Β-amino Ketones Research Articles

One-Pot Synthesis of β-Amino Carbonyl Compounds via the Mannich Reaction Using a Barium-Modified Bismuth-Phosphovanadate Catalyst: A Green and Eco-Friendly Approach

A simple and efficient one-pot three-component Mannich reaction for synthesizing β-amino ketones is developed, using barium-modified bismuth phosphovanadate as a catalyst under room temperature conditions. The catalyst, prepared by thermal synthesis, was characterized by FT-IR, SEM, EDS, and XRD. The reaction involves the formation of C-C and C-N bonds through an enolizable carbonyl compound and an imine intermediate, yielding high amounts of the desired product. The method features low catalyst loading, fast reaction times, excellent yields, recyclability, and a clean reaction profile without by-products.

On-DNA Mannich Reaction for DNA-Encoded Library Synthesis.

The β-amino ketones produced through the Mannich reaction hold significant potential as candidates for various drugs. In this study, we optimized on-DNA Mannich reaction conditions and applied them to investigate the reactions of DNA-conjugated aldehydes with various amine and ketone building blocks. The developed on-DNA Mannich reaction preserved the DNA integrity and established viable routes for library production. These results underscore the potential of the Mannich reaction in DNA-encoded library (DEL) synthesis.

Light-Driven N-Heterocyclic Carbene-Catalyzed Multi-Component Reaction for the Synthesis of β-Amino Ketones.

A N-heterocyclic carbene-catalyzed (NHC) three-component reaction involving N-aminopyridinium salts, alkenes, and aldehydes for the synthesis of β-amino ketones is described. In this reaction, N-aminopyridinium salts and the Breslow intermediate, which is generated from NHC and aldehydes, are utilized to undergo a single-electron transfer process, forming a ketyl radical intermediate and amidyl radicals. Subsequent to the formation of the amidyl radical, it undergoes selective capture by alkenes, followed by radical cross-coupling to yield the desired β-amino ketones.

Stability studies of β-Amino- and β-Hydroxy difluoromethyl ketones in rat serum and rat liver microsomes

Although difluoromethyl ketones are used as tools in chemical biology and leads in drug discovery, the metabolic stability of these compounds is generally uncharacterized and must be inferred from in vivo pharmacological assays. In order to address this gap which impedes their wider use, we have synthesized and performed metabolic stability studies for thirty-nine β-amino and β-hydroxy difluoromethyl ketones. These investigations provide structure–stability relationships of the difluoromethyl ketones following incubation with rodent serum and liver microsomes.

Electrooxidative 1,3-Oxo/Carboamination of Arylcyclopropanes.

Herein, the work demonstrates an electrochemically paired electrolysis approach facilitating the efficient achievement of the electrooxidative 1,3-oxo/carboamination of arylcyclopropanes under mild conditions. The formation of 1,3-arylamination of arylcyclopropanes involves commercially available amine redox mediators through a radical-radical process. In addition, the successful execution of β-amino ketones also occurs under atmospheric conditions. The control experiments supported the existence of key benzylic radical intermediates in the reaction pathway.

Catalytic Asymmetric Desymmetrization of Cyclic 1,3-Diketones Using Chiral Boro-phosphates.

Herein, we report a chiral boro-phosphate-catalyzed reductive amination for the desymmetrization of 2,2-disubstituted 1,3-cyclopentadiones with pinacolborane as the reducing agent, delivering chiral β-amino ketones with an all-carbon quaternary stereocenter in good yields (≤94%), high enantioselectivities (≤97% ee), and excellent diastereoselectivities (>20:1 dr). This reaction has a broad substrate scope and high functional group tolerance. The importance of the chiral products was also demonstrated through the preparation of multifunctional building blocks and heterocycles.

Base mediated aza-[2 + 1] annulation and regioselective aziridine ring-opening cascade: mild synthesis of functionalized β-amino ketones from cyclic N-sulfonyl aldimines and α-carbonyl sulfonium salts.

