Nucleophilic Addition Research Articles

Recent advances in biological applications of mannich bases — An overview

Mannich bases are beta-amino ketone-carrying compounds that are the end products of the Mannich reaction. The Mannich reaction is essential in the synthesis of nitrogen-containing compounds. The Mannich reaction, a nucleophilic addition reaction that forms carbon-carbon bonds, is employed in the synthesis of numerous natural products, drugs and other compounds. There are several aminoalkyl chain bearing Mannich bases with high curative value, such as fluoxetine, atropine, ethacrynic acid, trihexyphenidyl, and many others. According to the literature, Mannich bases are highly reactive and have been demonstrated to have powerful anti-inflammatory, anticancer, antifilarial, antibacterial, antifungal, anticonvulsant, anthelmintic, antitubercular, analgesic, anti-HIV, antimalarial, antipsychotic, antiviral, antilipase activity and other properties. The primary source of, -α,β-unsaturated ketone, which can be produced by deaminating the hydrogen atom of the amine group, is responsible for the biological action of Mannich bases. However, a number of minor biological functions of Mannich bases have been reported, including their ability to control blood pressure or prevent platelet aggregation, their impact on parasites and ulcers, and their use as medications for mental health issues. Since there is a greater need for anticonvulsant pharmaceuticals, these anticonvulsant medications containing N-mannich base groups will exhibit an increase in lipophilic nature and hence have improved blood-brain barrier penetration. The overview concludes with a brief explanation of the potential of Mannich bases as inhibitors of various enzymes or ligands for various receptors.

Collective Total Synthesis of Mavacuran Alkaloids through Intermolecular 1,4‐Addition of an Organolithium Reagent**

AbstractWe report a synthetic endeavor towards the highly strained pentacyclic caged framework of the mavacuran alkaloids which culminated with the concise total synthesis of C‐fluorocurine, C‐profluorocurine, C‐mavacurine, normavacurine, 16‐epi‐pleiocarpamine and taberdivarine H. We designed a strategy involving late‐stage construction of the D ring by Michael addition of a vinylic nucleophile to a 2‐indolyl acrylate moiety. While the intramolecular Michael addition did not succeed, we were able to perform a diastereoselective unusual intermolecular 1,4‐addition of a functionalized vinyl lithium reagent to a readily accessible Michael acceptor with the assistance of the piperidine nitrogen atom through the formation of a complex as suggested by DFT computations. Final cyclization was achieved by nucleophilic substitution to form an ammonium intermediate. The first total syntheses of C‐profluorocurine and C‐fluorocurine were finalized by the dihydroxylation of C‐mavacurine and a pinacol rearrangement, respectively.

Collective Total Synthesis of Mavacuran Alkaloids through Intermolecular 1,4-Addition of an Organolithium Reagent.

We report a synthetic endeavor towards the highly strained pentacyclic caged framework of the mavacuran alkaloids which culminated with the concise total synthesis of C-fluorocurine, C-profluorocurine, C-mavacurine, normavacurine, 16-epi-pleiocarpamine and taberdivarine H. We designed a strategy involving late-stage construction of the D ring by Michael addition of a vinylic nucleophile to a 2-indolyl acrylate moiety. While the intramolecular Michael addition did not succeed, we were able to perform a diastereoselective unusual intermolecular 1,4-addition of a functionalized vinyl lithium reagent to a readily accessible Michael acceptor with the assistance of the piperidine nitrogen atom through the formation of a complex as suggested by DFT computations. Final cyclization was achieved by nucleophilic substitution to form an ammonium intermediate. The first total syntheses of C-profluorocurine and C-fluorocurine were finalized by the dihydroxylation of C-mavacurine and a pinacol rearrangement, respectively.

Reductive Hydrodehalogenation of Halogenated Carboxylic Acid Derivatives Using a DMSO/HCOONa·2H2O System.

