Activated heteroaromatics, nucleophilic

In many cases, substituents linked to a pyrrole, furan or thiophene ring show similar reactivity to those linked to a benzenoid nucleus. This generalization is not true for amino or hydroxyl groups. Hydroxy compounds exist largely, or entirely, in an alternative nonaromatic tautomeric form. Derivatives of this type show little resemblance in their reactions to anilines or phenols. Thienyl- and especially pyrryl- and furyl-methyl halides show enhanced reactivity compared with benzyl halides because the halogen is made more labile by electron release of the type shown below. Hydroxymethyl and aminomethyl groups on heteroaromatic nuclei are activated to nucleophilic attack by a similar effect. 

The development of diversification linkers allows introduction of an additional element of diversity. Upon completion of the synthesis sequence, the linker is activated facilitating nucleophilic release of the library members from support In the ideal case, as implemented with the acylsulfonamide linker (Scheme 4a), the activated linker is sufficiently reactive that limiting amounts of nucleophile may be added to provide pure product after resin filtration.181 Diversification linkers have been developed for the preparation of carboxylic acid derivatives (Scheme 4a), amines (Scheme 4b),191 aromatic (Scheme 4c) and even heteroaromatic compounds (Scheme 4d).1101... 

In addition, unstabilized enolate nucleophiles have been generated by decarboxylation of (3-ketocarboxylates. In this case, no additives are required to activate the nucleophile, but the highest yields and selectivities were obtained in the presence of two equivalents of DBU [82]. Although reactions of allylic carbonates containing aromatic, heteroaromatic, and aliphatic substituents occurred, only reactions to form aryl ketone products were published. 

In a series of important papers, MacMillan described the alkylation of electron rich aromatic and heteroaromatic nucleophiles with a,P-unsaturated aldehydes, using catalysts based upon the imidazoUdinone scaffold, further establishing the concept and utility of iminium ion activation. In line with the cycloaddition processes described above, the sense of asymmetric induction of these reactions can be rationalised through selective (F)-iminium ion formation between the catalyst and the a,P-unsaturated aldehyde substrate, with the benzyl arm of the catalyst blocking one diastereoface of the reactive Jt-system towards nucleophilic attack (Fig. 3). 

Two years after the discovery of the first asymmetric Br0nsted acid-catalyzed Friedel-Crafts alkylation, the You group extended this transformation to the use of indoles as heteroaromatic nucleophiles (Scheme 11). iV-Sulfonylated aldimines 28 are activated with the help of catalytic amounts of BINOL phosphate (5)-3k (10 mol%, R = 1-naphthyl) for the reaction with unprotected indoles 29 to provide 3-indolyl amines 30 in good yields (56-94%) together with excellent enantioselec-tivities (58 to >99% ee) [21], Antilla and coworkers demonstrated that A-benzoyl-protected aldimines can be employed as electrophiles for the addition of iV-benzylated indoles with similar efficiencies [22]. Both protocols tolerate several aryl imines and a variety of substituents at the indole moiety. In addition, one example of the use of an aliphatic imine (56%, 58% ee) was presented. 

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). 

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. 

The reducibility of a halogenated heteroaromatic system depends on the heteroaromatic ring, the kind of halogen, and the position of the substituent. Iodides are more easily reducible than bromides which, in turn, are easier than chlorides. Halogen substituents in positions activated toward nucleophilic attack are preferentially reduced. 

One of the most practical laboratory routes to highly fluorinated heteroaromatic compounds involves the use of potassium or other alkali metal fluorides in nucleophilic displacement of chlorine by fluorine, from aromatic systems activated toward nucleophilic attack. Reactivity of the alkali metal... 

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. 

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. 

Compounds of the type HC=C—CH=CHXR are not involved in a primary reaction with weak nucleophiles such as CH acids meanwhile, a final (secondary) cyclization with participation of active methylene groups happens to be feasible. Evidently, in most cases the energy gain in the heteroaromatic system realization is the decisive factor (81UK1252). 

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. 

N-Heteroaromatic compounds like pyridine, pyridazine, pyrazine, isoquinoline, and their derivatives42,250 react with diphenyl cyclopropenone in a formal (3+2) cycloaddition mode to the C=N bond of the heterocycle. As expected from the results discussed earlier (p. 67), the reaction is initiated by attack of nitrogen at the cyclopropenone C3 position and followed by stabilization of the intermediate betaine 390 through nucleophilic interaction of the Cl/C3 bond with the activated a-site of the heterocycle, giving rise to derivatives of 2-hydroxy pyrrocoline 391—394). In some cases, e.g. diphenyl cyclopropenone and pyridine42, further interaction with a second cyclopropenone molecule is possible under the basic conditions leading to esters of type 392. 

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. 

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