Cyclic N-sulfonyl aldimines are well-known aza-[2C]-synthons for various [2 + n] annulation reactions. Herein we describe a novel base mediated [2 + 1] annulation and a regioselective aziridine ring-opening reaction cascade, which provides an efficient and distinct synthetic strategy from readily available cyclic N-sulfonyl aldimines and α-carbonyl sulfonium salts leading to β-amino ketone derivatives through the corresponding fused tri-substituted aziridines. This one-pot, two-step process involves formation of C-C and C-N bonds and subsequent cleavage of a C-N bond. The features of the developed reaction include the use of mild reaction conditions, broad substrate scope, and excellent yields. The synthetic utility of this approach was demonstrated by gram-scale operation and further product derivatizations.

Cinchona Alkaloid-derived Polymer Catalysts for Asymmetric Aza-Michael Addition of Aniline to Chalcone

Chiral cinchona alkaloid-derived polymers having cinchona squaramide repeating units showed excellent catalytic performance in the asymmetric aza-Michael reaction between aniline and chalcone. By the use of the polymer organocatalyst, chiral β-amino ketones were yielded in a highly enantioselective manner (up to >99% ee) under solvent-free conditions. The insolubility of the polymer catalyst facilitated the separation of the catalyst from the reaction mixture. The recovered polymer was reused several times without any loss of its catalytic performance. The cinchona alkaloid-derived polymers reported in this paper catalyzed an aza-Michael addition reaction more effectively than already-reported catalysts. The reaction was excellent when the squaramide-linked polymer was used under solvent-free conditions. The polymer catalyst was recoverable by an easy separation from the reaction solution and reused without loss of the catalytic performance.

Theoretical Exploration of Mechanism and Ligand Effects of Asymmetric Hydrogenation of β-Amino Ketone Catalyzed by an Iridium-PNN Catalyst

Theoretical Exploration of Mechanism and Ligand Effects of Asymmetric Hydrogenation of β-Amino Ketone Catalyzed by an Iridium-PNN Catalyst

Desymmetric Reductive Amination of 1,3-Cyclopentadiones to Single Stereoisomer of β-Amino Ketones with an All-Carbon Quaternary Stereocenter by Engineered Amine Dehydrogenases

Regio- and stereoselective reductive amination of diketones offers an attractive method to access chiral β-amino ketones with multiple stereocenters which are unique scaffolds and building blocks for bioactive molecules, but it is still a great challenge in organic chemistry. In this study, mutant amine dehydrogenases (LsAmDHs) were created by directed evolution of a l-phenylalanine dehydrogenase from Lysinibacillus sphaericus to catalyze the desymmetric reductive amination of 2,2-disubstituted-1,3-cyclopentadiones. Using these beneficial LsAmDHs, the corresponding (2R, 3R)-β-amino ketones with an all-carbon quaternary stereocenter were prepared with up to 99% de and ee and up to 84% isolated yields. A cyclopenta[b]hydroquinoline derivative was obtained from 2-methyl-2-(2′-bromobenzyl)-1,3-cyclopentadione or 2-methyl-2-(2′-chlorobenzyl)-1,3-cyclopentadione via sequential enzymatic desymmetric reductive amination and an intramolecular Buchwald–Hartwig cross coupling reaction. Molecular docking and dynamics simulations provided some insights into the roles of key mutations on the improved activity and excellent stereoselectivity toward these un-native substrates. This study not only developed biocatalysts to realize the unprecedented desymmetric reductive amination of 2,2-disubstituted-1,3-cyclopentadiones to the single stereoisomer of the corresponding β-amino ketones but also suggested that engineering of amine dehydrogenase provides a useful tool to address the challenges in asymmetric reductive amination of diketones.

