Tertiary Skipped Diynes: A Pluripotent Building Block for the Modular and Diversity-Oriented Synthesis of Nitrogen Heterocycles

摘要

The development of diversity-oriented synthetic (DOS) methodologies to construct libraries of small molecules to explore chemical space is a current topic in modern organic synthesis.[1] An important challenge for these methodologies is the generation of skeletal diversity. This can be generated by using the so-called reagent-based DOS methodology, which utilises different reagents to transform a substrate into an array of products with distinct molecular skeletons.[2] In practice, two main reagent-based strategies are currently used: the densely functionalised molecule (different functionalities in the same molecule are sequentially transformed by different reagents) and the pluripotent functional group (the same functional group in the molecule is transformed by different reagents in different reactions).[3] The latter approach requires the use of building blocks containing functional group, or an array of interconnected functional groups, featuring a polyvalent reactivity profile. Skipped diynes 1[4] with a quaternary sp3 centre and two conjugated alkyne units constitute an example of such building blocks (Scheme 1; ai/di refer to acceptor/donor properties of position i).[5] A recent report from this ab has shown that these diynes are efficient precursors of chain-functionalised, tetrasubstituted pyrroles 2 by an efficient microwave-assisted domino reaction with primary amines (Scheme 2).[6] The necessary pyrrole connectivity is generated from the enamine intermediate I by a selective 5-endo-dig cyclisation reaction (a2 reactivity; anti-aza-Michael addition) via a transient pyrrolidine intermediate II that rearranges into the final pyrrole 2 by a sigmatropic [3,3]-Claisen rearrangement ([d0+ a2] reactivity). Herein, we report our preliminary results on the use of this C7 pluripotent array of organic functionalities for the generation of other important N-containing heterocycles.As a proof of concept, we describe a convenient approach to the regioselective domino synthesis of chain-functionalised, fully substituted pyrazoles 4 by using N-substituted hydrazine derivatives (R4NHNH2) as nucleophiles (Scheme 2). As an extension of this concept, we have also synthesised 1,4-diazepane derivatives 6 by using ethane-1,2- diamine derivatives as N-centred nucleophiles (Scheme 2).