Imine Intermediates Research Articles

Towards depeptidized aminoboronic acid derivatives through the use of borylated iminium ions.

Herein, we use α-boryl iminium intermediates to access progressively depeptidized branched β-aminoboronic acids that are functionalized with biologically relevant heterocycles. We investigate the interaction of these novel compounds with carbohydrates under physiological conditions and demonstrate their potential as synthetic building blocks.

Formation of stable imine intermediates in the coexistence of sulfamethoxazole and humic acid by electrochemical oxidation

The electrochemical degradation performance of sulfamethoxazole (SMX) was studied in the presence of humic acid (HA) by using a Ti/Ti4O7/β-PbO2 anode. The electrochemical degradation efficiency of SMX decreased from 93.4% to 45.8% in 50 min after the addition of 25 mg L−1 HA. The pseudo-first-order kinetic rate constant decreased by 71.4%, and the EEO value increased from 63.8 Wh L−1 to 90.9 Wh L−1. HA and its degradation intermediates could compete for free radicals, especially for ·OH, with SMX. The analytical results obtained using UPLC-ESI-Q-TOF-MS showed that 18 degradation intermediates were identified in the coexistence of SMX and HA. Four imine intermediates were formed through the reactions between the aniline moieties of SMX and quinone groups in the HA structure through covalent bonds. Furthermore, the relative abundances of the intermediates demonstrated that the imine intermediates were complex and stable during electrochemical degradation.

Photochemical Formal (4 + 2)-Cycloaddition of Imine-Substituted Bicyclo[1.1.1]pentanes and Alkenes.

Amines containing bridged bicyclic carbon skeletons are desirable building blocks for medicinal chemistry. Herein, we report the conversion of bicyclo[1.1.1]pentan-1-amines to a wide range of polysubstituted bicyclo[3.1.1]heptan-1-amines through a photochemical, formal (4 + 2)-cycloaddition of an intermediate imine diradical. To our knowledge, this is the first reported method to convert the bicyclo[1.1.1]pentane skeleton to the bicyclo[3.1.1]heptane skeleton. Hydrolysis of the imine products gives complex, sp3-rich primary amine building blocks.

An Iridium Catalytic System Compatible with Inorganic and Organic Nitrogen Sources for Dual Asymmetric Reductive Amination Reactions

AbstractAsymmetric reductive amination (ARA) is one of the most promising methods for the synthesis of chiral amines. Herein we report our efforts on merging two ARA reactions into a single‐step transformation. Catalyzed by a complex formed from iridium and a steric hindered phosphoramidite, readily available and inexpensive aromatic ketones initially undergo the first ARA with ammonium acetate to afford primary amines, which serve as the amine sources for the second ARA, and finally provide the enantiopure C2‐symmetric secondary amine products. The developed process competently enables the successive coupling of inorganic and organic nitrogen sources with ketones in the same reaction system. The Brønsted acid additive plays multiple roles in this procedure: it accelerates the formation of imine intermediates, minimizes the inhibitory effect of N‐containing species on the iridium catalyst, and reduces the primary amine side products.

An Iridium Catalytic System Compatible with Inorganic and Organic Nitrogen Sources for Dual Asymmetric Reductive Amination Reactions.

Asymmetric reductive amination (ARA) is one of the most promising methods for the synthesis of chiral amines. Herein we report our efforts on merging two ARA reactions into a single-step transformation. Catalyzed by a complex formed from iridium and a steric hindered phosphoramidite, readily available and inexpensive aromatic ketones initially undergo the first ARA with ammonium acetate to afford primary amines, which serve as the amine sources for the second ARA, and finally provide the enantiopure C2 -symmetric secondary amine products. The developed process competently enables the successive coupling of inorganic and organic nitrogen sources with ketones in the same reaction system. The Brønsted acid additive plays multiple roles in this procedure: it accelerates the formation of imine intermediates, minimizes the inhibitory effect of N-containing species on the iridium catalyst, and reduces the primary amine side products.

