Acyclic Imines Research Articles

Catalytic aza-Nazarov cyclization reactions to access α-methylene-γ-lactam heterocycles.

We have developed a catalytic aza-Nazarov reaction of N-acyliminium salts generated in situ from the reaction of a variety of cyclic and acyclic imines with α,β-unsaturated acyl chlorides to afford substituted α-methylene-γ-lactam heterocycles. The reactions proceed effectively in the presence of catalytic (20 mol %) amounts of AgOTf as an anion exchange agent or hydrogen-bond donors such as squaramides and thioureas as anion-binding organocatalysts. The aza-Nazarov cyclization of 3,4-dihydroisoquinolines with α,β-unsaturated acyl chlorides gives tricyclic lactam products 7 in up to 79% yield with full diastereocontrol (dr = >99:1). The use of acyclic imines in a similar catalytic aza-Nazarov reaction with 20 mol % of AgOTf results in the formation of α-methylene-γ-lactam heterocycles 19 in up to 76% yield and with good to high diastereoselectivities (4.3:1 to 16:1). We have demonstrated the scalability of the reaction with a gram-scale example. The relative stereochemistry of the α-methylene-γ-lactam products 19 has been determined via the single-crystal X-ray analysis of lactam 19l. In order to shed light on the details of the reaction mechanism, we have performed carefully designed mechanistic studies which consist of experiments on the effect of β-silicon stabilization, the alkene geometry of the α,β-unsaturated acyl chloride reactants, and adventitious water on the success of the catalytic aza-Nazarov reaction.

Copper-catalyzed asymmetric propargylation of imines enabled by a biphenol-based phosphoramidite ligand

Cu-catalyzed asymmetric propargylation of acyclic imines with electron-neutral protecting groups was established, providing the corresponding homopropargyl amines in excellent yields and high enantioselectivities.

Rigid P-Chiral Phosphorus Ligands for Highly Selective Palladium-Catalyzed (4+2) and (4+4) Annulations.

We developed novel shackled P-chiral ligands based on 1-phosphanorbornenes and oxazolines. They were subsequently evaluated in palladium-catalyzed (4+2) annulations, producing enantioenriched tetrahydropyran scaffolds in good yields with high site selectivity and enantioselectivity. Moreover, chemoselective (4+4) products were also achieved by using acyclic imines. In addition, density functional theory calculations were performed to afford the energy profile of the Michael addition step and ring formation step. This demonstrated that the enantioselective (4+2) annulations and the chemoselective reaction between (4+2) and (4+4) products were mostly under thermodynamic control.

Developing Ru-Catalysts for Asymmetric Transfer Hydrogenation of Acyclic Imines.

Asymmetric transfer hydrogenation (ATH) of acyclic imines has been rarely reported by using Ru-based catalysts. In this manuscript, employing Ru-catalysts with minimal stereogenicity in combination with formic acid/triethylamine as the hydrogen donor enables a highly efficient ATH of N-diphenylphosphinyl acyclic imines. These substrates that include various aryl alkyl and heteroaryl alkyl substituted imines were all compatible with this catalytic system, and the corresponding reduced amines were obtained with excellent enantiomeric excess (ee's) and yields.

2,5-Anhydro-d-Mannose End-Functionalized Chitin Oligomers Activated by Dioxyamines or Dihydrazides as Precursors of Diblock Oligosaccharides.