A practical and operationally simple hydrodehalogenation of halogenated carboxylic acid derivatives using a DMSO/HCOONa·2H2O system is developed. This protocol avoids the involvement of light irradiation, electrochemical apparatus, transition metals, radical initiators, strong bases, and other additional additives. Control experiments suggest that HCOONa might function as a hydride donor in the reduction process via nucleophilic substitution or addition to achieve the hydrodehalogenation.

Chemistry of Isoeugenol and Its Oxidation Products: Mechanism and Kinetics of Isoeugenol as a Skin Sensitizer.

Structurally similar phytochemical compounds may elicit markedly different skin sensitization responses. Eugenol and isoeugenol are natural phenylpropanoids found in various essential oils are frequently used as fragrance ingredients in consumer products due to their pleasing aromatic properties. Both compounds are also skin sensitizers with isoeugenol being a stronger sensitizer than eugenol. The most commonly accepted mechanisms for haptenation by eugenol involve formation of a quinone methide or an ortho-quinone intermediate. The mechanism for the increased skin response to isoeugenol remains elusive, although quinone methide intermediates have been proposed. The recent identification of diastereomeric 7,4'-oxyneolignans as electrophilic, thiol-depleting isoeugenol derivatives has revived interest in the possible role of elusive reactive intermediates associated with the isoeugenol's haptenation process. In the present work, integrated non-animal skin sensitization methods were performed to determine the ability of syn-7,4'-oxyneolignan to promote haptenation and activation of further molecular pathways in keratinocytes and dendritic cells, confirming it as a candidate skin sensitizer. Kinetic NMR spectroscopic studies using dansyl cysteamine (DCYA) confirmed the first ordered nature of the nucleophilic addition for the syn-7,4'-oxyneolignan. Computational studies reaffirmed the "syn" stereochemistry of the isolated 7,4'-oxyneolignans along with that of their corresponding DCYA adducts and provided evidence for the preferential stereoselectivity. A plausible rationale for isoeugenol's strong skin sensitization is proposed based on the formation of a hydroxy quinone methide as a reactive intermediate rather than the previously assumed quinone methide.

Expedient synthesis of 1,2,4-triazinyl substituted benzo[c]coumarins via double oxidation strategy

Herein, we report a convenient one-pot synthesis of 1,2,4-triazinyl derivatives of benzocoumarins. The proposed approach consists in the nucleophilic addition of tetrahydrobenzo annulated dimethoxycoumarin to 1,2,4-triazines followed by double oxidation of both dihydrotriazine and tetrahydrobenzo groups with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). The nucleophilic addition of the dimethoxycoumarin to 1,2,4-triazines was carried out in the presence of three-fold excess of methanesulfonic acid in DCM at room temperature and take place between positions 4 and 5 of coumarin and 1,2,4-triazine, respectively. The double oxidation step was achieved with 3.6 equivalent of DDQ. Selective oxidation of dihydrotriazine moiety, without affecting the tetrahydrobenzo fragment, was achieved using 1.2 equivalent of tetrachlorobenzoquinone (TCQ). The differences in the oxidation with TCQ and DDQ appear to be related to the higher oxidative potential of DDQ in contrast to TCQ. The advantages of the method are the elimination of the use of transition metals, the availability of starting materials, and the simplicity of the procedure. The proposed approach provides a two-step one-pot protocol for the synthesis of triazinyl benzocoumarins, precursors for the preparation of push-pull pyridinyl chromophore.

Transition Metal-Controlled Divergent Annulations of Azomethine Imines with Iodonium Ylides via C-Centered [1,2]-Rearrangement.

Transition metal-controlled divergent annulation reactions of azomethine imines with iodonium ylides via C-centered [1,2]-rearrangement have been developed. The azomethine imino group, as a switchable and transient directing group (DG), underwent intramolecular nucleophilic addition and in situ generated bicyclic diaziridine, which facilitated the C-centered [1,2]-rearrangement and subsequent divergent annulations in the presence of different metal complexes as the catalysts. The benzo[c]chromen-1-one and pyrano[de]isochromene scaffolds could be independently constructed with Rh(III) and Ru(II), respectively. It was worth noting that the azomethine imino group was employed first as the switchable DG through rearrangement progress.

