Synthesis of 3,3‐Disubstituted Oxindoles by Palladium‐Catalyzed Asymmetric Intramolecular α‐Arylation of Amides: Reaction Development and Mechanistic Studies

Palladium complexes incorporating chiral N‐heterocyclic carbene (NHC) ligands catalyze the asymmetric intramolecular α‐arylation of amides producing 3,3‐disubstituted oxindoles. Comprehensive DFT studies have been performed to gain insight into the mechanism of this transformation. Oxidative addition is shown to be rate‐determining and reductive elimination to be enantioselectivity‐determining. The synthesis of seven new NHC ligands is detailed and their performance is compared. One of them, L8 , containing a tBu and a 1‐naphthyl group at the stereogenic centre, proved superior and was very efficient in the asymmetric synthesis of fifteen new spiro‐oxindoles and three azaspiro‐oxindoles often in high yields (up to 99 %) and enantioselectivities (up to 97 % ee; ee=enantiomeric excess). Three palladacycle intermediates resulting from the oxidative addition of [Pd(NHC)] into the aryl halide bond were isolated and structurally characterized (X‐ray). Using these intermediates as catalysts showed alkene additives to play an important role in increasing turnover number and frequency.     

Access to Spiro and Fused Indole Derivatives from α,β‐Unsaturated Aldehydes Enabled by N‐Heterocyclic Carbene Catalysis

Spiro and fused indoles are attractive heterocyclic compounds with broad and promising activities in various therapeutic fields, and thus, have become the synthetic targets of organic chemists. In this account, we describe our recent progress in the synthesis of a series of spiro and fused indole derivatives through N‐heterocyclic carbene (NHC)‐catalyzed annulations of diverse NHC‐bound intermediates derived from α,β‐unsaturated aldehydes. Particularly, the novel synthesized isatin‐derived α‐bromoenals may be used as versatile 1,3‐biselectrophile synthons for combination with a range of bisnucleophiles for potentially divergent syntheses of skeletally diverse spirooxindoles in the future.     

Sulfonated N‐heterocyclic carbine‐silver (I) complexes: Synthesis,characterisation and biological evaluation

The synthesis, characterisation and biological activity of water‐soluble Ag(I)‐NHC complexes, general formula Na[(NHC)AgCl] where NHC is a sulfonated and sterically hindered N‐heterocyclic carbene, is reported. The Ag‐NHC complexes (2a–e) were synthesised by reacting the corresponding sulfonated NHC ligands with Ag₂O in the presence of NaCl or NaBr in methanol/water (1:1) solution. Synthesised silver (I)‐N‐heterocyclic carbene complexes have been characterised by NMR, micro‐analysis and HRMS spectroscopic methods. The IC₅₀ values of these complexes were determined by a proliferation BrdU enzyme‐linked immunosorbent assay (ELISA) against HeLa (human cervix carcinoma), HT29 (human adenocarcinoma) and L929 (mouse fibroblast) cell lines. These complexes have been highlighted as promising and original platforms for building new types of metalodrug. All new water‐soluble Ag(I) complexes demonstrated remarkable cytotoxic activity against HeLa, HT29 and L929 cell lines.     

Synthesis,characterization and catalytic activity in Suzuki–Miyaura coupling of palladacycle complexes with n‐butyl‐substituted N‐heterocyclic carbene ligands

A series of monomeric palladacycle complexes bearing n‐butyl‐substituted N‐heterocyclic carbenes, namely [Pd(NHC)X(dmba)] (dmba: dimethylbenzylamine and [Pd(NHC)X(ppy)]; NHC: 1‐n‐butyl‐3‐substituted benzylimidazol‐2‐ylidene; ppy: 2‐phenylpyridine), were prepared either by transmetallation from the corresponding silver carbene complexes or by the reaction of the corresponding acetate‐bridged palladacycle dimer with N‐heterocyclic carbene ligands in high yields. The palladium(II) complexes were characterized using elemental analyses, APCI‐MS, ¹H NMR and ¹³C NMR spectroscopies. These complexes are efficient in the Suzuki–Miyaura coupling reaction between phenylboronic acid and aryl bromides.     

Hydroboration of Arynes with N‐Heterocyclic Carbene Boranes

Arynes were generated in situ from ortho‐silyl aryl triflates and fluoride ions in the presence of stable N‐heterocyclic carbene boranes (NHC? BH₃). Spontaneous hydroboration ensued to provide stable B‐aryl‐substituted NHC‐boranes (NHC? BH₂Ar). The reaction shows good scope in terms of both the NHC‐borane and aryne components and provides direct access to mono‐ and disubstituted NHC‐boranes. The formation of unusual ortho regioisomers in the hydroboration of arynes with an electron‐withdrawing group supports a hydroboration process with hydride‐transfer character.     

