Activated heteroaromatics, nucleophilic substitution

A mechanism for heteroaromatic nucleophilic substitution which is under considerable active study at the present time is the SRN process, which often competes with the addition-elimination pathway. Srn reactions are radical chain processes, and are usually photochemi-cally promoted. An example is shown in Scheme 22, where (60) is formed by the SrnI pathway and (61) via an initial addition reaction (82JOC1036). 

All the reactions discussed in this review are aromatic nucleophilic substitutions in the ordinary sense. These reactions are briefiy described in the following sections with respect to their general kinetic features and mainly involve aza-activated six-membered ring systems, although a few studies of other heteroaromatic compounds are also available. 

The pyridine family of heteroaromatic nitrogen compounds is reactive toward nucleophilic substitution at the C(2) and C(4) positions. The nitrogen atom serves to activate the ring toward nucleophilic attack by stabilizing the addition intermediate. This kind of substitution reaction is especially important in the chemistry of pyrimidines. 

In contrast with aliphatic nucleophilic substitution, nucleophilic displacement reactions on aromatic rings are relatively slow and require activation at the point of attack by electron-withdrawing substituents or heteroatoms, in the case of heteroaromatic systems. With non-activated aromatic systems, the reaction generally involves an elimination-addition mechanism. The addition of phase-transfer catalysts generally enhances the rate of these reactions. 

Nucleophilic substitution of halogen atom in aromatic and heteroaromatic halides with a hydroxyamino group proceeds only in substrates that are activated by a strong electron-withdrawing substituent in the benzene ring (e.g. 27, equation 17). Despite this limitation this reaction is useful for synthesis of arylhydroxylamines and usually provides good yields of products. Along with activated aryl halides and sulfonates, activated methyl aryl ethers such as 28 can be used (equation 18). 

It has been indicated in CHEC-II <1996CHEC-II(7)431> that these systems tend to react by substitution rather than addition. Electrophilic reagents attack ring nitrogen atoms while, as is typical for 7t-deficient heteroaromatics, nucleophiles replace good leaving substituents especially at activated positions. However, to our knowledge, direct replacement of proton as with azines has not yet been observed. 

Very strong bases such as NaNH2 convert unactivated aryl halides into benzyne intermediates which react rapidly with nucleophiles to form the products of an apparently simple nucleophilic substitution. It is now clear that hetarynes are frequent intermediates in reactions of not too highly activated heteroaromatic halides. 

For the chemist practicing polysubstituted aromatic and heteroaromatic synthesis, methods steeped in classical electrophilic (1, Scheme 1) [1] and nucleophilic substitution [2] and SRN1 (2) [3] reactions have been joined and, not infrequently super-ceded, by vicarious substitution (3) [4] and by DoM (4) [5] processes. The Murai ortho CH activation (5) [6] is a recently evolving and potential competitive method to the DoM tactic. The 60 years since its discovery by Wittig and Gilman, and 40 years since its systematic study by the school of Hauser, the DoM reaction has advanced by the contributions of Christensen, Beak, Meyers, and many other... 

Transition metal activated nucleophilic substitution in heteroaromatic compounds 90BSF401. 

Quinoxalines are more reactive towards nucleophilic substitution than quinolines as a result of inductive activation by the additional ring nitrogen. If substituents are present in both the benzenoid and heteroaromatic ring, monosubstitution occurs predominantly in the latter. 

Since heteroaromatic compounds sometimes exhibit interesting physical properties and biological activities, construction of substituted heteroaromatics has drawn some attention. Heteroaromatics can be divided into two major categories. One is the tt-electron-sufhcient heteroaromatics, such as pyrrole, indole, furan, and thiophene those easily react with electrophiles. The other is the 7r-electron-deficient heteroaromatics, such as pyridine, quinoline, and isoquinoline those have the tendency to accept the nucleophilic attack on the aromatic ring. Reflecting the electronic nature of heteroaromatics, the TT-electron-deflcient ones are usually used as the electrophiles.t The rr-electron-sufficient heteroaromatics having simple structures, such as 2-iodofuran and 2-iodothio-phene, have also been utilized as the electrophiles. Not only the electronic nature of the heteroaromatics but also coordination of the heteroatom to the palladium complexes influence catalytic activity. This is another reason why the couphng reaction did not proceed efficiently in some cases. 

One of the merits of the above treatment, which justifies its inclusion in this review, is that it allows a quantitative comparison of the selectivity of nucleophilic heteroaromatic substitution (expressed by the reaction constant) with that for the analogous reaction with nitro-activated systems. Values for the latter are in the range 3.6 to 6.0. The fact that in both cases high p-values of similar magnitude are found is consistent with the hypothesis of similar mechanisms for both classes of compounds. 

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