Mechanisms and origins of stereoselectivity involved in NHC-catalyzed [3 + 3] Annulation of 2-bromoenals and β-ketothioamides: A DFT study

We reported a density functional theory (M06–2X) study of the possible mechanisms operating in a chemo- and stereoselective [3+3] annulation reaction of 2-bromoenal with β-ketothioamide catalyzed by a chiral NHC catalyst. DFT computations suggest the catalytic reaction involves nucleophilic addition, [1,2]-proton transfer, debromination, [1,3]-proton transfer, Michael addition, [1,5]-proton transfer, ring closure and catalyst dissociation, in which Michael addition is the chemo- and stereoselectivity-determining step and provides the SR-configured sipro-piperidinone predominantly. This result is consistent with the stereoselectivity observed in experiment. Nonconvalent interaction (NCI) analysis reveals that the origin of stereoselectivity is the different weak interactions (C–H···π, LP···π and π···π). The computational results should deepen our understanding of NHC catalysis, and may thus contribute to the design of new catalytic systems.

Radical-initiated diazo-retaining nucleophilic addition reaction of trifluorodiazoethane and diazoacetate with 2H‑azirines

A diethylzinc-air system is established to enable an unconventional diazo-retaining nucleophilic addition reaction of trifluorodiazoethane and diazoacetate with 2H-azirines. This transformation converted a broad range of cyclic 2H-azirines to valuable acyclic α-diazo amines in good yields. Further synthetic transformations provide access to β-CF3 amines, β-CF3-enamines, and CF3-oxazolines. Preliminary mechanistic studies reveal that dioxygen plays a crucial role in enabling this radical-initiated reaction, involving an in situ generated imine as the key intermediate.

Abstract 1215: Synthetic colibactins reveal the structural and biological mode-of-action of a microbial carcinogen

Abstract Certain Enterobacteriaceae strains contain a 54-kb biosynthetic gene cluster referred to as “pks” encoding the biosynthesis of a secondary metabolite, colibactin, that putatively alkylates host DNA via nucleophilic cyclopropane ring addition. While evidence suggests colibactin’s genotoxicity promotes mutagenesis and cancer, it has been impossible to directly test this hypothesis due to compound instability and sparse production. Recently synthesized stable colibactin analogs facilitate the first studies investigating the compounds structural mode of action. We tested the genotoxic capacity of two compounds: colibactin 742 and an analogous molecule with modified proposed DNA-binding residues (colibactin 746), in human cell lines and colonic organoids. To assess transcriptional pathways associated with acute colibactin response, we compared transcriptional profiles in a normal human colonic cell line (FHC) after short-term exposure to colibactin 742 or 746 and pks+ K. pneumoniae or an isogenic ΔclbP mutant. To determine the mutagenic and transformative potential of colibactin 742, we exposed the human colonic epithelial cell line HCT 116 to 742 or 746 for 32-51 days followed by a 30-day recovery period. We assessed changes in gene expression by RNAseq and mutagenesis by whole-genome sequencing followed by mutational signature fitting. 742 but not 746 caused DNA damage in cell lines and human colonoids, quantified by γH2AX phosphorylation. 742 recapitulated transcriptomic responses to pks+ K. pneumoniae infection, and significantly upregulated pathways associated with p53 signaling, senescence, and IL-1 signaling, relative to 746 treated cells. Moreover, chronic cyclical exposure significantly increased expression of BRCA1-associated DNA repair pathways and genes involved in cross-link repair or replication-associated DNA damage response, consistent with colibactin’s putative cross-linking activity. Whole-genome sequencing revealed an increase in single-base substitutions (SBS) and indels (ID) in 742 treated cells, with a higher proportion of [T>N] SBS and 1-4 bp insertion/deletions in T-rich homopolymers, respectively. We found that 742-induced mutations could be attributed to the proposed colibactin signature (SBS88), reactive oxygen species (ROS; SBS17), or mismatch-repair deficiency (MMRd; SBS44). Colibactin 742 treatment caused an increase in H2DCFDA staining in intestinal epithelial cells, and an increase in transcriptomic pathways associated with peroxisome biogenesis or oxidative phosphorylation, supporting the theory that colibactin 742 treatment caused ROS-induced mutations. ID signatures primarily recapitulated pks-associated mutations. These findings provide the first direct evidence supporting colibactin’s proposed mode-of-action. Furthermore, our study suggests colibactin may indirectly cause mutations attributed to ROS or MMRd. Citation Format: Michael W. Dougherty, Rafael Valdés-Mas, Kevin M. Wernke, Raad Z. Gharaibeh, Alberto Riva, Ye Yang, Marcus Muehlbauer, Eran Elinav, Jens Puschhof, Seth B. Herzon, Christian Jobin. Synthetic colibactins reveal the structural and biological mode-of-action of a microbial carcinogen [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1215.

