Nucleophilic Substitution Of Hydrogen Research Articles

Mechanistic Approach Toward the C4‐Selective Amination of Pyridines via Nucleophilic Substitution of Hydrogen

AbstractThe development of site‐selective functionalization of N‐heteroarenes is highly desirable in streamlined synthesis. In this context, direct amination of pyridines stands as an important synthetic methodology, with particular emphasis on accessing 4‐aminopyridines, a versatile pharmacophore in medicinal chemistry. Herein, we report a reaction manifold for the C4‐selective amination of pyridines by employing nucleophilic substitution of hydrogen (SNH). Through 4‐pyridyl pyridinium salt intermediates, 4‐aminopyridine products are obtained in reaction with aqueous ammonia without intermediate isolation. The notable regioselectivity was achieved by the electronic tuning of the external pyridine reagents along with the maximization of polarizability in the proton elimination stage. Further mechanistic investigations provided a guiding principle for the selective C−H pyridination of additional N‐heteroarenes, presenting a strategic avenue for installation of diverse functional groups.

Mechanistic Approach Toward the C4-Selective Amination of Pyridines via Nucleophilic Substitution of Hydrogen.

The development of site-selective functionalization of N-heteroarenes is highly desirable in streamlined synthesis. In this context, direct amination of pyridines stands as an important synthetic methodology, with particular emphasis on accessing 4-aminopyridines, a versatile pharmacophore in medicinal chemistry. Herein, we report a reaction manifold for the C4-selective amination of pyridines by employing nucleophilic substitution of hydrogen (SNH). Through 4-pyridyl pyridinium salt intermediates, 4-aminopyridine products are obtained in reaction with aqueous ammonia without intermediate isolation. The notable regioselectivity was achieved by the electronic tuning of the external pyridine reagents along with the maximization of polarizability in the proton elimination stage. Further mechanistic investigations provided a guiding principle for the selective C-H pyridination of additional N-heteroarenes, presenting a strategic avenue for installation of diverse functional groups.

Catalyst-free nucleophilic substitution of hydrogen in quinoline rings by acylethynylpyrroles: stereoselective synthesis of 2-(E-2-acylethenylpyrrolyl)quinolines

A new type of SNHAr reaction in the quinoline core under the action of available acylethynylpyrroles proceeds without halogenated reagents and any catalysts to stereoselectively afford 2-(E-2-acylethenylpyrrolyl)quinolines with a yield up to 78%.

Nucleophilic substitution of hydrogen in pyridine and its derivatives by organophosphorus nucleophiles in the presence of electron-deficient acetylenes

The review considers publications on a new easy functionalization of pyridinoids (pyridines, quinolines, isoquinolines, acridine, phenanthridine) by the electron-deficient acetylene (esters of acetylenecarboxylic acids, acylacetylenes, cyanoacetylenes)/P-nucleophile (phosphine chalcogenides, H -phosphonates) system. Particular attention is paid to the SN H reaction of regioselective cross-coupling of pyridines with secondary phosphine chalcogenides, initiated by acylacetylenes and leading to the formation of 4-chalcogenophosphorylpyridines. In these processes, acetylenes act as trimodal adjuvants by (1) activating the pyridine ring towards P-nucleophiles, (2) deprotonating the P-H bond, and (3) facilitating the nucleophilic addition of the P-centered anion to the heterocyclic fragment, followed by the release of selectively reduced (to E -alkenes) acetylenes.

Metal-Free Eliminative C-H Arylthiolation of 2H-Imidazole N-Oxides with Thiophenols

A synthetic strategy based on reactions of cyclic imine oxides, namely 2H-imidazole 1-oxides, with thiophenols mediated by acetyl chloride was successfully applied as a convenient tool to obtain a series of novel azaheterocyclic molecules, including water-soluble hydrochloride forms. Optimized reaction conditions found herein for the nucleophilic substitution of hydrogen (SNH) in non-aromatic azaheterocyclic substrates via the “addition-elimination” (SNH AE) scheme enabled 15 arylthiolated 2H-imidazoles to be prepared in yields of up to 90%. The developed methodology discloses an original synthetic way to obtain numerous azaheterocyclic molecules, which are of interest in the field of medicinal chemistry and materials science.

