5-halogeno aminolysis

The ease of displacing a chloro, bromo or iodo substituent in comparable pyrimidines by aminolysis is disappointingly similar. Using 2-halogeno-4,6-dimethyl- and 4-halogeno-... 

Note Even from the limited number of recent preparative results that follow, it is evident that the interannular activating effect of a 6/7-nitro group on a 2/3-halogeno substituent is appreciable and that the effect of an adjacent nitro group on a normally unreactive 5-, 6-, 7-, or 8-halogeno substituent is so substantial that aminolysis becomes a practical procedure. 

Note Aminolysis of halogeno esters may be accompanied by amide formation, depending on the amine and conditions employed. 

The paucity of data with the fluoro and bromo derivatives is more than made up by the wealth of information available in the case of the chloro derivative N3P3CI6. It is likely that the general conclusions drawn from the study of the chloro derivatives can also be applied to the other halogeno derivatives. Some examples of the aminolysis reactions are illustrated in Table 1. The general trends observed can be summarized as follows ... 

The ease of aminolysis of halogeno-l,5-naphthyridines is governed by several factors already outlined for nucleophilic displacement in general (Section 3.2) and alcoholysis (Section 3.2.1). The examples that follow are divided according to the number and position(s) of the halogeno substituent(s). 

Many amino-1,5-naphthyridines have been made by primary synthesis (see Chapter 1), by aminolysis of halogeno-1,5-naphthyridines (see Section 3.2.2), or by aminolysis of 1,5-naphthyridinones (see Section 4.1.2). Others have been made by direct amination, as illustrated in the following examples. 

As with alcoholysis, halogeno substrates undergo aminolysis with vigor that depends on the positions they occupy in the naphtyridine system and on the type of amine used. The following examples illustrate the general picture. 

The aminolysis of halogeno-l,7-naphthyridines is fairly well represented in the literature, but other potential reactions have seldom been used. Reported reactions are illustrated in the following examples. 

Note Potassium amide in liquid ammonia can be used for aminolysis of halogeno-1,7-naphthyridines, but it also induces fe/e-aminolysis.54 For example, 2-chloro-l,7-naphthyridine gave a separable mixture of 1,7-naphthyridin-2-amine and both the 4- and 8-isomers (KNH2, NH3, Et20, —33°C, 4 h 70% yield of the mixture) from which each product was isolated in low yield 834 also analogous examples.332 808 834... 

Halogeno substituents at the 2-, 4-, 5-, and 7-positions of 1,8-naphthyridine will be activated toward aminolysis and similar reactions those at the 3- and 6-positions will be only mildly so activated and extranuclear halogeno substituents will resemble at best that in benzyl chloride. 

Note The conversion of 1,8-naphthyridinones into amino-1,8-naphthyridines is usually done via a halogeno intermediate, but direct aminolysis is possible sometimes. 

Several methods of preparation have been covered already by primary synthesis (Chapter 22) and by aminolysis of halogeno-1,8-naphthyridines (Section 34.2),... 

Of the many possible reactions of halogeno-2,7-naphthyridines, only alcoholysis, aminolysis, and dehalogenation have been reported.01 60... 

All known examples of such amines have been made by primary synthesis (see Section 30.1), by direct amination (see Section 30.2.3), or by aminolysis of halogeno substrates (see Sections 30.2.1 and 30.3.2). 4-Phenyl-2,7-naphthyr-idin-1-amine (lophocladine B) was isolated from a red alga.1435... 

Detailed discussion of the preparation of a variety of alkyl- and arylpyrazines by primary syntheses, principally from aliphatic components, appears in Chapter II. These include, for example, the preparation of 2,5-disubstituted and 2,3,5,6-tetrasubstituted alkyl- and arylpyrazines from a-amino carbonyl compounds, which may be produced by many methods such as reduction of a-hydroxyimino carbonyl compounds, aminolysis of a-halogeno carbonyl compounds, oxidation of a-amino... 

Comparative A -oxide activation was likewise observed when other amines such as hexylamine, aniline, benzylamine, piperidine, and dimethylamine were used. It was also noted, in every example studied, that amination of the chloropyrazine A -oxide or alkylchloropyrazine 7V-oxide at elevated temperatures in a sealed vessel gave mixtures containing greater or lesser amounts of deoxygenated halogeno-pyrazine or aminopyrazine (921). Similar enhanced activation by theTV-oxide group was observed when 3-chloro-2,5-dimethylpyrazine and its 1-oxide in reaction with various amines were compared, although dialkyl substitution further retarded overall aminolysis (793,921). 

Note The indirect aminolysis of tautomeric phthalazinones may be done via halogeno, alkoxy, thioxo, alkylthio, or other such derivatives. Convenient one-pot syntheses are exemplified here. 

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