Introduction
Azaindoles and their derivatives exhibit significant biological activities, hence they are widely concerned in terms of drug optimization strategies. The four azaindole positional isomers, which associate a pyridine and a pyrrole ring by a fused C-C bond, possess all of the criteria necessary to be excellent bioisosteres of the indole or purine systems. The physicochemical and pharmacological properties such as solubility, pKa and lipophilicity, target binding ability and toxicity can be modulated and finely tuned using the azaindole instead of other bicyclic fused heterocycles.
Fig.1. Four azaindole positional isomers of azaindole
Synthesis
Fluorinated heterocyclic compounds have distinctively desirable properties suitable for use in pharmaceuticals and agrichemicals, especially their ability to penetrate the cell membrane barrier for drug absorption. The challenge in the synthesis of fluorinated azaindoles is the selective aromatic fluorination which can be usually achieved either by the Balz-Schiemann reaction or via electrophilic fluorination.
In 2003, C. Thibault et al. reported two approaches to synthesize 4-Fluoro-1H-pyrrolo [2,3-b] pyridine, also refer to 4-Fluoro-azaindole. The first approach took advantage of a regioselective Balz-Schiemann fluorination reaction, which required the synthesis of an intermediate amine. In second approach, feature is the efficient lithium-halogen exchange of the corresponding bromide, followed by quenching with an electrophilic fluorine source (Fig 2).
Fig.2. Two approaches to synthesize 4-Fluoro-1H-pyrrolo [2,3-b] pyridine
(Org. Lett., 2003, Vol. 5, No. 26)
Applications
Azaindoles derivatives, especially fluorinated azaindoles have been recognized as privileged structures in biological process modulation, in medicinal chemistry and drug discovery programs. Their commercial availability has steadily increased and synthetic innovation has been continuously updated. Several azaindole derivatives have emerged from medicinal chemistry programs, and some of these have evolved into drug candidates for treating human disease.
