Chiral Secondary Amine Research Articles

ChemInform Abstract: Design of Modified Amine Transfer Reagents Allows the Synthesis of α‐Chiral Secondary Amines via CuH‐Catalyzed Hydroamination.

AbstractThe described method for the synthesis of chiral secondary amines uses a modified monoalkylamine transfer reagent, which limits side and competitive reactions of previously reported methods.

ChemInform Abstract: Michael Addition Catalyzed by Chiral Secondary Amine Phosphoramide Using Fluorinated Silyl Enol Ethers: Formation of Quaternary Carbon Stereocenters.

A chiral secondary amine phosphoramide was developed and identified as a powerful catalyst for the Mukaiyama-Michael addition of fluorinated enol silyl ethers to tetrasubstituted olefins. The resulting products are obtained with high enantioselectivities and contain a quaternary carbon stereocenter bearing either a difluoroalkyl or monofluoroalkyl group.

ChemInform Abstract: Amine‐Promoted Asymmetric [4 + 2] Cycloadditions of α‐Acetoxymethyl Allenoate and Dual Activated Alkenes: Stereoselective Synthesis of Poly‐Substituted Cyclohexenes.

AbstractThe allenic ester (I) reacts with (S)‐benzylmorpholine (BMP) to generate a chiral diene intermediate which readily undergoes Diels—Alder reactions with acrylic nitriles (II) to offer functionalized cyclohexenes (III) after hydrolytic cleavage of the chiral secondary amine auxiliary.

Design of Modified Amine Transfer Reagents Allows the Synthesis of α-Chiral Secondary Amines via CuH-Catalyzed Hydroamination.

The CuH-catalyzed hydroamination of alkenes and alkynes using a silane and an amine transfer reagent represents a simple strategy to access chiral amine products. We have recently reported methods to prepare chiral amines with high efficiency and stereoselectivity using this approach. However, the current technology is limited to the synthesis of trialkylamines from dialkylamine transfer reagents (R2NOBz). When monoalkylamine transfer reagents [RN(H)OBz] were used for the synthesis of chiral secondary amines, competitive, nonproductive consumption of these reagents by the CuH species resulted in poor yields. In this paper, we report the design of a modified type of amine transfer reagent that addresses this limitation. This effort has enabled us to develop a CuH-catalyzed synthesis of chiral secondary amines using a variety of amine coupling partners, including those derived from amino acid esters, carbohydrates, and steroids. Mechanistic investigations indicated that the modified amine transfer reagents are less susceptible to direct reaction with CuH.

Chiral Secondary Amine Phosphoramide Catalyzed Michael Addition

Key words Michael addition - phosphoramides - quaternary carbon stereocenters - asymmetric catalysis

Use of (R)-Mandelic Acid as Chiral Co-Catalyst in the Michael Addition Reaction Organocatalyzed by (1S,4S)-2-Tosyl-2,5-diazabicyclo[2.2.1]heptane under Solvent-Free Conditions

AbstractThis article describes a study on the Michael addition reaction of cyclohexanone to nitroolefins catalyzed by the chiral secondary amine (1S,4S)-2-tosyl- 2,5-diazabicyclo[2.2.1]heptane. Reactions were carried out under solvent-free conditions to make them more environmentally friendly. Initially, the observed diastereoand enantioselectivities were moderate to good, but were significantly improved by lowering the reaction temperature. Furthermore, a variety of chiral acids were also tested as co-catalysts in both of their enantiomeric forms, which revealed that (R)-mandelic acid affords excellent results in terms of yield and stereoselectivity. Monitoring the reaction by MS-TOF allowed for the detection of key reaction intermediates, and a reasonable reaction mechanism in which both catalysts are involved is proposed.

ChemInform Abstract: Design of a Chiral Secondary Amine Ligand for Copper‐Catalyzed anti‐Selective Henry Reaction.

AbstractThe N‐monobenzyl (S)‐binap‐(R,R)‐dpen ligand (CBL) containing a secondary amine moiety promotes the Cu(OAc)2‐catalyzed Henry reaction with excellent enantioselectivity in an anti‐selective fashion.

