Efficient synthesis of unsymmetrical diaryl thioethers via TBAF-mediated denitrative substitution of nitroarenes with PhSTMS under mild and neutral conditions

Tetrabutylammonium fluoride(TBAF) effectively facilitated a denitrative substitution reaction of electron-deficient nitroarenes with phenylthiotrimethylsilane(PhSTMS) under mild and base-free neutral conditions at room temperature,providing a practical and efficient synthesis of useful unsymmetrical diaryl thioethers.Nitroarenes bearing ortho-and para-positioned electron-withdrawing groups are the most reactive substrates,indicating that this reaction most possibly proceeded via the nucleophilic aromatic substitution(S_NAr) mechanism.     

Nucleophilic aromatic substitution reaction of nitroarenes with alkyl- or arylthio groups in dimethyl sulfoxide by means of cesium carbonate

Treatment of nitroarenes having electron-withdrawing groups at the ortho or para position with alkanethiol in the presence of cesium carbonate in dimethyl sulfoxide at 25 °C leads to nucleophilic displacement of the nitro group with the alkylthio group. Cesium carbonate is superior to other bases such as potassium carbonate, sodium carbonate, and triethylamine. The cesium-mediated nucleophilic aromatic substitution reaction provides a mild yet powerful and user-friendly protocol for the synthesis of aryl sulfides.     

Regioselective functionalisation of nitrobenzene and benzonitrile derivatives via nucleophilic aromatic substitution of hydrogen by phosphorus-stabilized carbanions

The synthesis of P-benzylic products by reaction of anions stabilised by N-phosphorylphosphazenyl, N-methoxycarbonylphosphazenyl, phosphine borane complex, and phosphine oxide groups by displacement of hydrogen of a variety of electron-deficient benzene derivatives is described. Lithium phosphazenes were the most suitable nucleophiles for the substitution of hydrogen in nitrobenzene and some ortho-, meta-, and para- substituted nitrobenzenes. Lithiated phosphine borane complexes produced efficiently the substitution of the hydrogen at the para position of a cyano group in cyanobenzenes, whereas the anion of ethyldiphenylphosphine oxide lead to complex mixtures with all electrophiles assayed. The method reported here represents a convenient alternative to the vicarious nucleophilic substitution for the synthesis of benzylic phosphorus derivatives using phosphorus-stabilised anions that do not bear a leaving group at the carbanionic centre.     

Reactions of some ortho and para halogenated aromatic nitriles with ethylenediamine: selective synthesis of imidazolines

The reaction of ethylenediamine (EDA) with ortho and/or para halogenated benzonitriles did not lead to the imidazolines expected: a competitive aromatic nucleophilic substitution (S_NAr) was observed instead. The selective synthesis of these imidazolines was performed by nucleophilic addition of EDA to thiobenzamide derivatives. The difference in reactivity between the nitrile and thioamide derivatives was estimated by a frontier orbital approach at the RHF/6-31G** level which predicted a greater reactivity of substituted thiobenzamides towards the nucleophilic addition of EDA.     

Mechanisms of reactions of halogenated compounds: Part 7. Effects of fluorine and other groups as substituents on nucleophilic aromatic substitution

The effect of fluorine as a substituent group on nucleophilic aromatic substitution is discussed, where a fluorine atom located ortho to the point of substitution may be of variable activating influence, whereas fluorine located para is slightly deactivating and meta is activating. A rationale of these effects is presented and evidence to support polar influences by ortho fluorine is advanced. The influence of CN, CF₃, CF₂H and CFH₂ is also established by comparison of appropriate measured rate constants and compared with the activation effects of ring nitrogen.     

Nucleophilic aromatic substitution of hydrogen through lithiated phosphine borane complexes and N-phosphorylphosphazenes

Organophosphorus compounds containing nitroaryl and cyanoaryl groups have been prepared in good yield through nucleophilic aromatic substitution of hydrogen using α-lithiated phosphazenes and phosphine borane complexes as nucleophiles. In all cases, nearly exclusive replacement of the hydrogen in the para position with respect to the activating group has been observed.     

Appending aromatic moieties at the para- and meta-position of calixarene phenol rings via p-bromodienone route

The silver-mediated nucleophilic substitution on calixarene p-bromodienone derivatives (the ‘p-bromodienone route’) with activated aromatic substrates allows the introduction of aromatic moieties at the para- or meta-position of calixarene aromatic rings. Less reactive substrates mainly afford C-O para-coupled derivatives, while more activated ones mainly give inherently chiral, C-C meta-coupled products through a dienone-phenol rearrangement of the intermediate dienone derivative. Examples of C-C para-coupling and O-C coupling at the endo calixarene oxygen atom were also observed.     

