N-heterocyclic Carbene Precursors Research Articles

Synthesis, crystal structures, spectral investigations, conformational analysis and DFT studies of N- heterocyclic carbene precursors

Three new 2-hydroxyethyl substituted N-heterocyclic carbene (NHC) precursors were synthesized in this study. These NHC precursors were prepared from 1-(alkyl/aryl)benzimidazole and alkyl halides. Their structural characterizations were performed by elemental analysis, 1H NMR, 13C NMR, FT–IR and UV–Vis spectroscopy and single-crystal X-ray diffraction. The spectral features were also characterized by Density Functional Theory (DFT) at B3LYP/Lanl2dz//6-31G++(d,p) basis set. Two most stable conformers belonging to the compounds were found by potential energy surface (PES) scan, and the theoretical ground-state geometries were investigated. Among these conformers, the geometry of the conformer-I for all compounds matches almost well with the experimental results. 1H and 13C NMR chemical shifts were calculated with GIAO approach and compared to the observed ones. Detailed vibrational assignments of the wavenumbers of the conformers were carried out based on the potential energy distribution (PED). Natural bond orbital (NBO) analysis was used to analyze the stability of the molecules arising from hyperconjugative interactions and charge delocalization. The HOMO–LUMO energy gap of the stable conformers was calculated for comparing their chemical reactivity behavior. Molecular electrostatic potential (MEP) diagrams were used to get information about ?the size, shape, charge density distribution and site of chemical reactivity of each stable conformer. The 3D Hirshfeld surfaces and the associated 2D fingerprint plots were also carried out to obtain an insight into the behavior of the interactions in the compounds.

Well‐defined N‐heterocyclic carbene/ruthenium complexes for the alcohol amidation with amines: The dual role of cesium carbonate and improved activities applying an added ligand

Dehydrogenative amide bond formation from alcohols and amines has been regarded as an atom‐economic and sustainable process. Among various catalytic systems, N‐heterocyclic carbene (NHC)‐based Ru catalytic systems have attracted growing interest due to the outstanding properties of NHCs as ligands. Herein, an NHC/Ru complex (1) was prepared and its structure was further confirmed with X‐ray crystallography. In the presence of Cs2CO3, two NHC/Ru‐based catalytic systems were disclosed to be active for this amide synthesis. System A, which did not contain any added ligand, required a catalyst loading of 1.00 mol%. Interestingly, improved catalytic performance was realized by the addition of an NHC precursor (L). Optimization of the amounts of L and other conditions gave rise to system B, a much more potent system with the Ru loading as low as 0.25 mol%. Moreover, an NHC‐Ru‐carbonate complex 6 was identified from the refluxing toluene of 1 and Cs2CO3, and further investigations revealed that 6 was an important intermediate for this catalytic reaction. Based on the above results, we claimed that the role of Cs2CO3 was to facilitate the formation of key intermediate 6. On the other hand, it provided the optimized basicity for the selective amide formation.

Consecutive Intermolecular Reductive Amination/Asymmetric Hydrogenation: Facile Access to Sterically Tunable Chiral Vicinal Diamines and N-Heterocyclic Carbenes.

A highly enantioselective iridium- or ruthenium-catalyzed intermolecular reductive amination/asymmetric hydrogenation relay with 2-quinoline aldehydes and aromatic amines has been developed. A broad range of sterically tunable chiral N,N'-diaryl vicinal diamines were obtained in high yields (up to 95 %) with excellent enantioselectivity (up to >99 % ee). The resulting chiral diamines could be readily transformed into sterically hindered chiral N-heterocyclic carbene (NHC) precursors, which are otherwise difficult to access. The usefulness of this synthetic approach was further demonstrated by the successful application of one of the chiral vicinal diamines and chiral NHC ligands in a transition-metal-catalyzed asymmetric Suzuki-Miyaura cross-coupling reaction and asymmetric ring-opening cross-metathesis, respectively.

Modular Synthesis of New Bicyclic Carbene Precursors

: A series of new N-heterocyclic carbene (NHC) precursors, containing bicyclic pyrrolo[1,2- c]imidazole framework, were prepared from N-(tert-butoxycarbonyl)-L-proline (1-Boc-L-proline). The sequential attachment of nitrogen nucleophiles and subsequent ring closure gave the desired bicyclic NHC precursors in good yields. The structures of these new NHC precursors were determined on the basis of spectroscopic techniques, including NMR and MS.

