Alkylpyridinium Salts Research Articles

Nickel-Catalyzed Electroreductive Coupling of Alkylpyridinium Salts and Aryl Halides.

An electrochemical, nickel-catalyzed reductive coupling of alkylpyridinium salts and aryl halides is reported. High-throughput experimentation (HTE) was employed for rapid reaction optimization and evaluation of a broad scope of pharmaceutically relevant structurally diverse aryl halides, including complex drug-like substrates. In addition, the transformation is compatible with both primary and secondary alkylpyridinium salts with distinct conditions. Mechanistic insights were critical to enhance the efficiency of coupling using secondary alkylpyridinium salts. Systematic comparisons of the electrochemical and non-electrochemical methods revealed the complementary scope and efficiency of the two approaches.

2,6-Bis(pyrazol-1-yl)pyridine (1-bpp) as a General Ligand for the Negishi Alkylation of Alkylpyridinium Salts.

A Ni/1-bpp catalyst was demonstrated to be effective in the Negishi alkylation with multiple classes of alkylpyridinium salts, including α-primary and α-secondary. These conditions are also effective for benzylic pyridinium salts, demonstrating the successful Negishi alkylation of benzylic pyridinium salts for the first time. Further, 14 derivatives of 1-bpp were prepared with a variety of steric and electronic properties to study how these changes impact the success of the Negishi alkylation.

Deaminative Addition of Alkylpyridinium Salt to Aldehyde.

Here we show that a primary amine can engage in the nucleophilic addition to an aldehyde to synthesize an alcohol following preactivation of the amine. The enabling reagent for this radical-polar crossover process is CrCl2. This reaction is selective for aldehydes and compatible with numerous functional groups, which are not tolerated under classical Grignard-type conditions. Complementary to the well-established imine synthesis, this deaminative alcohol synthesis can broadly expand the chemical space constructed by aldehydes and amines.

Nickel-Catalyzed Deaminative Ketone Synthesis: Coupling of Alkylpyridinium Salts with Thiopyridine Esters via C-N Bond Activation.

A direct synthesis of ketones by the nickel-catalyzed deaminative cross-coupling of alkylpyridinium salts with thiopyridine esters has been reported. The reaction works well for both primary and secondary amines. This approach affords a highly valuable vista for the facile synthesis of ketones from easily accessible feedstock chemicals. The utility of this method is demonstrated through the functionalization of complex bioactives and pharmaceuticals.

Halogen Bond‐Catalyzed Oxidative Annulation of N‐Alkyl Pyridinium Salts and Alkenes with Air as a Sole Oxidant: Metal‐free Synthesis of Indolizines

AbstractThe utilization of ambient air as a sole oxidant is highly desired for the sustainability of chemical industry. Herein, we reported a mild and metal‐free synthesis of indolizines using pyridinium salts and alkenes with ambient air as a sole oxidant. In this reaction, a halogen bond donor (perfluoro‐1‐iodooctane, 10 mol%) was successfully applied to catalyze this desired oxidative [3+2] annulation. The C−I bond of halogen bond donor is crucial for this transformation, while the corresponding C−Br bond and C−F bonds gave much lower yields. Moreover, the phenolic hydroxyl increases the amount of side‐product, probably due to the strong interaction of phenolate anion and the halogen bond donor. Finally, with the rapid development of halogen bond catalysis, this halogen bond‐catalyzed strategy could continuously promote the synthesis of indolizines in a sustainable manner.

Repurposing amine and carboxylic acid building blocks with an automatable esterification reaction.

New methodologies to unite amines and carboxylic acids that complement the popular amide coupling can significantly expand accessible chemical space if they yield products distinct from the classic R-NHC(O)-R' amide arrangement. Here we have developed an amine-acid esterification reaction based on pyridinium salt activation of amine C-N bonds to create products of type R-OC(O)-R' upon reaction with alkyl and aryl carboxylic acids. The protocol is robust and facile as demonstrated by automation on open-source robotics.

Primary vs. secondary alkylpyridinium salts: a comparison under electrochemical and chemical reduction conditions.

This report details a systematic comparison of the scope of aryl bromides in nickel-catalyzed, reductive cross-electrophile couplings of primary vs. secondary alkylpyridinium salts using both electrochemical and chemical reductants. Facilitated by the use of high-throughput experimentation (HTE) techniques, 37 aryl bromides, including 13 complex, drug-like examples, were investigated. By using primary and secondary substrates differing only by one methylene, we observed that the trends in ArBr scope are similar between the primary and secondary alkylpyridinium salts, although distinctions were observed in isolated cases. In addition, the electrochemical conditions compared favorably to those using chemical reductants, especially among the more complex, drug-like aryl halides.

