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See detailSynthèse et applications catalytiques d'adduits zwitterioniques de carbènes N-hétérocycliques
Hans, Morgan ULg

Doctoral thesis (2015)

In 1991, Arduengo isolated and fully characterized the first N-Heterocyclic Carbene (NHC), thereby confirming the existence of these stable divalent carbon species postulated almost thirty years earlier ... [more ▼]

In 1991, Arduengo isolated and fully characterized the first N-Heterocyclic Carbene (NHC), thereby confirming the existence of these stable divalent carbon species postulated almost thirty years earlier by Wanzlick. Since then, the enthusiasm for these highly nucleophilic and strongly basic compounds has steadily increased in the scientific community. Their reactivity with respect to organic compounds is very rich and is relatively well documented since the middle of the 1960’s. Their strong electron-donicity and their moderate pi-acidity make them almost universal ligands. NHC complexes have indeed been prepared with practically all the metals from the periodic table. Their high nucleophilicity also allowed to successfully employ them as organocatalysts. The state of the art in these three fields as well as the properties of NHCs and their electronic and steric characterizations are discussed in the introduction of this manuscript. The second chapter is devoted to the synthesis and characterization of imidazol(in)ium dithiocarboxylates (NHC•CS2 adducts), carboxylates (NHC•CO2 adducts) and thiocarboxylates (NHC•COS adducts) and to their applications in organic synthesis and in coordination chemistry. First, because NHC•CO2 adducts do not require any reagents to generate free carbenes in solution, we proposed them as precursors of NHC to promote various Michael additions. Preliminary catalytic assays of a set of five representatives of this zwitterion family in a carba-Michael addition previously reported in the literature highlighted the net superiority of 1,3 dicyclohexylimidazolium carboxylate (ICy•CO2). Subsequently, we showed the efficiency of our catalytic system to promote sulfa-, and phospha-Michael additions. Eventually, the same precatalyst showed efficiency to initiate various sulfa-Michael/aldol organocascades. Second, we looked at the synthesis of a representative set of five imidazol(in)ium thiocarboxylates. Their characterization indicated a probable loss of the thiocarboxylate group. Hence, we tested their efficiency as carbene’s precursors in two benchmark reactions usually catalyzed by NHCs. 1,3-Dicyclohexylimidazolium thiocarboxylate (ICy•COS) turned out to be most effective to promote transesterification/acetylation, while 1,3 bis(2,4,6-trimethylphenyl)imidazolinium thiocarboxylate (SIMes•COS) afforded a quantitative yield in the benzoin condensation. Moreover, reaction of NHC•COS betaines with a half-equivalent of ruthenium dimer [RuCl2(p-cymene)]2 led to [RuCl2(p-cymene)(NHC•COS)] complexes in which the zwitterions were bonded to ruthenium by the sulfur atom only. This is a remarkable result because NHC•CO2 zwitterions behaved like efficient NHC precursors leading to metal-NHC complexes, while imidazol(in)ium dithiocarboxylates showed no signs of dissociation. They behaved as kappa2-S,S’ chelating ligands and led to metal-(S2C•NHC) complexes. Finally, catalytic tests of these new complexes bearing NHC•COS adducts in the Ring-Opening Metathesis Polymerization (ROMP) of cyclooctene, in the Atom Transfer Radical Polymerization (ATRP) of methyl methacrylate and in the synthesis of enol esters resulted in low yields. However, they provided evidence for the rearrangement of the starting complexes in Ru-NHC species under the experimental conditions adopted. The third chapter is devoted to the synthesis of azolium enolates and their characterization, as well as their involvement in the Staudinger reaction and to their coordination chemistry to ruthenium. Our interest initially focused on the general mechanism of the NHC-catalyzed Staudinger reaction. Literature reports two plausible mechanisms for the [2 + 2] cycloaddition between ketenes and electron-poor imines. The first one, called "Imine-first" involves an azolium amide, while the second one, called "Ketene-first" goes through an azolium enolate. Synthesis and full characterization of these two types of zwitterionic adducts combined with their catalytic assay in the reaction between diphenylketene and N-tosylbenzaldimine allowed us to acquire a strong experimental evidence in favor of the "Ketene-first" observed path. We were then interested by probing the diastereoselectivity observed during NHC catalyzed [2 + 2] cycloadditions between unsymmetrical ketenes and various N sulfonylbenzaldimines. In order to investigate the parameters that influenced the stereoselectivity during these reactions, we prepared and fully characterized two new betaines (S)IMes•EtPhC=C=O and we performed catalytic assays in the reaction between ethylphenylketene and different N-sulfonylbenzaldimines, during which we varied various experimental parameters. We showed that steric hindrance of the catalyst is critical, poorly hindered NHCs favoring cis diastereoisomers, while trans-beta-lactams were essentially produced when more congested catalysts were used. The reaction solvent is also a critical parameter, N,N-dimethylformamide allowing to obtain the best diastereoisomeric ratio, 16:84, in favor of the trans isomer. Finally, the reaction temperature and the nature of the substituent on the N-sulfonylated imine are less important. The last part of this chapter concerned the coordination of NHC•ketene adducts to ruthenium. Our starting hypothesis was that these betaines could provide simultaneously an NHC ligand and an alkylidene precursor (a ketene) to the metal. By this way and from adequate metallic precursors, we envisioned to synthetize second-generation Grubbs type complexes, benchmark catalysts for olefin metathesis, in one step and without the need to handle diazo compounds. Although the first exploratory experiments did not lead to the expected results, they provided crucial information to help achieve these syntheses in future investigations. [less ▲]