Synthesis, characterization, in vitro antimicrobial and anticancer studies of new platinum N-heterocyclic carbene (NHC) complexes and unexpected nickel complexes

A series of bidendate pyridine-functionalized metal N-heterocyclic carbene (NHC) complexes with various wingtip substituents (R = methyl, phenyl and tert-butyl) had been prepared from silver oxide-mediated transmetalation method. The basic backbone of the NHC ligands were prepared in two stepwise reactions: reduction of the commercially available 2-benzoylpyridine, followed by halogenation to yield 2-(chloro(phenyl)methyl)pyridine. Subsequent reactions with different imidazoles gave the desired imidazolium salts (or NHC precursors) with different R groups at the N wingtip (R = Me, Ph, t-Bu). Transmetalation of the imidazolium salts into platinum NHC complexes were achieved by using Ag2O mediated method with Pt(cod)Cl2 as the transmetalating agent. On the other hand, nickel NHC complexes were obtained via one pot synthesis method with nickel chloride as the transmetalating agent and reflux in the presence of a base. Following recrystallisation, the molecular structure of Pt NHC complex ( ± )-5a had been successfully elucidated via single crystal X ray diffraction (XRD) analysis. The six-membered ring of the platinum NHC complexes adopted a boat conformation with the phenyl ring arranged at the axial position. Meanwhile, two unexpected nickel complexes, i.e. a simple nickel coordination complex and a nickelate complex, were obtained and studied using XRD. These Pt NHC complexes and unexpected Ni complexes were evaluated for their in vitro antimicrobial and anticancer activities against a panel of pathogenic microorganisms and three selected human cancer cell lines, including breast (MCF7), colon (HCT116) and oral (H103) cancer cells. Generally, the Pt NHC complexes displayed enhanced antimicrobial activities upon coordination to metals, as compared to the corresponding imidazolium salts i.e. NHC precursors, with minimum inhibitory concentration (MIC) values in micromolar (μM) range. A couple of platinum NHC complexes synthesized exhibited antimicrobial activities with MIC as low as 2 μM, which are comparable to silver NHC complexes with renowned antimicrobial profiles. Similarly, upon coordination to the metals, the cytotoxic effects of the platinum NHC complexes increased significantly as compared to the imidazolium salts. Among all, platinum NHC complex (±)-5c displayed significant cytotoxicities towards the cancer cells with IC50 values that are two to three times lower than that of the anticancer drug cisplatin. In summary, evidences for influence of both wingtip substituents and metals on the biological activities of the complexes have been found.

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.

Synthetic Approaches to Chiral Non-C 2-symmetric N-Heterocyclic Carbene Precursors

N-Heterocyclic carbenes and their metal complexes have found applications in many organic transformations. Apart from the privileged C 2-symmetry present in modern enantioselective catalysis, ligands bearing C 1-symmetry have witnessed growing attention due to the better control of process stereoselectivity in many cases. The present review summarizes, for the first time, the seminal synthetic efforts for the preparation of N-heterocyclic carbene precursors exhibiting C 1-symmetry. The well-established methods will be discussed in the light of recent achievements, giving a direct opportunity for comparison of the existing methods, and simultaneously a chance to find the best synthetic pathway for the ideal chiral ligand.1 Introduction2 Five-Membered Rings2.1 Five-Membered Saturated (Imidazolinium) Ring2.1.1 Amino Alcohol Derivatives2.1.2 Amino Acid Derivatives2.1.3 Amine and Diamine Derivatives2.2 Five-Membered Unsaturated Ring2.2.1 Cyclization Strategy2.2.2 Functionalization of the Existing N-Imidazole Ring3 Triazolium Salts3.1 Substitution in Oxadiazolium Salts3.2 Lactam-Derived Triazolium NHC (The Leeper and Knight Methodology)3.3 Monoterpenoid-Derived NHC Triazolium Salts3.4 Modifications of the Existing Triazole Ring4 Thiazole-Derived Salts4.1 Cyclization of a Thiazolium Ring4.2 Modifications of the Existing Thiazole Ring5 Summary and Outlook

PEPPSI-Pd-NHC catalyzed Suzuki-Miyaura cross-coupling reactions in aqueous media

A series of unsymmetrical 1,3-disubstituted benzimidazolium chlorides were synthesized as N-heterocyclic carbene (NHC) precursors. These compounds were used to synthesize of the PEPPSI-type palladium NHC complexes. The structures of all compounds were characterized by 1H NMR, 13C NMR, FT-IR spectroscopy and elemental analyses. The catalytic activity of the PEPPSI-type palladium–NHC complexes has been evaluated with respect to the Suzuki-Miyaura cross-coupling reactions of phenyl boronic acid with various aryl halides in aqueous media.

