Nucleophilic aromatic substitution synthetic applications

The first widely used intermediates for nucleophilic aromatic substitution were the aryl diazonium salts. Aryl diazonium ions are usually prepared by reaction of an aniline with nitrous acid, which is generated in situ from a nitrite salt.81 Unlike aliphatic diazonium ions, which decompose very rapidly to molecular nitrogen and a carbocation (see Part A, Section 4.1.5), aryl diazonium ions are stable enough to exist in solution at room temperature and below. They can also be isolated as salts with nonnucleophilic anions, such as tetrafluoroborate or trifluoroacetate.82 Salts prepared with 0-benzenedisulfonimidate also appear to have potential for synthetic application.83... 

Aromatic nitro compounds undergo nucleophilic aromatic substitutions with various nucleophiles. In 1991 Terrier s book covered (1) SNAr reactions, mechanistic aspects (2) structure and reactivity of anionic o-complexes (3) synthetic aspects of intermolecular SNAr substitutions (4) intramolecular SNAr reactions (5) vicarious nucleophilic substitutions of hydrogen (VNS) (6) nucleophilic aromatic photo-substitutions and (7) radical nucleophilic aromatic substitutions. This chapter describes the recent development in synthetic application of SNAr and especially VNS. The environmentally friendly chemical processes are highly required in modem chemical industry. VNS reaction is an ideal process to introduce functional groups into aromatic rings because hydrogen can be substituted by nucleophiles without the need of metal catalysts. 

Scheme 9 demonstrates the further synthetic application of the thus obtained N,0-acetals. Substitution of the alkoxy or acyloxy group by nucleophiles like enol ethers, enol esters, enamines, other electron-rich olefins, CH-acidic compounds, electron-rich aromatics, isocyanides, trimethylsilyl cyanide, organometallics, vinyl and allyl silanes, hydroxy functions, or trialkylphosphites either catalyzed by Lewis acids or proton acids leads to the product of the amidoalkylation reaction (path a). In the presence of stereocenters as control elements, diasteroselective amidoalkylation reactions can be performed as shown in a large number of examples. On the other side, as Nyberg showed for the first time [196], elimination with formation of enecarbamates [208] and enamides [196,208,209] followed by reaction with electrophiles or nucleophiles (path b) also is possible. 

Both the required salts were easily accessible from 19 as described in Section 14.5.3. The viability of this approach has been shown by successful completion of a simple synthesis of (+/-)-0-methyljoubertiamine from 84 [4]. A detailed crystallographic study of conformational effects in an extended series [109,128] of 1-aryl-substituted cyclohexadienyliron complexes had established, as expected, that ortho substituents on the aromatic ring substantially impeded the nucleophile s approach, and could switch the control to predominantly a> control by the aryl group. However, with an o-alkoxy substituent, the conformation with the substituent below the plane of the dienyl system is easily accessible (and characterized in an X-ray structure [128]) opening the way for more ambitious synthetic applications [109]. This conformational effect has been put to use in a formal total synthesis (entry 19) of lycoramine (87) from 88 [106]. Electronic effects from additional donor substituents also flatten the ring and open up the aryl-substituted position [128], effects that will be put to work in ongoing work towards maritidine and crinine. The completed O-methyljoubertiamine and lycoramine syntheses make multiple use of the metal to form both bonds at the aryl-substituted quaternary center, and so can be classified as iterative ( —> f/ V V ) synthetic routes. 

We have recently reported ( ) several synthetic studies of weak nucleophile SnAr reactions. In the latter cases (26f-1), new synthetic methodology was reported for the direct introduction of fluoroalkoxy groups into a variety of aromatic systems. These reports represent synthetically useful procedures for obtaining some otherwise inaccessible fluoroalkoxy materials but, unfortunately, they require the use of a dipolar, aprotic solvent (usually hexamethylphosphoramide, HMPA) and, in some cases, elevated temperatures. However, because of their diverse and important applications ( ), the syntheses of these and other organofluoro compounds continue to be of interest. For example, two recent reports of useful fluoroalkoxy materials include the insecticide activity exhibited by fluoroalkoxy substituted 1,3,4-oxadiazoles... 

Arynic substitution is a versatile technique of functional group transformation in aromatic systems and has found varied applications in preparation of simple compounds and in multi-step synthesis.3 4,3 The present section comprises examples illustrative of its synthetic scope. Attention is also drawn to some allied strategies which, when used in conjunction with the nucleophilic coupling of arynes, have opened convenient routes to complex natural products. 

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