Enzyme-catalyzed addition of diazo compounds to in-situ generated imines

The nucleophilic addition of diazo compounds with imines is known for a long time. While a number of bases, organocatalysts, etc., have been used to catalyze this reaction no enzyme is explored so far. Herein, we report a biocatalytic nucleophilic addition of diazo compounds with in-situ generated imines by the reaction between 2-amino pyridine and benzaldehyde using an α-amylase enzyme under sustainable reaction conditions. To prove the generality of this transformation differently substituted 2-amino pyridines, benzaldehydes along with ethyl diazoacetate were tested, and afforded the corresponding products in moderate to good yields. Moreover, control experiments are performed those suggest that the reaction might be getting catalyzed in the natural active-site of the α-amylase enzyme.

Modular and practical diamination of allenes

Vicinal diamines are privileged scaffolds in medicine, agrochemicals, catalysis, and other fields. While significant advancements have been made in diamination of olefins, diamination of allenes is only sporadically explored. Furthermore, direct incorporation of acyclic and cyclic alkyl amines onto unsaturated π systems is highly desirable and important, but problematic for many previously reported amination reactions including the diamination of olefins. Herein, we report a modular and practical diamination of allenes, which offers efficient syntheses of β,γ-diamino carboxylates and sulfones. This reaction features broad substrate scope, excellent functional group tolerability, and scalability. Experimental and computational studies support an ionic reaction pathway initiated with a nucleophilic addition of the in situ formed iodoamine to the electron deficient allene substrate. An iodoamine activation mode via a halogen bond with a chloride ion was revealed to substantially increase the nucleophilicity of the iodoamine and lower the activation energy barrier for the nucleophilic addition step.

Synthetic applications of biologically important Mannich bases: An updated review

Mannich bases are the beta-amino ketones carrying compounds. Mannich reaction is a nucleophilic addition reaction (nucleophiles such as halogen ions (I-, Br-, Cl- ), the hydroxide ion (OH- ), cyanide ion (CN-), ammonia and water, which involves the condensation of three components, viz., ammonia or a primary amine or a secondary amine or with amides, a non-enolizable aldehyde, usually formaldehyde and a compound containing an active hydrogen atom. These three compounds condense with the concomitant release of the water molecule to produce a new base known as a mannich base, in which the active hydrogen is replaced by an amino methyl group. During the past decades, there has been a great deal of interest in the synthesis of mannich bases. Mannich base can be synthesized by using microwave irradiation, one pot, catalyst-free, retrospective asymmetric synthesis, solvent-free and ultrasonic-assisted synthetic techniques. The literature studies enlighten the fact that mannich bases are a key step in the synthesis of a wide variety of natural products, pharmaceuticals and so forth. Mannich bases play a vital role in the coordination chemistry and the development of metal complexes. Mannich bases have remained an important and popular area of research due to their simple synthesis, adaptability and diverse range of applications. Thus, mannich bases and their derivatives may be further used for enormous biological applications with potent effects.

