Heterocyclizations following halogenation

Heterocyclic nuclear halogen atoms undergo the following reactions which are typical of aryl halides ... 

The activity of PK and NRPSs is often precluded and/or followed by actions upon the natural products by modifying enzymes. There exists a first level of diversity in which the monomers for respective synthases must be created. For instance, in the case of many NRPs, noncanonical amino acids must be biosynthesized by a series of enzymes found within the biosynthetic gene cluster in order for the peptides to be available for elongation by the NRPS. A second level of molecular diversity comes into play via post-synthase modification. Examples of these activities include macrocyclization, heterocyclization, aromatization, methylation, oxidation, reduction, halogenation, and glycosylation. Finally, a third level of diversity can occur in which molecules from disparate secondary metabolic pathways may interact, such as the modification of a natural product by an isoprenoid oligomer. Here, we will cover only a small subsection of... 

Nucleophilic substitutions are in many cases facile processes in heterocyclic chemistry. Also, in the area of the present chapter, many such routine transformations have been carried out. Such transformations are summarized in Table 6, where the structures of the starting compounds, products, the reagents, yields, and references are listed. These include reactions of halogen, methoxy, and methylsulfanyl derivatives with amines or alkoxides. One exceptional case (Table 6, entry 9) should be pointed out this exchange reaction, unlike the others in this table, proceeds via an elimination-addition mechanism. A few related transformations that follow more complicated pathways and therefore could not be classified unambiguously into this table, can be found in Table 7 in Section 11.17.5.6.5. 

Types of compounds are arranged according to the following system hydrocarbons and basic heterocycles hydroxy compounds and their ethers mercapto compounds, sulfides, disulfides, sulfoxides and sulfones, sulfenic, sulfinic and sulfonic acids and their derivatives amines, hydroxylamines, hydrazines, hydrazo and azo compounds carbonyl compounds and their functional derivatives carboxylic acids and their functional derivatives and organometallics. In each chapter, halogen, nitroso, nitro, diazo and azido compounds follow the parent compounds as their substitution derivatives. More detail is indicated in the table of contents. In polyfunctional derivatives reduction of a particular function is mentioned in the place of the highest functionality. Reduction of acrylic acid, for example, is described in the chapter on acids rather than functionalized ethylene, and reduction of ethyl acetoacetate is discussed in the chapter on esters rather than in the chapter on ketones. 

With this section, the classification in the Handbook of Heterocyclic Chemistry has been followed thus a general survey of the effect of rings on the reactions of substituents is followed by a survey of the effect of rings on reactions of individual substituents in the order fused benzene rings, C-linked, AMinked, <9-linked, S-linked substituents, halogens, and metals. Substituents attached to cyclic nitrogen and sulfur are dealt with as described below. 

An instance of an apparent electrophilic aromatic substitution (in this case 61 is an aromatic substrate, of Scheme 31), which actually is an electrophilic addition, is the halo-genation of 2-aminothiazole derivatives which was usually considered a simple attack of the electrophilic reagent on the heterocyclic aromatic substrate activated by the amino group see reaction 12. When the bromination of 2-aminothiazole derivatives is carried out in nucleophilic solvents (ROH) and at low temperatures, the partially saturated derivatives (64) of Scheme 33 were isolated in 80-95% yields133. By heating 64, the usual halogenated 2-aminothiazoles are obtained, as indicated by Scheme 33. An apparent electrophilic aromatic substitution is actually an addition reaction to the C=C double bond the elimination reaction is the following, separate step. 

However, acylation reactions of N-unsubstituted pyrazolines with halogen anhydrides of acids are very often followed by the destruction of the heterocyclic ring owing to the ease of breaking the C(5)—Nq) bond located at the (3-position of the azomethine group [140, 141, 142, 166]. For example, pyrazoline 108 treated with halogen anhydrides of acids yields a,(3-unsaturated ketone 109 and diacyl-hydrazine 110 [166] (Scheme 2.29). 

In intramolecular arylations, a new bond is created between two aromatic moieties of the same molecule or between an aromatic nucleus and an atom of a side-chain. Many intramolecular arylation reactions of homocyclic and heterocyclic aromatic halides have been studied mainly in view of their synthetic applications, and it is not always clear which mechanistic pathway is followed. The reaction may start with homolytic or heterolytic dissociation of the carbon-halogen bond and proceed by attack of the aryl radical or aryl cation on another part of the molecule. Electrocyclization followed by elimination of hydrogen halide is another possibility. Especially when heteroatoms such as nitrogen, sulphur or phosphorus are involved, the initial step may be a nucleophilic attack on the carbon atom bearing the halide atom. 

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