Electrophilic Imine Research Articles

Direct Asymmetric Synthesis of α-Aminoimines from 1,2-Bis-N-Sulfinylimines by Using Allyl Boronic Acids.

A unique direct asymmetric synthesis of α-aminoimines is realized, through rapid and exclusive mono-allylation of chiral bis-N-sulfinylimines using allylboronic acids. The highly selective allylation was possible as electrophilic imine functional group in the product α-aminoimines remained unreactive towards allyl boronic acid nucleophiles. Notably, by varying the geometry and chiral auxiliary, all four isomers of the α-aminoimines were accessed from readily available precursors. A range of allyl nucleophiles, which are tricky to generate by other means possessing highly reactive functional groups also took part in this reaction, expanding the scope further. The applicability of the products α-aminoimines were further demonstrated by accessing a range of structurally diverse chiral cyclic and acyclic 1,2-diamines bearing adjacent stereocenters through addition of a second nucleophile or aza-Prins-type cyclization by exploiting the nucleophilicity of the tethered alkene moiety. Moreover, the leaving group aptitude of sulfinyl auxiliary attached to imine, was exploited to access valuable chiral α-aminonitriles under thermal conditions without employing any reagents. Detailed DFT calculation revealed a chair-like transition state likely operating for the allylboration reaction across imine.

Direct Asymmetric Synthesis of α‐Aminoimines from 1,2‐Bis‐N‐Sulfinylimines by Using Allyl Boronic Acids

AbstractA unique direct asymmetric synthesis of α‐aminoimines is realized, through rapid and exclusive mono‐allylation of chiral bis‐N‐sulfinylimines using allylboronic acids. The highly selective allylation was possible as electrophilic imine functional group in the product α‐aminoimines remained unreactive towards allyl boronic acid nucleophiles. Notably, by varying the geometry and chiral auxiliary, all four isomers of the α‐aminoimines were accessed from readily available precursors. A range of allyl nucleophiles, which are tricky to generate by other means possessing highly reactive functional groups also took part in this reaction, expanding the scope further. The applicability of the products α‐aminoimines were further demonstrated by accessing a range of structurally diverse chiral cyclic and acyclic 1,2‐diamines bearing adjacent stereocenters through addition of a second nucleophile or Prins‐type cyclization by exploiting the nucleophilicity of the tethered alkene moiety. Moreover, the leaving group aptitude of sulfinyl auxiliary attached to imine, was exploited to access valuable chiral α‐aminonitriles under thermal conditions without employing any reagents. Detailed DFT calculation revealed a chair‐like transition state, arising from corresponding allylboroxine species, likely operating for the allylboration reaction across imine.

Diastereo- and Enantioselective Palladium-Catalyzed Cycloadditions of 5-Vinyloxazolidine-2,4-diones with Electrophilic Imines.

Despite the importance of the 4-imidazolidinone scaffold in bioactive compounds or organocatalysts, methodologies to access these nitrogenated heterocycles remain scarce. This manuscript describes a novel preparation of 4-imidazolidinones via a diastereo- and enantioselective (3 + 2) cycloaddition between 5-vinyloxazolidine-2,4-diones (VOxD) and electrophilic imines under palladium catalysis. This work supports the synthetic potential of VOxD as a promising equivalent of the C-C(═O)-N synthon.

Base-mediated homologative rearrangement of nitrogen-oxygen bonds of N-methyl-N-oxyamides.

Due to the well known reactivity of C(O)-N functionalities towards canonical C1-homologating agents (e.g. carbenoids, diazomethane, ylides), resulting in the extrusion of the N-centered fragment en route to carbonyl compounds, formal C1-insertions within N-O bonds still remain obscure. Herein, we document the homologative transformation of N-methyl-N-oxyamides - with high tolerance for diverse O-substituents - into N-acyl-N,O-acetals. Under controlled basic conditions, the N-methyl group of the same starting materials acts as a competent precursor of the methylene synthon required for the homologation. The logic is levered on the formation of an electrophilic iminium ion (via N-O heterolysis) susceptible to nucleophilic attack by the alkoxide previously expulsed. The procedure documents genuine chemocontrol and flexibility, as judged by the diversity of substituents placed on both amide and nitrogen linchpins. The mechanistic rationale was validated through experiments conducted on D-labeled materials which unambiguously attributed the origin of the methylene fragment to the N-methyl group of the starting compounds.

