Mannich Addition Reactions Research Articles

Recent Progress in Synthesis of Alkyl Fluorinated Compounds with Multiple Contiguous Stereogenic Centers.

Organic fluorides are widely used in pharmaceuticals, agrochemicals, material sciences, and other fields due to the special physical and chemical properties of fluorine atoms. The synthesis of alkyl fluorinated compounds bearing multiple contiguous stereogenic centers is the most challenging research area in synthetic chemistry and has received extensive attention from chemists. This review summarized the important research progress in the field over the past decade, including asymmetric electrophilic fluorination and the asymmetric elaboration of fluorinated substrates (such as allylic alkylation reactions, hydrofunctionalization reactions, Mannich addition reactions, Michael addition reactions, aldol addition reactions, and miscellaneous reactions), with an emphasis on synthetic methodologies, substrate scopes, and reaction mechanisms.

Synthesis of Aminoalkyl Sclareolide Derivatives and Antifungal Activity Studies.

Sclareolide was developed as an efficient C-nucleophilic reagent for an asymmetric Mannich addition reaction with a series of N-tert-butylsulfinyl aldimines. The Mannich reaction was carried out under mild conditions, affording the corresponding aminoalkyl sclareolide derivatives with up to 98% yield and 98:2:0:0 diastereoselectivity. Furthermore, the reaction could be performed on a gram scale without any reduction in yield and diastereoselectivity. Additionally, deprotection of the obtained Mannich addition products to give the target sclareolide derivatives bearing a free N-H group was demonstrated. In addition, target compounds 4-6 were subjected to an antifungal assay in vitro, which showed considerable antifungal activity against forest pathogenic fungi.

Carbene-Catalyzed Activation of Formyl-phenylacetic Esters for Access to Chiral Dihydroisoquinolinones.

A carbene-catalyzed reaction to synthesize chiral dihydroisoquinolinones via an o-quinodimethane (o-QDM) intermediate is disclosed. o-QDM reacts with cyclic sulfonic imines via annulation to afford highly enantioenriched dihydroisoquinolinone products. ESI-HRMS studies suggest a stepwise Mannich addition and acylation reaction pathway, and the pathways of the catalytic and uncatalyzed background reactions are evaluated via DFT calculations.

Greener Approaches to Selected Asymmetric Addition Reactions Relevant to Drug Development

Asymmetric organic synthesis is of paramount importance in the development of drugs. Asymmetric addition reactions such as aldol reaction, Michael addition, and Mannich addition reactions are important carbon-carbon bond-forming reactions and have been employed in the synthesis of a broad range of biologically important molecules. Many of these reactions have been developed under solvent-free conditions or in greener solvents like water. Several reactions have been developed at room temperature or by using a non-conventional energy source such as microwave irradiation. Several greener catalysts have been developed for such reactions. The present review article discusses the application of green chemistry parameters in the development of selected asymmetric addition reactions leading to biologically important molecules during the last ten years. Asymmetric aldol reactions, asymmetric Michael reactions, and different asymmetric addition reactions involving imines such as Mannich reaction, aza-benzoin reaction, etc. in aqueous media or under solvent-free conditions have been reviewed. Application of different types of catalysts such as prolinamides, 1,2-diamines, polymer and magnetic nanoparticle-supported chiral catalysts is demonstrated.

Applications of 3,5‐Dialkyl‐4‐nitroisoxazoles and Their Derivatives in Organic Synthesis#

AbstractThe methyl/methylene group present at the 5th position of 3,5‐dialkyl‐4‐nitroisoxazoles show characteristic reactivity because of the presence of −NO2 at the 4th position in the structure. This methyl/methylene is used for the generation of carbanion that undergo Knoevenagel condensation, vinylogous nitroaldol (Henry type), Mannich and Michael addition reactions. The unsaturated systems generated by Knoevenagel condensation are used for 1,4‐ and 1,6‐Michael addition, epoxidation, aziridination, cycloaddition ([2+1], [2+2], [2+3] and [4+2]) cascade/domino/tandem and dihydroxylation reactions. This resulted into the generation of many functionalized and complex organic molecules in asymmetric and racemic forms. Along with these, the isoxazole moiety has also been used as −COOH equivalent by basic/oxidative hydrolysis. This review describes recent literature on the synthetic applications of 3,5‐dialkyl‐4‐nitroisoxazoles and their derivatives for the generation of functionalized/complex heterocyclic compounds using above mentioned type of reactions and concepts.