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See detailProbing the Diastereoselectivity of Staudinger Reactions Catalyzed by N-Heterocyclic Carbenes
Hans, Morgan ULg; Wouters, Johan; Demonceau, Albert ULg et al

in Chemistry : A European Journal (2015), 21(30), 10870-10877

The reaction of ethylphenylketene with 1,3-dimesitylimidazol-2-ylidene (IMes) or 1,3-dimesitylimidazolin-2-ylidene (SIMes) afforded the corresponding azolium enolates in high yields. The two zwitterions ... [more ▼]

The reaction of ethylphenylketene with 1,3-dimesitylimidazol-2-ylidene (IMes) or 1,3-dimesitylimidazolin-2-ylidene (SIMes) afforded the corresponding azolium enolates in high yields. The two zwitterions were fully characterized by various analytical techniques. Their thermal stabilities were monitored by thermogravimetric analysis and the molecular structure of SIMes.EtPhC=C=O was determined by means of X-ray crystallography. A mechanism was proposed to account for the trans-diastereoselectivity observed in the [2+2] cycloaddition of ketenes and N-protected imines catalyzed by N-heterocyclic carbenes and an extensive catalytic screening was performed to test its validity. The steric bulk of the NHC catalyst markedly affected the cis/trans ratio of the model β-lactam product. The nature of the solvent used to carry out the Staudinger reaction also significantly influenced its diastereoselectivity. Conversely, the nature of the substituent on the N-sulfonated imine reagent and the reaction temperature were less critical parameters. [less ▲]

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See detailN-heterocyclic carbene catalyzed carba-, sulfa-, and phospha-Michael additions with NHC·CO2 adducts as precatalysts
Hans, Morgan ULg; Delaude, Lionel ULg; Rodriguez, Jean et al

in Journal of Organic Chemistry (2014), 79(6), 2758-2764

N-heterocyclic carbene catalyzed Michael additions have been revisited with 1,3-dialkyl- or 1,3-diarylimidazol(in)ium-2-carboxylates, that is, NHC·CO2 adducts, as the source of the free NHC catalysts in ... [more ▼]

N-heterocyclic carbene catalyzed Michael additions have been revisited with 1,3-dialkyl- or 1,3-diarylimidazol(in)ium-2-carboxylates, that is, NHC·CO2 adducts, as the source of the free NHC catalysts in solution. Using these precatalysts, a number of efficient carba-, sulfa-, and phospha-Michael additions were achieved very conveniently, without the need for an external strong base to generate the NHC by deprotonation of an azolium salt. To further expand the scope of the procedure, some NHC-catalyzed sulfa-Michael/aldol organocascades were also investigated. [less ▲]

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See detailSelected Recent Advances in the Synthesis of Bioactive Compounds Using Olefin Metathesis as a Key Step
Dassonneville, Benjamin ULg; Delaude, Lionel ULg; Demonceau, Albert ULg et al

in Current Organic Chemistry (2013), 17(22), 2609-2653

Synthesis of biologically active compounds is of paramount importance to the biomedical sciences for the development of novel therapeutic agents. Such substances often feature various types of unique and ... [more ▼]

