Neutral and Cationic Rare Earth Metal Alkyl and Benzyl Compounds with the 1,4,6-Trimethyl-6-pyrrolidin-1-yl-1,4-diazepane Ligand and Their Performance in the Catalytic Hydroamination/Cyclization of Aminoalkenes

A new neutral tridentate 1,4,6-trimethyl-6-pyrrolidin-1-yl-1,4-diazepane (L) was prepared. Reacting L with trialkyls M(CH2SiMe3)3(THF)2 (M = Sc, Y) and tribenzyls M(CH2Ph)3(THF)3 (M = Sc, La) yielded trialkyl complexes (L)M(CH2SiMe3)3 (M = Sc, 1; M = Y, 2) and tribenzyl complexes (L)M(CH2Ph)3 (M = Sc, 3; M = La, 4). Complexes 1 and 2 can be converted to their corresponding ionic compounds [(L)M(CH2SiMe3)2(THF)][B(C6H5)4] (M = Sc, Y) by reaction with [PhNMe2H][B(C6H5)4] in THF. Complexes 3 and 4 can be converted to cationic species [(L)M(CH2Ph)2]+ by reaction with [PhNMe2H][B(C6F5)4] in C6D5Br in the absence of THF. The neutral complexes 1-4 and their cationic derivatives were studied as catalysts for the hydroamination/cyclization of 2,2-diphenylpent-4-en-1-amine and N-methylpent-4-en-1-amine reference substrates and compared with ligand-free Sc, Y, and La neutral and cationic catalysts. The most effective catalysts in the series were the cationic L-yttrium catalyst (for 2,2-diphenylpent-4-en-1-amine) and the cationic lanthanum systems (for N-methylpent-4-en-1-amine). For the La catalysts, evidence was obtained for release of L from the metal during catalysis.

Scope and Mechanistic Study of the Ruthenium-Catalyzed \u3cem\u3eortho\u3c/em\u3e-C−H Bond Activation and Cyclization Reactions of Arylamines with Terminal Alkynes

The cationic ruthenium hydride complex [(PCy3)2(CO)(CH3CN)2RuH]+BF4- was found to be a highly effective catalyst for the C−H bond activation reaction of arylamines and terminal alkynes. The regioselective catalytic synthesis of substituted quinoline and quinoxaline derivatives was achieved from the ortho-C−H bond activation reaction of arylamines and terminal alkynes by using the catalyst Ru3(CO)12/HBF4·OEt2. The normal isotope effect (kCH/kCD = 2.5) was observed for the reaction of C6H5NH2 and C6D5NH2 with propyne. A highly negative Hammett value (ρ = −4.4) was obtained from the correlation of the relative rates from a series of meta-substituted anilines, m-XC6H4NH2, with σp in the presence of Ru3(CO)12/HBF4·OEt2 (3 mol % Ru, 1:3 molar ratio). The deuterium labeling studies from the reactions of both indoline and acyclic arylamines with DC⋮CPh showed that the alkyne C−H bond activation step is reversible. The crossover experiment from the reaction of 1-(2-amino-1-phenyl)pyrrole with DC⋮CPh and HC⋮CC6H4-p-OMe led to preferential deuterium incorporation to the phenyl-substituted quinoline product. A mechanism involving rate-determining ortho-C−H bond activation and intramolecular C−N bond formation steps via an unsaturated cationic ruthenium acetylide complex has been proposed

Relative Reactivity of the Metal-Amido versus Metal-Imido Bond in Linked Cp-Amido and Half-Sandwich Complexes of Vanadium

Treatment of (η5-C5H4C2H4NR)V(N-t-Bu)Me (R = Me, i-Pr) and CpV(N-p-Tol)(N-i-Pr2)Me (Cp = η5-C5H5) with B(C6F5)3 or [Ph3C][B(C6F5)4] results in formation of the corresponding cations, [(η5-C5H4C2H4NR)V(N-t-Bu)]+ and [CpV(N-p-Tol)(N-i-Pr2)]+. The latter could also be generated as its N,N-dimethylaniline adduct by treatment of the methyl complex with [PhNMe2H][BAr4] (Ar = Ph, C6F5). Instead, the analogous reaction with the linked Cp-amido precursor results in protonation of the imido-nitrogen atom. Sequential cyclometalation of the amide substituents gave cationic imine complexes [(η5-C5H4C2H4NCR'2)V(NH-t-Bu)]+ (R' = H, Me) and methane. Reaction of cationic [(η5-C5H4C2H4NR)V(N-t-Bu)]+ with olefins affords the corresponding olefin adducts, whereas treatment with 1 or 2 equiv of 2-butyne results in insertion of the alkyne into the vanadium-nitrogen single bond, affording the mono- and bis-insertion products [(η5-C5H4C2H4N(i-Pr)C2Me2)V(N-t-Bu)]+ and [(η5-C5H4C2H4N(i-Pr)C4Me4)V(N-t-Bu)]+. The same reaction with the half-sandwich compound [CpV(N-p-Tol)(N-i-Pr2)]+ results in a paramagnetic compound that, upon alcoholysis, affords sec-butylidene-p-tolylamine, suggesting an initial [2+2] cycloaddition reaction. The difference in reactivity between the V-N bond versus the V=N bond was further studied using computational methods. Results were compared to the isoelectronic titanium system CpTi(NH)(NH2). These studies indicate that the kinetic product in each system is derived from a [2+2] cycloaddition reaction. For titanium, this was found as the thermodynamic product as well, whereas the insertion reaction was found to be thermodynamically more favorable in the case of vanadium.

