Abstract
Pyrido[1,2-a]pyrimidin-2-ones represent a pharmaceutically interesting class of heterocycles. The structurally related pyrido[1,2-a]pyrimidin-4-ones are associated with a broad range of useful biological properties. Furthermore, quinolizinone-type scaffolds of these sorts with a bridgehead nitrogen are expected to display interesting physico-chemical properties. However, pyrido[1,2-a]pyrimidin-2-ones are largely under-represented in current small molecule screening libraries and the physical and biological properties of the pyrido[1,2-a]pyrimidin-2-one scaffold have been poorly explored (indeed, the same can be said for unsaturated bicyclic compounds with a bridgehead nitrogen in general). Herein, we report the development of a new strategy for the concise synthesis of substituted pyrido[1,2-a]pyrimidin-2-ones from readily available starting materials. The synthetic route involved the acylation of the lithium amide bases of 2-aminopyridines with alkynoate esters to form alkynamides, which were then cyclised under thermal conditions. The use of lithium amide anions ensured excellent regioselectivity for the 2-oxo-isomer over the undesired 4-oxo-isomer, which offers a distinct advantage over some existing methods for the synthesis of pyrido[1,2-a]pyrimidin-2-ones. Notably, different aminoazines could also be employed in this approach, which enabled access to several very unusual bicyclic systems with higher nitrogen contents. This methodology thus represents an important contribution towards the synthesis of pyrido[1,2-a]pyrimidin-2-ones and other rare azabicycles with a ring-junction nitrogen. These heterocycles represent attractive structural templates for drug discovery.
Highlights
Heterocyclic ring systems are the core scaffolds of a large proportion of all pharmaceuticals and agrochemicals.[1,2,3] heterocyclic chemical space has, to date, been explored in an uneven and unsystematic fashion.[2,4] Chemists have largely focused upon only a small subset of heterocyclic scaffolds, generally those that are both synthetically facile and have proven biological relevance.[4]
We report the development of a new strategy for the concise synthesis of substituted pyrido[1,2-a]pyrimidin-2-ones from readily available starting materials
Compared to one-pot thermal cyclisative condensation methods involving the combination of aminoazines and alkynoate esters, this new procedure offers a broader substrate scope; several previously unreported substituted pyrido[1,2-a]pyrimidin-2-one derivatives could be accessed using this new methodology, together with several extremely rare scaffolds with higher nitrogen contents through the use of the corresponding aminoazine substrates with higher nitrogen contents
Summary
Heterocyclic ring systems are the core scaffolds of a large proportion of all pharmaceuticals and agrochemicals.[1,2,3] heterocyclic chemical space has, to date, been explored in an uneven and unsystematic fashion.[2,4] Chemists have largely focused upon only a small subset of heterocyclic scaffolds, generally those that are both synthetically facile and have proven biological relevance.[4]. It was hoped that the new methodology would enable access to other related quinolizinone-type systems with higher nitrogen contents; such very rare derivatives would be expected to be even more polar than pyrido[1,2-a]pyrimidin-2ones and may have valuable properties such as enhanced aqueous solubility.
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