Concerted Nucleophilic Aromatic Substitution Reactions

Recent developments in experimental and computational chemistry have identified a rapidly growing class of nucleophilic aromatic substitutions that proceed by concerted (cS_NAr) rather than classical, two‐step, S_NAr mechanisms. Whereas traditional S_NAr reactions require substantial activation of the aromatic ring by electron‐withdrawing substituents, such activating groups are not mandatory in the concerted pathways.     

Functionalized N‐Aryl‐Substituted Cyclens by Nucleophilic Aromatic Substitution

The reaction of trifold protected cyclen with fluorinated dinitroarenes yields aryl‐substituted or aryl‐bridged cyclen derivatives in good yield. The two arene nitro groups, necessary for the nucleophilic aromatic substitution, are subsequently selectively reduced to amines and further functionalized by amide formation. As an example, a cyclen derivative bearing a heterocyclic oligoamide with potential DNA binding ability was prepared.     

Metal‐free Synthesis of Aryl Amines: Beyond Nucleophilic Aromatic Substitution

A mild and metal‐free approach to C?N coupling is described that employs diaryliodonium salt electrophiles and secondary aliphatic amine nucleophiles. This reaction results in direct ipso‐substitution of the iodonium moiety and unsymmetrical aryl(TMP)iodonium salts are primarily employed. Moreover, arene substituents and substitution patterns that currently pose a challenge to classical metal‐free methods are accommodated and the alicyclic amine nucleophiles used here are unprecedented in other contemporary metal‐free C?N coupling reactions.     

Synthesis of Aromatic Polythioethers Containing 1,3,5-Triazine Ring by Aromatic Nucleophilic Substitution Polymerization

Abstract

Reaction of 2,4-dichloro-6-phenyl-1,3,5-triazines with bis(4-mercaptophenyl) sulfide in the presence of a base in THF afforded the corresponding condensation polymer as a whole aromatic polythioether in moderate yield. The polymerization of several 2,4-dichloro-1,3,5-triazine derivatives with this dithiols also proceeded in the o-dichlorobenzene-water two-phase system by using phase transfer catalysts. The resulting polymers consisted of THF-soluble and -insoluble fractions. The x-ray diffraction pattern indicated that these THF-insoluble polymers have a highly crystalline nature. Further, the polymers obtained here showed high thermal stability.     

Nucleophilic Aromatic Substitution of Unactivated Aryl Fluorides with Primary Aliphatic Amines by Organic Photoredox Catalysis

In this work, a mild and transition-metal-free approach for the nucleophilic aromatic substitution (S_NAr) of unactivated fluoroarenes with primary aliphatic amines to form aromatic amines is reported. This reaction is facilitated by the formation of cationic fluoroarene radical intermediates in the presence of an acridinium-based organic photocatalyst under blue-light irradiation. Various electron-rich and electron-neutral fluoroarenes are competent electrophiles for this transformation. A wide range of primary aliphatic amines, including amino acid esters, dipeptides, and linear and branched amines are suitable nucleophiles. The synthetic utility of this protocol is demonstrated by the late-stage functionalization of several complex drug molecules.     

Nucleophilic Aromatic Substitution with Dianions: Reactions Driven by the Release of Coulomb Repulsion

The reactions of a nucleophilic dianion with a series of activated aryl bromides were studied in the gas phase. Nucleophilic aromatic substitution (S_NAr) as well as proton transfer reactions were observed. Rate constants and branching ratios were determined for all the reactions and the experimental data are supported by ab initio calculations. Reactions with bis-trifluoromethylbromobenzenes give only S_NAr reactions and the rate constants follow the expected pattern, with substituents at the ortho and para positions having the greatest impact. Reactions of polyfluorobromobenzenes give a mix of proton transfer (when possible) and S_NAr, with both bromide and fluoride acting as leaving groups. The latter is much less thermodynamically favorable but is the dominant pathway in each case. The selectivity of the reactions indicate that the products are determined early on the potential energy surface, before there is significant cleavage of the bond to the leaving group—the reaction is potentially directed by the initial formation of a hydrogen bond with the arene. The computational data also suggest that hydrogen bonding in the product ion–ion complexes can stabilize the system until there is sufficient charge separation to use the internal Coulomb repulsion to drive the reactions to products. Overall, the results highlight (1) the ability of multiply-charged systems to efficiently funnel their Coulomb repulsion into reaction processes that are intrinsically unfavorable, and (2) the high degree of selectivity that can be attained even in systems with multiple, low-barrier pathways.

Preparation of N-Arylated Heterocycles by Nucleophilic Aromatic Substitution

Nucleophilic aromatic substitution of fluorobenzoates and fluorophenylnitriles with weakly basic heterocycles readily occur. This synthetic methodology is utillized to produce potent angiotensin-II antagonists.     

Silyldefluorination of Fluoroarenes by Concerted Nucleophilic Aromatic Substitution

The reaction of readily generated silyl lithium reagents with various aryl fluorides to provide the corresponding aryl silanes is reported. DFT calculations reveal that the nucleophilic aromatic substitution of the fluoride anion by the silyl lithium reagent proceeds through concerted ipso substitution. In contrast to the classical nucleophilic aromatic substitution, this concerted ionic silyldefluorination also occurs on more electron‐rich aryl fluorides.     

Improved Synthesis of Valsartan via Nucleophilic Aromatic Substitution on Aryloxazoline

A highly efficient approach to the synthesis of the angiotensin II receptor antagonist valsartan (Diovan), one of the most important agents used in antihypertensive therapy today is described. The formation of the aryl–aryl bond represents the key step of its synthesis, which has been done by simple nucleophelic aromatic substitution on aryloxazoline with good yield and purity.     

Nucleophilic Aromatic Substitution Reactions of meso‐Bromosubporphyrin: Synthesis of a Thiopyrane‐Fused Subporphyrin

meso‐Bromosubporphyrin undergoes nucleophilic aromatic substitution (S_NAr) reactions with arylamines, diarylamines, phenols, ethanol, thiophenols, and n‐butanethiol in the presence of suitable bases to provide the corresponding substitution products. The S_NAr reactions also proceed well with pyrrole, indole, and carbazole to provide substitution products in moderate to good yields. Finally, the S_NAr reaction with 2‐bromothiophenol and subsequent intramolecular peripheral arylation reaction affords a thiopyrane‐fused subporphyrin.     

三氟乙烯基芳基醚的合成

三氟乙烯基芳基醚;四氟二溴乙烷;酚;三氟乙烯基芳基醚的合成     

Reactions of Nucleophilic Substitution in Bicyclic Nitroimidazodihydrooxazoles

This article describes numerous attempts of the S_N reaction of chlorine atom in chloromethyl group with nucleophilic compounds, such as the following: phenols, thiophenols, and amino compounds. The influences of ratios of nitroimidazodihydrooxazoles, nucleophiles and basic agent, and the polarity of solvent on the kind of formed products were established. Also, the comparison of reactivity with nucleophiles of close structural isomers of nitroimidazodihydrooxazoles has been made. The way of formation ring opening reaction products has been proposed.     

Nucleophilic Aromatic Substitution of Nitrobenzenes with Nitrite Ion

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On the Frontier Between Nucleophilic Aromatic Substitution and Catalysis

A study on the arylation of heteroatom nucleophiles by using activated haloarenes, with or without metal catalysts, is reported. A discussion concerning the involvement of traces of metals is presented, supported by an unexpected ''ligand'' effect in the absence of added metal catalysts. We believe that the frontier between nucleophilic aromatic substitution and catalysis will likely prove to be much harder to delimit than is generally thought.