Substitution, electrophilic other ring systems

Benzisoxazoles undergo electrophilic substitution in the benzo ring, but with nucleophiles the reaction occurs in the isoxazole moiety, often leading to salicylonitriles with 3-unsubstituted systems. The isomeric 2,1-benzisoxazoles are characterized by the ease with which they may be converted into other heterocyclic systems. 

A few other electrophilic substitution reactions of the ring systems in this chapter are shown in Scheme 26 also. 

Other seven-membered ring systems to have been successfully /3-lithiated include 5//-dibenz[6,/]azepine and its 10,11-dihydro derivative (83JHC341 84JHC197). The 4,5-dilithio derivatives 196 and 197 react successfully with electrophiles such as dialkylamides and D20 to give 4-substituted derivatives. Mention of the lithiation of these systems has also occurred in the patent literature (71USP3624072). 

Electrophilic aromatic substitution of other benzo-fused v-deficient systems generally follows predictable pathways. Thus, benzopyrylium salts are in general resistant to electrophilic substitution even in the benzo-fused ring. Chromones behave somewhat similarly, although substitution can be effected under forcing conditions. Coumarins, on the other hand, undergo nitration readily in the 6-position while bromination results in substitution at the 3-position as a consequence of addition-elimination. 

On the other hand, a proton directly bound to the 1,2,4-triazine ring can be replaced by halogen. This is an electrophilic substitution reaction at carbon, and, as expected for such a heavily aza-substituted ring system, it needs considerable activation by electron-donating substituents. The halogenation reaction is best known in bromination at the 6-position. From the published data it seems that either an amino group in the 3-position or an oxo group in the 5-position is necessary. The formation of 6-halo-substituted compounds has been reported for l,2,4-triazin-5-ones, l,2,4-triazine-3,5-diones, 3-amino-l,2,4-triazines and 3-amino-l,2,4-triazin-5-ones. 

There is little information available on the nitration, or other electrophilic substitutions, on fused five-membered ring systems. 

The reactivity of the five-membered heterocycles pyrrole, furan, thiophen and imidazole (Fig. 8-10) is characterised by interactions with electrophilic reagents. The precise nature of these reactions depends upon the particular ring system. Thiophens undergo facile electrophilic substitution, whereas the other compounds exhibit a range of polymerisation and other Lewis acid-initiated reactions upon treatment with electrophiles. We saw a number of examples of Lewis acid-promoted reactions of furans and pyrroles in Chapter 6. Although reactions of complexes of five-membered heterocyclic ligands have not been widely investigated, a few examples will illustrate the synthetic potential. 

One of the most important condensed ring systems is indole. Whether the indole nitrogen is substituted or not, the favored site of attack is C-3 of the heterocyclic ring. Bonding of the electrophile at that position permits stabilization of the intermediate by the nitrogen without disruption of the benzene aromaticity. Indole can exist in two tautomeric forms, the more stable enam-ine and the 3-H-indole or imine forms. C-2 to C-3 pi-bond of indole is more capable of cycloaddition reactions then the other pi bonds of the molecule. Inter molecular cyclo additions are not favorable, whereas intramolecular variants are often high-yielding. 

Benzene is aromatic because it has six electrons in a cyclic conjugated system. We know it is aromatic because it is exceptionally stable and it has a ring current and hence large chemical shifts in the proton NMR spectrum as well as a special chemistry involving substitution rather than addition with electrophiles. This chapter and the next are about the very large number of other aromatic systems in which one or more atoms in the benzene ring are replaced by heteroatoms such as N, O, and S. There are thousands of these systems with five- and six-membered rings, and we will examine just a few. 

It is important to recall that the reactivity pattern of phosphoies is very different from that of the related S, N, and O ring systems due to their limited aromatic character. For example, electrophilic substitution takes place only with a handful of phosphoies that have been specifically tailored via increasing the bulkiness of the P substituent (see Section 3.15.10.4, Scheme 83). In fact, electrophiles react at the phosphoms atom affording a panel of neutral and cationic CN 4 derivatives (Scheme 8). Phosphoies are also versatile synthons for the preparation of other heterocyclic systems via Diels-Alder reactions. The cycloaddition can involve the dienic moiety of the phosphole ring or can occur following a 1,5-shift of the P-substituent (Scheme 8). Finally, phosphoies can be transformed into phospholide ions, which are powerful nucleophiles that have found a variety of applications (Scheme 8). All these facets of phosphole reactivity are presented in this section. It should also be noted that CN 3 phosphoies exhibit a rich coordination chemistry toward transition metals (see Section 3.15.12.2). 

The ring system (1) did not undergo any other electrophilic substitution reactions (nitration, sulfonation, Friedel-Crafts, Vilsmeier formylation), was inert to sodamide, could not be metalated with butyllithium and could not be readily oxidized with hydrogen peroxide to an AC-oxide (66JOC265). Compound (1) could not be reduced at atmospheric pressure by hydrogen but at 3 atm using a palladium-charcoal catalyst the 5,6,7,8-tetrahydro derivative (90) was obtained (75G1291). 

The chemistry of all three heterocyclic ring systems contains some Su prises. Pyrrole, for example, is both an amine and a conjugated diene, its chemical properties are not consistent with either of these structural features. Unlike most other amines, pyrrole is not basic (Section 24.4) unlike most other conjugated dienes, pyrrole undergoes electrophilic substitution rather than addition reactions. The same is true of furan and thiophene Both react with electrophiles to give substitution products. 

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