Α-substituted Amines Research Articles

Visible-Light-Driven α-Substituted Amines Enabled by In Situ Formation of Amine Substrate Aggregates.

A visible-light-driven, photocatalyst-free, air-promoted, α-substituted reaction of amines with varying nucleophiles is described. The amine substrate aggregates formed in situ through physical π-π stacking by H2O regulation in organic solvent can absorb visible light and then generate iminium ion intermediates, which undergo nucleophilic substitution reactions with varying nucleophiles to afford α-substituted amines. This reaction features catalyst-free, good functional group tolerance, simple operation procedure, and green reaction conditions.

Efficient synthesis of β-substituted amines via combining deoxygenation of amides with photochemical organocatalysis

Catalytic deoxygenative conversion of amides to substituted amines is an efficient pathway for amine synthesis. α-Substituted amines are generally obtained by classic nucleophilic addition of nucleophiles to active electrophilic intermediates formed from amides. Here, we develop a deoxygenative reaction of amides that combines iridium catalysis and photochemical organocatalysis, giving structurally diverse β-substituted tertiary alkylamines with moderate to excellent yields (up to 93%) with broad substrate scope (57 examples). Mechanistic studies suggest that the combination of iridium (Ir)-catalyzed partial reduction of amides and photochemical organocatalysis of α-bromoketones under visible light plays a crucial role in cross-coupling of these two readily accessible feedstocks. The active electrophilic radicals from photochemical organocatalysis act as functionalization partners with the in-situ -formed enamine intermediates from the Ir-catalyzed reduction of amides instead of traditional nucleophilic addition to iminium ions, leading to formation of β-substituted amines. • Combination of Ir-catalyzed reduction of amide and photochemical organocatalysis • Coupling of active electrophilic radicals with enamine intermediates • Tandem catalysis: Ir catalysis, photochemical organocatalysis, Ir catalysis • Deoxygenative functionalization of amides to β-substituted amines Deoxygenative functionalization of ubiquitous amides to synthetically important amines is of great significance. Jiang et al. develop deoxygenative cross-coupling of amides with electrophilic radicals by rational combination of Ir-catalyzed reduction of amides with photochemical organocatalysis, leading to a suite of functionally and structurally diverse β-substituted amines.

Tandem-catalysis-enabled highly chemoselective deoxygenative alkynylation and alkylation of tertiary amides: a versatile entry to functionalized α-substituted amines

We report a unified relay catalysis strategy for the direct reductive alkynylation and reductive alkylation of tertiary amides to afford α-alkynylamines and α-branched amines.

Effect of the enamine pyramidalization direction on the reactivity of secondary amine organocatalysts

Chiral secondary amines are valuable catalysts for reactions that proceed through an enamine intermediate. Here, we explored the importance of the pyramidalization direction of the enamine-N on the reactivity of chiral enamines with a combination of computational, NMR spectroscopic, and kinetic experiments. Studies with peptidic catalysts that bear cyclic amines with different ring sizes revealed that endo-pyramidalized enamines are significantly more reactive compared to exo-pyramidalized analogs. The results show that the pyramidalization direction can have a greater effect than n→π* orbital overlap on the reactivity of chiral enamines. The data enabled the development of a catalyst with higher reactivity compared to the parent catalyst.

Transition metal-catalyzed α-alkylation of amines by C(sp3)‒H bond activation

α-Substituted amines are present in a myriad of biologically active natural and synthetic products. With the objective of developing atom-economical reactions, a panel of synthetic methods allowing the direct functionalization of C(sp3)‒H bonds adjacent to the nitrogen atom have been developed. The field remains dominated by the sequence α-lithiation/addition on an electrophile even if the use of reactive organolithium reagents is not compatible with all functional groups. Over the past ten years, an increasing interest has been devoted to metal-catalyzed CH-activation, some studies being specially dedicated to C(sp3)‒H bond activation. Notably, this approach has been envisioned to perform direct α-functionalization of amines. The aim of this article is to give an overview of synthetic methods for transition metal-catalyzed α-alkylation of amines by C(sp3)‒H bond activation.

C-H Functionalization of Amines via Alkene-Derived Nucleophiles through Cooperative Action of Chiral and Achiral Lewis Acid Catalysts: Applications in Enantioselective Synthesis.