Mechanistic Insight into Metal Ion-Catalyzed Transamination.

Several classes of biological reactions that are mediated by an enzyme and a co-factor can occur, to a slower extent, not only without the enzyme but even without the co-factor, under catalysis by metal ions. This observation has led to the proposal that metabolic pathways progressively evolved from using inorganic catalysts to using organocatalysts of increasing complexity. Transamination, the biological process by which ammonia is transferred between amino acids and α-keto acids, has a mechanism that has been well studied under enzyme/co-factor catalysis and under co-factor catalysis, but the metal ion-catalyzed variant was generally studied mostly at high temperatures (70-100°C), and the details of its mechanism remained unclear. Here, we investigate which metal ions catalyze transamination under conditions relevant to biology (pH 7, 20-50 °C) and study the mechanism in detail. Cu2+, Ni2+, Co2+, and V5+ were identified as the most active metal ions under these constraints. Kinetic, stereochemical, and computational studies illuminate the mechanism of the reaction. Cu2+ and Co2+ are found to predominantly speed up the reaction by stabilizing a key imine intermediate. V5+ is found to accelerate the reaction by increasing the acidity of the bound imine. Ni2+ is found to do both to a limited extent. These results show that direct metal ion-catalyzed amino group transfer is highly favored even in the absence of co-factors or protein catalysts under biologically compatible reaction conditions.

Cobalt-Catalyzed Hydrogenative Transformation of Nitriles

Here, we report the transformation of nitrile compounds in a hydrogen atmosphere. Catalyzed by a cobalt/tetraphosphine complex, hydrogenative coupling of unprotected indoles with nitriles proceeds smoothly in a basic medium, yielding C3 alkylated indoles. In addition, the direct hydrogenation of nitriles under the same conditions yielded primary amines. Isotope labeling experiments, along with a series of control experiments, revealed a reaction pathway that involves nucleophilic addition of indoles and 1,4-reduction of a conjugate imine intermediate. Different from reductive alkylation of indoles under an acidic condition, E1cB elimination is believed to occur in this base-promoted hydrogenative coupling reaction.

Synthesis of Demissidine Analogues from Tigogenin via Imine Intermediates.

A five-step transformation of a spiroketal side chain of tigogenin into an indolizidine system present in solanidane alkaloids such as demissidine and solanidine was elaborated. The key intermediate in the synthesis was spiroimine 3 readily obtained from tigogenin by its RuO4 oxidation to 5,6-dihydrokryptogenin followed by amination with aluminum amide generated in situ from DIBAlH and ammonium chloride. The mild reduction of spiroimine to a 26-hydroxy-dihydropyrrole derivative and subsequent mesylation resulted in the formation of 25-epidemissidinium salt or 23-sulfone depending on reaction conditions.

Microwave assisted novel one-pot three-component reaction for synthesis of 3-aminoimidazopyridines using molecular iodine

An expedient, cost-effective and metal-free green protocol has been developed for the preparation of 3-aminoimidazopyridines by the three-component reaction of arylglyoxal monohydrates, aromatic amines and 2-aminopyridines. This multicomponent reaction was executed under microwave irradiation in presence of catalytic amount of molecular iodine in ethanol, involving the formation of three new CN bonds via imine intermediate. Environmentally benign catalyst, eco-friendly medium, good yields, short reaction time and purification by simple crystallization are some distinguished features of this protocol. In addition, presented method is sustainable since produced water only as by product, avoidance of toxic catalyst and good amenability with principle of green chemistry.