A Heterogeneous, Highly Efficient, and Reusable Mo-Al2O3 Composites Based Organocatalyst for One Pot Three-Component Mannich Reaction for the Synthesis of β-aminocarbonyl Compounds

We have successfully developed a new Mo-Al2O3/p-TSA organocatalyst which has improved the yield of the Mannich reaction. This protocol has the advantage of mild conditions, high yield, easy work-up, environmentally friendly procedure, and the solid catalyst was recycled. The catalyst was analysed by XRD, SEM, and EDS techniques. The synthesized Mo-Al2O3composites were used in the presence of p-toluene sulfonic acid (p-TSA) conducts the one-pot three-component Mannich reaction and various β-amino ketones prepared with good yields and characterized by IR, 1H, and 13C NMR Techniques.

The regioselective Wacker oxidation of internal allylamines: synthesis of functionalized and challenging β-amino ketones.

A convenient and general protocol for the palladium-catalysed oxidation of internal allylamine derivatives to β-amino ketones is reported. The transformation occurs at room temperature and shows a wide substrate scope as well as high functional group and N-protecting group tolerance. We also describe potential applications of the method, e.g., the synthesis of bioactive molecules or simple transformations of selected β-amino ketones into other interesting building blocks.

Photocatalytic Oxo-Amination of Aryl Cyclopropanes through an Unusual SN2-Like Ring-Opening Pathway: Won >99% ee.

One-pot oxo-amination of unactivated cyclopropanes with safe, green dioxygen as an oxidant and low-cost amines as nitrogen sources has generated interest since this can directly result in uniform β-located difunctional units. Formation of the three-electron cation radical followed by the nucleophilic attack of amines to open the strained ring of cyclopropanes catalyzed by classic noble-complex photocatalysts was a promising strategy. However, this ring-opening pathway could not maintain the entire second-order nucleophilic substitution (SN2) conversion, which generally led to unsatisfactory enantioselectivity (enantiomeric excess (ee) value ∼60%). Here, we demonstrate that for such a one-step oxo-amination of cyclopropanes with benign dioxygen and pyrazoles, a highly uniform inversion of configuration could be first accomplished through a TiO2 photocatalyst. This strategy features low-cost, semiheterogeneous photocatalysis and environmentally friendly reaction conditions, without using any sacrificial reagent or additive. Importantly, our protocol not only provides a relatively broad substrate scope tolerant to a certain range of substituted cyclopropanes and pyrazoles, resulting in various β-amino ketone products (∼50 examples) with excellent conversions and yields, but also retains excellent enantioselectivity (ee value ∼99%). A concerted SN2 ring opening raised from an oxetane cation intermediate rather than a conventional three-electron cation radical prior to attaching to dioxygen was proposed.

Iridium-catalyzed enantioselective synthesis of chiral γ-amino alcohols and intermediates of (S)-duloxetine, (R)-fluoxetine, and (R)-atomoxetine

Chiral γ-amino alcohols are the prevalent structural motifs and building blocks in pharmaceuticals and bioactive molecules. Enantioselective hydrogenation of β-amino ketones provides a straightforward and powerful tool for the synthesis of chiral γ-amino alcohols, but the asymmetric transformation is synthetically challenging. Here, a series of tridentate ferrocene-based phosphine ligands bearing modular and tunable unsymmetrical vicinal diamine scaffolds were designed, synthesized, and evaluated in the iridium-catalyzed asymmetric hydrogenation of β-amino ketones. The system was greatly effective to substrates with flexible structure and functionality, and diverse β-tertiary-amino ketones and β-secondary-amino ketones were hydrogenated smoothly. The excellent reactivities and enantioselectivities were achieved in the asymmetric delivery of various chiral γ-amino alcohols with up to 99% yields, >99% ee values, and turnover number (TON) of 48,500. The gram-scale reactions with low catalyst loading showed the potential application in industrial synthesis of chiral drugs, such as (S)-duloxetine, (R)-fluoxetine, and (R)-atomoxetine.

Manganese-Catalyzed Asymmetric Formal Hydroamination of Allylic Alcohols: A Remarkable Macrocyclic Ligand Effect.

