Chiral bicyclic imidazolium salts as a new class of N-heterocyclic carbene precursors

A N(1)-C(5) bridged chiral bicyclic imidazole with a morpholine framework was synthesized from an enantiopure 2-amino alcohol. The resultant imidazole reacted with various electrophiles, including primary and secondary alkyl halides, benzyne, and an electron-deficient aryl halide, to give the corresponding imidazolium salts. Some of the imidazolium salts were found to have potential as the precursor of a chiral N-heterocyclic carbene catalyst; by the direct annulation of an enal and a ketone through the intermediacy of a homoenolate and an activated carboxylate, the target lactone was obtained in an enantiomerically enriched form (up to 66% ee).     

Synthesis and biological activity of ester- and amide-functionalized imidazolium salts and related water-soluble coinage metal N-heterocyclic carbene complexes

N-Heterocyclic carbene (NHC) ligand precursors, namely, HIm(A)Cl [1,3-bis(2-ethoxy-2-oxoethyl)-1H-imidazol-3-ium chloride] and HIm(B)Cl {1,3-bis[2-(diethylamino)-2-oxoethyl]-1H-imidazol-3-ium chloride}, functionalized with hydrophilic groups on the imidazole rings have been synthesized and were used in the synthesis of corresponding carbene complexes of silver(I) and copper(I), {[Im(A)]AgCl}, {[Im(A)]CuCl}, and {[Im(B)](2)Ag}Cl. Related Au(I)NHC complexes {[Im(A)]AuCl} and {[Im(B)]AuCl} have been obtained by transmetalation using the silver carbene precursor. These compounds were characterized by several spectroscopic techniques including NMR and mass spectroscopy. HIm(B)Cl and the gold(I) complexes {[Im(A)]AuCl} and {[Im(B)]AuCl} were also characterized by X-ray crystallography. The cytotoxic properties of the NHC complexes have been assessed in various human cancer cell lines, including cisplatin-sensitive and -resistant cells. The silver(I) complex {[Im(B)](2)Ag}Cl was found to be the most active, with IC(50) values about 2-fold lower than those achieved with cisplatin in C13*-resistant cells. Growth-inhibitory effects evaluated in human nontransformed cells revealed a preferential cytotoxicity of {[Im(B)](2)Ag}Cl versus neoplastic cells. Gold(I) and silver(I) carbene complexes were also evaluated for their ability to in vitro inhibit the enzyme thioredoxin reductase (TrxR). The results of this investigation showing that TrxR appeared markedly inhibited by both gold(I) and silver(I) derivatives at nanomolar concentrations clearly point out this selenoenzyme as a protein target for silver(I) in addition to gold(I) complexes.     

C-C and C-H bond activation reactions in N-heterocyclic carbene complexes of ruthenium

Thermolysis of Ru(PPh3)3(CO)H2 with the N-heterocyclic carbene bis(1,3-(2,4,6-trimethylphenyl)imidazol-2-ylidene) (IMes) results in C-C activation of an Ar-CH3 bond in one of the mesityl rings of the carbene ligand. Upon addition of IMes to Ru(PPh3)3(CO)H2 at room temperature in the presence of an alkene, C-H bond activation is observed instead. The thermodynamics of these C-C and C-H cleavage reactions have been probed using density functional theory.     

Structure and reactivity of "unusual" N-heterocyclic carbene (NHC) palladium complexes synthesized from imidazolium salts

The reaction between palladium acetate and IMES.HCl leads to the formation of a novel palladium complex. The X-ray crystal structure analysis reveals that the palladium is C(2) bound to one NHC ligand (the normal binding mode), whereas the second ligand is attached through the C(5) carbon of the second imidazolium. The metalation site on the imidazolium salt is strongly influenced by the presence of base. Furthermore, the binding mode of the NHC to Pd is shown to substantially affect the catalytic behavior of the palladium complexes in cross-coupling reactions.     

Cyclophane-type imidazolium salts with planar chirality as a new class of N-heterocyclic carbene precursors

Cyclophane-type imidazolium salts with planar chirality were synthesized from enantiopure 2-amino alcohols, of which the N(1) and N(3) positions were connected with a bridge. The structural profiles of the imidazolium salts and their derivative N-heterocyclic carbenes (NHCs) were investigated by means of several analyses. The chiral NHCs derived from these imidazolium salts were found to catalyze the asymmetric cross-annulation of an alpha,beta-unsaturated aldehyde with a ketone by means of the "conjugated" umpolung of the enal to give the target gamma-lactone with good to excellent enantioselectivity (up to 94% ee). Based on the expected structure of the NHCs and their intermediates, together with the absolute configuration of the products, a plausible mechanism for the stereocontrol was proposed.     

