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Medicinal Chemistry

Halogenated azidopyridines fill gap in click chemistry toolbox

Handled with care, the compounds could be useful building blocks for medicinal chemistry

by Mark Peplow, special to C&EN
November 17, 2021


Chemical structures of 4-azido-2-chloropyridine, 4-azido-3-fluoropyridine, and 3-azido-5-bromopyridine.
Researchers synthesized a selection of useful halogenated azidopyridines, three of which are shown here. 4-azido-3-fluoropyridine (center) is a shock sensitive explosive.

Azides have a reputation for being explosive, their N3 group a thermodynamic hair trigger primed to release nitrogen gas. But organic azides also play a vital role in synthesis. For example, the copper(I)-catalyzed cycloaddition between an azide and an alkyne to form a triazole—the classic click chemistry reaction—has become an indispensible tool in medicinal chemistry, chemical biology, and materials science.

Researchers at Bristol Myers Squibb (BMS) have now filled a gap in the click-chemistry toolbox, creating a selection of nine halogenated azidopyridines that could become useful building blocks for medicinal chemists (Org. Lett. 2021, DOI: 10.1021/acs.orglett.1c03201).

The work emerged from a BMS project that needed some pyridine molecules carrying an azide for click chemistry and a halogen that could be replaced by another molecular fragment at a later stage of a synthesis. To their surprise, the researchers found that only a handful of these halogenated azidopyridines had been reported.

“We suspected that perhaps these compounds had never been made before because they could be dangerous,” says Michael D. Mandler at BMS Research and Early Development in Princeton, New Jersey, who led the work. So the team set out to prepare a selection of the compounds and hit some of them with a hammer.

They made the compounds by reacting sodium azide with pyridines bearing two halogen atoms. This produced nine different fluoro-, chloro-, and bromo-azidopyridines in yields of 24–82%. The crystalline compounds were stable under ambient light and when heated to 100 °C in solution.

“There are only a very few reports of this sort of compound, and [the BMS researchers] prepare them very simply,” says Petr Beier of the Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, who has developed fluorinated azides for click chemistry and was not involved in the research. The compounds could be useful not only for click chemistry, Beier adds, but also in azide-based reactions used to tag biological molecules with fluorescent markers, for example.

Using a technique called differential scanning calorimetry, the BMS researchers found that the compounds began to decompose above 120 °C or so. Then they picked out the three compounds most likely to be shock sensitive and subjected them to a standard impact test that involves dropping a specialized hammer onto a very small sample. One of the compounds, 4-azido-3-fluoropyridine, went off with a bang.

The team says that other researchers should take particular care with this compound, and they should test the explosive potential of all halogenated azidopyridines before using them at larger scale.

Nevertheless, they proved to be handy synthetic compounds that were safe enough to use, forming triazoles in click reactions with a variety of alkynes that included groups such as ketones, alcohols, and amines. “Triazoles are very useful in chemical biology for linking two molecules together, because they form such a tight link,” Mandler says. “They’re very thermodynamically stable, so they are not broken down very easily by the body.”

The researchers combined some of the triazoles with amines in a palladium-catalyzed cross-coupling reaction and with alcohols in a halogen substitution reaction, forming compounds that were helpful in the team's medicinal chemistry project. “We would continue to investigate similar compounds, now that we have made them successfully and safely,” Mandler says.


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