Synthesis strategies to 3-alkyl-2-methoxy pyrazines

Abstract

Pyrazines are a class of heterocyclic compounds with multiple industrial applications spanning the flavours, fragrance, and pharmaceutical industries. The investigation of new synthetic routes leading to improved safety, efficiency and cost are advantageous to large scale synthesis in each of these sectors. One of our laboratories principle ambitions is to establish generic methodology that allows access to a wide range of novel heterocyclic cores such as pyrazines. To develop this chemistry, we selected three exemplifying structures namely, 2-butyl-3-methoxypyrazine, 2-propyl-3-methoxypyrazine, and 2-isobutyl-3-methoxypyrazine, with the eventual aim of enabling large scale production.

Prior to describing the synthesis of these compounds, a background literature review of current pyrazine preparation is provided. This includes the unique odour characters of this family, their application in the flavour and fragrance area and biological impacts as semiochemicals. A more comprehensive pyrazine natural formation also provided some insights and data to estimate the reaction conditions and starting materials required for the new synthesis.

The retrosynthesis of 2-alkoxy-3-methoxypyrazines is shown in the abstract figure. Firstly, the determination of key variables relating to yield based upon a known synthetic route suggested by Seifert et al. in 1970, was investigated.[1] Further literature sources were also reviewed to identify improvements for each step of the originally established scheme. Overall, around 50% yield of the selected target 2-isobutyl-3-methoxypyraizne were obtained and under milder reaction conditions. Secondly, a new route was considered for the synthesis of 2-isobutyl-3-methxoypyrazine via condensation of α,β-dicarbonyl and of α,β-diamine compounds. The method was based upon an approach by Ghosh et al. published in 2011.[2] The scope of this route was analysed and was adjusted to enable us to prepare 2-isobutyl-3-methoxypyrazines via a novel aromatisation procedure.