Carbene Precursors Research Articles

Photochemical Cyclopropenation of Alkynes with Diazirines as Carbene Precursors in Continuous Flow.

An efficient synthesis of 3-trifluoromethyl-3-aryl-cyclopropenes via the cyclopropenation reaction of alkynes with photolytically generated carbenes from diazirine compounds is described. This reaction is performed in continuous flow using readily available LEDs under mild reaction conditions. This new and efficient method describes the synthesis of 25 examples of 3-trifluoromethyl-3-aryl-cyclopropenes with yields up to 97%, achieved in continuous flow with a 5 min residence time. Control experiments highlighted that diazirines are more efficient than diazo compounds for this transformation.

Novel Ag(I)-NHC complex: synthesis, in vitro cytotoxic activity, molecular docking, and quantum chemical studies.

The importance of organometallic complexes in cancer biology has attracted attention in recent years. In this paper, we look for the in vitro cytotoxic capability of novel benzimidazole-based N-heterocyclic carbene (NHC) precursor (1) and its Ag(I)-NHC complex (2). For this purpose, these novel Ag(I)-NHC complex (2) was characterized by spectroscopic techniques (1H, 13C{1H} nuclear magnetic resonance (NMR), and Fourier-transform infrared spectroscopy (FT-IR)). Then, in vitro cytotoxic activities of NHC precursor (1) and Ag(I)-NHC complex (2) were investigated against MCF-7, MDA-MB-231 human breast, DU-145 prostate cancer cells, and L-929 healthy cells using MTT assay for 24, 48, and 72h incubation times. Ag(I)-NHC complex (2) showed promising in vitro cytotoxic activity against all cell lines for three incubation times, with IC50 values lower than 5µM. It was also determined that (NHC) precursor (1) were lower in vitro cytotoxic activity than Ag(I)-NHC complex (2) against all cell lines. Selectivity indexes (SIs) of Ag(I)-NHC complex (2) against cancer cells were found higher than 2 for 24 and 48h incubation time. Besides, the electronic structure and spectroscopic data of the newly synthesized precursor and its Ag-complex have been supported by density functional theory (DFT) calculations and molecular docking analysis. After, the anticancer activity of these compounds has been discussed considering the results of the frontier molecular orbital analysis. We hope that the obtained results from the experiments and computational tools will bring a new perspective to cancer research in terms of supported by quantum chemical calculations.

Synthesis of carbonates from CO2 and epoxides catalyzed by the system of N‐heterocyclic carbene, hydrogen bond donor, CrCl2, and tetrabutylammonium bromide

AbstractA three‐component catalytic system including pyridine‐bridged benzimidazolium salts, CrCl2, and tetrabutylammonium bromide (TBAB) was developed. Based on the control experiments and spectroscopic measurements, the role of the three components in the catalytic process was clarified, in which benzimidazolium salts were used as N‐heterocyclic carbene precursor, a new Cr complex generating from the coordination of CrCl2 with pyridine nitrogen and pyrazole nitrogen bearing benzimidazolium salts was employed as hydrogen bond donor, TBAB was used as nucleophilic reagent, respectively. Under mild conditions (50°C and 1 bar CO2), the terminal epoxides displayed high reactivity in the three‐component catalytic system. The catalytic system showed also high catalytic activity for the internal epoxides by increasing the temperature and CO2 pressure and/or prolonging the reaction time.

N‐Heterocyclic Carbenes with a Nido‐C2B9 Carborane Backbone

Main observation and conclusionThe steric and electronic properties of N‐heterocyclic carbenes (NHCs) can be modified by the exocyclic substituents at the nitrogen atoms, by 1—3 atoms’ replacements of the five‐membered imidazolium skeleton and by the changes of the backbones. Herein, we report the usage of nido‐C2B9 carborane anions as the backbones of NHCs. Stirring the mixture of secondary amino o‐carboranes (1b—1e), triethyl orthoformate and HBF4∙Et2O results in the unexpected cage‐opening of o‐carboranes to afford the nido‐C2B9 carborane anions supported N‐heterocyclic carbene precursors (4b—4e). Deprotonation of 4b with sodium hexamethyldisilazide at −78 oC affords the N‐heterocyclic carbene ligand, which was used to form an Au(I) NHC complex (5). DFT calculations revealed a high‐lying lone pair orbitals of the carbene ligands, predicting their strong σ‐donating abilities.