Asymmetric Mannich reactions of (S)-N-tert-butylsulfinyl-3,3,3-trifluoroacetaldimines with yne nucleophiles.

In the present work, arylethynes were studied as new C-nucleophiles in the asymmetric Mannich addition reactions with (S)-N-tert-butylsulfinyl-3,3,3-trifluoroacetaldimine. The reactions were conducted under operationally convenient conditions affording the corresponding Mannich adducts with up to 87% yield and 70:30 diastereoselectivity. The isomeric products can be separated using regular column chromatography to afford diastereomerically pure compounds. The purified Mannich addition products were deprotected to give the target enantiomerically pure trifluoromethylpropargylamines. A mechanistic rationale for the observed stereochemical outcome is discussed.

Synthesis of N-doped carbon quantum dots from bio-waste lignin for selective irons detection and cellular imaging.

Facile synthesis of carbon quantum dots with high fluorescence and excellent biocompatibility from plentiful and biocompatible materials still attracts much attention because of their great potential value in sensors and imaging. In this study, a highly fluorescent and super biocompatible N-doped carbon quantum dots derived from green precursor of aminated alkali lignin has been synthesized for cellular imaging. The amine-rich lignin carbon quantum dots (AL-CQDs) was firstly synthesized by introduction of secondary amine groups into lignin backbones via both Mannich and Machael addition reaction. The resulted AL-CQDs within the range of 4-10 nm exhibited excitation-dependent and pH-stable fluorescence properties and was employed for the detection of irons with a wide range from 100 nM to 1 mM and a low detection limit of 8 nM, in which the Fe3+ ions could be captured by the amine groups of the AL-CQDs to form an absorbent complex, resulting in a significant fluorescence quenching. Meanwhile, the AL-CQDs were successfully applied to cell imaging and intracellular irons detection benefited from low cytotoxicity and good biocompatibility. This work would shed much light on converting agricultural waste into bio-based nanomaterials and their potential applications.

One-Pot Synthesis of Diverse Collections of Benzoxazepine and Indolopyrazine Fused to Heterocyclic Systems.

The development of efficient and modular synthetic methods for the synthesis of diverse collection of privileged substructures needed for a drug design and discovery campaign is highly desirable. Benzoxazepine and indolopyrazine ring systems form the core structures of distinct members of biologically significant molecules. Several members of these families have gained attention due to their broad biological activities, which depend on the type of ring-fusion and peripheral substitution patterns. Despite the potential applications of these privileged substructures in drug discovery, efficient, atom-economic, and modular strategies for their access are underdeveloped. Herein, a one-step build/couple/pair strategy that uniquely allows access to diversely functionalized benzoxazepine and indolopyrazine scaffolds is described. The methodology features a one-pot combination of condensation, Mannich, oxidation, and aza-Michael addition reactions, employing a variety of functionalized anilines and aldehydes suitably poised with Micheal acceptor. Scandium triflate (Sc(OTf)3) in acetonitrile (ACN) was found to promote the construction of benzoxazepines scaffolds, while sodium metabisulfite (Na2S2O5) in aqueous EtOH rapidly enhanced the cascade reaction that led to diverse collections of indolopyrazine frameworks. These protocols represent modular, efficient, and atom-economic access of constrained benzoxazepine and indolopyrazine systems with more than 10 points of diversity and large substrate tolerance.

