Enantioselective Synthesis of α-Alkoxy-Phosphonates by Chiral Phase Transfer Catalysis

Abstract

Enantioselective PTC phosphorylation of aldehydes performed in a two phase (aq. NaOH/toluene) system mediated by chiral crown ether incorporating one or two sugar units. To avoid the rearrangement of hydroxy phosphonate 3 to nonchiral mixed phosphate ester 4 the hydroxy phosphonate was trapped by alkylation to give 5.     

Alkali Metal–Promoted Facile Synthesis of Secondary Amines from Imines and Carbodiimides

We present here an efficient method for the hydroboration of aldimines (-C=N-) with pinacolborane (HBpin) using an alkali metal catalyst, potassium benzyl. The reaction was accomplished with unprecedented catalytic efficiency under mild and solvent-free conditions to afford the high yield of the corresponding N-boryl amines up to 97%. Various functionalities on aldimines were incorporated for hydroboration. The corresponding boryl amines were subjected to further hydrolysis to yield the corresponding secondary amines with good yields up to 89%. This protocol for the reaction demonstrates an atom-economic and green method with diverse imines that bears excellent functional group tolerance. Chemoselective reduction of imines was also attained, with good yields of 74–89%. We also propose the most plausible mechanism involving the formation of metal hydride as the active pre-catalyst.     

Synthesis of Highly Substituted Pyridines through Copper-Catalyzed Condensation of Oximes and α,β-Unsaturated Imines

A copper-catalyzed condensation reaction of oxime acetates and α,β-unsaturated ketimines to give pyridine derivatives is reported. The reaction features mild conditions, high functional-group compatibility, and high regioselectivity with respect to unsymmetrical oxime acetates, thus allowing the preparation of a wide range of polysubstituted pyridines, many of which are not readily accessible by conventional condensation methods.     

Highly Stereoselective Reactions of γ-Sulfinyl Carbanions with Achiral Imines

Abstract

Lithium 2-p-tolylsulfinylbenzyl carbanions react with different N-substituted imines affording 1,2-diaryl ethyl (and propyl) amines with a high stereoselectivity control at both benzyllic (only dependent of the sulfur configuration) and iminic carbons. The anti:syn ratio, ranging between > 96: < 4 and < 2: > 98, dependent on the electronic density at nitrogen.     

Synthesis, Characterization and Structure of 3d Metal Nitrate Complexes with 1,8-Naphthyridine-N-Oxide

The complexes of 3d metal(Cr, Mn, Fe, Co, Ni, Cu, Zn) nitrates with 1 , 8-naphthyridine-N-oxide (NAPYO) were synthesized. The melting points and solubilities of the new complexes were determined and all the complexes were characterized by elemental analyses, IR spectra, UV spectra and molar conductance. The structures of both nickel complex and copper complex were determined by X-ray single crystal diffraction analyses.     

Synthesis of α-Aminophosphonates under Conditions of Phase-transfer Catalysis

An easy preparative synthesis of -aminophosphonates by reaction of azomethines with diethyl phosphite under conditions of phase-transfer catalysis was developed.     

Highly Enantioselective Catalytic Kinetic Resolution of α-Branched Aldehydes through Formal Cycloaddition with Homophthalic Anhydrides

A new catalytic methodology was developed to promote an efficient one-pot kinetic resolution of racemic aldehydes with selectivity (s*) of up to 91 (99:1 d.r., >99 % ee) in a cycloaddition reaction with enolizable anhydrides to afford dihydroisocoumarin products (a core prevalent in natural products and molecules of medicinal interest) containing three contiguous stereocentres.     

Tandem Insertion–[1,3]-Rearrangement: Highly Enantioselective Construction of α-Aminoketones

An enantioselective synthesis of α-aminoketone derivatives were readily available through a tandem insertion–[1,3] O-to-C rearrangement reaction. The rhodium salt and chiral N,N′-dioxide-indium(III) complex make up relay catalysis, which enables the O−H insertion of benzylic alcohols to N-sulfonyl-1,2,3-triazoles, and asymmetric [1,3]-rearrangement of amino enol ether intermediates, subsequently. Preliminary mechanistic studies suggested that the [1,3] O-to-C rearrangement step proceeded through an ion pair pathway.     

Enantioselective Intramolecular α-Arylation of Benzylamine Derivatives: Synthesis of a Precursor to Levocetirizine

A practical, transition metal-free method allows the enantioselective synthesis of α,α-diarylmethylamines by asymmetric α-arylation of benzylamines. Enantioselective lithiation of N′-aryl-N-benzyl-N-isopropyl ureas using a chiral lithium amide base generates a benzyllithium that undergoes an unactivated stereospecific intramolecular nucleophilic aromatic substitution to generate an α,α-diarylmethylamine in the form of its urea derivative, in up to >99 % ee. Treatment with acid induces an “azatropic shift” with retention of configuration, the product of which may be hydrolysed to the target amine.     

Ligand-Controlled Palladium-Catalyzed Carbonylation of Alkynols: Highly Selective Synthesis of α-Methylene-β-Lactones

The first general and regioselective Pd-catalyzed cyclocarbonylation to give α-methylene-β-lactones is reported. Key to the success for this process is the use of a specific sterically demanding phosphine ligand based on N-arylated imidazole ( L11 ) in the presence of Pd(MeCN)₂Cl₂ as pre-catalyst. A variety of easily available alkynols provide under additive-free conditions the corresponding α-methylene-β-lactones in moderate to good yields with excellent regio- and diastereoselectivity. The applicability of this novel methodology is showcased by the direct carbonylation of biologically active molecules including natural products.     