Chemo- and Enantioselective Insertion of Furyl Carbene into the N-H Bond of 2-Pyridones.

Asymmetric carbene insertion reactions represent one of the most important protocols to construct carbon-heteroatom bonds. The use of donor-acceptor diazo compounds bearing an ester group is however a prerequisite for achieving high enantioselectivity. Herein, we report a chemo- and enantioselective formal N-H insertion of 2-pyridones that has been accomplished for the first time with enynones as the donor-donor carbene precursors. DFT calculations indicate an unprecedented enantioselective 1,4-proton transfer from O to C. The rhodium catalyst provides a chiral pocket in which the steric repulsion and the π-π interaction of the propeller ligand play a critical role in determining the selectivities.

Chemo‐ and Enantioselective Insertion of Furyl Carbene into the N−H Bond of 2‐Pyridones

AbstractAsymmetric carbene insertion reactions represent one of the most important protocols to construct carbon–heteroatom bonds. The use of donor–acceptor diazo compounds bearing an ester group is however a prerequisite for achieving high enantioselectivity. Herein, we report a chemo‐ and enantioselective formal N−H insertion of 2‐pyridones that has been accomplished for the first time with enynones as the donor–donor carbene precursors. DFT calculations indicate an unprecedented enantioselective 1,4‐proton transfer from O to C. The rhodium catalyst provides a chiral pocket in which the steric repulsion and the π–π interaction of the propeller ligand play a critical role in determining the selectivities.

Copper-Catalyzed Ring-Opening/Borylation of Cyclopropenes

Copper-Catalyzed Ring-Opening/Borylation of Cyclopropenes

Rh(III)-Catalyzed Chemodivergent Annulations between Indoles and Iodonium Carbenes: A Rapid Access to Tricyclic and Tetracyclic N-Heterocylces.

Herein, we report an acid-controlled highly tunable selectivity of Rh(III)-catalyzed [4 + 2] and [3 + 3] annulations of N-carboxamide indoles with iodonium ylides lead to form synthetically important tricyclic and tetracyclic N-heterocycles. Here, iodonium ylide serves as a carbene precursor. The protocol proceeds under operationally simple conditions and provides novel tricyclic and tetracyclic scaffolds such as 3,4-dihydroindolo[1,2-c]quinazoline-1,6(2H,5H)-dione and 1H-[1,3]oxazino[3,4-a]indol-1-one derivatives with a broad range of functional group tolerance and moderate to excellent yields. Furthermore, the protocol synthetic utility was extended for various chemical transformations and was easily scaled up to a large-scale level.

Multicomponent Synthesis of Unsymmetrical 4,5-Disubstituted Imidazolium Salts as N-Heterocyclic Carbene Precursors: Applications in Palladium-Catalyzed Cross-Coupling Reactions.

Various novel (a)chiral 4,5-disubstituted 1-aryl-3-alkyl-imidazolium salts were synthesized via the multicomponent reaction of diketone derivatives, sterically congested arylamines, and alkylamines. Moreover, two novel unsymmetrical bulky cycloalkyl-based NHC-Pd complexes proved highly active as catalysts for Suzuki-Miyaura and Negishi cross-coupling reactions.

Copper-Catalyzed 1,1-Boroalkylation of Terminal Alkynes: Access to Alkenylboronates via a Three-Component Reaction.

A copper-catalyzed three-component reaction of terminal alkynes, diazo compounds, and B2pin2 to prepare trisubstituted alkenylboronates has been developed. This difunctionalization of alkynes selectively occurs at the terminal carbon atom and proceeds via a tandem sequence. The copper catalyst plays dual roles in the whole process, namely, the initial copper-catalyzed cross-coupling and the following copper-catalyzed stereoselective boration reaction. Typically, different carbene precursors selectively lead to Z- and E-alkenes.