Half-Sandwich Type Platinum-Group Metal Complexes of C-Glucosaminyl Azines: Synthesis and Antineoplastic and Antimicrobial Activities

While platinum-based compounds such as cisplatin form the backbone of chemotherapy, the use of these compounds is limited by resistance and toxicity, driving the development of novel complexes with cytostatic properties. In this study, we synthesized a set of half-sandwich complexes of platinum-group metal ions (Ru(II), Os(II), Ir(III) and Rh(III)) with an N,N-bidentate ligand comprising a C-glucosaminyl group and a heterocycle, such as pyridine, pyridazine, pyrimidine, pyrazine or quinoline. The sugar-containing ligands themselves are unknown compounds and were obtained by nucleophilic additions of lithiated heterocycles to O-perbenzylated 2-nitro-glucal. Reduction of the adducts and, where necessary, subsequent protecting group manipulations furnished the above C-glucosaminyl heterocycles in their O-perbenzylated, O-perbenzoylated and O-unprotected forms. The derived complexes were tested on A2780 ovarian cancer cells. Pyridine, pyrazine and pyridazine-containing complexes proved to be cytostatic and cytotoxic on A2780 cells, while pyrimidine and quinoline derivatives were inactive. The best complexes contained pyridine as the heterocycle. The metal ion with polyhapto arene/arenyl moiety also impacted on the biological activity of the complexes. Ruthenium complexes with p-cymene and iridium complexes with Cp* had the best performance in ovarian cancer cells, followed by osmium complexes with p-cymene and rhodium complexes with Cp*. Finally, the chemical nature of the protective groups on the hydroxyl groups of the carbohydrate moiety were also key determinants of bioactivity; in particular, O-benzyl groups were superior to O-benzoyl groups. The IC50 values of the complexes were in the low micromolar range, and, importantly, the complexes were less active against primary, untransformed human dermal fibroblasts; however, the anticipated therapeutic window is narrow. The bioactive complexes exerted cytostasis on a set of carcinomas such as cell models of glioblastoma, as well as breast and pancreatic cancers. Furthermore, the same complexes exhibited bacteriostatic properties against multiresistant Gram-positive Staphylococcus aureus and Enterococcus clinical isolates in the low micromolar range.

Amidine compounds as products of a piperidine reaction with acetonitrile in the presence of zinc(II) precursors

The influence of the zinc(II) starting material in the nucleophilic addition of piperidine (abbreviated as pipe) to acetonitrile to form amidine, piperidinoacetamidine (pipeam), was assessed. Thus, zinc(II) oxide, zinc(II) chloride or zinc(II) acetate were reacted with picolinic acid or pyrazinoic acid, piperidine and acetonitrile. The acid was used as a source of an N,O-donor ligand. The reactions with picolinic acid (picH) gave pipeamH[Zn(pic)3]·0.5H2O (1), an amidinium salt of a homoleptic complex [Zn(pic)3]–. The same product was obtained when [Zn(pic)(picH)Cl], an already known picolinate complex, was reacted under similar conditions. The chloride-containing mixtures produced another amidine compound, (pipeamH)Cl. The reactions with pyrazinoic acid (pyrazH) gave pipeamH[Zn(pyraz)3] (3), the amidinium salt of a homoleptic complex [Zn(pyraz)3]–. The acetate-containing mixture yielded acetamidinium acetate. The latter product indicates the presence of ammonia in the reaction. Notably, no amidine species was isolated when the coordinatively saturated pyrazinoate complex, [Zn(pyraz)2]n (2), was reacted with piperidine and acetonitrile. A detailed structural characterization of the new compounds and a discussion of their formation are presented.

