Halogenated heteroaromatic

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. 

L.S. Liebeskind et al. demonstrated that CuTC could be efficiently used to mediate the Ullmann reaction at room temperature under very mild conditions tolerating a wide variety of functional groups. One of the examples features an intramolecular process while the other demonstrates the coupling of halogenated heteroaromatics. 

In contrast to other commercial neonicotinoids, 4 has an alicyclic and racemic (RS)-(+)-TFM moiety instead of the halogenated heteroaromatic CPM and CTM moieties (see Chapter 29.3). The non-aromatic oxygen atom of the TFM residue is situated in the position corresponding to that of the aromatic nitrogen atom of the other heterocyclic moieties of neonicotinoids - consequently the TFM stmc-ture can be taken as an isostere of the CPM and CTM moiety [61]. 

R. Bishop, Crystal engineoing of halogenated heteroaromatic clathrate systems, in Frontiers in Crystal Engineering, eds. E. R. T. Tiekink and J. J. Vittal, WUey, Chicheste, 2006, vol. 1, pp. 91-116, Chapter 5. 

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. 

In accordance with the observed behavior of nitro-activated aromatic compounds, in all cases tested the displacement of halogens from A -heteroaromatic carbon by such reagents as sodium meth-oxide and sodium ethoxide in their respective alcohols [Eq. (2),... 

This is a problem that has been reported by several researchers in other cya-nation methods on heteroaromatic halides. (Hetero)aryl chlorides have also been tackled via in situ halogen exchange to (hetero)aryl bromides followed by sequential cyanation (Scheme 71). For this microwave-assisted process an equimolar amount of NiBr2 and a two-fold excess of NaCN were used. The only heteroaromatic chloride tested was 2-chloropyridine. Although the procedures described involve the use of significant amounts of nickel salts, a clear advantage is that the reactions can be performed in air. Moreover, the cyanat-ing reagents are easily removed since they are water soluble. 

These reaction conditions were applicable to the thiol esters of alkanoic, heteroaromatic, and halogenated acetic acids. 

Haloarenes routinely form XB. The same holds for haloheteroarenes and when the heteroaromatic ring is positively charged, the halogen becomes a particularly good XB donor [89-94]. This strategy has been applied with particular success in order to control the packing of bromo- and iodo-... 

Substitution of halogens on heteroaromatic rings is a common way to introduce new functionalities. The product from reaction 6 (Scheme 6) was required on a 100-g scale as an intermediate. In the literature, this exchange was done on a 5-g scale using ammonia in ethanol in a sealed tube under pressure for 6 h at 125-130°C with a yield of 76% (Bendich et al. 1954). Because of the lack of a suitable autoclave for high-pressure reactions, we choose the microwave reactor for scale-up trials. Using our Synthos 3000 equipment, we found suitable conditions with only minimal optimization at 170°C for 180 min and obtained the desired product on a 60-g scale in 83% yield. 

In West Germany pyridazinium compounds as represented by formula (120, R1 = halogen, alkyl, aryl R2 = H, alkyl R3 = substituted amino R4 = substituted alkyl, cycloalkyl) have been claimed as antibacterial agents [338]. In Australia, mercapto derivatives of several nitrogen heteroaromatics including pyridazine-derived compounds (121, R = CONH2, CH2NMe2) have been prepared in a search of amplifiers of phleomycin [339] however, only low activity has been observed in this series. 

Halogen substituents are of course easy to introduce to heteroaromatic rings, and they also enhance the acidity of the ring protons. n-BuLi will, for example, lithiate the tetrafluoropyridine 179 at —60°C in ether ° but with pyridine itself it leads to addition/reoxidation products . Addition to the ring is the major product with 2-fluoropyridine 180, though some metaUation can be detected selectivity in favour of metaUation is complete with LDA in THF at —75 °C or with phenyUithium and catalytic -Pr2NH at —50°C (Scheme 90) . Similar results are obtained with quinolines . 

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). 

The a-, f3- and y-halogeno substituents in pyridines and their benzo analogues are each more susceptible to nucleophilic substitution than is the case for halobenzenes because of the overall electron deficiency of the heteroaromatic ring. Furthermore, halogen substituents a and y to nitrogen are usually more reactive than /3-halogens and this is particularly so in pyridinium type systems. 

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