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Abstract
Structural misassignments are often seen for complex natural products, but this can also be an issue with seemingly simpler structures. In this paper, we describe how, using a 15N-labelled analogue, we established that the Dimroth rearrangement can occur in imidazo[1,2-a]pyrimidines and result in an incorrect regiochemical assignment of such compounds. These studies supported a rearrangement mechanism involving addition of hydroxide ion followed by ring opening. It was also observed that C(2) and C(3) substituted regioisomers could be readily distinguished using 1H NMR spectroscopy.
Highlights
The imidazo[1,2-a]pyrimidine scaffold is an emerging heterobicyclic scaffold of significant interest in the contemporary medicinal chemistry literature
Even though the first mention of a Dimroth-type ring opening in the literature dates back to 1888 [18], it is not uncommon for incomplete data to be provided for new analogues and regiochemical assignments made by comparison with existing literature data, as the use of more complicated and time-consuming X-ray studies to unequivocally assign the regiochemistry is frequently not carried out
We became interested in these ring systems whilst investigating access to a range of imidazo[1,2-a]pyrimidine analogues substituted at C2 and C6
Summary
The imidazo[1,2-a]pyrimidine scaffold is an emerging heterobicyclic scaffold of significant interest in the contemporary medicinal chemistry literature. In recent years there have been an increasing number of reports of activity of this class of compound against various different targets (mGlu, mGlu, D1, Lp-PLA2, TNF, PI3K, SUV39H2, IAP-BIR and DPP-4) [1e9] and in multiple therapeutic areas (AIDS, antiparasitic, antiproliferative, autotaxine associated disease, Peyronie's disease, spinal muscular atrophy) [10e15], as well as their use as blue fluorescent light emitters [16]. A feature of aza heterocycles such as imidazo[1,2-a]pyrimidines is that they can undergo the Dimroth rearrangement when subjected to appropriate reaction conditions. This transformation is described as a translocation of two heteroatoms in a heterocyclic system with or without changes in the ring structure, and it is an often undesired side reaction that occurs, usually in basic media, and as a result can lead to structure misassignments for the products. Even though the first mention of a Dimroth-type ring opening in the literature dates back to 1888 [18], it is not uncommon for incomplete data to be provided for new analogues and regiochemical assignments made by comparison (often erroneously) with existing literature data, as the use of more complicated and time-consuming X-ray studies to unequivocally assign the regiochemistry is frequently not carried out
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