Optimizing the Iodide/Iodonium/O2 Oxidation Cycle Enhances the Scope, Selectivity, and Yields of Hydroiodic Acid‐Catalyzed Multicomponent Cyclocondensation Reactions

AbstractCatalytic iodine in the presence of water acts indirectly as a source of Brønsted acid and, concurrently, generates iodonium ion and hydrogen peroxide, which mediate the final oxidative aromatization step in the multicomponent cyclocondensation of an aromatic amine and two aliphatic aldehyde compounds. The oxidative cycle in this and related iodine‐catalyzed reactions is seldom discussed, generally unoptimized, and rarely investigated in detail. This work establishes that two independent catalytic cycles (H+ and I−/I+) drive such multicomponent cyclocondensation/ oxidation reactions, provided that the oxidant is generated in sufficient concentration to inhibit oxidation of the dihydroquinoline by the intermediate iminium cation. The complementary dual catalytic cycles, when optimized, act in concert to suppress side product formation, which simplifies isolation and purification of the self‐aggregating products, and increases the efficiency and scope of the Wang‐Kozlov multicomponent reaction.magnified image

A hollow in hollow nanoreactor of H-PtCu@SiO2 for the selective transfer hydrogenation

Hollow metal nanoparticles have attracted great interest in heterogeneous catalysis research due to their unique structures as nanoreactors. Here, we report hollow PtCu nanoparticles encapsulated in microporous silica shells (H-PtCu@SiO2), which can serve as the nanoreactor with high catalytic activity and high stability. The H-PtCu@SiO2 nanoreactor shows the state-of-the-art catalytic performance for the transfer hydrogenation of benzonitrile to dibenzylamine, which achieves up to 100% conversion and 99% selectivity in only 0.5 h. The void-confinement effect of H-PtCu@SiO2 is crucial for the outstanding catalytic performance by encaging the reactants in the nanoreactor. The computation demonstrates the limiting diffusion effect of the silica shell toward the ammonia borane, thus reduces the concentration of reductant species and prolongs the lifetime of the intermediate imine to improve the selectivity of secondary amine. Moreover, the silica shells can effectively enhance the catalytic stability of the H-PtCu@SiO2 nanoreactor.

Direct α-Alkenylation of Cyclic Amines with Maleimides through Fe(III)-Catalyzed C(sp3)-H/C(sp2)-H Cross Dehydrogenative Coupling.

Presented herein is a novel and efficient α-C(sp3)-H alkenylation of cyclic amines with maleimides. Mechanistically, this C(sp3)-H/C(sp2)-H cross dehydrogenative coupling (CDC) reaction involves a cascade procedure including oxidative α-amino radical formation from the cyclic amine substrate and nucleophilic addition of the in situ formed α-amino radical onto the electron-deficient carbon-carbon double bond of maleimide followed by oxidation and β-elimination. Notably, this direct α-functionalization provides an effective alternative to the conventional ionic reaction mode, in which an imine or iminium intermediate is formed to react with electron-rich coupling partners other than electron-deficient ones. In general, this method features readily available and structurally diverse substrates, a green and economical catalyst, a unique reaction pathway, mild reaction conditions, high efficiency, and excellent atom economy. This new reaction enriches the application of Fe(III)-catalyzed C(sp3)-H activation and functionalization.

Reductive Amination of 5-Hydroxymethylfurfural by the Hydrogenation of Intermediate Imines in the Presence of a Pt/Al2O3 Catalyst in a Flow Reactor

Reductive Amination of 5-Hydroxymethylfurfural by the Hydrogenation of Intermediate Imines in the Presence of a Pt/Al2O3 Catalyst in a Flow Reactor

Spatiotemporal Resolved Live Cell Membrane Tracking through Photo-click Reactions Enriched in Lipid Phase.