Michael Addition Catalyzed by Chiral Secondary Amine Phosphoramide Using Fluorinated Silyl Enol Ethers: Formation of Quaternary Carbon Stereocenters.

A chiral secondary amine phosphoramide was developed and identified as a powerful catalyst for the Mukaiyama-Michael addition of fluorinated enol silyl ethers to tetrasubstituted olefins. The resulting products are obtained with high enantioselectivities and contain a quaternary carbon stereocenter bearing either a difluoroalkyl or monofluoroalkyl group.

Michael Addition Catalyzed by Chiral Secondary Amine Phosphoramide Using Fluorinated Silyl Enol Ethers: Formation of Quaternary Carbon Stereocenters

AbstractA chiral secondary amine phosphoramide was developed and identified as a powerful catalyst for the Mukaiyama–Michael addition of fluorinated enol silyl ethers to tetrasubstituted olefins. The resulting products are obtained with high enantioselectivities and contain a quaternary carbon stereocenter bearing either a difluoroalkyl or monofluoroalkyl group.

Dynamic covalent binding and chirality sensing of mono secondary amines with a metal-templated assembly

The recognition and analysis of mono-functionalized organics is an intensive area of research in organic chemistry. Toward this end, an in situ-generated metal-templated dynamic multi-component covalent assembly for the reversible binding and chirality sensing of mono secondary amines is presented. The reaction of pyridine-2-carboxyaldhyde, di(2-picolyl)amine, zinc triflate, tetrabutylammonium chloride, and a series of secondary amines, affords tripodal aminal zinc complexes. The dynamic nature of the system was demonstrated by component exchange of both amines and aldehydes. The equilibrium can be modulated by changing counteranions, concentrations, as well as structural feature of the amines. The competition between two iminium pathways resulted in a unique distribution of components. Due to the enantiotopicity of iminiums, decent diastereoselectivity was observed for chiral secondary amines. The resulting diastereomeric helical complexes were employed for the determination of enantiomeric excess with high accuracy.

Organocatalytic Enantioselective [3+2] Cycloaddition of Azomethine Ylides and Acrolein

AbstractThe [3+2]-cycloaddition reaction between acrolein and in situ generated acyclic azomethine ylides promoted by a chiral secondary amine to generate C-3 unsubstituted pyrrolidines has been studied in detail. Optimum conditions involve the use of the cheap and readily available l-Proline as catalyst to afford the pyrrolidine cycloadduct with complete diastereomeric control and up to 80% enantiomeric control.

Enantioselective Organocatalyzed Oxa‐Michael–Aldol Cascade Reactions: Construction of Chiral 4H‐Chromenes with a Trifluoromethylated Tetrasubstituted Carbon Stereocenter

AbstractThe first organocatalytic asymmetric synthesis of 4H‐chromenes bearing a trifluoromethylated tetrasubstituted carbon center is presented. Chiral secondary amines promote the oxa‐Michael–aldol cascade reaction between alkynals and 2‐trifluoroacetylphenols via iminium–allenamine activation to produce pharmaceutically important heterocycles with excellent enantioselectivities. The proposed reaction can be scaled‐up easily with maintenance of the excellent enantioselectivity.magnified image

ChemInform Abstract: Organocatalytic Asymmetric [4 + 2] Formal Cycloadditions of Cyclohexenylidenemalononitriles and Enals to Construct Chiral Bicyclo[2.2.2]octanes.

AbstractA range of bridged bicyclo[2.2.2]octane derivatives are highly regio‐ and stereoselectively obtained by reaction of cyclohexenylidenemalononitriles with α,β‐unsaturated aldehydes in the presence of proline‐type chiral secondary amine catalysts.