New 2-hydroxyethyl substituted N-Heterocyclic carbene precursors: Synthesis, characterization, crystal structure and inhibitory properties against carbonic anhydrase and xanthine oxidase

Here, the synthesis, spectral and the structural studies of 2-hydroxyethyl substituted N-heterocyclic carbene (NHC) precursors and the enzyme inhibition activities of the NHC precursors were investigated against the cytosolic carbonic anhydrase I and II isoenzymes (hCA I and hCA II), and xanthine oxidase (XO). The IC50 values of NHC precursors against these enzymes were determined by spectrophotometric method. The spectra of new NHC precursors have been obtained by using 1H NMR, 13C NMR, FTIR spectroscopy and elemental analysis techniques. The structure of a new NHC precursor was established by using single-crystal X-ray diffraction method. The results of inhibition experiment indicated that all 2-hydroxyethyl substituted NHC derivatives showed remarkable inhibition activity toward hCA I, hCA II and XO. The range of IC50 values for hCA I, hCA II and XO inhibition was determined as 0.1565–0.5127, 0.1524–0.5368 and 1.253–5.342 μM. Especially, trimethylbenzyl derivative of 2-hydroxyethyl substituted NHC precursor has demonstrated high inhibition effect on all studied enzymes due to steric bulk of this substituent.

Preparation of pyrido[1,2-c][1,2,4]triazole-based π-conjugated triazene as a Fe3+ ion fluorescent sensor

A highly efficient coupling reaction of N-heterocyclic carbene precursors with sulfonyl azides has been developed, affording a variety of pyrido[1,2-c][1,2,4]triazole-based π-conjugated triazenes. The present reaction proceeds under very mild conditions with good functional group tolerance. The resulting triazenes exhibit selective and sensitive fluorescent response toward Fe3+ ion.

Asymmetric Transfer Hydrogenation of α,β‐Unsaturated Carbonyl Compounds to Saturated Alcohols as Catalyzed by Iridium Complexes of Tricyclic Bioxazoline‐Fused Imidazole‐Derived N‐Heterocyclic Carbene Ligands

AbstractA series of chiral iridium(I) (1‐3)e complexes of bioxazoline fused imidazole derived N‐heterocyclic carbene (NHC) ligands successfully carried out asymmetric transfer hydrogenation of α, β‐unsaturated ketones in good to excellent yields (ca. 36‐91%) and in low enantioselectivites (ca. 5‐31% ee) at 1 mol % of the catalyst (1‐3)e loading in the presence of NaOH as a base in i‐PrOH at 75° C in 3 hours of reaction time. The iridium(I) (1‐3)e complexes were synthesized directly from the bioxazoline fused imidazole derived NHC precursors namely {(3R,7R)‐3,7‐di‐R‐2,3,7,8‐tetrahydrodioxazolo[3,2‐c:3′,2′‐e]imidazol‐4‐ium trifluoromethanesulfonate, R=s‐butyl (1 d), i‐butyl (2 d), i‐propyl (3 d)} by the treatment with {(COD)IrCl}2 (COD=1,5‐cyclooctadiene) in presence of t‐BuOK as a base at room temperature. The chiral bioxazoline fused imidazole NHC ligand precursors (1‐3)d were synthesized from the commercially available optically pure amino acids by a sequence of reactions without requiring any chiral resolution.

NHC stabilized Pd nanoclusters in the Mizoroki–Heck reaction within microemulsion: exploring the role of imidazolium salt in rate enhancement

Significant rate enhancement of the Mizoroki–Heck reaction by in situ generated palladium nanoclusters within the confined space of water-in-oil mixed microemulsion in the presence of novel imidazo[1,5-α]pyridinium chlorides as N-heterocyclic carbene (NHC) precursors is reported.

Simple NMR predictors of catalytic hydrogenation activity for [Rh(cod)Cl(NHC)] complexes featuring fluorinated NHC ligands.