N-[1-(2-Chlorophenyl)-2-{1-methyl-5-nitro-4-[(phenylsulfonyl)methyl]-1H-imidazol-2-yl}ethyl]-4-methylbenzenesulfonamide

In continuation of our research program to develop original synthetic methods using TDAE methodology on nitroheterocyclic substrates, we were able to generate for the first time a stable carbanion in position 2 of the 5-nitroimidazole scaffold. Starting from a 2-chloromethyl-4-phenylsulfonylmethyl-5-nitroimidazole intermediate, prepared by the vicarious nucleophilic substitution of hydrogen (VNS) reaction, we selectively introduced a N-tosylbenzylimine moiety at position 2 without reducing the sulfone at position 4, leading to the formation of N-[1-(2-chlorophenyl)-2-{1-methyl-5-nitro-4-[(phenylsulfonyl)methyl]-1H-imidazol-2-yl}ethyl]-4-methylbenzenesulfonamide in 47% yield. This new synthetic method using TDAE should allow access to new 2-substituted 5-nitroimidazole derivatives with various electrophiles such as carbonyls and other N-tosylbenzylimines.

Indolyl-Derived 4H-Imidazoles: PASE Synthesis, Molecular Docking and In Vitro Cytotoxicity Assay

The strategy of the nucleophilic substitution of hydrogen (SNH) was first applied for the metal-free C-H/C-H coupling reactions of 4H-imidazole 3-oxides with indoles. As a result, a series of novel bifunctional azaheterocyclic derivatives were obtained in yields up to 95%. In silico experiments on the molecular docking were performed to evaluate the binding possibility of the synthesized small azaheterocyclic molecules to the selected biotargets (BACE1, BChE, CK1δ, AChE) associated with the pathogenesis of neurodegenerative diseases. To assess the cytotoxicity for the synthesized compounds, a series of in vitro experiments were also carried out on healthy human embryo kidney cells (HEK-293). The leading compound bearing both 5-phenyl-4H-imidazole and 1-methyl-1H-indole moieties was defined as the prospective molecule possessing the lowest cytotoxicity (IC50 > 300 µM on HEK-293) and the highest binding energy in the protein–ligand complex (AChE, −13.57 kcal/mol). The developed compounds could be of particular interest in medicinal chemistry, particularly in the targeted design of small-molecule candidates for the treatment of neurodegenerative disorders.

Synthesis of quinoxaline derivatives via aromatic nucleophilic substitution of hydrogen.

The electrophilic nature of quinoxaline has been explored in the vicarious nucleophilic substitution (VNS) of hydrogen with various carbanions as nucleophiles in an attempt to develop a general method for functionalizing the heterocyclic ring. Only poorly stabilized nitrile carbanions were found to give the VNS products. 2-Chloroquinoxaline gave products of SNAr of chlorine preferentially. A variety of quinoxaline derivatives containing cyanoalkyl, sulfonylalkyl, benzyl or ester substituents, including fluorinated ones, have been prepared in the VNS reactions with quinoxaline N-oxide.

Oxidative Nucleophilic Substitution of Hydrogen for the Synthesis of Aminated Nitro-Substituted Heteroarenes

Oxidative Nucleophilic Substitution of Hydrogen for the Synthesis of Aminated Nitro-Substituted Heteroarenes

SNH Amidation of 5-Nitroisoquinoline: Access to Nitro- and Nitroso Derivatives of Amides and Ureas on the Basis of Isoquinoline.

For the first time, amides and ureas based on both 5-nitroisoquinoline and 5-nitrosoisoquinoline were obtained by direct nucleophilic substitution of hydrogen in the 5-nitroisoquinoline molecule. In the case of urea and monosubstituted ureas, only 5-nitrosoisoquinoline-6-amine is formed under anhydrous conditions.

Amination of Nitro-Substituted Heteroarenes by Nucleophilic Substitution of Hydrogen.

An open-air method for the transition metal-free direct amination of nitro(hetero)arenes by anilines is disclosed. In this methodology, an aromatic C-H bond is substituted via oxidative nucleophilic aromatic substitution of hydrogen (ONSH). Density functional theory calculations and mechanistic studies support a dianion pathway with oxidation by molecular oxygen as the rate-limiting step.

Direct C-H/C-H Coupling of the Azoloannulated Pteridines with Electron Rich (Hetero)Aromatic Compounds.

The methods for modification of azoloannulated pteridines with (hetero)aromatic nucleophiles using a nucleophilic substitution of hydrogen (SNH) methodology have been developed in this work. Stable intermediate σH-adducts, as well as products of an unexpected intramolecular rearrangement of diadducts, have been isolated and characterized. The potential of the proposed approach for obtaining donor-acceptor systems, in which the pteridine fragment of the molecule acts as an acceptor, was demonstrated. The main photophysical properties of the obtained D-A compounds have been studied.

