Helical Chiral N-Heterocyclic Carbene Ligands in Enantioselective Gold Catalysis.

The first chiral helicene-NHC gold(I) complexes efficient in enantioselective catalysis were prepared. The L-shaped chiral ligand is composed of an imidazo[1,5-a]pyridin-3-ylidene (IPy) scaffold laterally substituted by a configurationally stable [5]-helicenoid unit. The chiral information was introduced in a key post-functionalization step of a NHC-gold(I) complex bearing a symmetrical anionic fluoreno[5]helicene substituent, leading to a racemic mixture of complexes featuring three correlated elements of chirality, namely central, axial and helical chirality. After HPLC enantiomeric resolution, X-ray crystallography and theoretical calculations enabled structural and stereochemical characterization of these configurationally stable NHC-gold(I) complexes. The high potential in asymmetric catalysis is demonstrated in the benchmark cycloisomerization of N-tethered 1,6-enynes with up to 95 : 5 er.

Redox-Switchable Behavior of Transition-Metal Complexes Supported by Amino-Decorated N-Heterocyclic Carbenes.

The coordination chemistry of the N-heterocyclic carbene ligand IMes(NMe2)2, derived from the well-known IMes ligand by substitution of the carbenic heterocycle with two dimethylamino groups, was investigated with d6 [Mn(I), Fe(II)], d8 [Rh(I)], and d10 [Cu(I)] transition-metal centers. The redox behavior of the resulting organometallic complexes was studied through a combined experimental/theoretical study, involving electrochemistry, EPR spectroscopy, and DFT calculations. While the complexes [CuCl(IMes(NMe2)2)], [RhCl(COD)(IMes(NMe2)2)], and [FeCp(CO)2 (IMes(NMe2)2)](BF4) exhibit two oxidation waves, the first oxidation wave is fully reversible but only for the first complex the second oxidation wave is reversible. The mono-oxidation event for these complexes occurs on the NHC ligand, with a spin density mainly located on the diaminoethylene NHC-backbone, and has a dramatic effect on the donating properties of the NHC ligand. Conversely, as the Mn(I) center in the complex [MnCp(CO)2 ((IMes(NMe2)2)] is easily oxidizable, the latter complex is first oxidized on the metal center to form the corresponding cationic Mn(II) complex, and the NHC ligand is oxidized in a second reversible oxidation wave.

Synthesis and Properties of Partially Saturated Fluorenyl-Derived [n]Helicenes Featuring an Overcrowded Alkene.

The straightforward, multigram-scale synthesis of the partially saturated H6 -fluoreno[n]helicenes (n=5 or 7) featuring a central, overcrowded alkene is described. The key cyclization step was based on an intramolecular McMurry reaction from the corresponding 1,5-diketones. Chiral stationary phase HPLC analysis and isomer separation indicate that each helicenic compound is constituted of three diastereoisomers at room temperature, i. e. the configurationally stable (R,R,P)/(S,S,M) pair of enantiomers and an apparently achiral compound resulting from the rapid interconversion between the (R,S,P) and (S,R,M) enantiomers. The partially saturated H6 -fluoreno[n]helicenes are oxidatively aromatized to give an efficient access to the corresponding fluoreno[n]helicenes. The chiroptical properties (vibrational and electronic circular dichroism) of the chiral, enantiopure compounds have been measured and analyzed by quantum-chemical calculations, confirming their helicoidal nature.

Experimental and Theoretical Insights into the Electronic Properties of Anionic N-Heterocyclic Dicarbenes through the Rational Synthesis of Their Transition Metal Complexes.