Rh(II)-catalyzed condensation of 3-diazotetramic acids with nitriles delivers novel druglike 5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-4-ones

Previously reported 3-diazotetramic acids have been successfully involved in Rh(II)-catalyzed condensation with aliphatic and aromatic nitriles delivering compounds bearing a hitherto unexplored polysubstituted fused oxazole scaffold. The latter was found to be somewhat labile to the addition of nucleophiles (water and benzylamine) which leads to oxazole ring opening and may constitute an entry into polysubstituted pyrrolinones after due investigation of scope.

Copper-catalyzed conjugate addition of allene-derived nucleophiles to alkenyl-substituted carboxamides

Catalytic Michael addition reaction represents a fundamental importance in organic synthetic chemistry. Whereas corresponding conversions toward intrinsically low reactive enamide remains an ongoing challenging. We herein report a copper-catalyzed conjugate addition of allenes to β-substituted alkenyl amides, one of the most challenging Michael acceptors. The present method utilizes readily available allenes as the latent carbon-based nucleophiles and simple, common β-substituted alkenyl amides as starting materials, unlike previous methods that usually preinstall an activating group to improve the reactivity of amide or uses highly reactive stoichiometric quantities of organometallics. Hence, this approach shows good functional group compatibility and can be implemented under mild reaction conditions with excellent level of chemo- and regioselectivities.

Rhenium-Catalyzed Decarboxylative Coupling of Cyclic Enol Carbonates with Silyl Enol Ethers and Ketene Silyl Acetals

The Lewis acid-catalyzed decarboxylative coupling of cyclic enol carbonates, prepared by the fixation of carbon dioxide onto propargyl alcohols, with silyl enol ethers including ketene silyl acetals, was developed to afford 1,4-dicarbonyl compounds in good-to-high yields. As the plausible reaction mechanism, it was proposed that the decarboxylative formation of an oxyallyl cation intermediate or its equivalent and the sequential nucleophilic addition of silyl enol ethers proceeded to afford 1,4-dicarbonyl products. In addition, the synthetic utility of the obtained-1,4-dicarbonyl compounds was also demonstrated by applying them to the construction of multisubstituted heterocycles.

Stereoselective synthesis of linear oxa-triquinanes and oxa-diquinanes via Lewis acid mediated nucleophilic addition to oxonium ions: study of nucleophile-dependent selectivity

Stereoselective synthesis of linear oxa-triquinanes and oxa-diquinanes via Lewis acid mediated nucleophilic addition to oxonium ions: study of nucleophile-dependent selectivity

Isolation, Reactivity, and Tunable Properties of a Strained Antiaromatic Osmacycle.

Strain and antiaromaticity in compounds are recognized as two substantial destabilizing features, and consequently, realization of dual destabilizing features in a single molecule is challenging and far more difficult in a single ring. Moreover, transformation of an antiaromatic framework to different antiaromatic or aromatic species is a significant subject in antiaromatic chemistry and has attracted increasing interest. In this work, we isolated a highly strained antiaromatic metallacycle in which a cyclic metal vinylidene unit is embedded. Computational studies revealed its ring strain energies and antiaromatic character and showed that the metal incorporation and the phosphonium substituents play a crucial role in its stabilization. The mechanism of its formation has been illustrated by density functional theory (DFT) calculations and the isolation of a key intermediate. We further discovered diverse reactivities and structural reshuffling of this unusual strained antiaromatic complex according to its two destabilizing characters. We obtained two isomers of metallaindenes fused with oxiranes from the direct oxidation of the metal vinylidene or by nucleophilic addition to an isolated metallacyclocumulene formed by the reaction of metal vinylidene with hydroxide ion, achieving a reconfiguration of the antiaromatic framework. Transformations of the antiaromatic metallacycle by electrophiles to various aromatic metallaindynes have been achieved, and that a condensed Fukui function was employed to confirm the regioselectivity of the electrophilic additions, and the acid/base-induced aromaticity switch along with tunable photophysical properties were investigated. These interesting transformations not only enrich the chemistry of metal vinylidenes and antiaromatics and could also perform potentially as switchable optical materials.