Catalytic transformations of α-amino C-H bonds to afford valuable enantiomerically enriched α-substituted amines, entities that are prevalent in pharmaceuticals and bioactive natural products, have been developed. Typically, such processes are carried out under oxidative conditions and require precious metal-based catalysts. Here, we disclose a strategy for an enantioselective union of N-alkylamines and α,β-unsaturated compounds, performed under redox-neutral conditions, and promoted through concerted action of seemingly competitive Lewis acids, B(C6F5)3, and a chiral Mg-PyBOX complex. Thus, a wide variety of β-amino carbonyl compounds may be synthesized, with complete atom economy, through stereoselective reaction of an in situ-generated enantiomerically enriched Mg-enolate and an appropriate electrophile.

Enantioselective Three-Component Synthesis of α-Substituted Amines

Enantioselective Three-Component Synthesis of α-Substituted Amines

Palladium-Catalyzed Enantioselective Three-Component Synthesis of α-Substituted Amines.

The first general palladium-catalyzed, enantioselective three-component synthesis of α-arylamines starting from sulfonamides, aldehydes, and arylboronic acids has been developed. These reactions generate a wide array of α-arylamines with high yields and enantioselectivities. Notably, this process is tolerant to air and moisture, providing an operationally simple approach for the synthesis of chiral α-arylamines.

Copper‐Catalyzed Cross‐Coupling of Imines, Acid Chlorides, and Organostannanes: A Multicomponent Synthesis of α‐Substituted Amides.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Intramolecular [4 + 2] Cycloadditions of Iminoacetonitriles: A New Class of Azadienophiles for Hetero Diels—Alder Reactions.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Parallel Solution-Phase Asymmetric Synthesis of α-Branched Amines

A general method is reported for the parallel solution-phase asymmetric synthesis of α-substituted amines based on the stereoselective addition of organomagnesium reagents to enantiomerically pure tert-butanesulfinyl imines. The sulfinyl imines are prepared in high yields by condensation of tert-butanesulfinamide with aldehydes, followed by quenching and removal of the titanium species with diatomaceous earth saturated with water. Addition of organomagnesium reagents then proceeds with high diastereoselectivities. After aqueous workup following the organometallic addition, liquid/liquid separation is readily accomplished using 1PS filter cartridges. Acidic alcoholysis of the resulting sulfinamide products, followed by acid/base extraction and isolation, affords the desired amine hydrochlorides. The effectiveness of this sequence of reaction and workup procedures was demonstrated by the parallel synthesis of 10 α-substituted amines in excellent overall yields (72−84%) and high enantiopurities (80−97% ee). ...

Choosing the Right Reagent for the Determination of the Absolute Configuration of Amines by NMR: MTPA or MPA?

Molecular mechanics, semiempirical (AM1), aromatic shielding effect calculations, and dynamic NMR experiments demonstrate that MTPA amides are constituted by three main conformers, sp, ap3, and ap1 due to restricted rotation around the Cα−CO and the Cα−Ph bonds. Unlike MTPA esters, where the three rotamers have almost identical populations, in MTPA amides rotamer sp is more populated than the other two and has a shielding rather than deshielding character. This produces larger ΔδRS values for MTPA amides than for MTPA esters. Therefore, inference of absolute configuration with this reagent should be correspondingly more reliable for amines than for alcohols. Assignment of absolute configuration of chiral primary α-substituted amines with MTPA gives similar ΔδRS values than with MPA. A graphical description of the aromatic magnetic field distribution in MTPA and MPA amides, and its use to correlate the average chemical shifts with the absolute configuration of the amine, is presented.

An approach to α-substituted amines

A number of amines have been alkylated at the position alpha to nitrogen via free radical methodology. N-(2-Iodobenzyl) and N-(2-iodobenzoyl)‘protected’ amines have been used to generate radicals which rapidly undergo a 1,5-hydrogen shift to give more stable α-amino radicals. These can subsequently be trapped by electron deficient alkenes to give α-alkylated amines.

Additions and Corrections - A Synthesis of α-Substituted Amines.

Additions and Corrections - A Synthesis of α-Substituted Amines.

Polar characteristics and conformations of certain ?-substituted amines

1. Measurements on the dipole moments and molar Kerr constants of α-substituted amines indicate that the substituent in such compounds is predominantly trans-oriented with respect to the unshared electron pair of the N atom, thus permitting n-σ* interaction. 2. The plane of the imide rings of the N-aminomethylated cyclic imides is shielded by the C-H bonds.

Reactions of organolithium reagents with amines; syntheses of ketones and α-substituted amines from primary amines

Reactions of organolithium reagents with amines; syntheses of ketones and α-substituted amines from primary amines