Synthesis of pH Dependent Pyrazole, Imidazole, and Isoindolone Dipyrrinone Fluorophores using a Claisen-Schmidt Condensation Approach

Abstract

Methine-bridged conjugated bicyclic aromatic compounds are common constituents of a range of biologically relevant molecules such as porphyrins, dipyrrinones, and pharmaceuticals. Additionally, restricted rotation of these systems often results in highly to moderately fluorescent systems as observed in 3H,5H-dipyrrolo[1,2-c:2',1'-f]pyrimidin-3-ones, xanthoglows, pyrroloindolizinedione analogs, BODIPY analogs, and the phenolic and imidazolinone ring systems of Green Fluorescent Protein (GFP). This manuscript describes an inexpensive and operationally simple method of performing a Claisen-Schmidt condensation to generate a series of fluorescent pH dependent pyrazole/imidazole/isoindolone dipyrrinone analogs. While the methodology illustrates the synthesis of dipyrrinone analogs, it can be translated to produce a wide range of conjugated bicyclic aromatic compounds. The Claisen-Schmidt condensation reaction utilized in this method is limited in scope to nucleophiles and electrophiles that are enolizable under basic conditions (nucleophile component) and non-enolizable aldehydes (electrophile component). Additionally, both the nucleophilic and electrophilic reactants must contain functional groups that will not inadvertently react with hydroxide. Despite these limitations, this methodology offers access to completely novel systems that can be employed as biological or molecular probes.

Figure 1.

Light excitation and relaxation processes for methine-linked bicyclic aromatic systems. (A) Methine-linked bicyclic aromatic systems, without restricted bond rotation, typically undergo aphotoisomerization/non-radiative decay process when excited with radiation. (B) Methine-linked bicyclic aromatic systems, with restricted bond rotation, typically enter an excited singlet state and relax via fluorescence when excited with radiation.

Figure 2.

Structures of methine-linked aromatic ring systems that possess restricted rotation.

Figure 3.

Vinylogous enolate generation, aldol addition, and condensation steps for pyrrolinone analog synthesis.

Figure 4.

Dipyrrinone Analog Products 16–15.