Synthesis of biologically active compounds is of paramount importance to the biomedical sciences for the development of novel therapeutic agents. Such substances often feature various types of unique and complex structures, which make them challenging targets for synthetic efforts. Their total synthesis offers the chance to implement the use of newly developed, efficient and highly selective synthetic procedures and/or strategies in a complex environment. In this respect, thanks to the development of increasingly efficient molybdenum and ruthenium catalysts, olefin metathesis is now an integral part of modern synthetic methods. This review article will highlight with selected examples from the recent literature assets and limitations of the olefin metathesis reaction in the synthesis of biologically active compounds. [less ▲]

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See detailMechanistic Insight into the Staudinger Reaction Catalyzed by N-Heterocyclic Carbenes
Hans, Morgan ULg; Wouters, J.; Demonceau, Albert ULg et al

in Chemistry : A European Journal (2013), 19(19), 9668-9676

Four zwitterions were prepared by treating 1,3-dimesitylimidazolin-2-ylidene (SIMes) or 1,3-dimesitylimidazol-2-ylidene (IMes) with either N-tosyl benzaldimine or diphenylketene. They were isolated in ... [more ▼]

Four zwitterions were prepared by treating 1,3-dimesitylimidazolin-2-ylidene (SIMes) or 1,3-dimesitylimidazol-2-ylidene (IMes) with either N-tosyl benzaldimine or diphenylketene. They were isolated in high yields and characterized by IR and NMR spectroscopy. The molecular structures of three of them were determined by using X-ray crystallography and their thermal stability was monitored by using thermogravimetric analysis. The imidazol(in)ium-2-amides were rather labile white solids that did not show any tendency to tautomerize into the corresponding 1,2,2-triaminoethene derivatives. They displayed a mediocre catalytic activity in the Staudinger reaction of N-tosyl benzaldimine with diphenylketene. In contrast, the imidazol(in)ium-2-enolates were orange-red crystalline materials that remained stable over extended periods of time. Despite their greater stability, these zwitterions turned out to be efficient promoters for the model cycloaddition under scrutiny. As a matter of fact, their catalytic activity matched those recorded with the free carbenes. Altogether, these results provide strong experimental insight into the mechanism of the Staudinger reaction catalyzed by N-heterocyclic carbenes. They also highlight the superior catalytic activity of the imidazole-based carbene IMes compared with its saturated analogue SIMes in the reaction under consideration. [less ▲]

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See detailOlefin metathesis as key step in the synthesis of bioactive compounds: Challenges in the total synthesis of (-)-kendomycin
Bicchielli, Dario; Borguet, Yannick ULg; Delaude, Lionel ULg et al

in Current Organic Synthesis (2012), 9(3), 397-405

In this short review article, we highlight the application of the olefin metathesis reaction as a key step in the total synthesis of (-)-kendomycin, a macrocyclic polyketide ansamycin exhibiting ... [more ▼]

In this short review article, we highlight the application of the olefin metathesis reaction as a key step in the total synthesis of (-)-kendomycin, a macrocyclic polyketide ansamycin exhibiting pronounced activity as an endothelin receptor antagonist and antiosteoporotic agent, as well as important antibiotic potency against multiresistant bacteria and remarkable cytotoxicity versus a series of human tumour cell lines. By selecting this example from the recent literature, we hope to illustrate the great synthetic ability of olefin metathesis, while also revealing some problems encountered in the syntheses. © 2012 Bentham Science Publishers. [less ▲]

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See detailSynthesis and organocatalytic applications of imidazol(in)ium-2- thiocarboxylates
Hans, Morgan ULg; Wouters, Johan; Demonceau, Albert ULg et al

in European Journal of Organic Chemistry (2011), (35), 7083-7091

Five imidazol(in)ium-2-thiocarboxylates bearing cyclohexyl, mesityl, or 2,6-diisopropylphenyl substituents on their nitrogen atoms were prepared from the corresponding imidazol(in)ium chlorides or ... [more ▼]

Five imidazol(in)ium-2-thiocarboxylates bearing cyclohexyl, mesityl, or 2,6-diisopropylphenyl substituents on their nitrogen atoms were prepared from the corresponding imidazol(in)ium chlorides or tetrafluoroborates in a one-pot, two-step procedure involving the in situ generation of free N-heterocyclic carbenes (NHCs) with a strong base followed by trapping with carbonyl sulfide. The resulting NHC•COS zwitterions were isolated in high yields and characterized by IR and NMR spectroscopy. The molecular structure of SIMes•COS was determined by X-ray diffraction analysis. Experimental data and DFT calculations indicated that the negative charge on the thiocarboxylate anion is preferentially delocalized on the sulfur atom. Thermogravimetric analysis showed that the NHC•COS zwitterions undergo thermolysis at temperatures ranging between 110 and 180 °C in the solid state. They are also rather labile in solution. Unlike the related NHC•CS2 betaines, which are highly stable, crystalline materials, they displayed the same type of behavior as the analogous carboxylate adducts, which readily lose their CO2 moiety upon heating or dissolution. Thus, imidazol(in)ium-2-thiocarboxylates acted as convenient NHC precursors in two model organocatalytic transformations. Of the five thiocarboxylates examined, ICy•COS was the most efficient at promoting the acylation of benzyl alcohol with vinyl acetate, whereas SIMes•COS afforded the highest activity in benzoin condensation. [less ▲]

