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Transformations enabling the synthesis of α‐alkyl, α′‐2‐azinyl amines by addition of 2‐heteroaryl‐based nucleophiles to in situ‐generated and non‐activated alkyl‐substituted iminium ions are extremely rare. Approaches involving classical 2‐azinyl organometallics, such as the corresponding Grignard reagents, often fail to produce the desired products. Here, we report an operationally straightforward solution to this problem through the development of a multicomponent coupling process wherein a soft 2‐azinyl indium nucleophile, generated in situ from the corresponding 2‐iodo heteroarene and indium powder, adds to an iminium ion that is also formed directly in the reaction. This modular carbonyl azinylative amination (CAzA) displays a broad scope and only a metal reductant is needed to generate a reactive 2‐azinyl nucleophile. Beyond the addition to iminium ions, the 2‐azinyl addition to polyfluoromethyl ketones forms the corresponding tertiary alcohols. Together, the products of these reactions possess a high degree of functionality, are typically challenging to synthesize by other methods, and contain motifs recognized as privileged in the context of pharmaceuticals and agrochemicals. [ABSTRACT FROM AUTHOR]

Multicomponent reactions involving three or more reactants are commonly used to prepare dihydropyrimidinone with various bioactivities. This study reports the different routes for the synthesis of benzaldehyde-based dihydropyrimidinone via the Biginelli reaction and investigates the yield of the obtained products. The synthesis was performed via routes A, B, C, D, and E based on the formation of iminium, enamine, and Knoevenagel intermediates between urea, benzaldehyde, and ethyl acetoacetate. Route A, through a one-pot reaction via iminium, produced dihydropyrimidinone with a yield of 58%. The product from route B via iminium was obtained in 62% yield. Route C and D occurred via enamine at room temperature, and reflux gave the product 31% and 40% yield, respectively. Route E involving Knoevenagel intermediate provided the product in a 38% yield. 1H NMR, FTIR, and MS spectroscopic techniques were used for structure elucidation.

The rational combination of two catalysts to expedite the construction of chiral complex biologically and pharmacologically relevant chiral compounds has widely gained momentum over the past decade. In particular, enamine or iminium catalysis ensuing from the activation of aldehyde or ketone by chiral amine catalysts in conjugation with other organocatalytic cycles has facilitated several asymmetric transformations to yield the enantioenriched products. Regardless of the considerable discussion on the various dual catalytic approaches, literature lacks a comprehensive review focusing on the enamine and iminium‐based dual organocatalytic systems. Thus, this review article has discussed the noteworthy achievements in the field of asymmetric catalysis and synthesis catalyzed by the enamine and iminium‐based dual organocatalytic systems. [ABSTRACT FROM AUTHOR]

Multicomponent reactions involving three or more reactants are commonly used to prepare dihydropyrimidinone with various bioactivities. This study reports the different routes for the synthesis of benzaldehyde-based dihydropyrimidinone via the Biginelli reaction and investigates the yield of the obtained products. The synthesis was performed via routes A, B, C, D, and E based on the formation of iminium, enamine, and Knoevenagel intermediates between urea, benzaldehyde, and ethyl acetoacetate. Route A, through a one-pot reaction via iminium, produced dihydropyrimidinone with a yield of 58%. The product from route B via iminium was obtained in 62% yield. Route C and D occurred via enamine at room temperature, and reflux gave the product 31% and 40% yield, respectively. Route E involving Knoevenagel intermediate provided the product in a 38% yield. ¹H NMR, FTIR, and MS spectroscopic techniques were used for structure elucidation. [ABSTRACT FROM AUTHOR]

A mixture of B(2,6-F SB 2 sb C SB 6 sb H SB 3 sb ) SB 3 sb and the corresponding tetrabutylammonium borohydride salt effectively isomerizes iminium ion B 38 b to form iminium B 41 b via a sequence of hydride donation to form B 39 b followed by hydride abstraction. The ammonium borohydride then eliminates H SB 2 sb to reform the active B(C SB 6 sb F SB 5 sb ) SB 3 sb catalyst and amine B 72 b . Interestingly, the Lewis acid B(2,6-F SB 2 sb C SB 6 sb H SB 3 sb ) SB 3 sb is significantly less electron-deficient than B(C SB 6 sb F SB 5 sb ) SB 3 sb , which is almost exclusively used in organoborane-mediated hydride abstraction with amines. Keywords: boron; hydride abstraction; amines; iminium; functionalization EN boron hydride abstraction amines iminium functionalization 2117 2128 12 10/31/23 20231127 NES 231127 Graph 1 Introduction Organoboranes are widely used as reagents and building blocks in synthetic chemistry. [Extracted from the article]