Organocatalytic Enamine-Activation of Cyclopropanes for Highly Stereoselective Formation of Cyclobutanes

A novel organocatalytic activation mode of cyclopropanes is presented. The reaction concept is based on a design in which a reactive donor-acceptor cyclopropane intermediate is generated by in situ condensation of cyclopropylacetaldehydes with an aminocatalyst. The mechanism of this enamine-based activation of cyclopropylacetaldehydes is investigated by the application of a combined computational and experimental approach. The activation can be traced to a favorable orbital interaction between the π-orbital of the enamine and the σ*C-C orbital of the cyclopropyl ring. Furthermore, the synthetic potential of the developed system has been evaluated. By the application of a chiral secondary amine catalyst, the organocatalytically activated cyclopropanes show an unexpected and highly stereoselective formation of cyclobutanes, functionalizing at the usually inert sites of the donor-acceptor cyclopropane. By the application of 3-olefinic oxindoles and benzofuranone, biologically relevant spirocyclobutaneoxindoles and spirocyclobutanebenzofuranone can be obtained in good yields, high diastereomeric ratios, and excellent enantiomeric excesses. The mechanism of the reaction is discussed and two mechanistic proposals are presented.

Design of a Chiral Secondary Amine Ligand for Copper-Catalyzed anti-Selective Henry Reaction

A series of chiral binaphthyl-containing diphenylethylene­diamine (binaph-dpen) ligands was designed and synthesized for the copper-catalyzed asymmetric Henry reaction. The <i>N</i>-monobenzyl (<i>S</i>)-binaph-(<i>R</i>,<i>R</i>)-dpen ligand, with a secondary amine portion, promoted the Cu(OAc)₂-catalyzed Henry reaction with excellent enantioselectivity in an <i>anti</i>-selective manner.

Enantioselective Formation of 3-Substituted Indolinoazepines via Organocatalyzed Conjugate Addition of Indoloazepines to Propargyl Aldehyde

An enantioselective Michael addition has been developed to give 3-substituted indolinoazepines by using indoloazepines as nucleophiles and propargyl aldehyde as electrophile under the promotion of a combination of a chiral secondary amine and trichloro acetic acid. By following the optimized protocol, a library of chiral indolinoazepines with a different substitution pattern was obtained in good to excellent yields and excellent enantioselectivities.

A new organocatalytic concept for asymmetric α-alkylation of aldehydes.

The organocatalytic asymmetric α-alkylation of aldehydes by 1,6-conjugated addition of enamines to p-quinone methides is described. Employing a newly developed class of chiral secondary amine catalysts, α-diarylmethine-substituted aldehydes with two contiguous stereocenters have been synthesized in a simple manner with good diastereocontrol and excellent enantioselectivity.

Base free catalyzed enantioselective Michael reaction of bis(phenylsulfonyl)methane to α,β -unsaturated aldehydes under iminium activation.

The Michael reaction of bis(phenylsulfonyl)methane with α,β-unsaturated aldehydes in the presence of catalytic amounts of a chiral secondary amine is presented. This transformation proceeds in good to excellent yields furnishing the corresponding Michael adducts in excellent enantioselectivities. Furthermore, other chiral building blocks are accessible from the obtained adducts by carrying out selective manipulation of the functional groups present at their structure, being possible to obtain a wide variety of sulfones with good results.

Organocatalytic domino reactions: synthesis of densely functionalized cyclohexene derivatives

A highly enantioselective domino reaction of α,β-unsaturated aldehydes and 4-acetyl-5-oxohexanal catalyzed by a chiral secondary amine catalyst has been developed, providing an efficient synthetic approach for the synthesis of densely functionalized chiral cyclohexene derivatives with high yields (up to 96%) and enantioselectivities (up to 97%ee) under mild conditions.

ChemInform Abstract: An Asymmetric Normal‐Electron‐Demand Aza‐Diels—Alder Reaction via Trienamine Catalysis.

AbstractThe cycloaddition of indol‐3‐ones (I) and 2,4‐dienals (II) via trienamine catalysis of a chiral secondary amine yields multifunctional tricyclic pyrido[1,2‐a]indoles (III) bearing a quaternary chiral center in good stereoselectivities.