Bis(arene)metal compounds: I. Nucleophilic substitution of bis(η6-chlorobenzo-trifluoride)chromium(0) with thiophenoxide

The ortho, meta and para complexes of bis(η⁶-chlorobenzotrifluoride)chromium(0) were made by metal-vapor synthesis. Nucleophilic substitutions by thiophenoxide of these complexes are compared to nucleophilic substitutions by thiophenoxide on the uncoordinated arenes. It was found that substitution at the chloro position is more facile on the complexes than on the free arenes. Substitution of the chloro on the meta-isomer sandwich was more facile than substitution of the chloro on the ortho-isomer sandwich, contrary to the observed reactivity pattern in the free arenes.     

Vicarious nucleophilic substitution reactions in azolopyridazines controlled by methyl substituents

Azolopyridazines, when treated with bromomethyl phenylsulfone in DMSO-t-BuOK at room temperature, yield mainly typical VNS reaction products, while 7-methylazolopyridazines under the same conditions undergo annulation with simultaneous conventional ipso nucleophilic substitution of the chlorine at C6. Consequently, methyl substitution offers a convenient means of controlling the course of VNS carbanion substitution. These competitive reactions illustrate the role of charge distribution and steric hindrance for the course of the nucleophilic substitution, and the methylated azolopyridazines appear to be convenient substrates for highly efficient propose annulation in fused azolopyridazine systems.     

Ortho-selectivity in SNAr substitutions of 2,4-dihaloaromatic compounds. Reactions with anionic nucleophiles

The nucleophilic addition of organic anions to aromatic compounds with halogens positioned both ortho and para to activating groups was studied in a variety of solvents. Substrates showed strong preferences for ortho substitution in most cases. Evidence is presented for activating group-dependent coordination, which contributes to very high ortho-selectivity in nonpolar solvents. This also drives the overall reaction rate in these solvents, and is of close to the same magnitude of rate increase derived from polar solvents. para-Products are maximized by using crown ethers in protic solvents. Solvent effects overall are very different from corresponding reactions with amine nucleophiles due primarily to the different charges present in the transition states, and to solvation of the nucleophile.     

Origin of the Regioselectivity in the Gas‐Phase Aniline+CH3+ Electrophilic Aromatic Substitution

Nonadiabatic ab initio molecular dynamics simulations are carried out to monitor the attack of CH₃⁺ on aniline in the gas phase to form the corresponding σ complexes. The reaction is ultrafast and is governed by a single electron transfer within 30 fs, which involves two sequential conical intersections and finally produces a radical pair. Positive‐charge allocation in the aromatic compound is found to govern the substitution pattern in ortho, meta, or para position. Although the major products in the first step of the electrophilic aromatic substitution are the ortho and para σ complexes, initially 26 % of the simulated trajectories also form meta complexes, which then undergo H shifts, mainly to the para position.     

Sterically Facilitated Intramolecular Nucleophilic NMe2 Group Substitution in the Synthesis of Fused Isoxazoles: Theoretical Study

The influence of steric repulsion between the NMe₂ group and a second ortho-(peri-)substituent in the series of 1-dimethylaminonaphthalene and N,N-dimethylanilene ortho-oximes on the ease of the NMe₂ group’s intramolecular nucleophilic substitution is studied. Possible reaction intermediates for three mechanisms are calculated (ωB97xd/def-2-TZVP), and their free Gibbs energies are compared to model reaction profiles. Supporting experiments have proved the absence of studied reactivity in the case of simple 2-dimethylaminobenzaldoxime, which allowed us to establish reactivity limits. The significant facilitation of NMe₂ group displacement in the presence of bulky substituents is demonstrated. The possibility of fused isoxazoles synthesis via the intramolecular nucleophilic substitution of a protonated NMe₂ group in the aniline and naphthalene series is predicted.     

Stereoselective syntheses of tri- and tetrapeptide analogues by dynamic resolution of α-halo amides in nucleophilic substitution

Dynamic resolution of α-bromo and α-chloro acetamides in nucleophilic substitution with amine nucleophiles in the presence of TBAI has been investigated for stereoselective syntheses of tri- and tetrapeptide analogues. Mechanistic investigations suggest that primary pathway of the asymmetric induction is a dynamic kinetic resolution and real intermediate for the substitution is α-iodo acetamides. Also, application of this mild and simple methodology to stereoselective preparations of N-carboxyalkyl, N-aminoalkyl and N-hydroxyalkyl peptide analogues is demonstrated.     