The synthesis and characterization of cyclic (alkyl)(amino)carbene, bicyclic (alkyl)(amino)carbene and cyclic (amino)(barrelene)carbene copper (I) complexes is reported. These complexes are obtained via a scalable, versatile, green, and cost/user‐friendly strategy. [ABSTRACT FROM AUTHOR]

Herein, advanced intermediates were synthesized through Ugi four-component reactions of isocyanides, aldehydes, masked amino aldehyde, and carboxylic acids, including N-protected amino acids. The presence of a masked aldehyde enabled acid-mediated deprotection and subsequent cyclization via the carbonyl carbon and the amide nitrogen. Utilizing N-protected amino acid as a carboxylic acid component, Ugi intermediates could be cyclized from two possible directions to target 3,4-dihydropyrazin-2(1H)-ones. Cyclization to the amino terminus (westbound) and to the carboxyl terminus (eastbound) was demonstrated. Deliberate selection of building blocks drove the reaction regioselectively and yielded diverse heterocycles containing a 3,4-dihydropyrazin-2(1H)-one core, pyrazin-2(1H)-one, and piperazin-2-one, as well as a tricyclic framework with a 3D architecture, 2,3-dihydro-2,6-methanobenzo[h][1,3,6]triazonine-4,7(1H,5H)-dione, from Ugi adducts under mild reaction conditions. The latter bridged heterocycle was achieved diastereoselectively. The reported chemistry represents diversity-oriented synthesis. One common Ugi advanced intermediate was, without isolation, rapidly transformed into various nitrogen-containing heterocycles. [ABSTRACT FROM AUTHOR]

Herein, advanced intermediates were synthesized through Ugi four-component reactions of isocyanides, aldehydes, masked amino aldehyde, and carboxylic acids, including N-protected amino acids. The presence of a masked aldehyde enabled acid-mediated deprotection and subsequent cyclization via the carbonyl carbon and the amide nitrogen. Utilizing N-protected amino acid as a carboxylic acid component, Ugi intermediates could be cyclized from two possible directions to target 3,4-dihydropyrazin-2(1H)-ones. Cyclization to the amino terminus (westbound) and to the carboxyl terminus (eastbound) was demonstrated. Deliberate selection of building blocks drove the reaction regioselectively and yielded diverse heterocycles containing a 3,4-dihydropyrazin-2(1H)-one core, pyrazin-2(1H)-one, and piperazin-2-one, as well as a tricyclic framework with a 3D architecture, 2,3-dihydro-2,6-methanobenzo[h][1,3,6]triazonine-4,7(1H,5H)-dione, from Ugi adducts under mild reaction conditions. The latter bridged heterocycle was achieved diastereoselectively. The reported chemistry represents diversity-oriented synthesis. One common Ugi advanced intermediate was, without isolation, rapidly transformed into various nitrogen-containing heterocycles.

The article reports that the 2001 Nobel Prize was shared by Sharpless, and Noyori and Knowles, for their seminal work on asymmetric transition metalcatalysed oxidation and reduction reactions. Topics include personal list for the best development in organic chemistry; and an organic chemist with research interests focussed on carbohydrate chemistry and biology.

The unexpected formation of an oxazole ring has occurred during synthesis of a copper(I) cyanide network polymer as part of our ongoing studies of the structural chemistry of these networks. Crystals of the title compound were formed during the synthesis of a previously reported CuCN network solid containing protonated N-methylethanolamine and have been characterized by single crystal X-ray structure analysis. The structure shows well-defined oxazole-2-iminium cations sitting in continuous channels along the short a-axis of the crystal in a new three-dimensional copper(I) cyanide polymeric network. Evidently, a reaction has occurred between the cyanide ion and the protonated N-methylethanolamine base.