Exploring the Synthetic Potential of γ-Lactam Derivatives Obtained from a Multicomponent Reaction-Applications as Antiproliferative Agents.

A study on the reactivity of 3-amino α,β-unsaturated γ-lactam derivatives obtained from a multicomponent reaction is presented. Key features of the substrates are the presence of an endocyclic α,β-unsaturated amide moiety and an enamine functionality. Following different synthetic protocols, the functionalization at three different positions of the lactam core is achieved. In the presence of a soft base, under thermodynamic conditions, the functionalization at C-4 takes place where the substrates behave as enamines, while the use of a strong base, under kinetic conditions, leads to the formation of C-5-functionalized γ-lactams, in the presence of ethyl glyoxalate, through a highly diastereoselective vinylogous aldol reaction. Moreover, the nucleophilic addition of organometallic species allows the functionalization at C-3, through the imine tautomer, affording γ-lactams bearing tetrasubstituted stereocenters, where the substrates act as imine electrophiles. Taking into account the advantage of the presence of a chiral stereocenter in C-5 substituted γ-lactams, further diastereoselective transformations are also explored, leading to novel bicyclic substrates holding a fused γ and δ-lactam skeleton. Remarkably, an example of a highly stereoselective formal [3+3] cycloaddition reaction of chiral γ-lactam substrates is reported for the synthesis of 1,4-dihidropyridines, where a non-covalent attractive interaction of a carbonyl group with an electron-deficient arene seems to drive the stereoselectivity of the reaction to the exclusive formation of the cis isomer. In order to unambiguously determine the substitution pattern resulting from the diverse reactions, an extensive characterization of the substrates is detailed through 2D NMR and/or X-ray experiments. Likewise, applications of the substrates as antiproliferative agents against lung and ovarian cancer cells are also described.

Photoredox Cross-Dehydrogenative Coupling of N-Aryl Glycines Mediated by Mesoporous Graphitic Carbon Nitride: An Environmentally Friendly Approach to the Synthesis of Non-Proteinogenic α-Amino Acids (NPAAs) Decorated with Indoles.

Indole-decorated glycine derivatives are prepared through an environmentally benign cross-dehydrogenative coupling between N-aryl glycine analogues and indoles (yield of ≤81%). Merging heterogeneous organocatalysis and photocatalysis, C–H functionalization has been achieved by selective C-2 oxidation of N-aryl glycines to afford the electrophilic imine followed by Friedel–Crafts alkylation with indole. The sustainability of the process has been taken into account in the reaction design through the implementation of a metal-free recyclable heterogeneous photocatalyst and a green reaction medium. Scale-up of the benchmark reaction (gram scale, yield of 69%) and recycling experiments (over seven runs without a loss of efficiency) have been performed to prove the robustness of the protocol. Finally, mechanistic studies were conducted employing electron paramagnetic resonance spectroscopy to unveil the roles of the photocatalyst and oxygen in the formation of odd-electron species.

One-step synthesis of imidazoles from Asmic (anisylsulfanylmethyl isocyanide).

Substituted imidazoles are readily prepared by condensing the versatile isocyanide Asmic, anisylsulfanylmethylisocyanide, with nitrogenous π-electrophiles. Deprotonating Asmic with lithium hexamethyldisilazide effectively generates a potent nucleophile that efficiently intercepts nitrile and imine electrophiles to afford imidazoles. In situ cyclization to the imidazole is promoted by the conjugate acid, hexamethyldisilazane, which facilitates the requisite series of proton transfers. The rapid formation of imidazoles and the interchange of the anisylsulfanyl for hydrogen with Raney nickel make the method a valuable route to mono- and disubstituted imidazoles.

Tertiary Amine Synthesis by Radical Carbonyl Alkylative Amination

Highly efficient access to structurally diverse branched tertiary amines is a long-standing challenge in synthetic chemistry. In a recent paper published in Nature, Gaunt and co-workers disclose a practical strategy for the construction of synthetically intractable tertiary amines through visible-light-mediated radical carbonyl alkylative amination of aldehydes, amines, and alkyl halides.