Synthesis,cytotoxicity and antibacterial studies of symmetrically and non‐symmetrically benzyl‐ or p‐cyanobenzyl‐substituted N‐Heterocyclic carbene–silver complexes

From the reaction of 1H‐imidazole ( 1a ), 4,5‐dichloro‐1H‐imidazole ( 1b ) and 1H‐benzimidazole ( 1c ) with p‐cyanobenzyl bromide ( 2 ), symmetrically substituted N‐heterocyclic carbene (NHC) [( 3a–c )] precursors, 1‐methylimidazole ( 5a ), 4,5‐dichloro‐1‐methylimidazole ( 5b ) and 1‐methylbenzimidazole ( 5c ) with benzyl bromide ( 6 ), non‐symmetrically substituted N‐heterocyclic carbene (NHC) [( 7a–c )] precursors were synthesized. These NHC? precursors were then reacted with silver(I) acetate to yield the NHC‐silver complexes [1,3‐bis(4‐cyanobenzyl)imidazole‐2‐ylidene] silver(I) acetate ( 4a ), [4,5‐dichloro‐1,3‐bis(4‐cyanobenzyl)imidazole‐2‐ylidene] silver(I) acetate ( 4b ), [1,3‐bis(4‐cyanobenzyl)benzimidazole‐2‐ylidene] silver(I) acetate ( 4c ), (1‐methyl‐3‐benzylimidazole‐2‐ylidene) silver(I) acetate ( 8a ), (4,5‐dichloro‐1‐methyl‐3‐benzylimidazole‐2‐ylidene) silver(I) acetate ( 8b ) and (1‐methyl‐3‐benzylbenzimidazole‐2‐ylidene) silver(I) acetate ( 8c ) respectively. The four NHC‐precursors 3a–c, 7c and four NHC–silver complexes 4a–c and 8c were characterized by single crystal X‐ray diffraction. The preliminary antibacterial activity of all the compounds was studied against Gram‐negative bacteria Escherichia coli, and Gram‐positive bacteria Staphylococcus aureus using the qualitative Kirby‐Bauer disc‐diffusion method. All NHC–silver complexes exhibited medium to high antibacterial activity with areas of clearance ranging from 4 to 12 mm at the highest amount used, while the NHC‐precursors showed significantly lower activity. In addition, all NHC–silver complexes underwent preliminary cytotoxicity tests on the human renal‐cancer cell line Caki‐1 and showed medium to high cytotoxicity with IC₅₀ values ranging from 53 ( ± 8) to 3.2 ( ± 0.6) µM. Copyright © 2010 John Wiley & Sons, Ltd.     

New palladium(II)–N‐heterocyclic carbene complexes containing benzimidazole‐2‐ylidene ligand derived from menthol: synthesis,characterization and catalytic activities

A new series of sterically hindered ligands containing (1R,2S,4R)‐(+)‐menthoxymethyl group attached to benzimidazole‐based N‐heterocyclic carbene (NHC), palladium–bis‐NHC complexes and (κ²‐C,N)‐palladacyclic NHC complexes have been synthesized and characterized using appropriate spectroscopic techniques. Catalytic performance of the palladium complexes has been investigated for allylic alkylation, Suzuki and Heck carbon–carbon coupling reactions. These complexes smoothly catalyse the carbon–carbon bond formation reactions. Copyright © 2016 John Wiley & Sons, Ltd.     

Binuclear meta‐xylyl‐linked Ag(I)‐N‐heterocyclic carbene complexes of N‐alkyl/aryl‐alkyl‐substituted bis‐benzimidazolium salts: synthesis,crystal structures and in vitro anticancer studies

Salts of meta‐xylyl‐linked N‐ethyl/n‐butyl/benzyl‐substituted bis‐benzimidazolium having hexafluorophosphate counterions have been synthesized. The corresponding binuclear Ag(I)‐N‐heterocyclic carbene complexes were prepared by the reaction of Ag₂O. The N‐heterocyclic carbene (NHC) ligand precursor 7 and Ag(I)–NHC complexes 10 and 11 have been structurally characterized by single‐crystal X‐ray diffraction technique. All of the reported compounds have been tested for their anticancer activity using human colorectal (HCT 116) cancer cell lines. Sterically varied benzimidazolium salts displayed significant activity against HCT 116 cell line, yielding IC₅₀ values in the range 0.1–19.4 µ m , while Ag(I)–carbene complexes showed exceptionally good activity (0.2–1.3 µ m ) against tested cancer cell lines. Copyright © 2013 John Wiley & Sons, Ltd.     

