6-Azaindole core

To overcome the electronic and steric barriers embedded in this architecture, the synthetic approaches starting from pyridine were generally comprised of lengthy sequences and harsh reaction conditions, as demonstrated by the approaches depicted above. These inherent limitations led us to rethink our strategy to the requisite 6-azaindole core. 

While we were developing approaches to the 6-azaindole core, we were simultaneously interrogating the functionalization of C7 using intermediates... 

The ability to functiOTialize the 6-azaindole (at C7) by first preparing the corresponding bromide, followed by subsequent installation of the triazole, allowed us to capitalize on the route to the unfunctionalized 6-azaindole core 69 (described in Secticm 2.1). 

Thus far, we had established a flexible synthetic route to several key intermediates, along with the 6-azaindole core equipped with a suitable functional group handle at C7. Our next task was to evaluate the order in which the appendages could be attached to the core, namely the C3-ketoacid side chain, the N1 prodmg, and the C7-triazole (Figure 8). 

A tetrameric structure with the Zn40 core can also be formed with the 7-azaindolate ligand, [Zn40(C7H5N2)6], and has been structurally characterized. The tetramer displays intense photoluminescence at 448 nm in the solid state and 425 nm in acetonitrile with a lifetime and quantum yield of 0.1 ps and 0.17 ps respectively.280... 

Pyrrolopyrazine is a core structure that has drawn some attention from the pharmaceutical industry, both as a surrogate structure for indole or azaindole and as a novel kinase inhibitor [120]. The synthesis of 6,7-diphenylpyrrolopyrazines (238) was achieved via a Pd-catalyzed heteroannulation of 237, utilizing both conventional and microwave heating conditions. The reaction proceeded under microwave irradiation conditions to yield the desired products in modest yield [121]. 

In terms of SAR information, substituting the indole structure (azaindoles X or Y = N) yielded inactive or compounds of low cytotoxicity. The same holds true for N-alkylation or substitution of the methoxy-group in the indole core structure of (12a) vs. a methyl group. In summary, the results from the cellular cytotoxicity screening suggested the benefit of the 5-methoxy-indolyl-group for potent antitumour activity. 

There are limited literature examples of cyclizations around a pyrrole nucleus to access fused heterocycles, potentially indicating that the reactivity of the system to cyclization is extremely sensitive, either to the substitution pattern or to the oxidation state of the forming ring. With this in mind, we considered approaches that began with a simple pyrrole analogue, where we hoped to form the pyridine side of the azaindole (or its equivalent) upon ring closure— rapidly forming the core of the molecule. 

Research of a more fundamental nature - not directly geared toward finding useful applications - has been reported on two other groups of molecules. 7-Azaindole is another biologically relevant molecule since it is closely related to indole, the core of the amino acid tryptophan. Tryptophan is an important reporter molecule in protein spectroscopy, and replacement of the indole group by an azaindole makes it even more suitable for its simpler decay characteristics and red-shifted spectrum [90]. It was also extensively investigated by Kasha and coworkers [91], and has been the subject of much theoretical work[92].The tendency of 7-azaindole to form dimers in particular solvents has also led to the study of double proton transfer reactions in the excited state [93, 94]. Some of these issues are complicated by the possible presence of anion fluorescence [95] (Figure 1.13). 

---