Catalytic Reductive Aldol and Mannich Reactions of Enone, Acrylate, and Vinyl Heteroaromatic Pronucleophiles.

Catalytic reductive coupling of enone, acrylate, or vinyl heteroaromatic pronucleophiles with carbonyl or imine partners offers an alternative to base-mediated enolization in aldol- and Mannich-type reactions. In this review, direct catalytic reductive aldol and Mannich reactions are exhaustively catalogued on the basis of metal or organocatalyst. Stepwise processes involving enone conjugate reduction to form discrete enol or (metallo)enolate derivatives followed by introduction of carbonyl or imine electrophiles and aldol reactions initiated via enone conjugate addition are not covered.

Enantio- and Diastereoselective Double Mannich Reaction between Ketones and Imines Catalyzed by Zn-ProPhenol.

Herein we present a Zn-ProPhenol-catalyzed double Mannich reaction between ynones and imines that generates 1,3-diamines in excellent yield as well as diastereo- and enantioselectivity (>99.5% ee). With 2.2 equiv of a single imine electrophile, we obtain pseudo-symmetrical diamines whereas, with two different imine partners, we obtain unsymmetrically substituted 1,3-diamines with three contiguous stereocenters. In addition, we showcase the utility of these double Mannich adducts by transforming the 1,3-diamine motif into a variety of interesting products.

Copper-Catalyzed Enantioselective Reductive Cross-Coupling of Aldehydes and Imines.

A copper-catalyzed enantioselective reductive cross-coupling using aromatic aldehydes and imines, producing chiral β-amino alcohols, is described. The catalytic formation of enantioenriched chiral α-alkoxyalkylcopper(I) species from aromatic aldehydes and the subsequent reaction with imine electrophiles are attractive features of this protocol.

Imines as acceptors and donors in N-heterocyclic carbene (NHC) organocatalysis.

The synthetic potential of imines as electrophiles or as a source of nucleophilic coupling partner in N-heterocyclic carbene (NHC) catalysis for the synthesis of various nitrogen heterocycles and functionalized amines is highlighted in this Feature Article. Electrophilic imines are suitable candidates for intercepting the NHC-derived acyl anions, homoenolate equivalents, and (di)enolates for the synthesis of α-amino ketones and a variety of lactam derivatives. Moreover, enamines generated from imines bearing α-hydrogen could be trapped with α,β-unsaturated acylazoliums for the synthesis of functionalized dihydropyridinones. NHCs are also useful for the umpolung of imines for the generation of aza-Breslow intermediates thus leading to the synthesis of indoles, quinolines, dihydroquinoxalines etc. A concise account of the diverse reactivity of imines in NHC catalysis has been presented.

Copper-Catalyzed Asymmetric Formal Hydroaminomethylation of Alkenes with N,O-Acetals to Access Chiral β-Stereogenic Amines: Dual Functions of the Copper Catalyst

Chiral amines are synthetically versatile intermediates used for the preparation of a wide range of biologically active compounds and drugs. Compared with the well-developed synthesis of α-stereoge...

The Use of Calcium Carbide as Acetylene Source in a Three-Component Coupling with ω-Chlorinated Ketones and Primary Amines.

Calcium carbide was used in a CuI -catalysed three-component coupling with ω-chlorinated ketones and primary amines to generate terminal 2-alkynyl-N-heterocycles. The formation of an imine and the subsequent intramolecular substitution results in an active electrophilic iminium species, which can be alkynylated by in situ formed copper acetylide. A number of aliphatic primary (functionalised) amines and aliphatic or aromatic alkynes together with different alkyl- or aryl-substituted γ- or δ-chloroketones could be used. Simple acid-base workup instead of column chromatography can be applied to obtain the resulting 2-alkynylpyrrolidines and 2-alkynylpiperidines.

Brønsted Base-Catalyzed Umpolung Intramolecular Cyclization of Alkynyl Imines.