The synthesis of tetrahydroquinoline derivatives from dimethyl anilines and enamides has been developed by Fe(III)‐phenanthroline complex under aerobic condition. The oxidation of tertiary anilines involving a single electron transfer of Fe(phen)3(PF6)3 afforded the iminium ion intermediate, which reacted with electron‐rich alkenes to build a six‐membered N‐heterocycles containing quaternary carbon center via the oxidative Povarov reaction process. [ABSTRACT FROM AUTHOR]

Vitrimers are a class of polymeric materials with outstanding properties. Intramolecular substitution reactions lead to a dynamic exchange within the polymer network which enables thermoreversible stress relaxation in yet permanently crosslinked materials. In this paper, the acid‐mediated autocatalysis is explored as a rearrangement pathway for vinylogous urethane vitrimers. The autocatalysis enables transimination reactions, resulting in a dynamic exchange among the enamine‐one species, without an excess of free amines. Therefore, the enamine‐ones are protonated by a Brønsted acid and turn into electrophilic iminium‐ones, thus enabling fast backward and substitution reactions with water and free amines. This work provides an in‐depth investigation of the mechanism by kinetic studies of selected compounds. In addition, novel elastomeric and thermosetting poly(vinylogous urethane) networks with and without free amine groups and additional para‐toluene sulfonic acid as a Brønsted catalyst are prepared by bulk polymerization of hexane‐1,6‐diylbis(3‐oxobutanoate) and tris(2‐aminoethyl)amine. The underlying exchange mechanisms are determined by stress‐relaxation experiments with stress relaxation times of 0.3–54 000 s at 110 °C. [ABSTRACT FROM AUTHOR]

A Petasis reaction of 2-pyridinecarbaldehydes with various amines and 4-substituted 1,2-oxaborol-2(5H)-ols was developed. In the presence of HCl, the reaction proceeded smoothly under very mild conditions and the corresponding desired products were obtained in medium to excellent yields. This method allows the access a wide range of highly functionalized allylic alcohols, which might be useful compounds in medicinal and material chemistry. [ABSTRACT FROM AUTHOR]

Two C2-symmetric bisiminium salt species containing biphenylazepinium units and derived from two chiral diamines were prepared and tested as organocatalysts for asymmetric epoxidation. [ABSTRACT FROM AUTHOR]

The o -carboranyllithium species Li 2 C 2 B 10 H 10 adds to the triple C N bond of a nitrile to afford a stable zwitterionic iminium salt 3 with a nido -C 2 B 9 carborane tether. The novel carborane product 3 has been characterized by means of IR and NMR spectroscopy and mass spectrometry. In addition, the structure of 3 has been studied by a combination of single-crystal X-ray diffraction and density functional theory (DFT) calculations, which proves that the five-membered open face of the nido -carborane cluster and the planar exo -polyhedral five-membered ring have partial conjugation. [ABSTRACT FROM AUTHOR]

Gefitinib (GEF), an inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, is widely used for the treatment of cancers, particularly non-small cell lung cancer. However, its clinical use is limited by multiple adverse effects associated with GEF, such as liver and lung injuries, severe nausea, and diarrhea. Although, the exact mechanism of GEF adverse effects are still unknown, xenobiotic-induced bioactivation is thought to play a significant role in GEF induced toxicity. Using a metabolomic approach, we investigated the metabolic pathways of GEF in human and mouse liver microsomes. Thirty four GEF metabolites and adducts were identified and half of them are novel. The potential reactive metabolites, two aldehydes and one iminium, were identified for the first time. The previously reported GSH adducts and primary amines were observed as well. The aldehyde and iminium pathways were further confirmed by using methoxylamine and potassium cyanide as trapping reagents. Using recombinant CYP450 isoforms, CYP3A4 inhibitor, and S9 from Cyp3a -null mice, we confirmed CYP3A is the major enzyme contributing to the formation of aldehydes, GSH adducts, and primary amines in liver. Multiple enzymes contribute to the formation of iminium. This study provided us more knowledge of GEF bioactivation and enzymes involved in metabolic pathways, which can be utilized for understanding the mechanism of adverse effects associated with GEF and predicting possible drug-drug interactions. Further studies are suggested to determine the roles of these bioactivation pathways in GEF toxicity. [ABSTRACT FROM AUTHOR]