The lithiation of the NHC ligand backbone in Cp(CO)2Mn(IMes) followed by transmetalation on the C4 carbenic position with Cp(CO)2FeI led to the heterobimetallic complex Cp(CO)2Mn(µ-dIMes)Fe(CO)2Cp bearing the anionic ditopic imidazol-2,4-diylidene dIMes ligand. Subsequent treatment of the later with TfOH induced a selective decoordination of the [Cp(CO)2Mn] fragment to form the cationic abnormal NHC complex [Cp(CO)2Fe(aIMes)](OTf), which was further derivatized to the bis(iron) dIMes complex [Cp(CO)2Fe(µ-dIMes)Fe(CO)2Cp](OTf) by reaction with tAmOK and Cp(CO)2FeI. The effect of the metalation at the C4 or C2 position on the imidazole ring on the electronic donation properties of the associated C2 and C4 carbenic centers in the dIMes ligand was quantified through systematic experimental and theoretical studies of IMes, aIMes, and dIMes complexes. The evaluation of the catalytic activity of the series of cationic Fe(II) complexes based on IMes, aIMes, and dIMes ligands in a benchmark ketone hydrosilylation showed the superiority of the bimetallic derivative.

Phosphorescent Cationic Heterodinuclear IrIII /MI Complexes (M=CuI , AuI ) with a Hybrid Janus-Type N-Heterocyclic Carbene Bridge.

A novel class of phosphorescent cationic heterobimetallic IrIII /MI complexes, where MI =CuI (4) and AuI (5), is reported. The two metal centers are connected by the hybrid bridging 1,3-dimesityl-5-acetylimidazol-2-ylidene-4-olate (IMesAcac) ligand that combines both a chelating acetylacetonato-like and a monodentate N-heterocyclic carbene site coordinated onto an IrIII and a MI center, respectively. Complexes 4 and 5 have been prepared straightforwardly by a stepwise site-selective metalation with the zwitterionic [(IPr)MI (IMesAcac)] metalloproligand (IPr=1,3-(2,6-diisopropylphenyl)-2H-imidazol-2-ylidene) and they have been fully characterized by spectroscopic, electrochemical, and computational investigation. Complexes 4 and 5 display intense red emission arising from a low-energy excited state that is located onto the "Ir(C^N)" moiety featuring an admixed triplet ligand-centered/metal-to-ligand charge transfer (3 IL/1 MLCT) character. Comparison with the benchmark mononuclear complexes reveals negligible electronic coupling between the two distal metal centers at the electronic ground state. The bimetallic systems display enhanced photophysical properties in comparison with the parental congeners. Noteworthy, similar non-radiative rate constants have been determined along with a two-fold increase of radiative rate, yielding brightly red-emitting cyclometalating IrIII complexes. This finding is ascribed to the increased MLCT character of the emitting state in complexes 4 and 5 due to the smaller energy gap between the 3 IL and 1 MLCT manifolds, which mix via spin-orbit coupling.

N-Heterocyclic Carbenes as Key Intermediates in the Synthesis of Fused, Mesoionic, Tricyclic Heterocycles.

Coupling between 5-bromoimidazo[1,5-a]pyridinium salts and malonate or arylacetate esters leads to a facile and straightforward access to the new mesoionic, fused, tricyclic system of imidazo[2,1,5-cd]indolizinium-3-olate. Mechanistic studies show that the reaction pathway consists of nucleophilic aromatic substitution on the cationic, bicyclic heterocycle by an enolate-type moiety and in the nucleophilic attack of a transient free N-heterocyclic carbene (NHC) species on the ester group; the relative order of these two steps depends on the nature of the starting ester. This work highlights the valuable implementation of free NHC species as key intermediates in synthetic chemistry, beyond their classical use as stabilizing ligands or organocatalysts.

An Original L-shape, Tunable N-Heterocyclic Carbene Platform for Efficient Gold(I) Catalysis.

The synthesis and characterization of original NHC ligands based on an imidazo[1,5-a]pyridin-3-ylidene (IPy) scaffold functionalized with a flanking barbituric heterocycle is described as well as their use as tunable ligands for efficient gold-catalyzed C-N, C-O, and C-C bond formations. High activity, regio-, chemo-, and stereoselectivities are obtained for hydroelementation and domino processes, underlining the excellent performance (TONs and TOFs) of these IPy-based ligands in gold catalysis. The gold-catalyzed domino reactions of 1,6-enynes give rise to functionalized heterocycles in excellent isolated yields under mild conditions. The efficiency of the NHC gold 5Me complex is remarkable and mostly arises from a combination of steric protection and stabilization of the cationic AuI active species by ligand 1Me .