Efficient N-heterocyclic carbene nickel pincer complexes catalyzed cross coupling of benzylic ammonium salts with boronic acids

Pyridine-bridged bis-benzimidazolylidene nickel complexes exhibited very high catalytic activity toward cross coupling of inactive (hetero)aryl benzylic ammonium salts with (hetero)aryl and alkenyl boronic acids under mild reaction conditions. Even at 2 mol% catalyst loading, a wide range of substrates for both coupling partners with different steric and electronic properties were well tolerated.     

Binaphthyl-bridged bis-imidazolinium salts as N-heterocyclic carbene ligand precursors in the palladium-catalyzed Heck reaction

Two new bis-imidazolinium salts (4a, 4b) have been synthesized as precursors of N-heterocyclic carbenes (NHCs) from the commercially available (R)-2,2′-dihydroxy-1,1′-binaphthalene. The two bis-imidazolinium salts were used as efficient precursor of NHC ancillary ligands in the palladium-catalyzed Heck reaction. Good to excellent yields and high stereoselectivities were obtained with ethyl acrylate, acrylonitrile, and acrylamide as starting materials. The structure of bis-imidazolinium salt 4b was further c...     

C-H activation reactions of ruthenium N-heterocyclic carbene complexes: application in a catalytic tandem reaction involving C-C bond formation from alcohols

A series of ruthenium hydride N-alkyl heterocyclic carbene complexes has been investigated as catalysts for a tandem oxidation/Wittig/reduction reaction to give C-C bonds from alcohols. The C-H-activated carbene complex Ru(IiPr(2)Me(2))'(PPh(3))(2)(CO)H (9) proves to be the most active precursor catalyzing the reaction of PhCH(2)OH and Ph(3)P=CHCN in 3 h at 70 degrees C. These results provide (a) a rare case in which N-alkyl carbenes afford higher catalytic activity than their N-aryl counterparts and (b) a novel example of the importance of NHC C-H activation in a catalytic cycle.     

Synthesis of the first rNHC (remote N-heterocyclic carbene) complexes with no heteroatom in the carbene carbon-containing ring

Two cationic carbene complexes with no heteroatom in the ring containing the carbene carbon, trans-bromo(2-methyl-2,6-dihydroisoquinolin-6-ylidene)bis(triphenylphosphine)palladium(II) triflate (3) and trans-chloro(1,2-dimethyl-1,7-dihydroquinolin-7-ylidene)bis(triphenylphosphine)palladium(II) triflate (4), were synthesized by oxidative substitution of Pd(PPh3)4 with N-methylated 6-bromoisoquinolinium and 7-chloro-2-methylquinolinium cations, respectively. Compound 3 was also prepared by methylation of neutral trans-bromo(2-methylisoquinolin-6-yl)bis(triphenylphosphine)palladium(II) (5). All complexes were unambiguously characterized by NMR and X-ray crystallographic studies.     

Comparison of the photochemistry of organometallic N-heterocyclic carbene and phosphine complexes of manganese

Time-resolved IR (TRIR) studies on (η(5)-C(5)H(4)Me)Mn(L)(CO) (L = 1,3-diethyl-4,5-dimethylimidazol-2-ylidene, PPh(3)) indicate that the rate of reaction with CO is ca. 10(2) slower for the N-heterocyclic carbene intermediate, which DFT calculations suggest is due to the presence of a strong MnH-C agostic bond. The reactivity of these intermediates in alkane solvents is governed by such interactions rather than solvent coordination to the unsaturated metal centre.     

Experimental and computational investigation of C-N bond activation in ruthenium N-heterocyclic carbene complexes