A highly enantio- and diastereoselective synthesis of 3-aminocyclopenta[ b]indoles has been developed through formal [3+2] cycloaddition reaction of enecarbamates and 3-indolylmethanols. This transformation is catalyzed by a chiral phosphoric acid that achieves simultaneous activation of both partners of the cycloaddition. Mechanistic data are also presented that suggest that the reaction occurs through a stepwise pathway. [ABSTRACT FROM AUTHOR]

Metal-catalyzed isomerization of N- and O-allylic systems is emerging as an effective method to form synthetically useful iminium and oxocarbenium intermediates. In the presence of tethered nucleophiles, several recent examples illuminate this approach as a powerful strategy for the synthesis of structurally complex and diverse heterocycles. In this Concept article, we attempt to cover this area of research through a selection of recent versatile examples. [ABSTRACT FROM AUTHOR]

A new efficient synthesis of functionalized perfluoroalkyl fluorophosphates by oxidative addition of Me2NCH2F to the electron-deficient phosphanes (C2F5) nPF3− n ( n=0-3) is reported. The initially formed zwitterionic, hexacoordinated phosphates [(C2F5) nF5− nP(CH2NMe2−CH2NMe2)] are converted into the corresponding phosphonium salts [(Me3PCH2NMe2]+[(C2F5) nF5− nP(CH2NMe2)]− by treatment with PMe3. In addition [(C2F5)3F2P(CH2NMe2CH2NMe2)] can undergo a 1,3-methyl shift from the internal to the terminal nitrogen-a structural characterization was achieved from the CF3 analogue. Reaction of [(C2F5)3F2P(CH2NMeCH2NMe3)] and PMe3 gave rise to the formation of the zwitterionic phosphonium phosphate [(C2F5)3F2P(CH2NMeCH2PMe3)], which was fully characterized by X-ray diffraction analysis. Moreover, an efficient one-pot synthesis of Cs+[(C2F5)3F2P(CH2NMe2)]− was pursued. This salt turned out to be a useful nucleophile in several alkylation reactions. [ABSTRACT FROM AUTHOR]

A protected aldehyde was attached via a two-carbon spacer to a peptide backbone amide nitrogen during a traditional Merrifield solid-phase synthesis. Acid-mediated unmasking of the aldehyde triggered the regioselective formation of cyclic N-acyliminiums between the aldehyde and the neighboring peptide amide nitrogen. In the absence of an internal nucleophile, the cyclic iminiums formed dihydropyrazinones, a six-membered peptide backbone con-straint between two peptide amides. In the presence of an internal nucleophile, tetrahydropyrazinopyrimidinediones or tetrahydroimidazopyrazinediones were formed via tandem N-acyliminium ion cyclization-nucleophilic addition. The outcome of this nucleophilic addition was dependent on the substituent on the nitrogen nucleophile. [ABSTRACT FROM AUTHOR]

Ornithine cyclodeaminase (OCD) is an NAD⁺-dependent deaminase that is found in bacterial species such as Pseudomonas putida. Importantly, it catalyzes the direct conversion of the amino acid L-ornithine to L-proline. Using molecular dynamics (MD) and a hybrid quantum mechanics/molecular mechanics (QM/MM) method in the ONIOM formalism, the catalytic mechanism of OCD has been examined. The rate limiting step is calculated to be the initial step in the overall mechanism: hydride transfer from the L-ornithine's Cα-H group to the NAD⁺ cofactor with concomitant formation of a Cα=NH₂ ⁺ Schiff base with a barrier of 90.6 kJ mol-1. Importantly, no water is observed within the active site during the MD simulations suitably positioned to hydrolyze the Cα=NH₂ ⁺ intermediate to form the corresponding carbonyl. Instead, the reaction proceeds via a non-hydrolytic mechanism involving direct nucleophilic attack of the δ-amine at the Cα-position. This is then followed by cleavage and loss of the α-NH₂ group to give the Δ¹-pyrroline-2-carboxylate that is subsequently reduced to L-proline. [ABSTRACT FROM AUTHOR]

Abstract: Lycopodium alkaloids are unique (and often impressive in terms of structures) polycyclic alkaloids that attract great interest from a biological point of view and that also provide ideal targets for total synthesis. Propylpiperidine units closely related to pelletierine are involved in the biosynthesis of these alkaloids. Therefore, stable pelletierine-like compounds, especially a (R)-phenylglycinol-based oxazolopiperidine analog, were prepared and their reactivity investigated. The compounds described in this work expand the tool-box of small building blocks in the piperidine series and pelletierine analogs and could be suitable for the synthesis of Lycopodium alkaloids following biosynthetically inspired strategies. [Copyright &y& Elsevier]