A series of imidazolium salts precursors for N-heterocyclic carbenes (NHCs) featuring fluoroaryl substituents have been prepared along with their selenides and rhodium complexes. Tests of the catalytic activity of the [Rh(cod)Cl(NHC)] complexes in the transfer hydrogenation of acetophenone with iPrOH shows that the rhodium complexes bearing fluorinated NHCs are better than their non-fluorinated counterparts. The order of activity being 4-F-C6H4 < 2,4-F2-C6H3 < 2,4,5-F3-C6H2 < 2,6-F2-C6H3 < 2,4,6-F3-C6H2. This order of reactivity is consistent with a number of simple NMR measures of the electronic properties of these systems, including 1JCH of the NHC·HBF4 salts, δ(77Se) of the NHC selenides and 1JRh-C and δ(13Ccarbene) of the [Rh(cod)Cl(NHC)] complexes.

The catalytic effects of in situ prepared N-heterocyclic carbenes from benzimidazole salts in Suzuki–Miyaura cross-coupling reaction and uses in catalytic preparation of 1,3,5-triphenyl-1,3,5-triazinane-2,4,6-trione from phenyl isocyanate

Many benzimidazole salts bearing a 3-phenylpropyl substituent (1a-1h) were synthesized and their structures were identified by $^{1}$H NMR, $^{13}$C NMR, and IR spectroscopic methods and elemental analysis. These N-heterocyclic carbene (NHC) precursors were used as a part of a catalytic system including Pd(OAc)$_{2}$ and the base in the Suzuki--Miyaura cross-coupling reaction under microwave irradiation. They were also used as catalysts in the cyclotrimerization of phenyl isocyanate to yield 1,3,5-triphenyl-1,3,5-triazinane-2,4,6-trione. It has been observed that benzimidazole salts made a positive contribution to both catalytic reactions as a NHC precursor.

Acidity Scale of N-Heterocyclic Carbene Precursors: Can We Predict the Stability of NHC-CO2 Adducts?

The acidity scale (∼14 p K units) of more than 90 triazolium, imidazolium, and imidazolinium based NHC precursors in DMSO was established systematically by a well-developed computational model. The substituent effects on the acidities of these NHC precursors were analyzed through acidity comparison and Hammett correlation. The binding energy (Δ G1) of the reaction between NHC and CO2 was also calculated and linearly correlates with the basicity of the corresponding NHC, which implies that the stability of the NHC-CO2 adduct is essentially dictated by the basicity of NHC.

Cooperative Multifunctional Organocatalysts for Ambient Conversion of Carbon Dioxide into Cyclic Carbonates

A series of pincer-type compounds possessing an N-heterocyclic carbene precursor and a carboxyl group as proton transfer agent were synthesized and used as organocatalysts for the cycloaddition of epoxides with CO2. In this context, we have demonstrated the high activity of these one-component organocatalysts in the CO2 transformation to cyclic carbonates under ambient conditions (room temperature, 1 bar of CO2). The catalytic potential of these multifunctional organocatalysts on challenging internal epoxides is particularly deserving of mention because organocatalysts that are able to mediate the cycloaddition reaction of internal epoxides with CO2 under mild conditions remain scarce. The intramolecular synergistic activation mechanism was elucidated by control experiments and DFT calculations.

NHC in Imidazolium Acetate Ionic Liquids: Actual or Potential Presence?

Ionic liquids (ILs) are considered in the majority of cases green solvents, due to their virtually null vapor pressure and to the easiness in recycling them. In particular, imidazolium ILs are widely used in many fields of Chemistry, as solvents or precursors of N-heterocyclic carbenes (NHCs). The latter are easily obtained by deprotonation of the C2-H, usually using strong bases or cathodic reduction. Nevertheless, it is known that weaker bases (e.g., triethylamine) are able to promote C2-H/D exchange. From this perspective, the possibility of deprotonating C2-H group of an imidazolium cation by means of a basic counter-ion was seriously considered and led to the synthesis of imidazolium ILs spontaneously containing NHCs. The most famous of this class of ILs are N,N'-disubstituted imidazolium acetates. Due to the particular reactivity of this kind of ILs, they were appointed as “organocatalytic ionic liquids” or “proto-carbenes.” Many papers report the use of these imidazolium acetates in organocatalytic reactions (i. e., catalyzed by NHC) or in stoichiometric NHC reactions (e.g., with elemental sulfur to yield the corresponding imidazole-2-thiones). Nevertheless, the actual presence of NHC in N,N'-disubstituted imidazolium acetate is still controversial. Moreover, theoretical studies seem to rule out the presence of NHC in such a polar environment as an IL. Aim of this Mini Review is to give the reader an up-to-date overview on the actual or potential presence of NHC in such an “organocatalytic ionic liquid,” both from the experimental and theoretical point of view, without the intent to be exhaustive on N,N'-disubstituted imidazolium acetate applications.