The Coupling of Carbon and Nitrogen Substituents with Nitroarenes: Vicarious Nucleophilic Substitution of Hydrogen in Nitroarenes

Abstract: In recent years, nitroarenes have been extensively exploited as green, efficient electrophilic arylation reagents used in a variety of organic syntheses. Transition-metal-free cross-coupling reactions and vicarious nucleophilic substitution (VNS) have become practical and reliable synthetic methods to access momentous functionalized organic compounds. Thus, the introduction of various substituents into nitroarenes has attracted considerable attention as important synthetic approaches due to their simplicity and practicality. In this review, we comprehensively summarize the coupling of several carbon and nitrogen substituents with nitroarenes via nucleophilic substitution under mild conditions, followed by the application of these transversions in the construction of carbon and heterocyclic rings.

A BF3-mediated C–H/C–Li coupling of 1,3,7-triazapyrene with 2-thienyllithium in the design of push–pull fluorophores and chemosensors for nitroaromatics

A BF3-mediated strategy of oxidative nucleophilic substitution of hydrogen affords mono- and bis-substituted thiophene-derived 1,3,7-triazapyrene fluorophores of interest in the design of luminescent materials and chemosensors for nitroaromatics.

Metal-Free C-H/C-H Coupling of 2H-Imidazole 1-Oxides with Polyphenols toward Imidazole-Linked Polyphenolic Compounds.

The methodology of nucleophilic substitution of hydrogen (SNH) was successfully applied as a convenient synthetic tool to afford azaheterocyclic derivatives of phenols of various architectures. A series of 26 novel imidazole-linked polyphenolic compounds were first prepared in 72-95% yields through the direct metal-free C-H/C-H coupling of polyphenols with 2H-imidazole 1-oxides. Comprehensive studies on the reaction condition optimization, scope, and limitations enabled the development of a straightforward method toward novel bifunctional derivatives bearing both phenolic and imidazole scaffolds of particular interest in the design of challenging molecules for versatile applications in medicinal chemistry and materials science.

Seleno-Functionalization of BODIPY Fluorophores Assisted by Oxidative Nucleophilic Hydrogen Substitution

Background: The most current reported methods of chalcogen insertion into BODIPY’s nuclei are based on nucleophilic substitution reactions of halogenated derivatives, metal-catalyzed cross-coupling reactions, or assistance by radical mechanisms. Recent reports describe Oxidative Nucleophilic Hydrogen Substitution (ONHS) reactions involving the functionalization of BODIPY nuclei by thiols, but the generalities of the strategy for other chalcogens was not yet demonstrated. Herein we report our contribution on the selenium-functionalization of BODIPY by ONHS in high yield. Objective: Aryl-Se-functionalization of 2,6-brominated BODIPY’s nuclei by ONHS reaction. Method: The procedure consists of a direct reaction of 2,6-brominated BODIPYs with in situ generated PhSeH in THF, at room temperature, under a nitrogen atmosphere. The corresponding products were isolated and purified by conventional flash column chromatography. Full structure characterization was performed by 1H, 13C, 19F, and 77Se NMR and DFT calculation. Results: Densely functionalized 2,6-dibrominated/3,5-diseleno-BODIPYs were obtained as corresponding products, leading to versatile molecular scaffolds. Their structural features were contrary to those initially expected by the original experimental applied conditions. A mechanistic investigation was performed to conclude that ONHS reaction is governing the transformation, thereby damaging the nucleophilic substitution of the halogen atoms. Conclusion: To sum up, new densely functionalized BODIPY derivatives were synthesized by a highly selective, simple, fast, metal-free, and efficient insertion of PhSe- residues into the 3,5-positions, governed by an Oxidative Nucleophilic Hydrogen Substitution (ONHS) reaction in high yields. It was observed that the presence of halogen (Br) into the 2,6-positions of the BODIPY core is mandatory for the ONHS reaction, which is completely inert when the 2,6-hydrogenated analogues are used in the same experimental conditions.

Pyrrolizinone‐Fused BOPYINs: Characterization and Selective C‐O Bond Formation Mechanism

AbstractTwo novel pyrrolizinone‐fused BOPYINs (DAB−M and DAB−U) were prepared in one‐step through the oxidative and/or oxidative nucleophilic substitution of hydrogen (ONSH) reaction. Selective methoxyl substitution of α‐unsubstituted BOPYIN was developed, in which C−O and C=O bonds were formed and demonstrated by the single crystal structure of DAB−M. The absorption and emission spectra of both compounds showed red shift and large Stokes Shift compared with starting material DAB. Based on the TD‐DFT calculation, the electron transfer direction is totally different from DAB due to the carbonyl group on pyrrolizinone unit. Besides, a reasonable mechanism has been proposed and evidenced by quantum calculation in which the relative free energy has been exhibited.