Diblock oligosaccharides based on renewable resources allow for a range of new but, so far, little explored biomaterials. Coupling of blocks through their reducing ends ensures retention of many of their intrinsic properties that otherwise are perturbed in classical lateral modifications. Chitin is an abundant, biodegradable, bioactive, and self-assembling polysaccharide. However, most coupling protocols relevant for chitin blocks have shortcomings. Here we exploit the highly reactive 2,5-anhydro-d-mannose residue at the reducing end of chitin oligomers obtained by nitrous acid depolymerization. Subsequent activation by dihydrazides or dioxyamines provides precursors for chitin-based diblock oligosaccharides. These reactions are much faster than for other carbohydrates, and only acyclic imines (hydrazones or oximes) are formed (no cyclic N-glycosides). α-Picoline borane and cyanoborohydride are effective reductants of imines, but in contrast to most other carbohydrates, they are not selective for the imines in the present case. This could be circumvented by a simple two-step procedure. Attachment of a second block to hydrazide- or aminooxy-functionalized chitin oligomers turned out to be even faster than the attachment of the first block. The study provides simple protocols for the preparation of chitin-b-chitin and chitin-b-dextran diblock oligosaccharides without involving protection/deprotection strategies.

Diastereoselectivity in Passerini Reactions of Chiral Aldehydes and in Ugi Reactions of Chiral Cyclic Imines

Diastereoselectivity in Passerini and Ugi reactions of chiral aldehydes/imines remains challenging. Moreover, the Ugi reaction of chiral acyclic imines is complicated by their easy racemization/epimerization, whereas this problem is nearly completely suppressed using chiral cyclic imines in a modification called Ugi‐Joullié reaction. Thus 3‐component modification also allows a better diastereoselectivity thanks to the higher steric rigidity of rings. This review presents an overview of the current knowledge on diastereoselective Passerini reaction of chiral aldehydes, and on diastereoselective Ugi‐Joullié reaction of chiral cyclic imines, focusing on the results gathered by the authors' research group.

Photocatalytic enantioselective \u03b1-aminoalkylation of acyclic imine derivatives by a chiral copper catalyst

Copper-based asymmetric photocatalysis has great potential in the development of green synthetic approaches to chiral molecules. However, there are several formidable challenges associated with such a conception. These include the relatively weak visible light absorption, short excited-state lifetimes, incompatibility of different catalytic cycles, and the difficulty of the stereocontrol. We report here an effective strategy by means of single-electron-transfer (SET) initiated formation of radicals and photoactive intermediates to address the long-standing problems. Through elaborate selection of well-matched reaction partners, the chiral bisoxazoline copper catalyst is engaged in the SET process, photoredox catalysis, Lewis acid activation and asymmetric induction. Accordingly, a highly enantioselective photocatalytic α-aminoalkylation of acyclic imine derivatives has been accessed. This strategy sheds light on how to make use of diverse functions of a single transition metal catalyst in one reaction, and offers an economic and simplified approach to construction of highly valuable chiral vicinal diamines.

An Asymmetric Reductase That Intercepts Acyclic Imino Acids Produced in Situ by a Partner Oxidase.

Acyclic imines are unstable in aqueous conditions. For this reason, known imine reductases, which enable the synthesis of chiral amines, mainly intercept stable cyclic imines. Here we report the detailed biochemical and structural characterization of Bsp5, an imino acid reductase from the d-2-hydroxyacid dehydrogenase family that reduces acyclic imino acids produced in situ by a partner oxidase. We determine a 1.6 Å resolution structure of Bsp5 in complex with d-arginine and coenzyme NADPH. Combined with mutagenesis work, our study reveals the minimal structural constraints for its biosynthetic activity. Furthermore, we demonstrate that Bsp5 can intercept more complex products from an alternate oxidase partner, suggesting that this oxidase-imino acid reductase pair could be evolved for biocatalytic conversion of l-amino acids to d-amino acids.

Advances in the Organocatalytic Asymmetric Mannich Reaction of Six‐Membered Unsaturated Heterocycles: Methodology and Application

AbstractThe organocatalytic asymmetric Mannich reaction has always been an area of active interest in the community of chemistry. The Mannich products, optically active β‐amino−carbonyl compounds, can be used as important intermediates for biologically active molecules. Compared with the well‐researched acyclic imines, the organocatalytic asymmetric Mannich reactions of cyclic unsaturated substrates have been on the rise in recent years, which provide an exciting platform for the construction of various enantioenriched nitrogen‐containing polyheterocycles. In this minireview, we will summarize the advances in the field of organocatalytic asymmetric Mannich and related reactions, including decarboxylative Mannich reactions and Mannich involved cascade processes of six‐membered unsaturated heterocycles, and their applications in the synthesis of natural products and pharmaceuticals.