New silver N[sbnd]heterocyclic carbenes complexes: Synthesis, molecular docking study and biological activities evaluation as cholinesterase inhibitors and antimicrobials

We focused our study for the conception and the synthesis of a new series of Silver (I) N-heterocyclic carbene complexes which were obtained from the corresponding N-heterocyclic carbene (NHC) precursors and their unsymmetrical benzimidazolium salts. These new Ag-NHC complexes were screened for their antibacterial, antifungal, and anti-cholinesterase activities. The biological activities of synthesized products were compared with standard drugs. N-heterocyclic carbenes 2a-f and complexes 3a-f exhibited moderate antibacterial and antifungal activities. The results proved that the compounds indicated moderate to excellent activity against both AChE and BuChE. It was found that most of the complexes displayed good AChE and BuChE inhibitory activities. In particular, compounds 3c and 3e were the most potent inhibitors in the series with IC50 values of 8.56 ± 1.17 μM and 5.05 ± 0.30 μM against AChE and BChE, respectively. Docking studies revealed that compounds 3c and 3e bind manly to the catalytic anionic site (CAS) of the AChE, and BChE respectively.

Gold(I) N-heterocyclic carbene precursors for focused electron beam-induced deposition.

Seven gold(I) N-heterocyclic carbene (NHC) complexes were synthesized, characterized, and identified as suitable precursors for focused electron beam-induced deposition (FEBID). Several variations on the core Au(NHC)X moiety were introduced, that is, variations of the NHC ring (imidazole or triazole), of the alkyl N-substituents (Me, Et, or iPr), and of the ancillary ligand X (Cl, Br, I, or CF3). The seven complexes were tested as FEBID precursors in an on-substrate custom setup. The effect of the substitutions on deposit composition and growth rate indicates that the most suitable organic ligand for the gold precursor is triazole-based, with the best deposit composition of 15 atom % gold, while the most suitable anionic ligand is the trifluoromethyl group, leading to a growth rate of 1 × 10−2 nm3/e−.

A Theoretical Study of 2-hydroxyethyl Substituted NHC Precursors Containing ortho–, meta– and para– methylbenzyl: Global Reactivity Descriptors and Prediction of Biological Activities

In this work, three 2-hydroxyethyl substituted N-heterocyclic carbene (NHC) precursors containing ortho–, meta– and para– methylbenzyl fragments are characterized theoretically. Theoretical calculations are performed to gain insight into these three molecules’ electronic properties (HOMO-LUMO energy, MEP and global reactivity descriptors) and biological behaviors. Also, atomic charges are calculated and molecular orbital analysis is performed. In order to investigate the stability of the molecules resulting from hyperconjugative interactions and charge delocalization, natural bond orbital (NBO) analysis is used. A predictive study for the biological activities is carried out using PASS (prediction of activity spectra for biologically active structures) online software. Biological activity predictions showed the substance P antagonist, analgesic and antiinflammatory activities of the compounds.

Marine furanocembranoids-inspired macrocycles enabled by Pd-catalyzed unactivated C(sp3)-H olefination mediated by donor/donor carbenes

Biomimetic modularization and function-oriented synthesis of structurally diversified natural product-like macrocycles in a step-economical fashion is highly desirable. Inspired by marine furanocembranoids, herein, we synthesize diverse alkenes substituted furan-embedded macrolactams via a modular biomimetic assembly strategy. The success of this assembly is the development of crucial Pd-catalyzed carbene coupling between ene-yne-ketones as donor/donor carbene precursors and unactivated Csp3‒H bonds which represents a great challenge in organic synthesis. Notably, this method not only obviates the use of unstable, explosive, and toxic diazo compounds, but also can be amenable to allenyl ketones carbene precursors. DFT calculations demonstrate that a formal 1,4-Pd shift could be involved in the mechanism. Moreover, the collected furanocembranoids-like macrolactams show significant anti-inflammatory activities against TNF-α, IL-6, and IL-1β and the cytotoxicity is comparable to Dexamethasone.

Synthesis of 2-aminothiazoles via rhodium-catalyzed carbenoid insertion/annulation of sulfoxonium ylides with thioureas

Sulfoxonium ylides as carbene precursors couple smoothly with thioureas in the presence of 5 mol% of rhodium(II) acetate dimmer via carbenoid insertion to afford the corresponding 2-aminothiazoles with high chemoselectivity, providing a facile and efficient approach to access a variety of 2-aminothiazole derivatives with good functional groups tolerance.