A set of photo-switchable monopeptides derived from cis-β-dibenzodiazocine-l-alanine (cis-DBDAA) have been designed and synthesized, which are capable of photo-click reacting with diaryltetrazoles or diarylsydnones in a hydrophobic phospholipid bilayer environment. The DBDAA monopeptides include both a hydrophobic tail on C-terminal, providing high affinity toward lipid membrane, and a modularized functional moiety on N-terminal, enabling rapid optimization of the self-assembly strength to form multifunctional supramolecules. With the cis-DBDAA monopeptides photo-switched into trans-configuration, we were able to disrupt the supramolecular assembly through an efficient photo-click reaction across the lipid bilayer of liposomes. We reveal that the performance of the photo-click reactions between the monopeptides and photo-generated nitrile imine intermediates is significantly enhanced by enrichment of both reactants in the hydrophobic membrane lamel of liposomes. Enrichment of the DBDAA monopeptide in lipid phase serves as a convenient method to introduce bioorthogonal chemical handles on live cell membranes, which enables fluorescence labelling of single cell's membrane with high spatiotemporal resolution to facilitate the studies on cell membrane dynamics.

Selective hydrogenation of benzonitrile and its homologues to primary amines over platinum

Various supported precious metal (Pt, Rh, Ru, Ir) catalysts have been screened in the reduction of benzonitrile (BN), benzyl cyanide (BC) and 3-phenylpropionitrile (PPN) to benzylamine (BA), 2-phenylethylamine (PEA) and 3-phenylpropylamine (PPA), using our method for selective, heterogeneous, palladium-catalysed hydrogenation of nitriles to primary amines developed previously. A readily available platinum on carbon catalyst (10% Pt/C) afforded the best results obtaining complete conversion of nitriles, as well as comparatively high isolated yields (58–70%) and selectivities to primary amines (57–68%) under mild and optimized conditions [6 bar, 30 °C, two immiscible solvents (dichloromethane/water or toluene/water), acidic additives (NaH2PO4, (NH4)H2PO4 or H2SO4)]. Contrary to the typical high secondary amine selectivity of platinum, surprisingly, this Pt/C catalyst proved to be much more effective and selective in the formation of PEA and PPA than a Pd/C one applied earlier. To clear the divergences in the primary amine selectivity observed, quantum chemical calculations (DFT) were accomplished related to the adsorption interactions between the imine intermediates and platinum.

Unlocking Iminium Catalysis in Artificial Enzymes to Create a Friedel-Crafts Alkylase.

The construction and engineering of artificial enzymes consisting of abiological catalytic moieties incorporated into protein scaffolds is a promising strategy to realize non-natural mechanisms in biocatalysis. Here, we show that incorporation of the noncanonical amino acid para-aminophenylalanine (pAF) into the nonenzymatic protein scaffold LmrR creates a proficient and stereoselective artificial enzyme (LmrR_pAF) for the vinylogous Friedel–Crafts alkylation between α,β-unsaturated aldehydes and indoles. pAF acts as a catalytic residue, activating enal substrates toward conjugate addition via the formation of intermediate iminium ion species, while the protein scaffold provides rate acceleration and stereoinduction. Improved LmrR_pAF variants were identified by low-throughput directed evolution advised by alanine-scanning to obtain a triple mutant that provided higher yields and enantioselectivities for a range of aliphatic enals and substituted indoles. Analysis of Michaelis–Menten kinetics of LmrR_pAF and evolved mutants reveals that different activities emerge via evolutionary pathways that diverge from one another and specialize catalytic reactivity. Translating this iminium-based catalytic mechanism into an enzymatic context will enable many more biocatalytic transformations inspired by organocatalysis.

Computational Insights into Privileged Stereocontrolling Interactions Involving Chiral Phosphates and Iminium Intermediates.

