Dearomatization Of Pyridines Research Articles

Formal meta-C-H-Fluorination of Pyridines and Isoquinolines through Dearomatized Oxazinopyridine Intermediates.

Organofluorine compounds, including fluorinated pyridines and isoquinolines, play a crucial role in pharmaceuticals, agrochemicals, and materials science. However, step-economic selective C-H-functionalization to access these fluorinated azaarenes is still underexplored, with selective meta-C-H-fluorination proving to be especially elusive. Here we present a practical method for formal meta-C-H-fluorination of pyridines and isoquinolines. By applying an oxazinoazaarene-based temporary pyridine dearomatization strategy with Selectfluor as an electrophilic F-source, fluorination of pyridines was achieved with exclusive C3-selectivity in moderate to good yields. The same strategy can also be applied to the formal meta-C-H-fluorination of isoquinolines. Late-stage-functionalization of drugs, drug precursors, and ligands as well as a large-scale one-pot dearomatization-fluorination-rearomatization reaction further demonstrate the synthetic utility of this approach.

Oxidative Dearomatization of Pyridines.

Dearomatization of pyridines is a well-established synthetic approach to access piperidines. Although remarkably powerful, existing dearomatization processes have been limited to the hydrogenation or addition of carbon-based nucleophiles to activated pyridiniums. Here, we show that arenophile-mediated dearomatizations can be applied to pyridines to directly introduce heteroatom functionalities without prior substrate activation. The arenophile platform in combination with olefin oxidation chemistry provides access to dihydropyridine cis-diols and epoxides. These previously elusive compounds are now readily accessible and can be used for the downstream preparation of diversely functionalized piperidines.

Recent Strategies in the Nucleophilic Dearomatization of Pyridines, Quinolines, and Isoquinolines.

Dearomatization reactions have become fundamental chemical transformations in organic synthesis since they allow for the generation of three-dimensional complexity from two-dimensional precursors, bridging arene feedstocks with alicyclic structures. When those processes are applied to pyridines, quinolines, and isoquinolines, partially or fully saturated nitrogen heterocycles are formed, which are among the most significant structural components of pharmaceuticals and natural products. The inherent challenge of those transformations lies in the low reactivity of heteroaromatic substrates, which makes the dearomatization process thermodynamically unfavorable. Usually, connecting the dearomatization event to the irreversible formation of a strong C-C, C-H, or C-heteroatom bond compensates the energy required to disrupt the aromaticity. This aromaticity breakup normally results in a 1,2- or 1,4-functionalization of the heterocycle. Moreover, the combination of these dearomatization processes with subsequent transformations in tandem or stepwise protocols allows for multiple heterocycle functionalizations, giving access to complex molecular skeletons. The aim of this review, which covers the period from 2016 to 2022, is to update the state of the art of nucleophilic dearomatizations of pyridines, quinolines, and isoquinolines, showing the extraordinary ability of the dearomative methodology in organic synthesis and indicating their limitations and future trends.

Diastereoselective dearomative cycloaddition of bicyclobutanes with pyridinium ylides: a modular approach to multisubstituted azabicyclo[3.1.1]heptanes.

Diastereoselective (3+3) cycloaddition between bicyclobutanes and pyridinium ylides forms azabicyclo[3.1.1]heptanes via pyridine dearomatization. These reactions proceed under ambient conditions with no need for photochemistry or catalysis, and tolerate a wide range of functional gorups. The resulting multicyclic ring systems have diverse synthetic handles for further transformations, making them potentially valuable for the design of Csp3-rich drug candidates. These include semi-reduction of the dihydropyridine, and diastereoselective photochemical skeletal rearrangement to give a tetrasubstituted cyclobutane.

Dearomatization of Pyridines: Stereoselective Synthesis of Functionalized [1,2,4]Triazolo[4,3-a]pyridines.

The stereoselective preparation of functionalized [1,2,4]triazolo[4,3-a]pyridines from N-tosylhydrazones and pyridines was developed through the dearomatization of pyridines. The current transformation features good step- and atom-economy, high diastereoselectivity, and the efficient formation of four new carbon-heteroatom bonds in the corresponding product tetrahydro pyridines.

A Pyridine Dearomatization Approach for the Gram Scale Synthesis of (±)-Sparteine.

Both enantiomers of sparteine have suffered from pricing and supply chain variability, which has inspired efforts toward efficient chemical synthesis. Here, we build upon our reported synthesis of the matrine-type lupin alkaloids in order to synthesize (±)-sparteine. Specifically, selective quenching of the cyclization between glutaryl chloride and pyridine with methanol provides a functionalized quinolizidine core that was elaborated to (±)-sparteine in six additional steps on gram scale. This synthesis provides a scalable route to sparteine from inexpensive commodity chemicals utilizing a dearomative cyclization. In addition, this route provides concise access to (±)-lupinine.

