Panayiotis A. Procopiou

Intramolecular hydroamination of aminoalkenes by calcium and magnesium complexes: a synthetic and mechanistic study.

The beta-diketiminate-stabilized calcium amide complex [{ArNC(Me)CHC(Me)NAr}Ca{N(SiMe(3))(2)}(THF)] (Ar = 2,6-diisopropylphenyl) and magnesium methyl complex [{ArNC(Me)CHC(Me)NAr}Mg(Me)(THF)] are reported as efficient precatalysts for hydroamination/cyclization of aminoalkenes. The reactions proceeded under mild conditions, allowing the synthesis of five-, six-, and seven-membered heterocyclic compounds. Qualitative assessment of these reactions revealed that the ease of catalytic turnover increases (i) for smaller ring sizes (5 > 6 > 7), (ii) substrates that benefit from favorable Thorpe-Ingold effects, and (iii) substrates that do not possess additional substitution on the alkene entity. Prochiral substrates may undergo diastereoselective hydroamination/cyclization depending upon the position of the existing stereocenter. Furthermore, a number of minor byproducts of these reactions, arising from competitive alkene isomerization reactions, were identified. A series of stoichiometric reactions between the precatalysts and primary amines provided an important model for catalyst initiation and suggested that these reactions are facile at room temperature, with the reaction of the calcium precatalyst with benzylamine proceeding with DeltaG(o)(298 K) = -2.7 kcal mol(-1). Both external amine/amide exchange and coordinated amine/amide exchange were observed in model complexes, and the data suggest that these processes occur via low-activation-energy pathways. As a result of the formation of potentially reactive byproducts such as hexamethyldisilazane, calcium-catalyst initiation is reversible, whereas for the magnesium precatalyst, this process is nonreversible. Further stoichiometric reactions of the two precatalysts with 1-amino-2,2-diphenyl-4-pentene demonstrated that the alkene insertion step proceeds via a highly reactive transient alkylmetal intermediate that readily reacts with N-H sigma bonds under catalytically relevant conditions. The results of deuterium-labeling studies are consistent with the formation of a single transient alkyl complex for both the magnesium and calcium precatalysts. Kinetic analysis of the nonreversible magnesium system revealed that the reaction rate depends directly upon catalyst concentration and inversely upon substrate concentration, suggesting that substrate-inhibited alkene insertion is rate-determining.

Heterofunctionalization catalysis with organometallic complexes of calcium, strontium and barium

Despite the routine employment of Grignard reagents and Hauser bases as stoichiometric carbanion reagents in organic and inorganic synthesis, a defined reaction chemistry encompassing the heavier elements of Group II (M = Ca, Sr and Ba) has, until recently, remained unreported. This article provides details of the recent progress in heavier Group II catalysed small molecule transformations mediated by well-defined heteroleptic and homoleptic complexes of the form LMX or MX2; where L is a mono-anionic ligand and X is a reactive σ-bonded substituent. The intra- and intermolecular heterofunctionalization (hydroamination, hydrophosphination, hydrosilylation and hydrogenation) of alkenes, alkynes, dienes, carbodiimides, isocyanates and ketones is discussed.

A recyclable ‘boomerang’ polymer-supported ruthenium catalyst for olefin metathesis

Abstract Polymer supported ruthenium catalyst 8 was found to be an effective catalyst for ring closing metathesis. The rate of reaction and activity was found to be comparable to that of homogeneous catalyst 1 . In addition, the catalyst could be recycled and re-used up to three times by simple filtration. The residual ruthenium/catalyst content in the product mixtures using catalyst 8 were found to be much reduced compared with the homogeneous catalyst 1 .

Heavier Alkaline Earth Catalysts for the Intermolecular Hydroamination of Vinylarenes, Dienes, and Alkynes

The heavier group 2 complexes [M{N(SiMe(3))(2)}(2)](2)(1, M = Ca; 2, M = Sr) and [M{CH(SiMe(3))(2)}(2)(THF)(2)] (3, M = Ca; 4, M = Sr) are shown to be effective precatalysts for the intermolecular hydroamination of vinyl arenes and dienes under mild conditions. Initial studies revealed that the amide precatalysts, 1 and 2, while compromised in terms of absolute activity by a tendency toward transaminative behavior, offer greater stability toward polymerization/oligomerization side reactions. In every case the strontium species, 2 and 4, were found to outperform their calcium congeners. Reactions of piperidine with para-substituted styrenes are indicative of rate-determining alkene insertion in the catalytic cycle while the ease of addition of secondary cyclic amines was found to be dependent on ring size and reasoned to be a consequence of varying amine nucleophilicity. Hydroamination of conjugated dienes yielded isomeric products via η(3)-allyl intermediates and their relative distributions were explained through stereoelectronic considerations. The ability to carry out the hydroamination of internal alkynes was found to be dramatically dependent upon the identity of the alkyne substituents while reactions employing terminal alkynes resulted in the precipitation of insoluble and unreactive group 2 acetylides. The rate law for styrene hydroamination with piperidine catalyzed by [Sr{N(SiMe(3))(2)}(2)](2) was deduced to be first order in [amine] and [alkene] and second order in [catalyst], while large kinetic isotope effects and group 2 element-dependent ΔS(++) values implicated the formation of an amine-assisted rate-determining alkene insertion transition state in which there is a considerable entropic advantage associated with use of the larger strontium center.