Oxidative Coupling of Anionic Abnormal N-Heterocyclic Carbenes: Efficient Access to Janus-Type 4,4'-Bis(2H-imidazol-2-ylidene)s.

The oxidative coupling of anionic imidazol-4-ylidenes protected at the C2 position with [MnCp(CO)2 ] or BH3 led to the corresponding 4,4'-bis(2H-imidazol-2-ylidene) complexes or adducts, in which the two carbene moieties are connected through a single C-C bond. Subsequent acidic treatment of the later species led to the corresponding 4,4'-bis(imidazolium) salts in good yields. The overall procedure offers practical access to a novel class of Janus-type bis(NHC)s. Strikingly, the coplanarity of the two NHC rings within the mesityl derivative 4,4'-bis(IMes), favored by steric hindrance along with stabilizing intramolecular C-H⋅⋅⋅π aryl interactions, allows the alignment of the π-systems and, as a direct consequence, significant electron communication through the bis(carbene) scaffold.

Buttressing Effect as a Key Design Principle towards Highly Efficient Palladium/N-Heterocyclic Carbene Buchwald-Hartwig Amination Catalysts.

The backbone substitution of the standard 1,3-bis(2,6-diisopropylphenyl)-2H-imidazol-2-ylidene (IPr) ligand by dimethylamino groups was previously shown to induce a dramatic improvement in the catalytic efficiency of the corresponding Pd-PEPPSI (pyridine-enhanced pre-catalyst preparation, stabilization, and initiation) pre-catalysts in N-arylation reactions. Herein, a thorough structure/activity study towards rationalizing this beneficial effect has been described. In addition to the previously reported IPrNMe2 and IPr(NMe2)2 ligands, the new IPrNiPr2 and IPr(NMe2,Cl) ligands, which bear one bulkier diisopropylamino group and a combination of dimethylamino and chloro substituents, respectively, have been designed and analyzed in the study. The influence of the backbone substitution was found to be steric in origin and is related to the well-known buttressing effect encountered in arene chemistry. The usefulness and versatility of this approach was demonstrated through the development of a highly efficient catalytic system for the challenging arylation of bulky α,α,α-trisubstituted primary amines. The optimized system based on the [PdCl(η3 -cinnamyl)(IPr(NMe2)2 )] or [PdCl(η3 -cinnamyl)(IPrNiPr2 )] pre-catalysts operates under unprecedented mild conditions (catalyst loadings: 0.5-2 mol %, reaction temperatures: 40-60 °C) with a wide substrate scope.

Ruthenium Catalysts Supported by Amino-Substituted N-Heterocyclic Carbene Ligands for Olefin Metathesis of Challenging Substrates.

N-Heterocyclic carbene (NHC) ligands IMesNMe2 and IMes(NMe2)2 derived from the well-known IMes ligand by substituting the carbenic heterocycle with one and two dimethylamino groups, respectively, were employed for the synthesis of second-generation Grubbs- and Grubbs-Hoveyda-type ruthenium metathesis precatalysts. Whereas the stability of the complexes was found to depend on the degree of dimethylamino-substitution and on the type of complex, the backbone-substitution was shown to have a positive impact on their catalytic activity in ring-closing metathesis, with a more pronounced effect in the second-generation Grubbs-type series. The new complexes were successfully implemented in a number of challenging olefin metathesis reactions leading to the formation of tetra-substituted C=C double bonds and/or functionalized compounds.

Buchwald-Hartwig Amination of (Hetero)Aryl Tosylates Using a Well-Defined N-Heterocyclic Carbene/Palladium(II) Precatalyst.

The cross-coupling of aryl tosylates with amines and anilines was achieved by using for the first time a Pd-NHC system based on the popular Pd-PEPPSI precatalyst platform in which the anchoring imidazol-2-ylidene ligand IPr((NMe2)2) incorporates two dimethylamino groups as backbone substituents enhancing both the electronic and steric properties of the carbene. The system optimization and its application scope are disclosed.

Skeleton decoration of NHCs by amino groups and its sequential booster effect on the palladium-catalyzed Buchwald-Hartwig amination.