Reactivity of triplet diradical intermediates in aqueous media for transition-metal-free Csp2–H alkylation

Alkyl pyridinium salts have been used in dipolar cycloaddition reactions with π-unsaturated compounds and in reductive single-electron transfer reactions as convenient radical precursors. Here, we report a distinct reaction pathway involving triplet diradical intermediates in the coupling reaction between alkyl pyridinium ylides and electrophilic N -heterocyclic molecules. We demonstrate that alkyl pyridinium ylides generated from alkyl pyridinium salts under basic aqueous conditions can undergo addition into iminoamido N -heterocycles, generating triplet diradical intermediates that can lead to C–H alkylated products. The proposed reaction mechanism is supported by electron paramagnetic resonance and radical scavenging experiments. Notably, a wide substrate scope and excellent level of functional group tolerance are attained under cost-effective and straightforward conditions, which reveal the amenability of this protocol in the pharmaceutical and chemical industries. • Triplet diradical intermediate • C–H alkylation and benzylation • Alkyl pyridinium ylides • Functionalization of N -heterocycles Ghosh et al. report the transition-metal-free C(sp 2 )–H alkylation of N -heterocycles with alkyl pyridinium ylides. The distinct mechanistic pathway in which triplet diradical intermediates are formed by the addition of pyridinium ylides into N -heterocyclic molecules provides an alternative use for nitrogen ylides.

Cover Feature: Photoredox‐Induced Deaminative Radical‐Cationic Three‐Component Couplings with N‐Alkylpyridinium Salts and Alkenes (ChemPhotoChem 11/2021)

The Cover Feature shows a radical three-component coupling driven by visible light photoredox catalysis. Single electron transfer (SET) reduction of N-alkylpyridinium salts liberates nucleophilic carbon radicals that successively couple with an acceptor and a donor alkene, enabling a stereoselective synthesis of new succinimide derivatives. Cover image made by Marcin Henk Kowalski. More information can be found in the Communication by Malte Brasholz and co-workers.

Photoredox‐Induced Deaminative Radical‐Cationic Three‐Component Couplings with N‐Alkylpyridinium Salts and Alkenes

AbstractN‐Benzyl‐ and N‐2°‐alkylpyridinium salts were engaged in visible‐light‐driven, photoredox‐induced radical‐cationic three‐component couplings with N‐methylmaleimide and acrylonitrile as radical acceptors, in combination with 1,1‐diarylethylenes as donor alkenes. These multicomponent coupling reactions could be achieved under mild conditions, with high efficiency, and to furnish diverse 3,4‐disubstituted pyrrolidin‐2,5‐dione products with high stereoselectivity. In addition, 2,3‐diaryl‐1,3‐butadienes could be utilized as alternative donor alkene components, to furnish diastereomerically pure 1,2,3‐trisubstituted 1,3‐butadienes as the coupling products.

α-Chiral Amines via Thermally Promoted Deaminative Addition of Alkylpyridinium Salts to Sulfinimines.

A deaminative reaction of Katritzky alkylpyridinium salts and sulfinimines has been developed to deliver enantiopure α-chiral amines. The success of this method relied on the discovery of a thermally promoted deamination via single-electron transfer of an anion-π complex of the alkylpyridinium cation with potassium carbonate. This method boasts excellent diastereoselectivity over the α-stereocenter as well as broad functional group and heterocycle tolerance.

Silver-Promoted (4 + 1) Annulation of Isocyanoacetates with Alkylpyridinium Salts: Divergent Regioselective Synthesis of 1,2-Disubstituted Indolizines.

An unprecedented silver-promoted regioselective (4 + 1) annulation of isocyanoacetates with pyridinium salts is reported. The established protocol provides controlled, facile, and modular access to a range of synthetically useful N-fused heterocyclic scaffolds containing indolizines, pyrrolo[1,2-a]quinolines, pyrrolo[2,1-a]isoquinolines, and 1H-imidazo[4,5-a]indolizin-2(3H)-ones. A mechanistic pathway involving nucleophilic addition/protonation/elimination/cycloisomerization is proposed.

Deaminative Reductive Methylation of Alkylpyridinium Salts.

Methyl groups can imbue valuable properties in organic molecules, often leading to enhanced bioactivity. To enable efficient installation of methyl groups on simple building blocks and in late-stage functionalization, a nickel-catalyzed reductive coupling of secondary Katritzky alkylpyridinium salts with methyl iodide was developed. When coupled with formation of the pyridinium salt from an alkyl amine, this method allows amino groups to be readily transformed to methyl groups with broad functional group and heterocycle tolerance.

