Electrophilic reactions hetero-substituted electrophiles

In the case of phenazine, substitution in the hetero ring is clearly not possible without complete disruption of the aromatic character of the molecule. Like pyrazine and quinoxa-line, phenazine is very resistant towards the usual electrophilic reagents employed in aromatic substitution reactions and substituted phenazines are generally prepared by a modification of one of the synthetic routes employed in their construction from monocyclic precursors. However, a limited range of substitution reactions has been reported. Thus, phenazine has been chlorinated in acid solution with molecular chlorine to yield the 1-chloro, 1,4-dichloro, 1,4,6-trichloro and 1,4,6,9-tetrachloro derivatives, whose gross structures have been proven by independent synthesis (53G327). 

Being aware of the fact that a hetero-substituted carbon-carbon double bond is convertible into a carbonyl group, one can use a-hetero-substituted lithio-alkenes 2 as nucleophilic acylation reagents 142 and 143, which display the umpoled d reactivity, provided that the carbanionic character is effective. Depending on the hetero-snbstitnent X, the conversion of the vinyl moiety into a carbonyl gronp can be effected either by hydrolysis or by ozonolysis. The former procednre has been applied preferentially in the case of lithiated vinyl ethers, whereas the latter has been nsed in particnlar for cleavage of the double bond in such products that result from the reaction of hthiated vinyl bromides with electrophiles (Scheme 17). 

For reviews of the Pd-catalyzed acylation and other cross-coupling reactions with a-hetero-substituted organic electrophiles, see ... 

It is often very useful to be able to alkylate a readily available chiral a-hetero-substitut-ed carboxylic acid in an enantiospecific manner, as a means of using the chiral center and at the same time building-up the rest of the target carbon skeleton. Such a reaction has been devised by Seebach and coworkers524. In this process a-hydroxy- and a-mercaptocar-boxylic acids were first reacted with pivaldehyde, to produce a 1,3-dioxolanone or 1,3-oxathiolanone. This was followed by reaction with base and alkylation by an alkyl halide and subsequent hydrolysis to regenerate the hydroxyl or mercapto group (equation 70). The product was obtained in greater than 95% ee. Similar reactions with other electrophiles were also successful. 

The reactions of the homocyclic ring of benzofuroxans, which are described in detail in Section 4.22.3.3, provide access to numerous derivatives. Nucleophilic displacement of halides is facile when activating nitro groups are present, allowing alkoxy, aryloxy, thio and amino groups to be introduced. Electrophilic substitutions, e.g. nitration, are also valuable. Further transformations may also be performed on benzo-ring substituents. Such modifications include acetoxy to hydroxy acetamido to amino and acyl halides to esters and amides. Some reactions of the substituents of monocyclic furoxans allow hetero-substituted analogues of benzofuroxans to be prepared. For example, pyridazinofuroxans are formed by condensation of diacylfuroxans with hydrazine. 

The DTBB-catalyzed lithiation of 4-hetero-substituted dibenzothiins (68), such as phenoxathiin (68a), phenothiazine (68b) and thianthrene (68c), at low temperature gives the corresponding functionalized organolithium intermediates (69), which by reaction with different electrophiles afford, after hydrolysis, the expected functionalized... 

Reactions of aromatic and heteroaromatic rings are usually only found with highly reactive compounds containing strongly electron donating substituents or hetero atoms (e.g. phenols, anilines, pyrroles, indoles). Such molecules can be substituted by weak electrophiles, and the reagent of choice in nature as well as in the laboratory is usually a Mannich reagent or... 

It should be expected that the orientation and rate of electrophilic substitution in the isoxazole nucleus would be affected by both hetero atoms. Because of the electron-accepting effect of the nitrogen atom, electrophilic substitution of the isoxazole nucleus should proceed less readily than in the case of benzene and should occur essentially at the position jS to the nitrogen atom, just as in pyridine and other azoles. Simultaneously the electron-donating oxygen atom should facilitate such reactions in isoxazole as compared with the substitution in pyridine. These predictions are confirmed by the available experimental evidence. 

In the reactions of electrophilic substitution, isoxazole is far less active than the five-membered heterocycles with one hetero atom and pyrazole. It is closer to pyridine, but more reactive. 

These hetero cycles, mainly Fx, are especially deactivated toward electrophilic substitution (S Ar) under standard conditions being the reaction with acid, FT as electrophile, also slow. However, some specific Bfxs have been depicted as nucleophile toward good electrophiles like NO2 and- = N (Fig. 6) [47,53]. 

---