Synthesis of Stannylated Aryl Imines and Amines via Aryne Insertion Reactions into Sn−N Bonds

The reaction of in situ generated arynes with stannylated imines to provide ortho-stannyl-aniline derivatives is reported. The readily prepared trimethylstannyl benzophenone imine is introduced as an efficient reagent to realize the aryne σ-insertion reaction. The imine functionality is an established N-protecting group and insertions proceed with good yields and good to excellent regioselectivities. The product anilines are valuable starting materials for follow-up chemistry thanks to the rich chemistry offered by the trimethylstannyl moiety.     

Silver-Catalyzed Highly Regioselective Synthesis of α-Carbonyl Furans from Enynones

A general and efficient method for the synthesis of a wide range of α-carbonyl furans is described here. The cyclization of enynone is catalyzed by AgBF₄ in a fluorous biphasic system of perfluorodecalin and N,N-dimethylformamide. A variety of chain ketone and cyclic ketone substrates were used to investigate the scope of the reactions.     

Catalysis of highly stereoselective Mannich-type reactions of ketones with α-imino esters by a pyrrolidine-sulfonamide. Synthesis of unnatural α-amino acids

The novel pyrrolidine-sulfonamide I has been prepared and used successfully to catalyze Mannich-type reactions between ketones and α-imino esters. The process is used to efficiently synthesize functionalized α-amino acid derivatives with excellent levels of regio-, diastereo-, and enantio-selectivity.     

Enantioselective Synthesis of Tertiary α-Hydroxyketones from Unfunctionalized Ketones: Palladium-Catalyzed Asymmetric Allylic Alkylation of Enolates

Aiming high: The title reaction for the synthesis of tertiary α-hydroxyketones is reported. Protected 1,2-enediol carbonates, the starting materials, were accessed from simple and readily available enol carbonates. Highly functionalized tertiary α-hydroxyketones can be obtained in high yield with excellent enantioselectivity using this method.     

Stannous Chloride Reduction of Nitroalkenes in Amines. Synthesis and Cycloaddition of α-Dialkylaminoaldoxime

α-Dialkylamino aldoximes 12 were prepared by stannous chloride reduction of nitroalkenes in amines. An intramolecular Michael addition-deoxygenation mechanism is suggested. α-Allylamino aldoxime underwent an efficient Intramolecular Oxime Olefin Cycloaddition (IOOC) giving 13     

Development of an Enantioselective Allylic Alkylation of Acyclic α-Fluoro-β-ketoesters for Asymmetric Synthesis of 3-Fluoropiperidines

The first useful enantioselective Pd-catalyzed asymmetric allylic alkylation of α-fluoro-β-ketoesters has been achieved using the Trost family of chiral ligands yielding products in up to 92 % ee. This work provides new insights regarding the typically modest selectivities associated with acyclic α-fluoroenolates and shows experimental evidence that the typically poor levels of enantiocontrol associated with these systems are not necessarily due to the presence of E/Z enolate mixtures. Finally, this methodology allows the easy preparation of useful 3-fluoropiperidine intermediates, and it is demonstrated that these systems are applicable to a range of functionalization reactions leading to new building blocks for the discovery of bioactive products.     

One-Pot Synthesis of Heterobimetallic Metal–Organic Frameworks (MOFs) for Multifunctional Catalysis

A one-pot synthesis of bimetallic metal–organic frameworks (Co/Fe-MOFs) was achieved by treating stoichiometric amounts of Fe and Co salts with 2-aminoterephthalic acid (NH₂-BDC). Monometallic Fe (catalyst A) and Co (catalyst F) were also prepared along with mixed-metal Fe/Co catalysts (B–E) by changing the Fe/Co ratio. For mixed-metal catalysts (B–E) SEM energy-dispersive X-ray (EDX) analysis confirmed the incorporation of both Fe and Co in the catalysts. However, a spindle-shaped morphology, typically known for the Fe-MIL-88B structure and confirmed by PXRD analysis, was only observed for catalysts A–D. To test the catalytic potential of mixed-metal MOFs, reduction of nitroarenes was selected as a benchmark reaction. Incorporation of Co enhanced the activity of the catalysts compared with the parent NH₂-BDC-Fe catalyst. These MOFs were also tested as electrocatalysts for the oxygen evolution reaction (OER) and the best activity was exhibited by mixed-metal Fe/Co-MOF (Fe/Co batch ratio=1). The catalyst provided a current density of 10 mA cm⁻² at 410 mV overpotential, which is comparable to the benchmark OER catalyst (i.e., RuO₂). Moreover, it showed long-term stability in 1 m KOH. In a third catalytic test, dehydrogenation of sodium borohydride showed high activity (turnover frequency=87 min⁻¹) and hydrogen generation rate (67 L min⁻¹ g⁻¹ catalyst). This is the first example of the synthesis of bimetallic MOFs as multifunctional catalysts particularly for catalytic reduction of nitroarenes and dehydrogenation reactions.     

Cu/Pd Synergistic Dual Catalysis: Asymmetric α-Allylation of an α-CF3 Amide

Despite the burgeoning demand for fluorine-containing chemical entities, the construction of CF₃-containing stereogenic centers has remained elusive. Herein, we report the strategic merger of Cu^I/base-catalyzed enolization of an α-CF₃ amide and Pd⁰-catalyzed allylic alkylation in an enantioselective manner to deliver chiral building blocks bearing a stereogenic carbon center connected to a CF₃, an amide carbonyl, and a manipulable allylic group. The phosphine complexes of Cu^I and Pd⁰ engage in distinct catalytic roles without ligand scrambling to render the dual catalysis operative to achieve asymmetric α-allylation of the amide. The stereoselective cyclization of the obtained α-CF₃-γ,δ-unsaturated amides to give tetrahydropyran and γ-lactone-fused cyclopropane skeletons highlights the synthetic utility of the present catalytic method as a new entry to non-racemic CF₃-containing compounds.