A unique family of chiral peraza N6 -macrocyclic ligands, which are conformationally rigid and have a tunable saddle-shaped cavity, is described. Utilizing their manganese(I) complexes, the first example of earth-abundant transition metal-catalyzed asymmetric formal anti-Markovnikov hydroamination of allylic alcohols was realized, providing a practical access to synthetically important chiral γ-amino alcohols in excellent yields and enantioselectivities (up to 99 % yield and 98 % ee). The single-crystal structure of a MnI complex indicates that the manganese atom coordinates with the chiral dialkylamine moiety in a bidentate fashion. Further DFT calculations revealed that five of the six nitrogen atoms in the ligand were engaged in multiple noncovalent interactions with Mn, an isopropanol molecule, and a β-amino ketone intermediate via coordination, hydrogen bonding, and/or CH⋅⋅⋅π interactions in the transition state, showing a remarkable role of the macrocyclic framework.

Hf(OTf)4-Catalyzed Three-Component Synthesis of N-Carbamate-Protected β-Amino Ketones.

Hafnium(IV) triflate (Hf(OTf)4) has been identified as a potent catalyst for the direct three-component synthesis of β-carbamate ketones. This new method, featuring a low catalyst loading, fast reaction rate, and solvent-free conditions, provided facile access to a diversity of carbamate-protected Mannich bases. A mechanistic investigation indicated that the three-component reaction proceeds via sequential aldol condensation and aza-Michael addition, but not the Mannich-type pathway.

Ammonium Chloride Promoted One-Pot, Three-Component Mannich Reaction: An Efficient Synthesis of β-Amino Ketones and β-Amino Esters

Ammonium chloride was found to efficiently reagent for the one pot-three component Mannich reaction between aromatic aldehyde, ketone and amine in ethanol at room temperature to furnish β-amino ketones in good to excellent yields. The said protocol was further applied for the direct synthesis of β-amino esters, which are important precursors for the synthesis of β-amino acids. This protocol is potentially applicable for the development of a clean and environment-friendly strategy for the synthesis of β-amino ketones and found applications in the synthesis of potent biologically active molecules due to its simple experimental conditions, inexpensive reagents and straight forward product isolation procedure.

Metal-free photosensitized intermolecular carboimination of alkenes: a green and direct access to both β-amino acids and β-amino ketones.

β-Amino carbonyl substructures are privileged motifs in natural products and active pharmaceutical compounds. Here, we report a photoinduced metal-free and highly regioselective intermolecular carboimination method via the simultaneous introduction of amino and carbonyl groups into the CC double bond in one step, providing straightforward, green and general access to both β-amino acid and β-amino ketone motifs from readily available alkene feedstocks. The mild reaction conditions, excellent functional group tolerance and product diversity should make this a broadly applicable carboimination approach of very broad interest to organic and medicinal chemists.

Synthesis of methylene-bridged α,β-unsaturated ketones: α-Csp3-H methylenation of aromatic ketones using Selectfluor as a mild oxidant.

A three starting material four component reaction (3SM-4CR) is developed for the synthesis of α,β-unsaturated ketones and β-amino ketones in good yields. The reaction employs tetramethylethylenediamine (TMEDA) as a methylene and terminal olefin source, and Selectfluor as a mild oxidant. TMEDA worked as a dual synthon to provide two carbons in this metal-free transformation process. The scope and versatility of the methods have been demonstrated with 23 examples. A Selectfluor-promoted oxidative reaction mechanism is proposed based on the results of the experimental studies.

Efficient access to β-amino acid ester/β-amino ketone derivatives via photocatalytic radical alkoxycabonylimidation/carbonylimidation of alkenes

A photocatalytic protocol for the synthesis of β-amino acid ester and β-amino ketone derivatives is developed using simple and easy-to-synthesize oxime oxalate and oxime phenylglyoxylate as difunctionalization reagents.