Among all strategies used by organic chemists to control the stereoselectivity of reactions, organocatalysis, which consists in using the chirality of a small organic molecule, is an increasingly popular method. The proline-catalyzed aldol reaction was one of the first reported cases that demonstrated the power of organocatalysis in the field of asymmetric synthesis. Previous theoretical contributions focused on the reaction mechanism using quantum mechanics (QM) methods. We here present a theoretical study about one specific step of the proline-catalyzed aldol reaction, namely, the conversion of the iminium intermediate into the corresponding enamine. It consists of an intramolecular rearrangement that involves the transfer of a hydrogen atom. First, we investigate this transfer using modern QM models, that is, density functional theory calculations with the M06-2X functional. On the basis of these QM results, we then assess the performance of a reactive force field, ReaxFF, used in combination with molecular dynamics simulations in order to provide a complementary light on this reaction. [ABSTRACT FROM AUTHOR]

The search for new catalysts with superior performance and broad applicability remains a central theme in asymmetric organocatalysis. Inspired by Nature as well as by numerous previous efforts, we have developed chiral primary-tertiary diamines as both functional and mechanistic enzyme mimics, showing unprecedented scope in enamine-aldol reactions and significant potential in the reactions of acroleins. Our endeavors focusing on this type of catalysts are summarized in this account. 1 Introduction 2 General Features of Primary-Tertiary Vicinal Diamine/TfOH; Multifunctional Catalysis 3 Asymmetric Supramolecular Primary Amine Catalysis; Roles of the Hydrophobic Cavity 4 Asymmetric Direct Aldol Reaction of Aliphatic Ketones 5 Asymmetric Direct Cross-Aldol Reaction of Aldehydes 6 Asymmetric Retro-Aldol and Transfer-Aldol Reactions 7 Iminium Catalysis with Chiral Primary-Tertiary Diamines 8 Bifunctional Catalysis of Primary-Tertiary Diamines in the Baylis-Hillman Reaction 9 Conclusion, Remarks, and Outlook. [ABSTRACT FROM AUTHOR]

Abstract: The enantiopure non-natural amino acids have been synthesized by insitu generation of iminium and iminium triflates from lactams using triflic anhydride in pyridine buffered media. These molecules with remote chiral centers may be useful in synthesis of natural product particularly Kopsia derived alkaloids. [Copyright &y& Elsevier]

An unprecedented acetic acid-catalyzed efficient access to N-alkylpyrroles from reaction of 4-hydroxy- l-proline with a variety of aldehydes has been achieved in good to excellent yields under mild reaction conditions. [ABSTRACT FROM AUTHOR]

The regioselective and diastereoselective cyclization of acyliminium intermediates generated from aminocyclopropanes on unprotected indoles is presented. The recent results obtained in our group are compared with previous intermolecular reactions with aminocyclopropanes as well as with other cyclization methods involving iminium ions and unprotected indoles. A first speculative analysis of possible reaction mechanisms allows rationalizing the observed selectivity. The high potential of the method for the synthesis of natural alkaloids is demonstrated in the formal synthesis of aspidospermidine and the total synthesis of goniomitine. [ABSTRACT FROM AUTHOR]

Abstract: Reaction of O-propargyl salicylaldehyde and related compounds with dialkylamines in the presence of copper(I) iodide gave 4-(alkylamino)-3-methylenechroman derivatives in good yields through the loss of one alkyl group of the dialkylamine. The reaction also worked well by employing 2-amino benzaldehyde derivatives to afford 4-(alkylamino)-3-methylene-1,2,3,4-tetrahydroquinolines. A deuterium-labeling experiment suggested that the α-hydrogen of the dialkylamine was transferred intramolecularly into the terminal methylene. This result indicated the reaction mechanism, which involved the formation of iminium ion between the aldehyde and the dialkylamine followed by ene-type C–C bond formation with inverse electron demand and hydrolysis. [Copyright &y& Elsevier]