A challenging synthetic modification of PEPPSI-type palladium pre-catalysts consisting of a stepwise incorporation of one and two amino groups onto the NHC skeleton was seen to exert a sequential enhancement of the electronic donor properties. This appears to be positively correlated with the catalytic performances of the corresponding complexes in the Buchwald-Hartwig amination. This is illustrated, for example, by the quantitative amination of 4-chloroanisole by morpholine within 2 h at 25 °C with a 2 mol% catalyst/substrate ratio or by a significant reduction of catalytic loading (down to 0.005 mol%) for the coupling of aryl chlorides with anilines (max TON: 19,600).

The ambivalent chemistry of a free anionic N-heterocyclic carbene decorated with a malonate backbone: the plus of a negative charge.

The anionic heterocycle "[maloNHC](-)", ([1](-)), is the archetype of a growing family of N-heterocyclic carbenes incorporating an anionic backbone; here, a malonate group. A comprehensive experimental exploration of its chemistry as a free entity (in the form of its lithium salt [1]·Li) is presented, and rationalized using DFT calculations at the B3LYP/6-31+G** level of theory. For the sake of comparison, similar computations were performed on other representative carbene types. Reactions of [1]·Li with a broad series of electrophilic reagents were used to ascertain its intrinsic nature as a nucleophilic carbene. Unexpectedly, [1]·Li was also seen to react with the nucleophilic tert-butylisocyanide, to give an anionic ketenimine, which could be subsequently derivatized, either into an imine by protonation of the ketenimine moiety, or into a neutral ketenimine by alkylation of the intracyclic malonate moiety. Further experiments on the electrophilic behavior of [1]·Li revealed its unexpected reactivity toward p-chlorobenzaldehyde, resulting in a formal C-H activation and the first structurally characterized keto-tautomer of the Breslow intermediate. Finally, [1]·Li remarkably activates polar E-H bonds, including N-H bonds from ammonia and amines, Si-H bonds, and B-H bonds. Importantly, DFT calculations indicate the importance of counterion effects. In particular, the key to the observed reactivity appears to be a modulation of energy levels associated with a dynamic variability of the Li-O distance between the remote malonate group and the counterion.

Atypical lipomatous tumor of the oropharynx: A case report.

Atypical lipomatous tumor or well-differentiated liposarcoma is a rare condition in the laryngopharynx. We present a case of a 63 year-old male with progressive dysphagia who later manifested with a mass that regurgitates outside the oral cavity. Surgical removal was done via a transoral approach, followed by adjuvant radiotherapy.

Systematic review of intraoperative radiation therapy for head and neck cancer.

Multidisciplinary treatments with surgery, radiation therapy, and chemotherapy are the cornerstones in the management of locally advanced head and neck malignancies. In most cases, radiation is delivered via external beam radiation therapy (EBRT). Intraoperative radiation therapy (IORT), on the other hand, is the delivery of precise doses of radiation to selected target volumes within the exposed surgical field while at the operating room. Most studies on its use on head and neck cancers are limited to single-institutional retrospective case series. We performed a systematic review to consolidate the existing literature on IORT for head and neck malignancies. Fifty-two studies representing a mixed population of 2,389 patients were included in this review. IORT via electrons (intraoperative electron radiation therapy), brachytherapy (intraoperative high dose-rate brachytherapy) or photons was administered in numerous settings, but most commonly as part of a reirradiation regimen following salvage surgery for recurrent tumours. Often, additional EBRT was also planned postoperatively. This review illustrates that IORT is a promising treatment modality in head and neck cancer. Multiple single-institutional studies spanning several decades have demonstrated benefit in terms of local control with reasonable toxicity. However, randomised trials comparing it with current standards of care are still needed.

Half-sandwich manganese complexes Cp(CO)2Mn(NHC) as redox-active organometallic fragments.