Mechanistic Study of Gold(I)-Catalyzed Intermolecular Hydroamination of Allenes

The intermolecular hydroamination of allenes occurs readily with hydrazide nucleophiles, in the presence of 3-12% Ph_3PAuNTf_2. Mechanistic studies have been conducted to establish the resting state of the gold catalyst, the kinetic order of the reaction, the effect of ligand electronics on the overall rate, and the reversibility of the last steps in the catalytic cycle. We have found the overall reaction to be first order in gold and allene and zero order in nucleophile. Our studies suggest that the rate-limiting transition state for the reaction does not involve the nucleophile and that the active catalyst is monomeric in gold(I). Computational studies support an “outersphere” mechanism and predict that a two-step, no intermediate mechanism may be operative. In accord with this mechanistic proposal, the reaction can be accelerated with the use of more electron-deficient phosphine ligands on the gold(I) catalyst

Recent Advances in the Synthetic and Mechanistic Aspects of the Ruthenium-catalyzed Carbon-heteroatom Bond Forming Reactions of Alkenes and Alkynes

The group’s recent advances in catalytic carbon-to-heteroatom bond forming reactions of alkenes and alkynes are described. For the C–O bond formation reaction, a well-defined bifunctional ruthenium-amido catalyst has been successfully employed for the conjugate addition of alcohols to acrylic compounds. The ruthenium-hydride complex (PCy3)2(CO)RuHCl was found to be a highly effective catalyst for the regioselective alkyne-to-carboxylic acid coupling reaction in yielding synthetically useful enol ester products. Cationic ruthenium-hydride catalyst generated in-situ from (PCy3)2(CO)RuHCl/HBF4·OEt2 was successfully utilized for both the hydroamination and related C–N bond forming reactions of alkenes. For the C–Si bond formation reaction, regio- and stereoselective dehydrosilylation of alkenes and hydrosilylation of alkynes have been developed by using a well-defined ruthenium-hydride catalyst. Scope and mechanistic aspects of these carbon-to-heteroatom bond forming reactions are discussed

Asymmetric additions to dienes catalysed by a dithiophosphoric acid.

Chiral Brønsted acids (proton donors) have been shown to facilitate a broad range of asymmetric chemical transformations under catalytic conditions without requiring additional toxic or expensive metals. Although the catalysts developed thus far are remarkably effective at activating polarized functional groups, it is not clear whether organic Brønsted acids can be used to catalyse highly enantioselective transformations of unactivated carbon-carbon multiple bonds. This deficiency persists despite the fact that racemic acid-catalysed Markovnikov additions to alkenes are well known chemical transformations. Here we show that chiral dithiophosphoric acids can catalyse the intramolecular hydroamination and hydroarylation of dienes and allenes to generate heterocyclic products in exceptional yield and enantiomeric excess. We present a mechanistic hypothesis that involves the addition of the acid catalyst to the diene, followed by nucleophilic displacement of the resulting dithiophosphate intermediate; we also report mass spectroscopic and deuterium labelling studies in support of the proposed mechanism. The catalysts and concepts revealed in this study should prove applicable to other asymmetric functionalizations of unsaturated systems

Metal-mediated intramolecular hydroamination and hydro(acy)alkoxylation reactions

This PhD thesis describes work undertaken to effect asymmetric catalysis in hydroamination and hydro(acy)alkoxylation reactions of allenes. The introductory Chapter provides an overview of recent advances in asymmetric heterofunctionalisation reactions of allenes. This includes intra- and inter-molecular reactions involving C-N and C-O bond formations. Chapter 2 begins by comparing the preparation of a γ-allenic alcohol by two different synthetic routes and its subsequent use in intramolecular hydroalkoxylation reactions using copper(II) and silver(I) salts. From this study, the ability of silver diphosphine complexes to facilitate enantioselective hydroalkoxylation reactions in a 5-exo-trig fashion was discovered. Extensive reaction optimisation was undertaken, however only moderate ee’s and conversions were observed. In Chapter 3, the use of other metal Lewis acids to catalyse hydroalkoxylation reactions of γ-allenic alcohols is presented. DFT calculations undertaken by a colleague (Prof H. S. Rzepa) were used to rationalise the observed regioselectivities with silver(I), zinc(II), and tin(II) triflates. From DFT calculations, the metal counteranion was found to be intimately involved in the C-O bond formation. In the following two Chapters, the possibility of asymmetric synthesis by using chiral anionic ligands is discussed. In Chapter 4, additional γ-allenic alcohols and β-allenic acids were synthesised for intramolecular hydroalkoxylation or hydroacyalkoxylation reactions respectively. In Chapter 5, the respective γ-allenic amines were prepared for intramolecular hydroamination. In both cases, the outcome, scope and limitations of the reaction are discussed. In Chapter 6, an overall conclusion and future work is discussed. The last Chapter contains experimental procedures and characterisation data of all the compounds synthesised during the course of this project