A combination of experimental studies and density functional theory calculations is used to study C-N bond activation in a series of ruthenium N-alkyl-substituted heterocyclic carbene (NHC) complexes. These show that prior C-H activation of the NHC ligand renders the system susceptible to irreversible C-N activation. In the presence of a source of HCl, C-H activated Ru(I(i)Pr(2)Me(2))'(PPh(3))(2)(CO)H (1, I(i)Pr(2)Me(2) = 1,3-diisopropyl-4,5-dimethylimidazol-2-ylidene) reacts to give Ru(I(i)PrHMe(2))(PPh(3))(2)(CO)HCl (2, I(i)PrHMe(2) = 1-isopropyl-4,5-dimethylimidazol-2-ylidene) and propene. The mechanism involves (i) isomerization to a trans-phosphine isomer, 1c, in which hydride is trans to the metalated alkyl arm, (ii) C-N cleavage to give an intermediate propene complex with a C2-metalated imidazole ligand, and (iii) N-protonation and propene/Cl(-) substitution to give 2. The overall computed activation barrier (ΔE(++)(calcd)) corresponds to the isomerization/C-N cleavage process and has a value of +24.4 kcal/mol. C-N activation in 1c is promoted by the relief of electronic strain arising from the trans disposition of the high-trans-influence hydride and alkyl ligands. Experimental studies on analogues of 1 with different C4/C5 carbene backbone substituents (Ru(I(i)Pr(2)Ph(2))'(PPh(3))(2)(CO)H, Ru(I(i)Pr(2))'(PPh(3))(2)(CO)H) or different N-substituents (Ru(IEt(2)Me(2))'(PPh(3))(2)(CO)H) reveal that Ph substituents promote C-N activation. Calculations confirm that Ru(I(i)Pr(2)Ph(2))'(PPh(3))(2)(CO)H undergoes isomerization/C-N bond cleavage with a low barrier of only +21.4 kcal/mol. Larger N-alkyl groups also facilitate C-N bond activation (Ru(I(t)Bu(2)Me(2))'(PPh(3))(2)(CO)H, ΔE(++)(calcd) = +21.3 kcal/mol), and in this case the reaction is promoted by the formation of the more highly substituted 2-methylpropene.     

Carbamoyl-substituted N-heterocyclic carbene complexes of palladium(II): application to Sonogashira cross-coupling reactions

[reaction: see text]. The first examples of N-carbamoyl-substituted heterocyclic carbene Pd(II) complexes are described. These thermal and hydrolytically stable complexes are readily prepared from carbamoyl imidazolium salts and efficiently promote Sonogashira cross-coupling reactions under mild conditions. Cesium carbonate is also shown to be an effective base for the coupling of aryl bromides.     

Oxidative addition of aryl chlorides to palladium N-heterocyclic carbene complexes and their role in catalytic arylamination

Density functional theory has been used to investigate various solvated species that may be formed from palladium bis N-heterocyclic carbene complexes, [Pd(cyclo-C{NRCH}₂)₂], (PdL₂) in benzene solution. Formation of an η²-arene complex is shown to stabilise a monocarbene species, PdL(η²-C₆H₅X), where the arene is either the solvent or a reacting aryl halide. Oxidative addition of an aryl chloride has been modelled, and the most likely transition state has been established as a PdL(arylchloride) species, with just one carbene ligand coordinated to the palladium. The catalytic cycle for aryl amination has been investigated and the oxidative addition of the aryl halide shown to be the rate determining step. Reductive elimination of the aryl amine has a lower activation energy. Oxidative addition of alkyl halides has been shown to be less favourable because of the absence of an unsaturated group, such as the aryl ring, to bond to the palladium.     

Dynamic behaviour attributed to chiral carbohydrate substituents of N-heterocyclic carbene ligands in square planar nickel complexes

Nickel complexes having acetylated glucopyranosyl group incorporated N-heterocyclic carbene (NHC) ligands with methyl or benzyl groups as an N-substituent exhibit two kinds of dynamic behaviours in solution (1)H NMR spectroscopy. One of the dynamic behaviours is attributed to the anti- and syn-rotamers, which occur by the rotation of the unsymmetrical NHC ligands around the axes of the Ni-C bonds. The other is attributed to the diastereomers of the syn-rotamers, which occur by opposite rotation of the imidazolylidene rings and the chiral carbohydrate group incorporated into the NHC ligands. Crystallographic analysis of the nickel complex having the NHC ligand with acetylated glucopyranosyl and benzyl groups as N-substituents showed CH-π interaction between the glucopyranosyl unit of each NHC ligand and the phenyl ring of the other NHC ligand in the complex in the solid state.     

A direct and practical approach for the synthesis of N-heterocyclic carbene coinage metal complexes

A novel direct and practical synthetic route leading to N-heterocyclic carbene coinage metal complexes has been developed by using air stable, commercial available Au(III) salt [MAuCl₄·2H₂O], CuCl_n (n=1,2) or AgCl, and imidazolium salts as starting materials. The reaction proceeded without sacrificing carbene transfer agent (Ag₂O) or using highly sensitive free NHC.