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See detailSynthesis and Catalytic Evaluation of Ruthenium-Arene Complexes Bearing Imidazol(in)ium-2-thiocarboxylate Ligands
Hans, Morgan ULg; Willem, Quentin ULg; Wouters, Johan et al

in Organometallics (2011), 30(22), 6133-6142

Five new complexes with the generic formula [RuCl(2)(p-cymene)(SOC.NHC)] (2-6) were isolated in high yields by reacting the [RuCl(2)(p-cymene)](2) dimer with a range of imidazol(in)ium-2-thiocarboxylate ... [more ▼]

Five new complexes with the generic formula [RuCl(2)(p-cymene)(SOC.NHC)] (2-6) were isolated in high yields by reacting the [RuCl(2)(p-cymene)](2) dimer with a range of imidazol(in)ium-2-thiocarboxylate zwitterions bearing cyclohexyl, 2,4,6-trimethylphenyl (mesityl), or 2,6-diisopropylphenyl groups on their nitrogen atoms in CH(2)Cl(2) at -20 degrees C. All the products were fully characterized by IR and NMR spectroscopy, and the molecular structures of [RuCl(2)(p-cymene)(SOC.IMes)] (3) and [RuCl(2)(p-cymene)(SOC.SIMes)] (5) were determined by X-ray diffraction analysis. Coordination of the NHC.COS ligands took place via the sulfur atom. A remarkable shielding of the methine proton on the p-cymene isopropyl group was observed by (1)H NMR spectroscopy for complexes 3-6. It is most likely caused by the aromatic ring current of a neighboring mesityl or 2,6-diisopropylphenyl substituent. The catalytic activity of compounds 2-6 was probed in the ring-opening metathesis polymerization (ROMP) of cyclooctene, in the atom transfer radical polymerization (ATRP) of methyl methacrylate, and in the synthesis of enol esters from 1-hexyne and 4-acetoxybenzoic acid. In all these reactions, the [RuCl(2)(p-cymene)(SOC.NHC)] complexes displayed performances slightly inferior to those exhibited by [RuCl(2)(p-cymene)(NHC)] species that result from the reaction of [RuCl(2)(p-cymene)](2) with NHC.CO(2) inner salts. However, they were significantly better catalyst precursors than the much more robust chelates of the [RuCl(p-cymene)(S(2)C.NHC)PF(6) type obtained by coordination of NHC.CS(2) betaines to the ruthenium dimer. These results suggest that the Ru-(SOC.NHC) motif undergoes a dethiocarboxylation under the experimental conditions adopted for the catalytic tests and leads to the same elusive Ru-NHC active species as the preformed [RuCl(2)(p-cymene)-(NHC)] family of complexes. [less ▲]

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See detailMicrowave-Assisted Synthesis of 1,3-Dimesitylimidazolinium Chloride
Hans, Morgan ULg; Delaude, Lionel ULg

in Wipf, Peter (Ed.) Organic Syntheses. Volume 87 (2010)

A procedure for the microwave-assisted synthesis of 1,3-dimesitylimidazolinium chloride on a preparative scale is described starting from simple, commercially available reagents. Prior to a microwave ... [more ▼]

A procedure for the microwave-assisted synthesis of 1,3-dimesitylimidazolinium chloride on a preparative scale is described starting from simple, commercially available reagents. Prior to a microwave-assisted cyclization, it involves the formation of N,N'-dimesitylethane-1,2-diamine dihydrochloride via condensation of glyoxal with two equivalents of mesitylamine, followed by reduction of the intermediate Schiff base with sodium borohydride under acidic conditions. All three steps proceed readily under normal atmosphere. Laboratory grade solvents and reagents taken straight from the bottles do not require any additional purification. The two intermediates and the final product are isolated in high yield and purity by simple filtration and washing and may be used without any further purification for most applications. [less ▲]

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