Novel Pentafluorophenyl- and Alkoxyphenyl-Appended 2,2′-Bipyridine Push–Pull Fluorophores: A Convenient Synthesis and Photophysical Studies

AbstractA convenient method for the synthesis of new highly in non-polar solvents soluble photoactive pentafluorophenyl-substituted and extended alkoxyphenyl-substituted 2,2′-bipyridines is reported. The synthetic strategy for the preparation of such ligands involves a sequence of several structural transformations, such as O-alkylation, nucleophilic substitution of hydrogen (SN H) in 1,2,4-triazine precursors via the ‘addition–elimination’ scheme, and the subsequent conversion of the obtained 1,2,4-triazines into 2,2′-bipyridines by means of the aza-Diels–Alder reaction. The photophysical properties of the synthesized novel pentafluoroaryl-substituted 2,2′-bipyridines were comprehensively studied. The obtained photophysical data indicate the competitive advantages of the herein reported pentafluoroarylated push–pull fluorophores, bearing extended aliphatic moieties, over their analogues containing benzoxy or phenolic fragments in terms of improvement in quantum yield and well-pronounced positive solvatochromism confirmed by the mathematical analysis according to the Lippert–Mataga equation.

Direct Amination of Nitroquinoline Derivatives via Nucleophilic Displacement of Aromatic Hydrogen.

The vicarious nucleophilic substitution of hydrogen (VNS) reaction in electron-deficient nitroquinolines was studied. Properties of all new products have been characterized by several techniques: MS, HRMS, FTIR, GC-MS, electronic absorption spectroscopy, and multinuclear NMR. The structures of 4-chloro-8-nitroquinoline, 8-(tert-butyl)-2-methyl-5-nitroquinoline, 9-(8-nitroquinolin-7-yl)-9H-carbazole and (Z)-7-(9H-carbazol-9-yl)-8-(hydroxyimino)quinolin-5(8H)-one were determined by single-crystal X-ray diffraction measurements. The 9-(8-nitroquinolin-7-yl)-9H-carbazole and (Z)-7-(9H-carbazol-9-yl)-8-(hydroxyimino)quinolin-5(8H)-one illustrate the nitro/nitroso conversion within VNS reaction. Additionally, 9-(8-isopropyl-2-((8-isopropyl-2-methyl-5-nitroquinolin-6-yl)methyl)-5-nitrosoquinolin-6-yl)-9H-carbazole is presented as a double VNS product. It is postulated that the potassium counterion interacts with the oxygen on the nitro group, which could influence nucleophile attack in that way.

A REP-FAMSEC Method as a Tool in Explaining Reaction Mechanisms: A Nucleophilic Substitution of 2-Phenylquinoxaline as a DFT Case Study.

In search for the cause leading to low reaction yields, each step along the reaction energy profile computed for the assumed oxidative nucleophilic substitution of hydrogen (ONSH) reaction between 2-phenylquinoxaline and lithium phenylacetylide was modelled computationally. Intermolecular and intramolecular interaction energies and their changes between consecutive steps of ONSH were quantified for molecular fragments playing leading roles in driving the reaction to completion. This revealed that the two reactants have a strong affinity for each other, driven by the strong attractive interactions between Li and two N-atoms, leading to four possible reaction pathways (RP-C2, RP-C3, RP-C5, and RP-C10). Four comparable in energy and stabilizing molecular system adducts were formed, each well prepared for the subsequent formation of a C–C bond at either one of the four identified sites. However, as the reaction proceeded through the TS to form the intermediates (5a–d), very high energy barriers were observed for RP-C5 and RP-C10. The data obtained at the nucleophilic addition stage indicated that RP-C3 was both kinetically and thermodynamically favored over RP-C2. However, the energy barriers observed at this stage were very comparable for both RPs, indicating that they both can progress to form intermediates 5a and 5b. Interestingly, the phenyl substituent (Ph1) on the quinoxaline guided the nucleophile towards both RP-C2 and RP-C3, indicating that the preferred RP cannot be attributed to the steric hindrance caused by Ph1. Upon the introduction of H2O to the system, both RPs were nearly spontaneous towards their respective hydrolysis products (8a and 8b), although only 8b can proceed to the final oxidation stage of the ONSH reaction mechanism. The results suggest that RP-C2 competes with RP-C3, which may lead to a possible mixture of their respective products. Furthermore, an alternative, viable, and irreversible reaction path was discovered for the RP-C2 that might lead to substantial waste. Finally, the modified experimental protocol is suggested to increase the yield of the desired product.