Highly Enantioselective Synthesis of 11‐Substituted 10,11‐Dihydrodibenzo[b,f][1,4]thiazepines through a Proline‐Catalyzed Mannich Reaction of Seven‐Membered Cyclic Imines with Ketones

AbstractHighly enantioselective Mannich addition reactions of N,S‐heterocyclic dibenzo[b,f][1,4]thiazepines as seven‐membered cyclic imine substrates with ketones were developed by using proline as an organocatalyst. Substituted dibenzo[b,f][1,4]thiazepines and various unsymmetrical alkyl methyl ketones were used as substrates and optimized reaction conditions offered an efficient method to synthesize optically active 11‐substituted 10,11‐dihydrodibenzo[b,f][1,4]thiazepine derivatives that contained a carbonyl functional group in 91–99 % ee. Furthermore, we found that the reactions could also be performed on a gram scale, whilst maintaining high yields and enantioselectivities. The carbonyl group of the Mannich products also underwent diastereoselective reduction, thus yielding a new hydroxy‐substituted chiral stereogenic center with moderate‐to‐excellent diastereoselectivities, good yields, and without the loss of enantiomeric excess.

Asymmetric Synthesis of Quaternary β‐Perfluorophenyl‐β‐amino‐indolin‐2‐ones

Reported herein is a design and synthesis of N‐tert‐butylsulfinyl‐(perfluoro)benzaldimine, and a study of its reactivity and stereocontrolling properties in Mannich addition reactions with indolinone derived tertiary enolates generated in situ. The corresponding products, quaternary β‐perfluorophenyl‐β‐amino‐indolin‐2‐ones, were obtained with good to excellent yields and diastereoselectivity, underscoring the exciting synthetic potential of this newly introduced pentafluorophenyl‐containing chiral imine.

Asymmetric synthesis of C–F quaternary α-fluoro-β-amino-indolin-2-ones via Mannich addition reactions; facets of reactivity, structural generality and stereochemical outcome

An asymmetric detrifluoroacetylative Mannich reaction between in situ generated tertiary enolates and sulfinyl-imines has been explored. The reaction provides a new access to α-fluoro-β-amino-indolin-2-ones with tetrasubstituted fluorinated stereogenic center.

ChemInform Abstract: Direct Carbon—Carbon Bond Formation via Reductive Soft Enolization: A syn‐Selective Mannich Addition of α‐Iodo Thioesters.

The β-amino carboxylic acid moiety is a key feature of numerous important biologically active compounds. We describe a syn-selective direct Mannich addition reaction that uses α-iodo thioesters and sulfonyl imines and produces β-amino thioesters. Enolate formation is achieved by reductive soft enolization. The products of the reaction provide straightforward access to biologically important β-lactams through a variety of known reactions.

ChemInform Abstract: Asymmetric Synthesis of β‐Trifluoromethyl‐β‐amino Acids, Including Highly Sterically Constrained α,α‐Dialkyl Derivatives.

AbstractTitle compounds are synthesized via Mannich addition reaction of chiral trifluoroacetaldimine and lithium enolates of alkyl acetates.

In search of diamine analogs of the α,α-diphenyl prolinol privileged chiral organocatalyst. Synthesis of diamine derivatives of α,α-diphenyl-(S)-prolinol and their application as organocatalysts in the asymmetric Michael and Mannich reactions

This paper describes improved reaction conditions for the substitution of the hydroxyl group in (S)-diphenyl(pyrrolidin-2-yl)methanol by the azide group, which was then reduced to the diamine derivative. We examined two protecting groups (N-Bn and N-Boc) on the pyrrolidine nitrogen in order to functionalize the primary amino group into various amide, alkylated amine, sulfonamide, thiourea and triazole derivatives. Notably, carefully controlled conditions were required to generate the desired derivatives from the sterically hindered benzhydrylamine moiety. Unexpectedly, upon removal of the N-protecting group in derivatives containing electrophilic polar double bonds (CS, CO) cyclization took place, affording products such as amidines. The target compounds were evaluated as bifunctional organocatalysts in the asymmetric Michael and Mannich addition reactions. (S)-2-(Azidodiphenylmethyl)pyrrolidine (S)-7 was identified as the most efficient organocatalyst among the various diamine derivatives of α,α-diphenyl-(S)-prolinol prepared in this work.