Efficient N‐Heterocyclic Carbene/Ruthenium Catalytic Systems for the Alcohol Amidation with Amines: Involvement of Poly‐Carbene Complexes?

AbstractThe atom‐economic direct amidation of alcohols with amines has been recently highlighted as an attractive and promising transformation. Among the versatile reported catalytic systems, in situ generated N‐heterocyclic carbene (NHC)/ruthenium (Ru) catalytic systems have demonstrated their advantages such as easy operation and use of commercial Ru compounds. However, the existing catalyst loadings are relatively high, and additional insights for the in situ catalyst generation are still not well‐documented. In this work, a variety of benzimidazole‐based NHC precursors were initially synthesized. Through the screening of various NHC precursors and other reaction conditions, active in situ catalytic systems were discovered for the efficient amide synthesis. Notably, the catalyst loading is as low as 0.5 mol %. Furthermore, additional experiments were performed to validate the rationale for the superiority of the current catalytic systems over our previous system. It was observed that the ligand structure is one of the reasons for the higher activity. In addition, the higher ratio of the NHC precursor/[Ru] is another important factor for the improvement. Further HR‐MS analysis identified the formation of two mono‐NHC‐Ru species as major species and two Ru species bearing multiple NHC ligands as minor species. Hopefully, the efficient and readily‐accessible catalytic systems reported herein could demonstrate great potential for further practical applications.

Meta-Cyanobenzyl substituted benzimidazolium salts: Synthesis, characterization, crystal structure and carbonic anhydrase, α-glycosidase, butyrylcholinesterase, and acetylcholinesterase inhibitory properties.

meta-Cyanobenzyl-substituted N-heterocyclic carbene (NHC) precursors were synthesized by the reaction of a series of N-(alkyl)benzimidazolium with 3-bromomethyl-benzonitrile. These benzimidazolium salts were characterized by using 1 H NMR, 13 C NMR, FTIR spectroscopy, and elemental analysis techniques. The molecular and crystal structures of 2f and 2g complexes were obtained by using the single-crystal X-ray diffraction method. The derivatives of these novel NHC precursors were effective inhibitors of α-glycosidase (AG), the cytosolic carbonic anhydrase I and II isoforms (hCA I and II), butyrylcholinesterase (BChE), and acetylcholinesterase (AChE) with Ki values in the range of 1.01-2.12 nM for AG, 189.56-402.44 nM for hCA I, 112.50-277.37 nM for hCA II, 95.45-352.58 nM for AChE, and 132.91-571.18 nM for BChE. In the last years, inhibition of the CA enzyme has been considered as a promising factor for pharmacologic intervention in a diversity of disturbances such as obesity, glaucoma, cancer, and epilepsy.

N-Heterocyclic Carbene Promoted Decarboxylation of Lignin-Derived Aromatic Acids

Decarboxylation is an important reaction in organic synthesis and drug discovery, which is typically catalyzed by strong bases or metal-based catalysts bearing low yield and selectivity. For the first time, we demonstrated a new strategy of decarboxylation of hydroxyl cinnamic acids such as p-coumaric acid, ferulic acid, sinapinic acid, and caffeic acid in the presence of N-heterocyclic carbene (NHC) precursors (i.e., 1-ethyl-3-methyl imidazolium acetate [C2C1Im][OAc]), achieving high yields and selectivities up to 100% under relatively mild conditions. [C2C1Im][OAc] showed excellent recyclability as organocatalysis during three times of recycling using biphasic reaction system. A mechanistic study revealed that the decarboxylation was catalyzed by NHCs that were in-situ generated by self-deprotonation of [C2C1Im][OAc]. Our demonstrated route is especially appealing for the production of lignin-derived renewable aromatics.