Triazenide complexes of the heavier alkaline earths: Synthesis, characterization, and suitability for hydroamination catalysis

A series of triazenide complexes of the heavier alkaline earths, Ca, Sr and Ba, have been synthesized by either protonolysis or salt metathesis routes. Although complexes of the form [{Ar 2N 3}M{N(SiMe 3) 2}(THF) n ] (M = Ca, n = 2; M = Sr, n = 3; Ar = 2,6-diisopropylphenyl) and [{Ar 2N 3}Ca(I)(THF) 2] 2 could be isolated and characterized by X-ray crystallography, solution studies revealed the propensity of these species to undergo Schlenk-like redistribution with the formation of [{Ar 2N 3} 2M(THF) n ] (M = Ca, n = 1; M = Sr, n = 2). The latter compounds have been synthesized independently. In the case of the large barium dication, attempts to synthesize the heaviest analogue of the series, [{Ar 2N 3} 2Ba(THF) n ], failed and led instead to the isolation of the potassium barate complex [K{Ar 2N 3}Ba{N(SiMe 3) 2} 2(THF) 4]. Single crystal X-ray diffraction studies demonstrated that, although in all the aforementioned cases the triazenide ligand binds to the electrophilic group 2 metal centers via symmetrical kappa (2)- N, N-chelates, in the latter compound an unprecedented bridging mode is observed in which the triazenide ligand coordinates through both terminal and internal nitrogen centers. A series of density-functional theory computational experiments have been undertaken to assist in our understanding of this phenomenon. In further experiments, the calcium and strontium amide derivatives [{Ar 2N 3}M{N(SiMe 3) 2}(THF) n ] (M = Ca, n = 2; M = Sr, n = 3) proved to be catalytically active for the intramolecular hydroamination of 1-amino-2,2-diphenylpent-4-ene to form 2-methyl-4,4-diphenylpyrrolidine, with the calcium species demonstrating a higher turnover number than the strontium analogue ( 2a, TOF = 500 h (-1); 2b, TOF = 75 h (-1)). In these instances, because of ambiguities in the structural charcterization of the precatalyst in solution, such quantification holds little value and detailed catalytic studies have not been conducted.

Heavier Group 2 Metals and Intermolecular Hydroamination: A Computational and Synthetic Assessment

A density functional theory assessment of the use of the group 2 elements Mg, Ca, Sr, and Ba for the intermolecular hydroamination of ethene indicated that the efficiency of the catalysis is dependent upon both the polarity and the deformability of the electron density within the metal-substituent bonds of key intermediates and transition states. The validity of this analysis was supplemented by a preliminary study of the use of group 2 amides for the intermolecular hydroamination of vinyl arenes. Although strontium was found to provide the highest catalytic activity, in line with the expectation provided by the theoretical study, a preliminary kinetic analysis demonstrated that this is possibly a consequence of the increased radius and accessibility of this cation rather than a reflection of a reduced barrier for rate-determining alkene insertion.

Ring-Closing Metathesis : Novel Routes to Aromatic Heterocycles

Olefin metathesis has been established as an important and general reaction in synthetic organic chemistry. Recently, it has attracted interest as a powerful tool for the construction of aromatic heterocycles. The importance of heteroaromatic motifs in medicinal chemistry and biology, as well as the efficiency and wealth of metathesis transformations, have resulted in significant success in this rapidly developing area.

Synthesis and Structure−Activity Relationships of Long-acting β2 Adrenergic Receptor Agonists Incorporating Metabolic Inactivation: An Antedrug Approach

A series of saligenin beta(2) adrenoceptor agonist antedrugs having high clearance were prepared by reacting a protected saligenin oxazolidinone with protected hydroxyethoxyalkoxyalkyl bromides, followed by removal of the hydroxy-protecting group, alkylation, and final deprotection. The compounds were screened for beta(2), beta(1), and beta(3) agonist activity in CHO cells. The onset and duration of action in vitro of selected compounds were assessed on isolated superfused guinea pig trachea. Compound 13f had high potency, selectivity, fast onset, and long duration of action in vitro and was found to have long duration in vivo, low oral bioavailability in the rat, and to be rapidly metabolized. Crystalline salts of 13f (vilanterol) were identified that had suitable properties for inhaled administration. A proposed binding mode for 13f to the beta(2)-receptor is presented.

Heavier group-2-element catalyzed hydroamination of carbodiimides

Abstract The heteroleptic calcium amide [{ArNC(Me)CHC(Me)NAr}Ca{N(SiMe3)2}(THF)] (Ar = 2,6‐diisopropylphenyl) and the homoleptic heavier alkaline earth amides, [M{N(SiMe3)2}2(THF)2] (M = Ca, Sr and Ba) are reported as competent pre‐catalysts for the hydroamination of 1,3‐carbodiimides. Whilst the reaction scope is currently limited to reactions of aromatic amines with 1,3‐dialkylcarbodiimides, in most cases preparations in hydrocarbon solvents proceed rapidly at room temperature with catalyst loadings as low as 0.2 mol‐% and the guanidine reaction products crystallize directly from the reaction mixture. Initial studies are consistent with the intermediacy of heavier group‐2 guanidinate complexes.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

Synthesis of substituted pyridines and pyridazines via ring closing metathesis.

RCM can be used to make aromatic heterocycles, namely pyridines and, for the first time, pyridazines; the key step after RCM involves elimination of sulfinate to provide the aromatic system.