A simple primary-tertiary diamine has been explored as a novel catalyst for the Morita-Baylis- Hillman reaction of MVK and aryl aldehydes, and moderate to good chemical yields were obtained. Detailed mechanism study indicated that the diamine acted as a bifunctional cooperation catalyst via a bicyclic enamino-quaternary ammonium intermediate. [ABSTRACT FROM AUTHOR]

The geometric parameters, the charge distribution, and the energetics of N-methyl-2-( N-ethylanilino)-3-(indol-1-yl)-and N-methyl-2-( N-ethylanilino)-3-(indol-3-yl)maleimides and their conjugated acids were studied by density functional theory calculations at the B3LYP/6-31G(d) level. The mechanism of the tandem hydride transfer/cyclization sequence, which occurs after protonation of N-methyl-2-( N-ethylanilino)-3-(indol-1-yl)-and N-methyl-2-( N-ethylanilino)-3-(indol-3-yl)maleimides, was analyzed. The investigation of the potential energy surface for the tandem hydride transfer/cyclization of the iminium cation that formed upon protonation revealed that the hydride transfer followed by intramolecular cyclization at position 7 of the indole fragment in N-methyl-2-( N-ethylanilino)-3-(indol-1-yl)maleimide is the preferable process, unlike alternative intramolecular cyclization involving the cationic center at the C(2) atom of the indole fragment and the benzene ring of the N-ethylaniline fragment of the indoleninium cation in N-methyl-2-( N-ethylanilino)-3-(indol-3-yl)maleimide. A study of the key intermediates of the assumed reaction mechanism demonstrated that these intermediates are actually stationary points on the potential energy surface (minima and transition states). [ABSTRACT FROM AUTHOR]

Abstract: Hemiaminals of fluorinated aldehydes are very useful reagents. They are able, under Lewis acid activation, to generate iminium species which can react with various nucleophiles and provide diverse fluorinated compounds. By this methodology, β-fluoroalkylated enones, which are very interesting building blocks, have been easily obtained. Fluorinated homoallylamines have been also synthesized and used as starting material to prepare α-fluoroalkylated nitrogen heterocycles. Many other synthetic applications of these fluorinated iminium ions provide new bioactive compounds. [Copyright &y& Elsevier]

2,3,3-Trimethyl-7-nitro-3,4-dihydroisoquinolinium tetrafluoroborate is a highly efficient catalyst for the oxaziridinium-mediated epoxidation of a variety of olefins, including monosubstituted ones. [Copyright &y& Elsevier]

The reaction of precursors 3 with NBS in radical conditions does not yield any azetidine resulting from a 4-exo radical cyclisation with bromine atom transfer, or any brominated product at the glycinyl position. Instead, dibrominated adducts 4 and aminals 5 have been formed in good yields. We have investigated the mechanism of this puzzling transformation and shown that the homolytic abstraction of a hydrogen atom by a Br• radical does not take place at the capto-dative position but at the allylic one. The resulting α-bromo derivative 8 would then evolve into an iminium intermediate with concomitant production of bromine and of a succinimidyl anion, which explains the formation of products 4 and 5. To cite this article: C. Koerber et al., C.R. Chimie 6 (2003). [Copyright &y& Elsevier]

Reaction of cyclic ketones 2–6 and imines 15–17 in HF/SbF5 in presence of CCl4 yield hydroxy or fluoroderivatives, hydride abstraction occurring at a site located far from the functional group. Whereas ketones 2–5 yield only hydroxy derivatives, through cyclic carboxonium ion, imines 15, 16 N-protonated in the media conditions give only fluoroderivatives 18, 19, respectively, after quenching with HF–pyridine. Ring contraction is operative when starting from large membered ring ketones 24 and 25, and imine 26, leading to a mixture of hydroxy or fluoro cyclohexanones and/or cycloheptanones. [Copyright &y& Elsevier]

The reaction of chiral 2-trifluoromethyl-1,3-oxazolidines with various silylated nucleophiles under Lewis acid activation provides a stereoselective route to functionalized α-trifluoromethylamines. This methodology was successfully applied to the diastereoselective synthesis of trifluoromethylated homoallylic and propargylic amines, trifluoromethylated α-amino nitrile, β-aminoketone and β-aminoester. The α-amino nitrile and the β-amino ester were converted into (+)-3,3,3-trifluoroalanine and (+)-4,4,4-trifluoro-3-aminobutanoic acid in a one-step procedure. [Copyright &y& Elsevier]