Facile Access to Amido (Thio)xanthates under Eco-Friendly Conditions by One-Pot Three-Component Reaction (3-CR)

A straightforward three-component reaction (3-CR) for the preparation of a variety of biologically interesting amido (thio)xanthates has been developed. By the proper choice of a potassium (thio)xanthate salt, a cyclic or acyclic imine, and an acyl chloride as substrates a broad scope with respect to the substituents can be realized. This operationally simple one-pot method proceeds under mild and environmentally friendly conditions while potassium chloride is produced as the single waste-product.

ChemInform Abstract: From Heteroaromatic Acids and Imines to Azaspirocycles: Stereoselective Synthesis and 3D Shape Analysis.

AbstractStarting from acetic acid substituted indole, azaindole as well as pyrrole derivatives and cyclic as well as acyclic imines a broad range of spiropolycycles is prepared.

Cationic Iridium and Rhodium Complexes with C–N Chelating Primary Benzylic Amine Ligands as Potent Catalysts for Hydrogenation of Unsaturated Carbon–Nitrogen Bonds

Cationic half-sandwich C–N chelating Ir and Rh complexes [Cp*M(NCCH3){κ2(N,C)-NH2CR2-2-C6H4}]+SbF6– (1a, M = Ir, R = CH3; 1b, M = Ir, R = C6H5; 2a, M = Rh, R = CH3; 2b, M = Rh, R = C6H5) are synthesized by AgSbF6-mediated halide abstraction from neutral azametallacycles derived from tritylamine or cumylamine and are fully characterized by NMR spectroscopy and X-ray crystallography. The treatment of the cationic complex 1b with H2 gas under ambient conditions in the presence of triethylamine in THF-d8 quantitatively yielded hydrido(amine) complex [Cp*Ir(H){κ2(N,C)-NH2C(C6H5)2-2-C6H4}] (4). The C–N chelating Ir complex shows a higher catalytic activity than an N–N chelating complex, [Cp*Ir(NCCH3)(Tscydn)]+SbF6– (3; Tscydn = N-(p-toluenesulfonyl)-1,2-cyclohexanediamime), that has been previously used for the asymmetric hydrogenation of acyclic imines. For example, the cationic Ir complex 1a promoted the hydrogenation of N-(1-phenylethylidene)benzylamine under 30 atm at 30 °C in the presence of excess AgSbF6 ...

ChemInform Abstract: InspIRED by Nature: NADPH‐Dependent Imine Reductases (IREDs) as Catalysts for the Preparation of Chiral Amines

AbstractReview: 37 refs.

Alternative tandem cyclisation pathways in the reaction between imines and enones

Dihydroisoquinoline reacts with Danishefsky's diene under Lewis acidic conditions or neat, to give low to moderate yields of the formal aza-Diels–Alder, [4+2]-cycloadduct. However, using methoxyvinyl methylketone with Lewis acid catalysis does not give the aza-Diels–Alder adduct, rather a formal [2+2+2]-cycloaddition occurs to provide access to a diacetyl dihydropyridine. Increased Lewis acid loading results in reduced dihydropyridine formation, and instead, a trimerisation reaction of the methoxyvinyl methyl ketone occurs, to give 1,3,5-triacetylbenzene from a different formal [2+2+2]-cycloaddition. The formal [4+2]-cycloaddition reaction of methoxyvinyl methylketone requires a cyclic imine in order to form the dihydropyridine because the reaction with acyclic imines produced a dihydropyridine from a formal [1+2+1+2]-cycloaddition. Evidence resulting from the isolation of reaction intermediates and in situ spectroscopic studies, shows that the reaction between 3,4-dihydroisoquinoline and methyl vinyl ketone, catalysed by oxy-philic Lewis acids, proceeds via a Mannich-Michael pathway and an imminium ion species. All reactions occur by one-pot cascade routes.

