An easy-to-use, regioselective, and robust bis(amidate) titanium hydroamination precatalyst: mechanistic and synthetic investigations toward the preparation of tetrahydroisoquinolines and benzoquinolizine alkaloids

Amidate-supported titanium amido complexes are efficient and regioselective precatalysts for intermolecular hydroamination of terminal alkynes with primary amines. The synthesis and characterization of the first bis(amidate)-supported titanium-imido complex is reported. Its role as the active catalytic species is suggested in the course of product distribution studies using deuterated substrates. The bis(amidate)-supported precatalysts exhibit good functional-group tolerance, even performing hydroaminations in the presence of ester and amide groups. This functional-group tolerance was exploited in the synthesis of a variety of 1-substituted tetrahydroisoquinoline alkaloids and a one-pot hydroaminative procedure for the high yielding preparation of the benzo[a]quinolizine skeleton.     

Palladium Complexes Based on Ylide-Functionalized Phosphines (YPhos): Broadly Applicable High-Performance Precatalysts for the Amination of Aryl Halides at Room Temperature

Palladium allyl, cinnamyl, and indenyl complexes with the ylide-substituted phosphines Cy₃P⁺−C⁻(R)PCy₂ (with R=Me ( L1 ) or Ph ( L2 )) and Cy₃P⁺−C⁻(Me)PtBu₂ ( L3 ) were prepared and applied as defined precatalysts in C−N coupling reactions. The complexes are highly active in the amination of 4-chlorotoluene with a series of different amines. Higher yields were observed with the precatalysts in comparison to the in situ generated catalysts. Changes in the ligand structures allowed for improved selectivities by shutting down β-hydride elimination or diarylation reactions. Particularly, the complexes based on L2 (joYPhos) revealed to be universal precatalysts for various amines and aryl halides. Full conversions to the desired products are reached mostly within 1 h reaction time at room temperature, thus making L2 to one of the most efficient ligands in C−N coupling reactions. The applicability of the catalysts was demonstrated for aryl chlorides, bromides and iodides together with primary and secondary aryl and alkyl amines, including gram-scale applications also with low catalyst loadings of down to 0.05 mol %. Kinetic studies further demonstrated the outstanding activity of the precatalysts with TOF over 10.000 h⁻¹.     

Amidate ligand design effects in zirconium-catalyzed enantioselective hydroamination of aminoalkenes

In situ generated axially chiral zirconium biphenyl amidate complexes are efficient precatalysts for the enantioselective intramolecular hydroamination of aminoalkenes, generating α-substituted pyrrolidines and piperidine with up to 74% ee. Five new chelating amide proligands and three new zirconium amidate complexes have been prepared and fully characterized in this investigation of ligand structure/catalyst function. Solid-state molecular structures of the complexes suggest that the observed moderate and highly variable enantioselectivities are a consequence of the multiple isomers accessible to this family of complexes, including a κ²-(O,O)-bonding motif. Thermal stability studies of the complexes further revealed the tendency of these complexes to undergo diastereoselective dimerization to afford homochiral dimers. These dimeric precatalysts are less efficient when used for the cyclization of aminoalkenes in comparison to their monomeric precursors. These results illustrate the variable coordination modes accessible to amidate ligands and suggest steric factors that must be considered in advanced ligand design.     

Amidate complexes of titanium and zirconium: a new class of tunable precatalysts for the hydroamination of alkynes

A series of bis(amidate)group 4-bis(amido) complexes have been prepared, characterized and have been shown to be highly tunable precatalysts for both the intra- and intermolecular hydroamination of alkynes.     

Mizoroki-Heck coupling using immobilized molecular precatalysts: leaching active species from Pd pincers, entrapped Pd salts, and Pd NHC complexes

The Mizoroki-Heck reaction is a palladium-catalyzed reaction of both practical importance and scientific significance. Two challenges currently faced by practitioners of the Heck and other palladium-catalyzed coupling reactions are (i) minimizing the costs associated with this reaction by developing high TON catalysts or facilitating catalyst recovery and (ii) elucidating the nature of the active species when using various different precatalysts. These two challenges, one practical and one fundamental, served as our motivation in our studies of immobilized molecular palladium(II) complexes as precatalysts in Mizoroki-Heck reactions. This Forum Article describes our investigations in this area, highlighting our approach to the elucidation of the active catalyst by combining kinetic and poisoning studies of several different related precatalysts, our development of new, selective catalyst poisons, and our quest for stable, recyclable supported Heck, Suzuki, and Sonogashira coupling catalysts. Under high-temperature conditions (120 degrees C), all precatalysts studied are conclusively shown to decompose, liberating soluble, active palladium(0) species that are the true catalysts. Techniques for the elucidation of the nature of the truly active Pd species are enumerated.     