The unexpected formation of an oxazole ring has occurred during synthesis of a copper(I) cyanide network polymer as part of our ongoing studies of the structural chemistry of these networks. Crystals of the title compound were formed during the synthesis of a previously reported CuCN network solid containing protonated N-methylethanolamine and have been characterized by single crystal X-ray structure analysis. The structure shows well-defined oxazole-2-iminium cations sitting in continuous channels along the short a-axis of the crystal in a new three-dimensional copper(I) cyanide polymeric network. Evidently, a reaction has occurred between the cyanide ion and the protonated N-methylethanolamine base. [ABSTRACT FROM AUTHOR]

Indolizidine alkaloids, which have versatile bioactivities, are produced by various organisms. Although the biosynthesis of some indolizidine alkaloids has been studied, the enzymatic machinery for their biosynthesis in Streptomyces remains elusive. Here, we report the identification and analysis of the biosynthetic gene cluster for iminimycin, an indolizidine alkaloid with a 6-5-3 tricyclic system containing an iminium cation from Streptomyces griseus. The gene cluster has 22 genes, including four genes encoding polyketide synthases (PKSs), which consist of eight modules in total. In vitro analysis of the first module revealed that its acyltransferase domain selects malonyl-CoA, although predicted to select methylmalonyl-CoA. Inactivation of seven tailoring enzyme-encoding genes and structural elucidation of four compounds accumulated in mutants provided important insights into iminimycin biosynthesis, although some of these compounds appeared to be shunt products. This study expands our knowledge of the biosynthetic machinery of indolizidine alkaloids and the enzymatic chemistry of PKS., (© 2021 Wiley-VCH GmbH.)

Cyclic voltammetry data were obtained for several categories of fungicidal agents including quinones (akrobomycin, podosporin A), iminium ions and precursors (pyridazines, 15-azahomosterol, griseofulvin-4′-oxime), and metal derivatives of chelators (pyridine-2-aldehyde thiosemicarbazones). The reductions usually occurred in the range of −0.7 to +0.3 V. Reduction potentials provide information on the feasibility of electron transfer in vivo. Catalytic production of oxidative stress from redox cycling is a possible mode of action. Alternatively, there may be interference with normal electron transport chains. [ABSTRACT FROM AUTHOR]

Control freaks: Chiral amine catalysts prove to be highly proficient mediators in the asymmetric, polyconjugate addition of C‐, N‐, and S‐based nucleophiles to acyclic dienals and cyclic dienones. For high 1,6‐selectivities, the stereo spatial matching of the molecular orbitals and ionic charges of the reacting species are key. But can we widen the scope and how far can we go with remote, iminium‐stereocontrol? [ABSTRACT FROM AUTHOR]

A key 7-allyl-8-hydroxy-6-azabicyclo[3.2.1]octan-3-one intermediate in a synthesis of the alkaloid peduncularine is obtained enantioenriched, by desymmetrisation of an achiral 6,7-epoxy-8-azabicyclo[3.2.1]octan-3-one (epoxytropinone). Chiral lithium amide-assisted enantioselective silyl enol ether formation then TMSOTf/allyltrimethylsilane/2,6-lutidine-induced rearrangement−allylation proceeded in up to 80:20 er, but modest overall yield. Chiral amines or (thio)ureas replacing 2,6-lutidine gave up to 76:24 er directly from epoxytropinone. A direct, simplified (base-free) process using a BINOL-derived bis(sulfuryl)imide catalyst and allyltrimethylsilane proved the most promising (80%, 83:17 er). Image 1 [ABSTRACT FROM AUTHOR]

Abstract: Calculated reaction energies, NBO analyses, and natural charge distributions show that a trimethylsilyl group at the β carbon atom stabilizes the positive charge of an iminium cation more effectively than a tert-butyl group in the same position. Different from the classical β-silicon effect, where theoretical studies suggest that the positive charge is stabilized hyperconjugatively by interaction of the Si–C σ-bond with a formally empty 2p-orbital of suitable symmetry at the carbonium carbon, the stabilization in the case of iminium ions occurs by interaction of the Si–C σ-bond with the π∗ orbital of the Cbond. Stabilization of the silyl-substituted derivatives by hyperconjugation might be enhanced by interaction of the positive charge with a neighboring induced dipole. [Copyright &y& Elsevier]

