Hetero-Aromatic Compounds

Ten years ago we became interested in the possibility of using nitration as a process with which to study the reactivity of hetero-aromatic compounds towards electrophilic substitution. The choice of nitration was determined by the consideration that its mechanism was probably better imderstood than that of any other electrophilic substitution. Others also were pursuing the same objective, and a considerable amount of information has now been compiled. 

The diazonium ions 2.13 with electron-withdrawing substituents are not hetero-aromatic compounds and therefore do not strictly come within the scope of this book. They are formally related to the alkenediazonium ions. Nevertheless, they are discussed here because in their properties they bear a close resemblance to heteroaromatic and arenediazonium ions rather than to alkenediazonium ions. In par-... 

A higher reaction temperature is necessary when pyrazolones such as 15 and isoxazolones are used. The selectivity in these reactions depends on the substituent at the hetero-aromatic compound and the substituents at the dienophile moiety (Scheme 5.4) [10]. 

It is still not clear how these relationships can be rationalized. However, as (hetero-)aromatic compounds are rigid and are able to form or-stacks, numerous syntheses of PMOs with aromatic bridges have been reported, thereby introducing another sort of functionality into PMOs. 

Only a few additional examples of intermolecular photochemical vinylations of (hetero)aromatic compounds have been forthcoming. Coupling products are formed in the irradiation of dichloro- and dibromo-A-methylmaleimide in the presence of 1,3-dimethyluracils341 and of 3-bromocoumarin in the presence of naphthalene, phenanthrene, 1-methylpyrrole and other aromatic compounds342. The former reaction is accompanied by cyclobutane adduct formation, which is the mode of reaction of A-methylmaleimide itself. The mechanism of these vinylation reactions is not clear, but most probably an exci-plex (cf equation 20a) or a charge-transfer complex (cf equation 20b) is involved. 

Besides the mild conditions and excellent chemo- and regioselectivity the scope of this one-pot coupling-cycloaddition isoxazole synthesis is fairly broad. Due to acid chlorides as halide coupling partners, amines and hydroxy groups inevitably need to be protected prior to the reaction. Therefore, the use of acid chlorides 7 is principally limited to (hetero)aromatic compounds and derivatives without ot-hydrogen atoms. As an exception, the cyclopropyl group is tolerated as a... 

Table 8.4 Reaction of N-acyliminium ion pool with various aromatic and hetero-aromatic compounds...

Pavlik, J. W., Photoisomerization of Some Nitrogen containing Hetero Aromatic Compounds. In Horspool, W. M., Lenci, F. (eds), CRC Handbook of Organic Photochemistry and Photobiology, 2nd edn, CRC Press LLC, Boca Raton, FL, 2004, Chapter 97, pp. 1 22. 

Lithiated aromatic and hetero-aromatic compounds gave satisfactory results in THF, when the solution of RLi was added at a low temperature to an excess of carbamoyl chloride. However, with H2C=C(Li)SCH3 the result was poor [9]. The following guide lines are based on our experiments ... 

Halogenations of lithiated hetero-aromatic compounds may give less satisfactory results because of subsequent reactions, e.g. in the iodination of 3-lithiothiophene [9] ... 

Such di-halogenations are not likely to occur with benzene derivatives, since protons, ortho to the halogen introduced, are much less acidic than those in the hetero-aromatic compounds. 

The majority of the metallated hetero-aromatic compounds are obtained by direct metallation [1, 2, 5]. The hetero-atom effect (inductive, coordinative and polarizability influence) in most cases directs the metallation to the position a- to the hetero atom and gives rise to an easier deprotonation compared with that of benzene [1]. In some cases, bromine-lithium exchange offers the possibility of introducing the metal in a position that is not accessible by direct deprotonation. In incidental cases, Grignard compounds have been prepared from halogenated hetero aromates and magnesium. 

Since part of the product may remain in solution as the lithium thiolate or alcoholate, it is advisable to carry out the hydrolysis of the reaction mixtures in the presence of an equivalent amount of mineral acid. If the metallated hetero-aromatic compound has been obtained via lithiation with LDA, or with BuLi TMEDA, an additional amount of acid is required to neutralize the amine. Purification in many cases can be carried out by crystallization from an organic solvent. 

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