Mechanistic Studies Lead to Dramatically Improved Reaction Conditions for the Cu-Catalyzed Asymmetric Hydroamination of Olefins

Enantioselective copper(I) hydride (CuH)-catalyzed hydroamination has undergone significant development over the past several years. To gain a general understanding of the factors governing these reactions, kinetic and spectroscopic studies were performed on the CuH-catalyzed hydroamination of styrene. Reaction profile analysis, rate order assessment, and Hammett studies indicate that the turnover-limiting step is regeneration of the CuH catalyst by reaction with a silane, with a phosphine-ligated copper(I) benzoate as the catalyst resting state. Spectroscopic, electrospray ionization mass spectrometry, and nonlinear effect studies are consistent with a monomeric active catalyst. With this insight, targeted reagent optimization led to the development of an optimized protocol with an operationally simple setup (ligated copper(II) precatalyst, open to air) and short reaction times (<30 min). This improved protocol is amenable to a diverse range of alkene and alkyne substrate classes.National Institutes of Health (U.S.) (GM58160)National Institutes of Health (U.S.) (GM112197)National Institutes of Health (U.S.) (GM113311

Structural variation, dynamics, and catalytic application of palladium(II) complexes of di-N-heterocyclic carbene-amine ligands

A series of palladium(II) complexes incorporating di-NHC-amine ligands has been prepared and their structural, dynamic and catalytic behaviour investigated. The complexes [trans-(k(2)-(CN)-C-tBu(Bn)CN(Bn)C-tBu)PdCl2] (12) and [trans-(kappa(2)-(CN)-C-Mes(H)C-Mes)PdCl2] (13) do not exhibit interaction between the amine nitrogen and palladium atom respectively. NMR spectroscopy between - 40 and 25 degrees C shows that the di-NHC-amine ligand is flexible expressing C-s symmetry and for 13 rotation of the mesityl groups is prevented. In the related C-1 complex [(kappa(3)-(CN)-C-tBu(H)C-tBu)PdCl][CI] (14) coordination of NHC moieties and amine nitrogen atom is observed between -40 and 25 degrees C. Reaction between 12 - 14 and two equivalents of AgBF4 in acetonitrile gives the analogous complexes [trans-(kappa(2)-(CN)-C-tBu(Bn)C-tBu)PdCl2] (12) and [trans-(kappa(CN)-C-2Mes(H)C-Mes)PdCl2] (13) do not exhibit interaction between the amine nitrogen and palladium atom respectively. NMR spectroscopy between -40 ans 25 degrees C shows the di-NHC-amine ligand is flexible expressing C-s symmetry and for 13 rotation of the mesityl groups is prevented. In the related C-1 complex [kappa(3)-(CN)-C-tBu(H)C-tBu)PdCI][CI] (14) coordination of NHC moieties and amine nitrogen atom is observed between -40 and 25 degrees C.Reaction between 12-14 and two equivalents of AgBF4 in acetonitrile gives the analogous complexes [trans-(kappa(2)-(CN)-C-tBu(H)(CPd)-Pd-tBu(MeCN)(2)][BF4](2) (15), [trans-(kappa(CN)-C-2Mes(H)C-Mes)Pd(MeCN)(2)[BF4](2 (16)) and [(kappa(3)-(CN)-C-tBu(H)C-tBu)Pd(MeCN)][BF4](2) (17) indicating that ligand structure determines amine coordination. The single crystal X-ray structures of 12, 17 and two ligand imidazolium salt precursors C-tBu(H)N(Bn)C(H) (tBu)][CI](2) (2) and [C-tBu(H) N(H)C(H)(tBu)][BPh4](2) (4) have been determined. Complexes 12-14 and 15-17 have been shown to be active precatalysts for Heck and hydroamination reactions respectively

Enantioselective CuH-Catalyzed Anti-Markovnikov Hydroamination of 1,1-Disubstituted Alkenes

Enantioselective synthesis of β-chiral amines has been achieved via copper-catalyzed hydroamination of 1,1-disubstituted alkenes with hydroxylamine esters in the presence of a hydrosilane. This mild process affords a range of structurally diverse β-chiral amines, including β-deuterated amines, in excellent yields with high enantioselectivities. Furthermore, catalyst loading as low as 0.4 mol% could be employed to deliver product in undiminished yield and selectivity, demonstrating the practicality of this method for large-scale synthesis.National Institutes of Health (U.S.) (Award GM58160