Synthesis of [PdBr2(benzimidazole-2-ylidene)(pyridine)] complexes and their catalytic activity in the direct C[sbnd]H bond activation of 2-substituted heterocycles

A series of unsymmetrical 1,3-disubstituted benzimidazolium chlorides, 2a-f, having two nitrogen atoms substituted by various alkyl groups were synthesized as N-heterocyclic carbene (NHC) precursors in high yields. The benzimidazolium salts are readily converted into the corresponding PEPPSI-type palladium–NHC complexes 3a-f (PEPPSI = pyridine-enhanced precatalyst preparation, stabilization and initiation). The structures of all the compounds have been characterized by 1H NMR, 13C NMR and IR spectroscopy, as well as the X-ray diffraction technique (3a, 3d and 3e), which support the proposed structures. Next, the palladium-NHC-PEPPSI complexes were used as catalysts in the direct C(5)-arylation of 2-acetyl furan and 2-acetylthiophene with various aryl bromides. These complexes exhibited moderate to high catalytic activities and gave CH activation selectively at the C(5)-position of 2-acetylfuran and 2-acetylthiophene.

Larger scale Stahl oxidation with instant Cu removal in convenient synthesis of chiral bidentate N–heterocyclic carbene precursor

Commercially available N-Boc protected l-proline can be efficiently converted into a chiral, bidentate, aminoalkyl N-heterocyclic carbene ligand precursor in high yield (50% total after 4 steps) without column chromatography purification at any moment. The developed synthetic path includes: (1) redox step leading to an aldehyde, (2) imine condensation and in situ reduction to 1,2-diamine; (3) heterocyclization; (3) removal of the protecting group. Instant separation of Cu traces after the key Stahl oxidation at gram-scale was facilitated by the use of bis(isocyanide) scavenger, SnatchCat, forming insoluble, easy to remove RNC:→[Cu] complexes that allowed usto obtain crude intermediate suitably pure for next steps without tedious purification.

Effects of new NHC derivatives as ligands in the Suzuki–Miyaura reaction

A series of NHC-derivative ligands was synthesized from bisbenzimidazole salts as the precursor of N-heterocyclic carbene with chalcogens, carbon disulfide, and phenyl isothiocyanate reagents. These new ligands were used in the Suzuki–Miyaura cross-coupling reaction in the presence of palladium(II) acetate. Particularly, it was observed a remarkable ligand activity with tellurourea (5).

Co(III), Rh(III) & Ir(III)-Catalyzed Direct C-H Alkylation/Alkenylation/Arylation with Carbene Precursors.

Metal carbenes play a pivotal role in transition-metal-catalyzed synthetic transfer reactions. The metal carbene is generated either from a diazo compound through facile extrusion of N2 with a metal catalyst or in situ generated from other sources like triazoles, pyriodotriazoles, sulfoxonium ylides and iodonium-ylide. On the other hand, Co(III), Rh(III) & Ir(III)-catalyzed C-H functionalizations have been well established as a key synthetic step to enable the construction of various synthetic transformations. Interestingly, in recent years, merging of these two concepts C-H activation and carbene migratory insertion gained much attention, in particular group 9 metal-catalyzed arene C-H functionalizations with carbene precursors via carbene migratory insertion. In this review, we summarize recent advances in Co(III), Rh(III) & Ir(III)-catalyzed direct C-H alkylation/alkenylation/arylation with carbene precursors and also discuss key synthetic intermediates within the catalytic cycles.

Phosphorescent Cyclometalated Platinum(II) Imidazolinylidene Complexes

AbstractWe present the synthesis and characterization of six novel bidentate cyclometalated platinum(ii) complexes derived from saturated N‐heterocyclic carbene precursors, namely 1‐aryl‐3‐methyl‐1H‐4,5‐dihydroimidazolium salts. The title compounds were then synthesized by a multi‐step reaction, which includes an in situ generation of the silver carbene complex, followed by transmetalation to platinum and subsequent introduction of the β‐diketonate ligand. Structural characterization by NMR experiments and solid‐state structures prove the cyclometalation and the saturated backbone of the NHC motif. Photophysical and electrochemical properties of the platinum(ii) complexes were examined and studied in detail by DFT calculations. The title compounds are strongly emissive at room temperature in the sky‐blue region of the visible spectrum and show quantum yields of up to 71 % in a PMMA matrix.