Synthesis and reactions of reduced pyrazines

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Williams, A.J., 1979. Synthesis and reactions of reduced pyrazines. PhD, Nottingham Trent University.

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Abstract

The present work explores the chemistry of the little known l,2,3,4-tetrahydropyrazines and the possibility of their conversion into the 8 electron 1,4-dihydropyrasines by means of b-elimination reactions.

The cyclisation of p-toluenesulphonylarainoacetals, p-CH3C6H4SO2NHCH2CH(OR)2 , under various conditions was found to give either the 2,5-disubstituted piperazines (1-3) or the 2-substituted- l,2,3,A-tetrahydropyrazines (5-7). These two systems could be interconverted by elimination - addition reactions of water and/or alcohols. The hydroxy and alkoxy groups in (1-3) and (5-7) were also interconvertible by reaction with the appropriate reagent; an analogous reaction with thiophenol led to the synthesis of the 2-phenylthio- 1,2,3,4,-tetrahydropyrazine (3) which was oxidised to the corresponding sulphoxide.

Attempts to form esters of the 2-hydroxy-1,2,3,4-tetrahydropyrazine (7) are described and the reasons for their failure discussed.

The 2, 5-dichloropiperazine (4) was prepared from both (3) and (7) and, was converted into the 2-chloro-l,2,3,4-tetrahydropyrazine (9) by thermal elimination of one mole of HCl. Both the chloro compounds (4) and (9) were very reactive towards nucleophiles, and a range of nucleophilic substitution reactions of the 2-chloro-l,2,3,4-tetrahydropyrazine (9) was carried out to give interesting new products including e.g. (10) and (11).

Access- to the 2,3-disubstituted-l,2,3,4-tetrahydropyrazines such as (12) was provided by bromination of (7) or (9).

The reactions of the 2,3-dibromo-l,2,3,4.-tetrahydropyrazine (12) are reported; these include formation of hydrolysis and alcoholysis products, a novel trans-cis isomerisation, and conversion into a new fused heterocycle.

A related heterocyclic system was obtained by [4+2] cycloaddition of the tetrahydropyrazine (H) with tetrachloro-o-benzoquinone.

Oxidation of the 2-hydroxy- 1,2,3,4-tetrahydropyrazine (7) was carried out under various conditions; Jones reagent unexpectedly led to hydroxylation, of the double bond.

Attempts to synthesise the l, 4-dihydropyrazine (13) by a wariety of methods, including elimination of water, hydrogen chloride, bromine and phenylseleninic, acid from the appropriate substrates are described. Evidence for the transient formation of a l,4-dihydropyrazine is presented and the reasons for the failure to isolate the desired product are discussed.