The precise design of a catalyst for a given reaction is extremely difficult, often requiring a significant empirical screening campaign to afford products in high yields and enantiomeric excess. Design becomes even more challenging if one requires a catalyst that performs well for a diverse range of substrates. Such "privileged" catalysts exist, but little is known why they operate so generally. We report the results of computations which show that when substrate and catalyst features are conserved between significantly different mechanistic regimes, similar modes of activation can be invoked. As a validating case study, we explored a Hantzsch ester hydrogenation of α,β-unsaturated iminiums involving BINOL-derived chiral phosphates and find they impart asymmetric induction in an analogous fashion to their acid counterpart. Specifically, DFT calculations at the IEFPCM(1,4-dioxane)-B3LYP/6-311+G(d,p)//B3LYP/6-31G(d) level predicted enantioselectivity to be close to the experimental value (82% ee calculated, 96% ee experimental) and showed that the reaction proceeds via a transition state involving two hydrogen-bonding interactions from the iminium intermediate and nucleophile to the catalyst. These interactions lower the energy of the transition structure and provide extra rigidity to the system. This new model invokes "privileged" noncovalent interactions and leads to a new explanation for the enantioselectivity outcome, ultimately providing the basis for the development of general catalyst design principles and the translation of mechanistically disparate reaction profiles for the prediction of enantioselectivity outcomes using statistical models.

Transition-Metal-Free α Csp3 -H Cyanation of Sulfonamides.

This report describes the site-selective α-functionalization of sulfonylamide derivatives through the in-situ generation of imine intermediates. The N-F sulfonylamides, which could facilitate the elimination to generate imines, are coupled with TBACN to efficiently and mildly afford α-amino cyanides. Comparing with Strecker reaction, this transformation offers a complementary strategy to efficiently construct α-amino cyanides from direct α C-H functionalization of sulfonylamindes. The reaction is also characterized by broad substrate scope and flash chromatography column free workup. More importantly, the new two-electron pathway to generate imines through manipulation of the leaving group allows us to achieve excellent α site-selectivity.

2,3-Dihydroferroceno[3,4]pyrrolo[2,1-b]thiazol-5(8b)-ones: Synthesis, Structure and DFT Study on the Mechanism of Chemo- and Diastereoslective Annulations of (Sp)-2-Formylferrocenecarbonyl Fluoride and (Sp)-2-Formylferrocenecarboxylic Acid.

By means of the annulation of easy-to-handle yet sufficiently reactive (Sp)-2-formylferrocenecar- bonyl fluoride with the hydrochlorides of cysteamine and the methyl esters of enentiomer cysteines conducted in dichloromethane at room temperature in the presence of pyridine, the first members of 2,3-dihydroferroceno[3,4]pyrrolo[2,1-b]thiazol-5(8bH)-ones with the elements of planar- and central chirality were prepared as single enantiomers. An atom economic procedure was also elaborated for the synthesis of these organometallic heterocycles directly exploring (Sp)-2-formylferrocenecarboxylic acid in situ activated by CDI and TFA, sequentially added to the reaction mixture. The relative and consequently, the absolute, configuration of the isolated diastereomers was determined by NMR measurements supported by DFT structural optimization. On the basis of the results of synthetic control experiments and a series of further DFT modelling studies, including energetic and MO analysis of the iminium intermediates, we propose a mechanism for the thiazolidine-forming annulations that proceed via primary N-acylation followed by proton-mediated cyclocondensation and subsequent diastereoselective sulfhydryl-attack on the resulting iminium center.

Metal-based Heterogeneous Catalysts for One-Pot Synthesis of Secondary Anilines from Nitroarenes and Aldehydes.

Recently, N-substituted anilines have been the object of increasing research interest in the field of organic chemistry due to their role as key intermediates for the synthesis of important compounds such as polymers, dyes, drugs, agrochemicals and pharmaceutical products. Among the various methods reported in literature for the formation of C–N bonds to access secondary anilines, the one-pot reductive amination of aldehydes with nitroarenes is the most interesting procedure, because it allows to obtain diverse N-substituted aryl amines by simple reduction of nitro compounds followed by condensation with aldehydes and subsequent reduction of the imine intermediates. These kinds of tandem reactions are generally catalyzed by transition metal-based catalysts, mainly potentially reusable metal nanoparticles. The rapid growth in the last years in the field of metal-based heterogeneous catalysts for the one-pot reductive amination of aldehydes with nitroarenes demands for a review on the state of the art with a special emphasis on the different kinds of metals used as catalysts and their recyclability features.