Nucleophilic aromatic substitution approach

An interesting variant in which nucleophilic aromatic substitution is carried out on the crown nucleus rather than using the crown as nucleophile was reported by Haines . In this approach, hexafluorobenzene was stirred in 1,2-dimethoxyethane at room temperature with pentaethylene glycol and sodium hydride. A double nucleophilic aromatic substitution occurred affording 2, 3, 4 ,5 -tetrafluorobenzo-15-crown-5 as an oil in 38% yield. The reaction is illustrated below. 

An interesting alternative approach to the synthesis of a cryptand having nitrogen atoms in the bridges was presented by Newkome and coworkers. This group condensed triethanolamine with 2,6-dichloropyridine in a relatively straightforward but low yield (5%) nucleophilic aromatic substitution to form 7, illustrated below in Eq. (8.6). The identity of the compound was confirmed by X-ray structural analysis. 

The general approaches for the synthesis of poly(arylene ether)s include electrophilic aromatic substitution, nucleophilic aromatic substitution, and metal-catalyzed coupling reactions. Poly(arylene ether sulfone)s and poly(arylene ether ketone)s have quite similar structures and properties, and the synthesis approaches are quite similar in many respects. However, most of the poly(arylene ether sul-fone)s are amorphous while some of the poly(arylene ether)s are semicrystalline, which requires different reaction conditions and approaches to the synthesis of these two polymer families in many cases. In the following sections, the methods for the synthesis of these two families will be reviewed. 

Most syntheses of naturally occurring phenazines, though, are based on a two-step elaboration of the central heterocycle of the phenazine [78]. The first key step involves the generation of orf/zo-monosubstituted 88 or orf/zo, ortho -disubstituted diphenylamines 89-91 via nucleophilic aromatic substitution. Ring formation is then achieved by means of reductive or oxidative cyclization, for which a number of efficient methods are available. The main flaw of this approach is the synthesis of the substituted diphenylamines via nucleophilic aromatic substitution, as this reaction often can only be performed under strongly basic reaction conditions and at high temperatures. In addition, the diphenylamines required may only be achieved with certain substitution patterns with high yields. 

The nucleophilic aromatic substitution of 6-nitropiperonal with [ F]K(Kryptofix 2.2.2)F yielded 6-[ F]fluoropiperonal that was condensed with nitromethane. Reduction and subsequent hydrolysis of the intermediate nitroalkene provided the target compound 6-[ F]FDA. In comparison to more direct approaches which utilize electrophilic aromatic substitution with positive polarized p F]fluo-rine [140-142], this type of preparation is characterized by high specific radioactivity, which is requested for human PET studies with vasopressor compounds, like 6-FDA [139,143]. 

An early approach to suitable dialdehydes made use of a nucleophilic aromatic substitution process which enabled the synthesis of nitro-substituted complexes to be achieved (Scheme 27)159,160 Yery recently, a similar approach has been used to incorporate pyrimidine rings into macrocyclic complex structures (Scheme 28).161... 

Nucleophilic aromatic substitution is much more restrictive in its applications than electrophilic aromatic substitution. In nucleophilic aromatic substitution, a strong nucleophile replaces a leaving group such as a halide. The mechanism cannot be the Sn2 mechanism because aryl halides cannot achieve the correct geometry for backside displacement. The aromatic ring blocks approach of the nucleophile to the back of the carbon bearing the halogen. 

In al this we have estimated the stability of a carbonium ion on the same basis the dispersal or concentration of the charge due to electron release or electron withdrawal by the substituent groups. As wc shall see, the approach that has worked so well for elimination, for addition, and for electrophilic aromatic substitution works for still another important class of organic reactions in which a positive charge develops nucleophilic aliphatic substitution by the S l mechanism (Sec. 14.14). It works equally well for nucleophilic aromatic substitution (Sec. 25.9), in which a negative charge develops. Finally, we shall find that this approach will help us to understand acidity or basicity of such compounds as carboxylic acids, sulfonic acids, amines, and phenols. 

Figure 14.6 Nucleophilic approach to synthesis of 6-[18F]fluoroDOPA. The multistep synthesis introduces fluorine-18 in an initial nucleophilic aromatic substitution reaction.

A radical cyclization approach to spiro-oxindoles was revealed <05OL151>. Treatment of p-trityloxybenzamide 125 with triethylborane and tris(trimethylsilyl)silane gave cyclohexadienone 126 via an ipso cyclization. The nucleophilic aromatic substitution of aryl fluorides was utilized in an asymmetric approach to spiro-pyrrolidone oxindoles <05JA3670>. 

Nucleophilic aromatic substitution, based on an intramolecular attack of the phenoxide ion in the benzyne intermediate 87 (generated by dimsyl sodium treatment of 86), has been used by Castedo et al. (66) in a versatile synthesis of cularine alkaloids. However, N-attack competes with 0-attack in all instances to give dibenzopyrrocoline derivates (88), together with tetradehydrocularines (89). The main value of this approach is the easy conversion of 89 to norcularines, by catalitic hydrogenation to cularines, by quatemization with methyl iodide fol-... 

Nitrogen can be incorporated in the macroring by inclusion of a small-ring nitrogen heterocycle such as pyridine or pyrimidine. Three approaches should be noted. If the pyridyl unit is incorporated as a 2,6-bis(methyleneoxy)pyridine derived from lutidine, the precursor will normally be a lutidine dihalide or diol. In the case of sulfur, the diol would be a dithiol. If the pyridyl unit is to be attached by 2,6-aminomethyl groups, amide formation followed by reduction is a possibility. In the event that the heterocycle will be attached directly to a macroring heteroatom, nucleophilic aromatic substitution may be useful. 

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