Bis(imino)pyridine iron complexes for aldehyde and ketone hydrosilylation

Bis(imino)pyridine iron dinitrogen and dialkyl complexes are well-defined precatalysts for the chemo- and regioselective reduction of aldehydes and ketones. Efficient carbonyl hydrosilylation is observed at low (0.1-1.0 mol %) catalyst loadings and with 2 equiv of either PhSiH(3) or Ph(2)SiH(2), representing one of the most active iron-catalyzed carbonyl reductions reported to date.     

Direct enantioselective Michael addition of aldehydes to vinyl ketones catalyzed by chiral amines

Chiral amines such as (S)-2-[bis(3,5-dimethylphenyl)methyl]pyrrolidine and the C(2)-symmetric (2S,5S)-2,5-diphenylpyrrolidine can catalyze the direct enantioselective Michael addition of simple aldehydes to vinyl ketones. The conditions for this organocatalytic reaction have been optimized and it has been found that the chiral amines catalyze the formation of optically active substituted 5-keto aldehydes in good yields and enantioselectivities, using aldehydes and, e.g., methyl vinyl ketone as starting compounds. Taking into account that the chiral amine can activate the aldehyde and/or the enone, the mechanism for the reaction has been investigated. On the basis of intermediate synthesis, nonlinear effect, and theoretical investigations, the mechanism for the catalytic direct enantioselective Michael addition of aldehydes to vinyl ketones is discussed.     

Heavier alkaline Earth amides as catalysts for the Tischenko reaction

Homoleptic heavier alkaline earth amides, M{N(SiMe3)2}2(THF)2 (M = Ca, Sr, and Ba) are reported as precatalysts for the dimerization of aldehydes to the analogous carboxylic esters (Tischenko reaction). [reaction: see text].     

A new class of easily activated palladium precatalysts for facile C-N cross-coupling reactions and the low temperature oxidative addition of aryl chlorides

A new class of one-component Pd precatalysts bearing biarylphosphine ligands is described. These precatalysts are air- and thermally stable, are easily activated under normal reaction conditions at or below room temperature, and ensure the formation of the highly active monoligated Pd(0) complex necessary for oxidative addition. The use of these precatalysts as a convenient source of LPd(0) in C-N cross-coupling reactions is explored. The reactivity that is demonstrated in this study is unprecedented in palladium chemistry.     

Intermolecular hydroamination of oxygen-substituted allenes. New routes for the synthesis of N,O-chelated zirconium and titanium amido complexes

Intermolecular hydroamination of heteroatom-substituted allenes with a bulky arylamine was carried out using a bis(amidate) bis(amido) titanium(IV) complex (1) as a precatalyst. The reaction of 2,6-dimethylaniline with oxygen-substituted allene 2c or 2d in the presence of complex 1 gives the ketimine regioisomer as the exclusive product. Reduction of such ketimine products resulted in the formation of amino ethers that were further employed as proligands for the formation of N,O-chelating five-membered titana- and zirconacycles. Such sterically demanding N,O-chelating ligands result in the high-yielding preparation of mono-ligated products. Solid-state molecular structures of all the complexes revealed distorted trigonal bipyramidal geometry about the metal centers, with a dative bond between the metal and the oxygen donor atom. These new complexes obtained using hydroamination as the key-step in ligand preparation were also shown to be useful cyclohydroamination precatalysts in their own right.     

Highly chemoselective direct crossed aliphatic-aromatic acyloin condensations with triazolium-derived carbene catalysts

It has been shown for the first time that triazolium precatalysts promote (in the presence of base) highly chemoselective crossed acyloin condensation reactions between aliphatic and ortho-substituted aromatic aldehydes. An o-bromine atom can serve as a temporary directing group to ensure high chemoselectivity (regardless of the nature of the other substituents on the aromatic ring) which then can be conveniently removed. The process is of broad scope and is operationally simple as it does not require the preactivation of any of the coupling partners to ensure selectivity. Preliminary data indicate that highly enantioselective variants of the reaction are feasible using chiral precatalysts.     

Direct catalytic asymmetric aldol reactions of aldehydes

The development of a direct catalytic enantioselective aldol reaction of aldehydes with activated carbonyl compounds catalyzed by chiral amines is presented and the potential demonstrated by the synthesis of optically active beta-hydroxycarboxylic acid derivatives.     