Asymmetric synthesis of β-trifluoromethyl-β-amino acids, including highly sterically constrained α,α-dialkyl derivatives

Reported herein is asymmetric synthesis of β-trifluoromethyl-β-amino acids via Mannich addition reactions between (Ss)-N-(tert-butanesulfinyl)-3,3,3-trifluoroacetaldimine and lithium enolates of alkyl acetates. In particular, the scope of this approach allows for preparation of the previously illusive, highly sterically constrained α,α-dialkyl-β-trifluoromethyl-β-amino acids. The method affords the target products with good to excellent chemical yields and diastereoselectivities.

Recent Progress in the in situ Detrifluoro­acetylative Generation of Fluoro Enolates and Their Reactions with Electrophiles

AbstractDetrifluoroacetylative generation of fluoro enolates is an emerging area of high‐impact research. In this review article we provide, for the first time, a comprehensive and critical treatment of this subject. The reaction types reported to date include Mannich, aldol, and Michael addition and halogenation reactions. These processes can be very successfully conducted in asymmetric fashion, in stoichiometric or catalytic mode. In general, these reactions allow for synthetically rather simple and practical installation of CF2, CHF, and quaternary CF structural units into various types of organic compounds. In particular, the overall scientific importance, as well as the potential influence of this methodology for the development of useful approaches to the preparation of pharmaceutically valuable compounds is highlighted. Attractive features such as operationally convenient, mild reaction conditions, remarkable substrate generality, and excellent stereochemical outcome bode well for widespread applications of this innovative and synthetically advanced approach.

ChemInform Abstract: Synthesis of Trifluoromethyl‐Containing Vicinal Diamines by Asymmetric Decarboxylative Mannich Addition Reactions.

Herein is reported a study of asymmetric decarboxylative Mannich addition reactions between (Ss)-N-t-butylsulfinyl-3,3,3-trifluoroacetaldimine and Schiff bases derived from various aldehydes and lithium 2,2-diphenylglycinate. These reactions proceed with excellent diastereoselectivities and good chemical yields, providing a practical method for preparation of trifluoromethyl-containing vicinal diamines. The procedures can be conducted under convenient conditions, rendering this approach of high synthetic value.

ChemInform Abstract: Synthesis of α,α‐Difluoro‐β‐amino Carbonyl‐Containing Sulfonamides and Related Compounds.

AbstractMannich addition reactions between in situ generated α,α‐difluoroenolates and various N‐sulfonyl imines readily occur with exceptionally high reaction rates at ambient temperature.

Synthesis of trifluoromethyl-containing vicinal diamines by asymmetric decarboxylative mannich addition reactions.

Herein is reported a study of asymmetric decarboxylative Mannich addition reactions between (Ss)-N-t-butylsulfinyl-3,3,3-trifluoroacetaldimine and Schiff bases derived from various aldehydes and lithium 2,2-diphenylglycinate. These reactions proceed with excellent diastereoselectivities and good chemical yields, providing a practical method for preparation of trifluoromethyl-containing vicinal diamines. The procedures can be conducted under convenient conditions, rendering this approach of high synthetic value.

Synthesis of α,α-difluoro-β-amino carbonyl-containing sulfonamides and related compounds

Mannich addition reactions between in situ generated α,α-difluoroenolates and various N-sulfonyl imines readily occur with exceptionally high reaction rates at ambient temperature. The method features remarkable generality and enjoys operationally convenient conditions underscoring its practicality and methodological importance for preparation of sulfonamides bearing β-amino-α,α-difluoro ketone moiety.