• Enamine-zinc complexes. • Stereoselective addition on cyclic iminiums. • 2-Substituted nitrogen heterocycles. • (rac)-Homoconiine and coniine precursors synthesis. In the presence of ZnCl 2 , chiral protected amino-ketones and amino-aldehydes gave zinc enamino-complexes. Both enamine and iminium structures of these complexes were observed in 1H and 13C NMR spectra depending on the solvent. Introduction of either an allyl or a hydrogen substituent was performed using allylmagnesium chloride or NaBH 4 in excess leading to various heterocycles. With the amino-ketones diastereoselectivity (de = 50) was observed respectively. Homoconiine and coniine precursors were prepared by this strategy. [ABSTRACT FROM AUTHOR]

Accompanying pseudorotaxane formation between dibenzo[24]-crown-8 and dibenzylammonium salts in acetone-d6, iminium salts result from the well-known condensation reaction between ketones and amines, calling into question formation constants estimated by direct spectroscopic means in acetone. [Copyright &y& Elsevier]

Basic amine substituents provide several pharmacokinetic benefits relative to acidic and neutral functional groups, and have been extensively utilized as substituents of choice in drug design. On occasions, basic amines have been associated with off-target pharmacology via interactions with aminergic G-protein coupled receptors, ion-channels, kinases, etc. Structural features associated with the promiscuous nature of basic amines have been well-studied, and can be mitigated in a preclinical drug discovery environment. In addition to the undesirable secondary pharmacology, α-carbon oxidation of certain secondary or tertiary cycloalkyl amines can generate electrophilic iminium and aldehyde metabolites, potentially capable of covalent adduction to proteins or DNA. Consequently, cycloalkyl amines have been viewed as structural alerts (SAs), analogous to functional groups such as anilines, furans, thiophenes, etc., which are oxidized to reactive metabolites that generate immunogenic haptens by covalently binding to host proteins. Detailed survey of the literature, however, suggests that cases where preclinical or clinical toxicity has been explicitly linked to the metabolic activation of a cycloalkyl amine group are extremely rare. Moreover, there is a distinct possibility for the formation of electrophilic iminium/amino-aldehyde metabolites with numerous cycloalkyl amine-containing marketed drugs, since stable ring cleavage products have been characterized as metabolites in human mass balance studies. In the present work, a critical analysis of the evidence for and against the role of iminium ions/aldehydes as mediators of toxicity is discussed with a special emphasis on often time overlooked detoxication pathways of these reactive species to innocuous metabolites., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The recent discovery of the prenylated FMN (prFMN) cofactor has led to a renewed interest in the prFMN-dependent UbiD family of enzymes. The latter catalyses the reversible decarboxylation of alpha-beta unsaturated carboxylic acids and features widely in microbial metabolism. The flavin prenyltransferase UbiX synthesizes prFMN from reduced FMN and phosphorylated dimethylallyl precursors. Oxidative maturation of the resulting prFMN reduced species to the active prFMN iminium form is required for UbiD activity. Heterologous production of active holo-UbiD requires co-expression of UbiX, but the levels of prFMN incorporation and oxidative maturation appear variable. Detailed protocols and strategies for in vitro reconstitution and oxidative maturation of UbiD are presented that can yield an alternative source of active holo-UbiD for biochemical studies., (© 2019 Elsevier Inc. All rights reserved.)

In this chemical puzzle fluoromethyldimethylamine represents a versatile reactant for the synthesis of electron‐deficient, functionalized phosphates. Thus, the oxidative addition of the reagent to (C2F5)nPF3−n (n=1–3) selectively affords zwitterionic [(C2F5)nF5−nP(CH2NMe2CH2NMe2)] (n=1–3) in good yields. The course of the reaction involved the phosphoranide [P(C2F5)3F]−, which was evidenced independently. Treatment of [(C2F5)3F2P(CH2NMe2CH2NMe2)] with aqueous sodium hydroxide gave rise to the formation of the phosphate Na+[(C2F5)3F2P(CH2NMe2)]−. The nucleophilic nitrogen atom in the phosphates [(C2F5)nF5−nP(CH2NMe2)]− allows the synthesis of several novel functionalized perfluoroalkylfluorophosphates. See the Full Paper by B. Hoge et al. for more details. [ABSTRACT FROM AUTHOR]