InspIRED by Nature: NADPH-Dependent Imine Reductases (IREDs) as Catalysts for the Preparation of Chiral Amines.

Imine reductases (IREDs) are NADPH-dependent oxidoreductases that catalyse the asymmetric reduction of cyclic prochiral imines to amines, with excellent stereoselectivity. Since their discovery, stereocomplementary IREDs have been applied to the production of both (S) and (R) cyclic secondary amines, and the expansion in gene sequences recently identified has hinted at new substrate ranges that extend into acyclic imines and even suggest the possibility of asymmetric reductive amination from suitable ketone and amine precursors. Structural studies of various IREDs are beginning to reveal the complexities inherent in determining substrate range, stereoselectivity and mechanism in these enzymes, which represent a valuable emerging addition to the toolbox of available biocatalysts for chiral amine production.

Progress on the Catalytic Asymmetric Hydrogenation of Imines

Chiral amines are important synthetic intermediates in the preparation of many physiologically active compounds. Catalytic asymmetric hydrogenation of prochiral imines represents one of the most direct and convenient route to chiral amines and their derivatives. During the past two decades, significant progress has been made in the asymmetric hydrogenation of imines. Many highly enantioselective chiral catalysts have been disclosed, some new methods and strategies have been developed, and some challenging imines substrates have been efficiently hydrogenated in high enantioselectivities. Despite these achievements, catalytic asymmetric hydrogenation of imines still have challenges of low reactivity, narrow substrate scope, harsh hydrogenation conditions and difficulty in catalyst reuse. Therefore, development of new catalyst system with high reactivity and enantioselectivity as well as environmental friendship in the asymmetric hydrogenation of imines is of great interest. This review presents a brief overview on the progress in catalytic asymmetric hydrogenation of cyclic and acyclic imines.

The First Catalytic, Enantioselective Aza‐Henry Reaction of an Unactivated Cyclic Imine

AbstractThe aza‐Henry reaction is an efficient route to important chiral, vicinal diamines. Reports of the asymmetric version typically use electron‐deficient acyclic imines. We report the first example of a catalytic, asymmetric aza‐Henry reaction on an unfunctionalized cyclic imine that gives access to enantiopure diamine derivatives under experimentally straightforward conditions. The stereocentre is established through the initial nitromethane addition to the imine. The scalemic intermediate may be trapped through acylation, then crystallized.

Asymmetric Transfer Hydrogenation of Acetophenone N-Benzylimine Using [RuIICl((S,S)-TsDPEN)(η6-p-cymene)]: A DFT Study

Asymmetric transfer hydrogenation of the acyclic imine acetophenone N-benzylimine was studied by means of computational chemistry. Calculated transition states offer an explanation of why this proc...

Chemo- and Regioselectivity-Tunable Pd-Catalyzed Allylic Alkylation of Imines

α-Carbanions of cyclic and acyclic imines have been successfully applied as nucleophiles in the Pd-catalyzed allylic alkylation reaction. Tuning of chemo- and regioselectivity has been realized by using t-BuOK/THF and LDA/toluene to give branched and linear products, respectively, with high regio- and diastereoselectivities. A plausible mechanism is proposed on the basis of the experimental results and DFT calculations.

Facile synthetic pathway to β-hydroxy-β-trifluoromethyl imines and their derivatives

Synthetic approach based on mediated addition of different trifluoromethylated building blocks to selected acyclic imines giving access to a variety of β-hydroxy-β-trifluoromethyl imines are elaborated. A reaction between fluorinated adducts and imines proceed easily giving the condensation products in good to excellent yields. β-Hydroxy-β-trifluoromethyl imines possessing trifluoromethyl group and exhibiting strong intramolecular hydrogen bonding are great precursors to different β-hydroxy-β-trifluoromethyl ketones and alcohols.