Synthesis and antimicrobial activity of bulky 3,5‐di‐tert‐butyl substituent‐containing silver–N‐heterocyclic carbene complexes

A series of novel benzimidazolium bromides containing bulky 3,5‐di‐tert ‐butyl group were synthesized in high yields as N‐heterocyclic carbene (NHC) ligands. These NHC ligands were metallated with Ag₂O under moderate conditions to give novel silver–NHC complexes. The structures of all compounds were characterized using ¹H NMR, ¹³CNMR, infrared and elemental analysis techniques, which supported the proposed structures. The silver–NHC complexes were screened for their in vitro antimicrobial activities against the standard bacterial strains Enterococcus faecalis , Staphylococcus aureus , Escherichia coli and Pseudomonas aeruginosa and the fungal strains Candida albicans and C. tropicalis . The results showed that most of the silver–NHC complexes inhibited the growth of all bacterial strains and fungal strains and were found to display effective antimicrobial activity against different microorganisms.     

Palladium(II)‐N‐Heterocyclic Carbene Complexes: Efficient Catalysts for the Direct C‐H Bond Arylation of Furans with Aryl Halides

This paper contains the synthesis and characterization of the seven new benzimidazolium salts and their corresponding new palladium(II)‐NHC complexes with the general formula [PdX₂(NHC)₂], (NHC = N‐heterocyclic carbene, X = Cl or Br), and also their catalytic activity in direct C‐H bond arylation of 2‐substituted furan derivatives with aryl bromides and aryl chlorides. Under the optimal conditions, these palladium(II)‐NHC complexes showed the good catalytic performance for the direct C‐H bond arylation of 2‐substituted furans with (hetero)aryl bromides, and with readily available and inexpensive aryl chlorides. The C‐H bond arylation regioselectively produced C5‐arylated furans by using 1 mol% of the palladium(II)‐NHC catalysts in moderate to high yields.     

N‐Phenyl‐substituted carbene precursors and their silver complexes: synthesis,characterization and antimicrobial activities

A series of unsymmetrically substituted N‐heterocyclic carbene (NHC) precursors ( 1a , 1b , 1c , 1d , 1e ) were synthesized from the reaction of N‐phenylbenzimidazole with various alkyl halides. These compounds were used to synthesize NHC–silver(I) complexes ( 2a , 2b , 2c , 2d , 2e ). The five new 1‐phenyl‐3‐alkylbenzimidazolium salts ( 1a , 1b , 1c , 1d , 1e ) and their NHC–silver complexes ( 2a , 2b , 2c , 2d , 2e ) were characterized by the ¹H NMR, ¹³C NMR and FT‐IR spectroscopic methods and elemental analysis techniques. Also, the two NHC–silver complexes 2b and 2c were characterized by single‐crystal X‐ray crystallography, which confirmed the linear C―Ag―Cl arrangements. The antibacterial activities of the NHC precursor and NHC–silver complexes were tested against three Gram‐positive bacterial strains (Bacillus subtilis, Listeria monocytogenes and Staphylococcus aureus) and three Gram‐negative bacterial strains (Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa) using the microdilution broth method. The NHC–silver complexes showed higher antibacterial activity than the NHC precursors. In addition, silver complexes 2a , 2b , 2c , 2d showed high antibacterial activity against the Gram‐positive bacteria L. monocytogenes and S. aureus compared to the standard, tetracycline. Copyright © 2014 John Wiley & Sons, Ltd.     

Thermal and Photolytic Transformation of NHC–B,N‐Heterocycles: Controlled Generation of Blue Fluorescent 1,3‐Azaborinine Derivatives and 1H‐Imidazo[1,2‐a]indoles by External Stimuli

NHC–B,N‐heterocyclic compounds have been found to act as convenient precursors for obtaining either 1,3‐azaborinine or 1H‐imidazo[1,2‐a]indole derivatives, which are two different and rare classes of compounds. The formation of these two classes of compounds from the NHC–B,N‐heterocycles is highly selective depending on the external stimuli employed, and the resulting products have been studied for their interesting chemical and photophysical properties. The mechanism and possible reaction pathways of the unusual transformation are established by computational studies.     