Aqueous Oxidation of Sulfonamide Antibiotics: Aromatic Nucleophilic Substitution of an Aniline Radical Cation

Sulfonamide antibiotics are an important class of organic micropollutants in the aquatic environment. For several, sulfur dioxide extrusion products have been previously reported upon photochemical or dark oxidation. Using quantum chemical modeling calculations and transient absorption spectroscopy, it is shown that single‐electron oxidation from sulfadiazine produces the corresponding aniline radical cation. Density functional theory calculations indicate that this intermediate can exist in four protonation states. One species exhibits a low barrier for an intramolecular nucleophilic attack at the para position of the oxidized aniline ring, in which a pyrimidine nitrogen acts as a nucleophile. This attack can lead to a rearranged structure, which exhibits the same connectivity as the SO₂‐extruded oxidation product that was previously observed in the aquatic environment and characterized by NMR spectroscopy. We report a detailed reaction mechanism for this intramolecular aromatic nucleophilic substitution, and we discuss the possibility of this reaction pathway for other sulfonamide drugs.     

Base-promoted nucleophilic fluoroarenes substitution of CF bonds

With the use of KOH/DMSO as the superbase medium, the nucleophilic fluoroarene substitution for CF bonds is presented. The transformation proceeds smoothly with the use of fluoroarenes bearing not only electron-withdrawing group, but also electron-donating group and a variety of nucleophiles such as alcohols, phenols, amines, amides and nitrogen-heterocyclic compounds. The double nucleophilic substitution using ortho-difluoroarenes and nucleophiles bearing ortho-dinucleophilic groups results in the formation of 2,3-dihydro-1,4-benzodioxins, dibenzo[b,e][1,4]dioxins and 10H-phenoxazines in moderate to good yields.     

Polykis(pyrazol-1-yl)benzenes: preparation, structure, and complexation with copper and palladium

A series of polykis(pyrazol-1-yl)benzenes, potential chelating ligands for transition metals, have been prepared by nucleophilic substitution of fluorine in 1,2-difluoro-, 1,2,3,4-tetrafluoro-, 1,2,4,5-tetrafluoro-, and hexafluorobenzenes. The observed substitution pattern indicated formation of early TS, making activation by fluorines ortho- to the site of nucleophilic attack dominant. Complexation of the synthesized ligands with copper(II) and palladium(II) was analyzed by ESI mass spectrometry. X-ray structures were determined for palladium(II) complex with 1,2-bis(pyrazol-1-yl)benzene and copper(II) complex with 1,4-difluoro-2,3-bis(pyrazol-1-yl)benzene, revealing an unusual seven-membered chelate cycle formation.     

5-Amino-Substituted Derivatives of 4-Nitrofurazane: Synthesis,Structure, and Biological Activity

New amination reactions of 5-chloro-4-nitrobenzofurazane with different amines were studied. The reactions of 5-chloro-4-nitrobenzofurazane with 2,4,6-trichloro-, para-acetyl-, and para-carboxyethylanilines gave the products of aromatic nucleophilic substitution of the chlorine substituent in the nitrogenous heterocycle, the composition and structure of which was established by chemical, physical, and physicochemical methods and X-ray diffraction analysis. The thermal stability was studied by synchronous thermogravimetry and differential scanning calorimetry (TG?DSC). The synthesized compounds showed a high antibacterial and antimycotic activity against human and animal pathogenic microflora.     

Electrophilic and nucleophilic aromatic substitution: Analogous and complementary processes

Analysis of many variants of nucleophilic aromatic substitution of hydrogen proceeding according to an addition—elimination pattern reveals that this is the major reaction pathway, whereas nucleophilic replacement of halogen or another nucleofugal group is the secondary process, i.e.,ipso-substitution. In this respect electrophilic and nucleophilic aromatic substitution can be considered as analogous processes.This account is published in connection awarding Prof. M. Mgkosza the degree ofDoctor Honoris causa by the Russian Academy of Sciences for his investigations in the fields of physical organic chemistry and fine organic synthesis.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3. pp. 531–544, March, 1996.     

Regioselective upper rim substitution of calix[4]arenes

The electrophilic substitution of 25,27-dipropoxy-26,28-dinosyloxycalix[4]arene leads exclusively to the para-substitution of the alkylated phenol rings, while in the next step, the protecting nosyl group can be easily removed using a basic hydrolysis. The overall process yields dialkoxycalix[4]arenes with the substitution on the alkylated rings—the substitution pattern, which is complementary to the common dialkoxycalix[4]arenes with substituted nonalkylated phenolic units. The usefulness of this protection/deprotection procedure was documented by the synthesis of novel type of calixarene dipropoxy derivatives, and by the preparation of a novel anion receptor based on this substitution pattern.     

Nucleophilic substitution reaction of benzyl benzenesulfonates with anilines in methanol-acetonitrile mixtures. Part 3

Kinetic studies on the nucleophilic substitution reaction of para-nitrobenzyl benzenesulfonates with anilines in methanol-acetonitrile mixtures are reported. It was found that the reaction proceeds via a dissociative S_N2 mechanism with a more product -like transition state compared to that for substrate with a less electron attracting substituent. A stronger electron withdrawing substituent in the benzyl moiety and in the leaving group is shown to enhance both bond making and bond breaking but the enhancement of bond making was found to be greater than that of bond breaking.