Nickel-catalyzed deaminative Sonogashira coupling of alkylpyridinium salts enabled by NN2 pincer ligand

Alkynes are amongst the most valuable functional groups in organic chemistry and widely used in chemical biology, pharmacy, and materials science. However, the preparation of alkyl-substituted alkynes still remains elusive. Here, we show a nickel-catalyzed deaminative Sonogashira coupling of alkylpyridinium salts. Key to the success of this coupling is the development of an easily accessible and bench-stable amide-type pincer ligand. This ligand allows naturally abundant alkyl amines as alkylating agents in Sonogashira reactions, and produces diverse alkynes in excellent yields under mild conditions. Salient merits of this chemistry include broad substrate scope and functional group tolerance, gram-scale synthesis, one-pot transformation, versatile late-stage derivatizations as well as the use of inexpensive pre-catalyst and readily available substrates. The high efficiency and strong practicability bode well for the widespread applications of this strategy in constructing functional molecules, materials, and fine chemicals.

Microwave-Assisted Synthesis of Fluorescent Pyrido[2,3-b]indolizines from Alkylpyridinium Salts and Enaminones.

Pyridinium ylides are well recognized as dipoles for cycloaddition reactions. In its turn, the microwave-assisted interaction of N-(cyanomethyl)-2-alkylpyridinium salts with enaminones unexpectedly proceeds as a domino sequence of cycloisomerization and cyclocondensation reactions, instead of a 1,3-dipolar cycloaddition. The reaction takes place in the presence of sodium acetate as base and employs benign solvents. The optical properties of the resulting pyrido[2,3-b]indolizines were studied, showing green light emission with high fluorescence quantum yields.

Marine-Derived Macrocyclic Alkaloids (MDMAs): Chemical and Biological Diversity.

The curiosity and attention that researchers have devoted to alkaloids are due to their bioactivities, structural diversity, and intriguing chemistry. Marine-derived macrocyclic alkaloids (MDMAs) are considered to be a potential source of drugs. Trabectedin, a tetrahydroisoquinoline derivative, has been approved for the treatment of metastatic soft tissue sarcoma and ovarian cancers. MDMAs displayed potent activities that enabled them to be used as anticancer, anti-invasion, antimalarial, antiplasmodial, and antimicrobial. This review presents the reported chemical structures, biological activities, and structure–activity relationships of macrocyclic alkaloids from marine organisms that have been published since their discovery until May 2020. This includes 204 compounds that are categorized under eight subclasses: pyrroles, quinolines, bis-quinolizidines, bis-1-oxaquinolizidines, 3-alkylpiperidines, manzamines, 3-alkyl pyridinium salts, and motuporamines.

Copper‐Catalyzed Deaminative Difluoromethylation

AbstractThe difluoromethyl group (CF2H) is considered to be a lipophilic and metabolically stable bioisostere of an amino (NH2) group. Therefore, methods that can rapidly convert an NH2 group into a CF2H group would be of great value to medicinal chemistry. We report herein an efficient Cu‐catalyzed approach for the conversion of alkyl pyridinium salts, which can be readily synthesized from the corresponding alkyl amines, to their alkyl difluoromethane analogues. This method tolerates a broad range of functional groups and can be applied to the late‐stage modification of complex amino‐containing pharmaceuticals.

Copper-Catalyzed Deaminative Difluoromethylation.

The difluoromethyl group (CF2 H) is considered to be a lipophilic and metabolically stable bioisostere of an amino (NH2 ) group. Therefore, methods that can rapidly convert an NH2 group into a CF2 H group would be of great value to medicinal chemistry. We report herein an efficient Cu-catalyzed approach for the conversion of alkyl pyridinium salts, which can be readily synthesized from the corresponding alkyl amines, to their alkyl difluoromethane analogues. This method tolerates a broad range of functional groups and can be applied to the late-stage modification of complex amino-containing pharmaceuticals.

Nickel-Catalyzed Cross-Coupling of Alkyl Carboxylic Acid Derivatives with Pyridinium Salts via C-N Bond Cleavage.

The electrophile-electrophile cross-coupling of carboxylic acid derivatives and alkylpyridinium salts via C-N bond cleavage is developed. The method is distinguished by its simplicity and steers us through a variety of functionalized ketones in good to excellent yields. Besides acid chlorides, carboxylic acids were also employed as acylating agents, which enabled us to incorporate acid-sensitive functional groups such as MOM, BOC, and acetal. Control experiments with TEMPO revealed a radical pathway.

Nickel-Catalyzed Deaminative Acylation of Activated Aliphatic Amines with Aromatic Amides via C-N Bond Activation.

Deaminative functionalization of aliphatic primary amines has great synthetic utility. Herein, we describe a Ni-catalyzed reductive deaminative cross-electrophile coupling reaction between Katritzky salts and aromatic amides. This work provides examples of the synthesis of various ketones from alkylpyridinium salts, including both primary and secondary alkylamines. Given its mild reaction conditions and high functional group tolerance, this cross-coupling strategy is expected to be useful for late-stage functionalization of complex compounds.