Radical trans‐Hydroboration of Alkynes with N‐Heterocyclic Carbene Boranes

Hydroboration of internal alkynes with N‐heterocyclic carbene boranes (NHC‐boranes) occurs to provide stable NHC (E)‐alkenylboranes upon thermolysis in the presence of di‐tert‐butyl peroxide. The E isomer results from an unusual trans‐hydroboration, and the E/Z selectivity is typically high (90:10 or greater). Evidence suggests that this hydroboration occurs by a radical‐chain reaction involving addition of an NHC‐boryl radical to an alkyne to give a β‐NHC‐borylalkenyl radical. Ensuing hydrogen abstraction from the starting NHC‐borane provides the product and returns the starting NHC‐boryl radical. Experiments suggest that the observed trans‐selectivity results from kinetic control in the hydrogen‐transfer reaction.     

Triptycene‐Based Chiral and meso‐N‐Heterocyclic Carbene Ligands and Metal Complexes

Based on 1‐amino‐4‐hydroxy‐triptycene, new saturated and unsaturated triptycene‐NHC (N‐heterocyclic carbene) ligands were synthesized from glyoxal‐derived diimines. The respective carbenes were converted into metal complexes [(NHC)MX] (M=Cu, Ag, Au; X=Cl, Br) and [(NHC)MCl(cod)] (M=Rh, Ir; cod=1,5‐cyclooctadiene) in good yields. The new azolium salts and metal complexes suffer from limited solubility in common organic solvents. Consequently, the introduction of solubilizing groups (such as 2‐ethylhexyl or 1‐hexyl by O‐alkylation) is essential to render the complexes soluble. The triptycene unit infers special steric properties onto the metal complexes that enable the steric shielding of selected areas close to the metal center. Next, chiral and meso‐triptycene based N‐heterocyclic carbene ligands were prepared. The key step in the synthesis of the chiral ligand is the Buchwald–Hartwig amination of 1‐bromo‐4‐butoxy‐triptycene with (1S,2S)‐1,2‐diphenyl‐1,2‐diaminoethane, followed by cyclization to the azolinium salt with HC(OEt)₃. The analogous reaction with meso‐1,2‐diphenyl‐1,2‐diaminoethane provides the respective meso‐azolinium salt. Both the chiral and meso‐azolinium salts were converted into metal complexes including [(NHC)AuCl], [(NHC)RhCl(cod)], [(NHC)IrCl(cod)], and [(NHC)PdCl(allyl)]. An in situ prepared chiral copper complex was tested in the enantioselective borylation of α,β‐unsaturated esters and found to give an excellent enantiomeric ratio (er close to 90:10).     

Poly(ethylene glycol)‐ and glucopyranoside‐substituted N‐heterocyclic carbene precursors for the synthesis of arylfluorene derivatives using efficient palladium‐catalyzed aqueous Suzuki reaction

This paper reports an environmentally friendly and highly efficient synthesis of organic semiconductor materials via a Pd/N‐heterocyclic carbene (NHC)‐catalyzed Suzuki reaction in aqueous ethanol with high isolated yields (86–98%). Firstly, four glucopyranoside‐substituted NHC precursors with poly(ethylene glycol) (PEG) chains were synthesized and characterized. The NHC precursor with the longest PEG chain (n = 16) was found to be the most efficient ligand in the reactions of a wide range of aryl halides and arylboronic acids. The best catalyst system obtained in this work could be recycled five times without significant loss of catalytic activity.l Copyright © 2016 John Wiley & Sons, Ltd.     

Benzimidazole‐based silver(I)–N‐heterocyclic carbene complexes as anti‐bacterials: synthesis,crystal structures and nucleic acids interaction studies

A series of new benzimidazolium salts as N‐heterocyclic carbene (NHC) precursors has been synthesized. Reactions of these salts with Ag₂O with varying metal‐to‐salt ratio facilitate the formation of a series of new binuclear and mononuclear Ag(I)–NHC complexes. All compounds were characterized using physicochemical and spectroscopic techniques. Single‐crystal X‐ray diffraction study reveals a binuclear structure for one of the complexes and a mononuclear one for two others. These complexes exist as cationic Ag(I)–NHC complexes with the chelation of carbene carbons to the silver centre in an almost linear manner. The compounds were screened for their anti‐bacterial activities against Staphylococcus aureus (ATCC 12600) as a Gram‐positive bacterium and Escherichia coli (ATCC 25922) as a Gram‐negative bacterium. The results show that both bacteria appear markedly inhibited. Furthermore, the results suggest the possibility of steric variation as a modulation of the anti‐bacterial activities. The nuclease activities of the compounds were assessed using gel electrophoresis and the results indicate that these complexes can cleave or degrade DNA and RNA via a non‐oxidative mechanism. Copyright © 2014 John Wiley & Sons, Ltd.     