Asymmetric Mannich reactions with in situ generation of carbamate-protected imines by an organic catalyst

The instability of carbamate-protected alkyl imines has greatly hampered the development of catalytic asymmetric Mannich reactions suitable for the synthesis of optically active carbamate-protected chiral alkyl amines. A highly enantioselective Mannich reaction with in situ generation of carbamate-protected imines from stable alpha-amido sulfones catalyzed by an organic catalyst was developed. This reaction provides a concise and highly enantioselective route converting aromatic and aliphatic aldehydes into optically active aryl and alkyl beta-amino acids. [reaction: see text].     

Direct Enantioselective Three‐Component Synthesis of Optically Active Propargylamines in Water

An enantioselective three‐component reaction of aldehydes, amines, and alkynes in water by using a bis(imidazoline)–Cu^I catalysts having a hydrophobic substituent and sodium dodecyl sulfate as a surfactant was developed. The reaction was applied to a broad range of aldehydes and alkynes to give optically active propargylamines with excellent yields (up to 99 %) and enantiomeric excesses (up to 99 % ee).     

New environmentally-friendly solvent-free synthesis of imines using calcium oxide under microwave irradiation

Condensation of structurally diverse aldehydes including heterocyclic aldehydes, like furfural, with various amines in the presence of calcium oxide affording the corresponding imines in solvent-free conditions in good to excellent yields under microwave irradiation is described. A comparative study has been done under thermal conditions. The synergy between dry media and microwave irradiation in this reaction is evaluated by condensing less electrophilic aldehydes with poorly nucleophilic amines. The main advantages of this environmentally friendly protocol are the use of the non-toxic and inexpensive reagent calcium oxide and the considerable rate enhancement in comparison with a thermal reaction.     

A simple and efficient L-prolinamide-catalyzed alpha-selenenylation reaction of aldehydes

An efficient and simple l-prolinamide-catalyzed alpha-selenenylation reaction of aldehydes with N-(phenylseleno)phthalimide has been developed for the efficient preparation of alpha-phenylselenoaldehydes. Such compounds are versatile building blocks for the synthesis of alpha,beta-unsaturated aldehydes, allylic alcohols, and amines. [reaction: see text]     

Nickel-catalyzed multicomponent connection of dimethylzinc, alkynes, 1,3-butadiene, aldehydes, and amines

A nickel(0) species catalyzes the five-component connection reaction of dimethylzinc, alkynes, 1,3-butadiene, aldehydes, and amines, furnishing either 1 or 2 selectively in good yields depending on the kinds of amines, aromatic or aliphatic amines, respectively.     

Combinatorial approach to N-substituted aminocyclitol libraries by solution-phase parallel synthesis and preliminary evaluation as glucocerebrosidase inhibitors

Libraries of N-substituted aminocyclitol derivatives of the scyllo and racemic chiro series by means of parallel solution-phase methodology with the help of robotic technology are described. Chemical diversity has been introduced by reaction of selected scaffolds with a set of aldehydes, acyl chlorides, sulfonyl chlorides, chloroformates, and amines to afford the corresponding amines, amides, sulfonamides, carbamates and ureas, respectively. The optimized methodology has proven excellent, in terms of overall purities of the resulting libraries, for the production of amides. Sulfonamides and carbamates have been obtained in slightly lower purities, while amines afforded modest results. Selected library members have been evaluated as inhibitors of recombinant glucocerebrosidase with K(i) values ranging in the low micromolar scale for the most active members.     

Carboxylic acid catalyzed three-component aza-Friedel-Crafts reactions in water for the synthesis of 3-substituted indoles

[reaction: see text] The carboxylic acid catalyzed three-component aza-Friedel-Crafts reactions of aldehydes, primary amines, and indoles in water have been developed. The aza-Friedel-Crafts products could be easily transformed to various 3-substituted indoles including biologically active compounds. This system offers a novel efficient method for the synthesis of 3-substituted indoles.     

Willgerodt-Kindler reaction at room temperature: Synthesis of thioamides from aromatic aldehydes and cyclic secondary amines

A simple method for the synthesis of thioamide derivatives in DMSO at room temperature and at 120 °C has been developed. Total 27 compounds were prepared under both conditions via a one-pot, three component reaction between substituted aromatic aldehydes, elemental sulfur powder, and cyclic secondary amines. By optimizing the mole ratio of sulfur powder and amines, we have successfully carried out Willgerodt-Kindler reaction of aromatic aldehydes at room temperature. At 120 °C, it is catalyst free reaction with lower reaction time whereas at room temperature, due to the additional amine molecule, Willgerodt-Kindler reaction of aromatic aldehydes is successfully carried out at room temperature. On gram-scale, the reaction is successfully attempted under both conditions with good yields.