Recent Progresses in the Catalytic Stereoselective Dearomatization of Pyridines.

1,2- and 1,4-dihydropyridines and N-substituted 2-pyridones are very important structural motifs due to their synthetic versatility and vast presence in a variety of alkaloids and bioactive molecules. In this article, we gather and summarize the catalytic and stereoselective synthesis of partially hydrogenated pyridines and pyridones via the dearomative reactions of pyridine derivatives up to mid-2023. The material is fundamentally organized according to the type of reactivity (electrophilic/nucleophilic) of the pyridine nucleus. The material is further sub-divided taking into account the nucleophilic species when dealing with electrophilic pyridines and considering the reactivity manifold of pyridine derivatives behaving as nucleophiles at the nitrogen site. The latter more recent approach allows for an unconventional entry to chiral N-substituted 2- and 4-pyridones in non-racemic form.

Lewis Acid-Promoted Asymmetric Dearomatization of Pyridines with Grignard Reagents under Cu(I) Catalysis

Lewis Acid-Promoted Asymmetric Dearomatization of Pyridines with Grignard Reagents under Cu(I) Catalysis

Synthesis of Dihydropyridine Spirocycles by Semi-Pinacol-Driven Dearomatization of Pyridines

The identification of the beneficial pharmacokinetic properties of aza-spirocycles has led to the routine incorporation of these highly rigid and three-dimensional structures in pharmaceuticals. Herein, we report an operationally simple synthesis of spirocyclic dihydropyridines via an electrophile-induced dearomative semi-pinacol rearrangement of 4-(1'-hydroxycyclobutyl)pyridines. The various points for diversification of the spirocyclization precursors, as well as the synthetic utility of the amine and ketone functionalities in the products, provide the potential to rapidly assemble medicinally relevant spirocycles.

Iron Catalyzed Dearomatization of Pyridines into Annelated Azepine Derivatives in a One-Step, Three-Component Reaction.

Commercially available Fe(TTP)Cl catalyzes three-component dearomative formal cycloaddition reactions between pyridines, diazo compounds, and coumalates. Diversely substituted annelated seven-membered N-heterocycles could be generated in less than 10 min in one step at room temperature. The reaction is compatible to gram scale. The extension to benzimidazoles in place of pyridines has been successfully demonstrated. The mechanism of this reaction has been carefully examined by computational studies that corroborate the observed regioselectivities.

A Pyridine Dearomatization Approach to the Matrine-Type Lupin Alkaloids.

(+)-Matrine and (+)-isomatrine are tetracyclic alkaloids isolated from the plant Sophora flavescens, the roots of which are used in traditional Chinese medicine. Biosynthetically, these alkaloids are proposed to derive from three molecules of (-)-lysine via the intermediacy of the unstable cyclic imine Δ1-piperidine. Inspired by the biosynthesis, a new dearomative annulation reaction has been developed that leverages pyridine as a stable surrogate for Δ1-piperidine. In this key transformation, two molecules of pyridine are joined with a molecule of glutaryl chloride to give the complete tetracyclic framework of the matrine alkaloids in a single step. Using this dearomative annulation, isomatrine is synthesized in four steps from inexpensive commercially available chemicals. Isomatrine then serves as the precursor to additional lupin alkaloids, including matrine, allomatrine, isosophoridine, and sophoridine.

In silico reaction screening with difluorocarbene for N-difluoroalkylative dearomatization of pyridines

Quantum chemical calculations are mainly regarded as a method for mechanistic studies in organic chemistry, whereas their use for the simulation of unknown reactions could greatly assist in reaction development. Here we report a strategy for developing multicomponent reactions on the basis of the results of computational reaction simulations. In silico screening of multicomponent reactions with difluorocarbene using the artificial force induced reaction method suggested that cycloadditions between an azomethine ylide and a variety of coupling partners would proceed to generate the corresponding α,α-difluorinated N-heterocyclic compounds. The predicted reaction was successfully realized experimentally, leading to a multicomponent N-difluoroalkylative dearomatization of pyridines involving a pyridinium ylide-mediated 1,3-dipolar cycloaddition with a diverse range of electrophiles such as aldehydes, ketones, imines, alkenes and alkynes. Moreover, the performance of the cycloaddition could be explained by comparing the energy barrier of the desired pathway with that of the competitive undesired pathway, which was also identified by the artificial force induced reaction search.