A novel "umpolung" intramolecular cyclization of alkynyl imines, in which the electrophilic imine sp2 -carbon formally serves as a nucleophilic site, was developed under Brønsted base catalysis. The reaction involves the unprecedented catalytic generation of α-aminoester enolates from α-iminoesters via the 1,2-addition of the anion of a secondary phosphite to an imine moiety followed by the [1,2]-rearrangement of a dialkoxyphosphoryl moiety from carbon to nitrogen, which is a formal umpolung process, and the intramolecular addition to an alkyne. This is a rare example of a [1,2]-rearrangement of a dialkoxyphosphoryl moiety from carbon to nitrogen to generate an α-amino carbanion and the first catalytic carbon-carbon bond forming reaction utilizing the resulting carbanion as a nucleophile.

A Practical Guide for Predicting the Stereochemistry of Bifunctional Phosphoric Acid Catalyzed Reactions of Imines.

Chiral phosphoric acids have become powerful catalysts for the stereocontrolled synthesis of a diverse array of organic compounds. Since the initial report, the development of phosphoric acids as catalysts has been rapid, demonstrating the tremendous generality of this catalyst system and advancing the use of phosphoric acids to catalyze a broad range of asymmetric transformations ranging from Mannich reactions to hydrogenations through complementary modes of activation. These powerful applications have been developed without a clear mechanistic understanding of the reasons for the high level of stereocontrol. This Account describes investigations into the mechanism of the phosphoric acid catalyzed addition of nucleophiles to imines, focusing on binaphthol-based systems. In many cases, the hydroxyl phosphoric acid can form a hydrogen bond to the imine while the P═O interacts with the nucleophile. The single catalyst, therefore, activates both the electrophile and the nucleophile, while holding both in the chiral pocket created by the binaphthol and constrained by substituents at the 3 and 3' positions. Detailed geometric and energetic information about the transition states can be gained from calculations using ONIOM methods that combine the advantages of DFT with some of the speed of force fields. These high-level calculations give a quantitative account of the selectivity in many cases, but require substantial computational resources. A simple qualitative model is a useful complement to this complex quantitative model. We summarize our calculations into a working model that can readily be sketched by hand and used to work out the likely sense of selectivity for each reaction. The steric demands of the different parts of the reactants determine how they fit into the chiral cavity and which of the competing pathways is favored. The preferred pathway can be found by considering the size of the substituents on the nitrogen and carbon atoms of the imine electrophile, and the position of the nucleophilic site on the nucleophile in relation to the hydrogen-bond which holds it in the catalyst active site. We present a guide to defining the pathway in operation allowing the fast and easy prediction of the stereochemical outcome and provide an overview of the breadth of reactions that can be explained by these models including the latest examples.

Tandem Long Distance Chain-Walking/Cyclization via RuH2(CO)(PPh3)3/Brønsted Acid Catalysis: Entry to Aromatic Oxazaheterocycles.

A novel route to 1,3-oxazaheterocycles based on cooperative Ru-H/Brønsted acid catalysis is reported. The use of the commercially available RuH2(CO)(PPh3)3 complex allows for an efficient long distance chain-walking process while the Brønsted acid is responsible for generation of an electrophilic iminium ion which is trapped intramolecularly by an alcohol moiety. The alcohol, besides its nucleophilic function, also plays an important role in the stabilization of the Ru catalyst.

Rh(III)-Catalyzed Diastereoselective C-H Bond Addition/Cyclization Cascade of Enone Tethered Aldehydes.

The Rh(III)-catalyzed cascade addition of a C-H bond across alkene and carbonyl π-bonds is reported. The reaction proceeds under mild reaction conditions with low catalyst loading. A range of directing groups were shown to be effective as was the functionalization of alkenyl in addition to aromatic C(sp2)-H bonds. When the enone and aldehyde electrophile were tethered together, cyclic β-hydroxy ketones with three contiguous stereocenters were obtained with high diastereoselectivity. The intermolecular three-component cascade reaction was demonstrated for both aldehyde and imine electrophiles. Moreover, the first x-ray structure of a cationic Cp*Rh(III) enolate with interatomic distances consistent with an η3-bound enolate is reported.

ChemInform Abstract: Increasing the Reactivity of Amides Towards Organometallic Reagents: An Overview

AbstractReview: 151 refs.

ChemInform Abstract: Axially Chiral Broensted Acid Catalyzed Transformations of Electrophilic Imines

AbstractReview: 95 refs.