Oxidation of the half-sandwich MnI complexes Cp(CO)2Mn(NHC) bearing dialkyl-, arylalkyl- and diarylsubstituted N-heterocyclic carbene ligands (NHC = IMe, IMeMes, IMes) affords the corresponding stable MnII radical cations [Cp(CO)2Mn(NHC)](BF4) isolated in 92-95% yield. Systematic X-ray diffraction studies of the series of MnI and MnII NHC complexes revealed the expected characteristic structural changes upon oxidation, namely the elongation of the Mn-CO and Mn-NHC bonds as well as the diminution of the OC-Mn-CO angle. ESR spectra of [Cp(CO)2Mn(IMes)](BF4) in frozen solution (CH2Cl2/toluene 1 : 1, 70 K) allowed the identification of two conformers for this complex and their structural assignment using DFT calculations. The stability of these NHC complexes in both metal oxidation states, moderate oxidation potentials and the ease of detection of MnII species by a variety of spectroscopic techniques (UV-Vis, IR, paramagnetic 1H NMR, and ESR) make these compounds promising objects for applications as redox-active organometallic fragments.

Electronic tuning of a carbene center via remote chemical induction, and relevant effects in catalysis.

The present report develops the idea that an N-heterocyclic carbene incorporating a remote anionic functionality--here, a malonate group--as a backbone component of its heterocyclic framework, can be "post-functionalized" directly from its transition-metal complexes, upon simple addition of a variety of electrophiles interacting directly with the malonate group in the outer coordination sphere. From a palette of selected electrophilic reagents, it was thus possible to modulate the electronic donor properties of the carbene center over a rather broad range. Both the zwitterionic complex [Rh{malo-NHC}(cod)] and the cationic derivatives [Rh{malo-NHC(E)}(cod)](+) (where "malo-NHC(E)" represents the ligand modified by a selected electrophile "E") were used as pre-catalysts in two types of catalytic reactions, namely, the polymerization of phenylacetylene and the hydroboration of styrene. The results indicate that, in both cases, the zwitterionic species is by far the best catalyst, whereas a decrease in the ligand donicity induced by the added electrophile results in a concomitant reduction of catalytic activity. Apparent deviations to such a trend in the case of the hydroboration of styrene were rationalized in terms of an interaction between the reactive catecholborane substrate and the remote functionality of the N-heterocyclic carbene leading to an in situ modification of the nature of the active species. These observations serve as a useful basis to define the scope and limitations of the present conceptual approach in catalysis.

N-Cyclopropenio-imidazol-2-ylidene: An N-heterocyclic carbene bearing an N-cationic substituent.

A cationic NHC 1+ bearing an N-bound 2,3-bis(diisopropylamino)cyclopropenium group is reported. From an easily available dicationic imidazolium precursor, the coordination abilities and stereo-electronic properties of 1+ are evaluated by the formation of Pd(ii), Rh(i) and Au(i) complexes. The cationic gold(i) complex is implemented in representative intramolecular Au(i)-catalyzed cyclizations.

Manganese catalyzed α-methylation of ketones with methanol as a C1 source.

The direct α-methylation of ketones with methanol under hydrogen borrowing conditions using a well-defined manganese PN3P complex as a pre-catalyst was, for the first time, achieved. The reactions typically proceed at 120 °C for 20 h with 3 mol% pre-catalyst loading and in the presence of NaOtBu (50 mol%) as base. The scope of the reaction was extended to the α-methylation of esters.

A stable anionic N-heterocyclic carbene and its zwitterionic complexes.

Pyrimidinium betaïnes (1), readily accessible via a straightforward modular synthesis from a formamidine and a monosubstituted malonic acid, are readily deprotonated by nBuLi (or KHMDS) to give the stable carbene species [2]Li+ (abbreviated as maloNHC). The latter represents the archetype of a subgroup of N-heterocyclic carbenes incorporating a malonate as remote anionic functional group within their heterocyclic backbone. While playing the dual role of monodentate 2 e- L type donor and noncoordinating charge carrier X, such ligands are seen to provide a rational route to zwitterionic complexes, as illustrated here by three examples (Rh, Fe, Ag). In particular, the reaction of [2]Li+ with [RhCl(1,5-COD)]2 produces the neutral 14 e- complex Rh(maloNHC)(COD) (3) in which coordinative unsaturation at the metal is relieved in the solid state by an uncommon labile bonding interaction between the Cipso of one of the mesityl arms and the Rh center.