Cobalt-Catalyzed Selective Dearomatization of Pyridines to N–H 1,4-Dihydropyridines

Cobalt-Catalyzed Selective Dearomatization of Pyridines to <i>N</i>–H 1,4-Dihydropyridines

Mechanism and regioselectivity of [Cu-Fe] heterobimetallic-catalyzed hydroboration of pyridines: DFT investigation

Dearomatization of pyridine is important in organic synthesis while the control of its selectivity is difficult, the hydroboration catalyzed by transitional metal is an effective solution. In this work, the detailed reaction mechanism of hydroboration of pyridines catalyzed by [Cu-Fe] heterobimetallic catalyst was investigated by density functional theory (DFT) calculations. The catalytic mechanism and the influence factors of catalytic activity and regioselectivity were discussed. Our calculated results show that the hydroboration of pyridines catalyzed by the [Cu-Fe] heterobimetallic catalyst involves three processes: B-H bond activation, activated Bpin-pyridine formation, and Bpin-pyridine reduction addition. The activated Bpin-pyridine formation process is the rate-determining step. In the Bpin-pyridine reduction addition process, the addition reaction proceeds via the ionic intermediate mechanism, instead of the single electron transfer (SET) mechanism. Both the catalytic activity and the regioselectivity are determined by the atomic charge distribution. Our calculation results are consistent with and provide an explanation for the experimental observations, being particularly helpful for the further development of pyridine dearomatization and the design of other catalytic transformations.

Substituted Dihydropyridine Synthesis by Dearomatization of Pyridines.

Dearomatization is an effective method to transform readily available N‐heterocycles into partially saturated motifs. Manipulation of dihydro‐derivatives holds great potential and provides access to a variety of semi‐saturated N‐heterocyclic building blocks. However, current strategies are limited in scope and the use of sensitive reagents restricts the applicability in synthetic laboratories. Herein, we report the synthesis of a broad variety of N‐substituted 1,4‐ and 1,2‐dihydropyridines by very mild and selective reduction with amine borane for the first time.

Construction of Protoberberine Alkaloid Core through Palladium Carbene Bridging C–H Bond Functionalization and Pyridine Dearomatization

Compounds with a pyridoisoquinolinone core often appear as members of the protoberberine alkaloid family. Traditional methods to construct this framework normally rely on manipulation of sophistica...

Hydrogenation of Alkenes Catalyzed by a Non‐pincer Mn Complex

AbstractHydrogenation of substituted styrenes and unactivated aliphatic alkenes by molecular hydrogen has been achieved using a Mn catalyst with a non‐pincer, picolylphosphine ligand. This is the second reported example of alkene hydrogenation catalyzed by a Mn complex. Mechanistic studies showed that a Mn hydride formed by H2 activation in the presence of a base is the catalytically active species. Based on experimental and DFT studies, H2 splitting is proposed to occur via a metal‐ligand cooperative pathway involving deprotonation of the CH2 arm of the ligand, leading to pyridine dearomatization.

A One‐Pot Dearomative Approach to C4‐Alkylated Tetrahydropyridines and Tetrahydroquinolines

AbstractA regioselective one‐pot approach to the synthesis of C4‐alkylated tetrahydropyridines (THPs) and tetrahydroquinolines (THQs) by dearomatization of pyridines and quinolines has been developed. The transformation is achieved by the BF3 ⋅ OEt2‐mediated, C4‐selective addition of Grignard reagents, followed by a cascade of enamine protonation and the subsequent Et3SiH reduction of the resulting iminium ions. This protocol not only provides a facile synthetic approach to C4‐substituted THPs and THQs, but also offers a new strategy for the dearomatization of heteroaromatics.

Synthesis of Benzo-Fused 11H-Pyrido[2,1-b]quinazolin-11-ones by a Buchwald–Hartwig Coupling/Pyridine Dearomatization Sequence in Eucalyptol

The synthesis of a new library of polyheterocyclic 11H-pyrido[2,1-b]quinazolin-11-one derivatives was investigated. Satisfactory conditions were obtained via sequential C–N Buchwald–Hartwig coupling and pyridine dearomatization. In this work, traditional solvents were replaced by the bio-sourced eucalyptol, confirming the interest in it as a green solvent in chemistry.

Evidence for Simultaneous Dearomatization of Two Aromatic Rings under Mild Conditions in Cu(I)-Catalyzed Direct Asymmetric Dearomatization of Pyridine.

Bis(phosphine) copper hydride complexes are uniquely able to catalyze direct dearomatization of unactivated pyridines with carbon nucleophiles, but the mechanistic basis for this result has been unclear. Here we show that, contrary to our initial hypotheses, the catalytic mechanism is monometallic and proceeds via dearomative rearrangement of the phenethylcopper nucleophile to a Cpara-metalated form prior to reaction at heterocycle C4. Our studies support an unexpected heterocycle-promoted pathway for this net 1,5-Cu-migration beginning with a doubly dearomative imidoyl-Cu-ene reaction. Kinetics, substituent effects, computational modeling, and spectroscopic studies support the involvement of this unusual process. In this pathway, the CuL2 fragment subsequently mediates a stepwise Cope rearrangement of the doubly dearomatized intermediate to the give the C4-functionalized 1,4-dihydropyridine, lowering a second barrier that would otherwise prohibit efficient asymmetric catalysis.