Synthesis,crystal structures,spectral FT‐IR,NMR and UV–Vis investigations and Hirshfeld surface analysis of two new 2‐hydroxyethyl‐substituted N‐heterocyclic carbene precursors

This study discusses the synthesis of two new 2‐hydroxyethyl substituted N‐heterocyclic carbene (NHC) precursors. The NHC precursors were prepared from 1‐(alkyl/aryl)benzimidazole and alkyl halides. They were characterized using ¹H NMR, ¹³C NMR, FT‐IR, UV–Vis spectroscopy, and elemental analysis techniques. Molecular and crystal structures of 1 and 2 were determined using the single‐crystal X‐ray diffraction method. Crystal structure of the compounds features NHC precursors and chloride anions. Additionally in 2 , the asymmetric unit has a water molecule, which forms a tetrameric chloride‐hydrate assembly with the chloride anion. The chloride anions play an important role in the stabilization of crystal structures to form a two‐dimensional supramolecular architecture. The 3D Hirshfeld surface and the associated 2D fingerprint plots were also drawn to gain insights into the behavior of the interactions in the compounds.     

N‐Heterocyclic Carbene Catalyzed Oxidative Coupling of Alkenes/ α‐Bromoacetophenones with Aldehydes: A Facile Entry to α,β‐Epoxy Ketones

A novel, N‐heterocyclic carbene (NHC) catalyzed direct oxidative coupling of styrenes with aldehydes has been described for the synthesis of α,β‐epoxy ketones in good yields. This unprecedented regioselective oxidative coupling employs NBS/DBU/DMSO (DBU=1,8‐diazabicyclo [5.4. 0] undec‐7‐ene, DMSO=dimethylsulfoxide, NBS=N‐bromosuccinimide) as an oxidative system at ambient conditions. Additionally, first NHC‐catalyzed Darzens reaction of α‐bromoketones and aldehydes under mild reaction conditions has also been described. Interestingly, mechanistic studies have revealed the preferred reactivity of NHC with alkene/α‐bromoketone rather than aldehydes, thus proceeding via the ketodeoxy Breslow intermediate.     

New bis(N‐heterocyclic carbene) palladium complex immobilized on magnetic nanoparticles: as a magnetic reusable catalyst in Suzuki‐Miyaura cross coupling reaction

A new bis(N ‐heterocyclic carbene) (NHC) palladium complex supported on silica coated magnetic nanoparticles (MNPs) was prepared using the reaction of synthesized Pd‐NHC complex with MNPs. The Pd‐NHC complex was prepared using the reaction of a hydroxyl‐functionalized bis‐imidazolium ionic liquid. The Pd‐NHC organometallic complex was used as a heterogeneous recyclable and active catalyst in the Suzuki‐Miyaura reaction and various aryl halides were coupled with arylboronic acids in order to synthesize diverse biaryls in good to excellent yields. The prepared catalyst was characterized by use of some different microscopic and spectroscopic techniques including elemental analysis, FT‐IR spectroscopy, diffuse reflectance UV–Vis spectrophotometery, scanning electron microscopy (SEM), transmission electron microscopy (TEM), vibrating sample magnetometer (VSM) and X‐ray diffraction (XRD). The Pd‐NHC catalyst system is a magnetic reusable catalyst and it can be separated from the reaction mixture using an external magnetic field. The catalyst was reusable in the Suzuki‐Miyaura coupling reaction at least for 6 times without significant decreasing in its catalytic activity.     

The Thermal Rearrangement of an NHC‐Ligated 3‐Benzoborepin to an NHC‐Boranorcaradiene

An N‐heterocyclic‐carbene‐ligated 3‐benzoborepin with a bridged structure has been synthesized by double radical trans‐hydroboration of benzo[3,4]cycloundec‐3‐ene‐1,5‐diyne with an N‐heterocyclic carbene borane. The thermal reaction of the NHC‐ligated borepin at 150 °C gives an isolable NHC‐boranorcaradiene. Experiments and density functional theory calculations support a mechanism whereby the borepin initially rearranges to a boranorcaradiene by a thermal 6π‐electrocyclic reaction. This is followed by 1,5‐boron shift to give a rearranged boranorcaradiene. This shift occurs with stereoinversion at boron through a transition state with open‐shell diradical character. This is the first example of the isolation of a boranorcaradiene from a thermal reaction of a borepin.