐5‐ones

An unprecedented copper‐catalyzed intramolecular amidation of substituted 4‐iodopyrazoles generated either via Baylis–Hillman or Horner–Wadsworth–Emmons chemistry for the synthesis of pyrazolo[4,3‐b]pyridine‐5‐ones is described. In addition, the effect of the stereochemistry of the acrylamide on the cross‐coupling reaction has been investigated and it is demonstrated that only the Z‐isomer is favoured to undergo the intramolecular cyclization.     

Dendronized Polymer Architectures for Fuel Cell Membranes

Multi‐step synthetic pathways to low‐ion exchange capacity (IEC) polysulfone (PSU) with sulfonic acid functionalized aliphatic dendrons and sulfonated comb‐type PSU structures are developed and investigated in a comparative study as non‐fluorinated proton exchange membrane (PEM) candidates. In each case the side chains are synthesized and introduced in their sulfonated form onto an azide‐functionalized PSU via click chemistry. Three degrees of substitution of each architecture were prepared in order to evaluate the dependence on number of sulfonated side chains. Solution cast membranes were evaluated as PEMs for use in fuel cells by proton conductivity measurements, and in the case of dendronized architectures: thermal stability. The proposed synthetic strategy facilitates exploration of a non‐fluorous system with various flexible side chains where IEC is tunable by the degree of substitution.     

Iron(III)/Iodine‐Catalyzed C(sp2)?H Activation of α,β‐Unsaturated Aldehydes/Ketones with Amidines: Synthesis of 1,2,4,5‐Tetrasubstituted Imidazoles

An efficient methodology to access a library of 1,2,4,5‐tetrasubstituted imidazoles from a broad range of amidines and α,β‐unsaturated aldehydes/ketones via a C(sp²) H amination has been developed. This method represents a new and simple way to prepare highly substituted imidazoles from easily available starting materials, inexpensive catalysts, and with good functional group tolerance in good to excellent yields.

     

Direct azidation of isotactic polypropylene and synthesis of ‘grafted to’ derivatives thereof using azide–alkyne cycloaddition chemistry

Azido‐functionalized isotactic polypropylene was prepared via the direct C? H azidation of a commercially available polymer using a stable azidoiodinane. Including imidazole or benzimidazole in the reaction mixture was found to significantly improve the yields of the post‐polymerization modification. Although chain cleavage was observed, the methodology afforded high‐molecular‐weight (M _w > 100 kDa ) functionalized polypropylene containing up to 3 mol% of azido groups and enabled access to polypropylene‐graft ‐poly(ethylene glycol) copolymers via azide–alkyne cycloaddition chemistry. © 2016 Society of Chemical Industry     

Reactivity of Electrogenerated N‐Heterocyclic Carbenes in Room‐Temperature Ionic Liquids. Cyclization to 2‐Azetidinone Ring via C‐3/C‐4 Bond Formation

The intrinsic chemistry of imidazolium‐based room‐temperature ionic liquids, related to the acidity of the C‐2 imidazolium cation, can be modified via cathodic cleavage of the C‐2/hydrogen bond. N‐Heterocyclic carbenes, electrogenerated by electrolysis of imidazolium‐based room‐temperature ionic liquids, are stable bases that are strong enough to deprotonate bromoamides 1a–k yielding the azetidin‐2‐one ring via C‐3/C 4 bond formation. The electrosynthesis of β‐lactams 2a–k has been achieved under mild conditions, elevated yields and avoiding the use of toxic, volatile, molecular solvents.     

Expanding the Scope of Biocatalysis: Oxidative Biotransformations on Solid‐Supported Substrates

Oxidative biocatalytic reactions were performed on solid‐supported substrates, thus expanding the repertoire of biotransformations that can be carried out on the solid phase. Various phenylacetic and benzoic acid analogues were attached to controlled pore glass beads via an enzyme‐cleavable linker. Reactions catalyzed by peroxidases (soybean and chloro), tyrosinase, and alcohol oxidase/dehydrogenase gave a range of products, including oligophenols, halogenated aromatics, catechols, and aryl aldehydes. The resulting products were recovered following cleavage from the beads using α‐chymotrypsin to selectively hydrolyze a chemically non‐labile amide linkage. Controlled pore glass (CPG) modified with a polyethylene glycol (PEG) linker afforded substantially higher product yields than non‐PEGylated CPG or non‐swellable polymeric resins. This work represents the first attempt to combine solid‐phase oxidative biotransformations with subsequent protease‐catalyzed cleavage, and serves to further expand the use of biocatalysis in synthetic and medicinal chemistry.     

Copper(I)‐Catalyzed Synthesis of Novel 4‐(Trifluoromethyl)‐[1,2,3]triazolo[1,5‐a]quinoxalines via Cascade Reactions of N‐(o‐Haloaryl)alkynylimine with Sodium Azide

Novel tricyclic 4‐(trifluoromethyl)‐[1,2,3]triazolo[1,5‐a]quinoxalines were readily prepared from N‐(o‐haloaryl)alkynylimines and sodium azide via copper(I)‐catalyzed tandem reactions. This synthetic strategy provides an efficient way to access a library of novel heterocyclic compounds that are of interest in drug discovery.