Diazirine

Diazirines are a class of organic molecules consisting of a carbon bound to two nitrogen atoms, which are double-bonded to each other, forming a cyclopropene-like ring. Upon irradiation with ultraviolet light, diazirines form reactive carbenes, which can insert into C-H, N-H, and O-H bonds. Hence, diazirines have grown in popularity as small photo-reactive crosslinking reagents. They are often used in photoaffinity labeling studies to observe a variety of interactions, including ligand-receptor, ligand-enzyme, protein-protein, and protein-nucleic acid interactions.

A number of methods exist in the literature for the preparation of diazirines, which begin from a variety of reagents.

Generally, synthetic schemes that begin with ketones involve conversion of the ketone with the desired substituents to diaziridines. These diaziridenes are then subsequently oxidized to form the desired diazirines.

Diaziridines can be prepared from ketones by oximation, followed by tosylation (or mesylation), and then finally by treatment with ammonia. Generally, oximation reactions are performed by reacting the ketone with hydroxylammonium chloride under heat in the presence of a base such as pyridine. Subsequent tosylation or mesylation of the alpha substituted oxygen with tosyl or mesyl chloride in the presence of base yields the tosyl or mesyl oxime. The final treatment of the tosyl or mesyl oxime with ammonia produces the diaziridine.

Alternatively, diaziridines can be produced directly by the reaction of ketones with ammonia in the presence of an aminating agent such as a chloramine or hydroxyl amine O-sulfonic acid.

Diaziridines can be oxidized to diazirines by a number of methods. These include oxidation by chromium based reagents such as the Jones oxidation, oxidation by iodine and triethylamine, oxidation by silver oxide, oxidation by oxalyl chloride, or even electrochemical oxidation on a platinum-titanium anode.

Alternatively, diazirines can be formed in a one-pot process using the Graham reaction. In these schemes, amidines can be directly converted to diazirines by hypohalite oxidation. This reaction yields a halogenated diazirine, which can further be modified.

The resulting aforementioned halodiazirine can undergo an exchange reaction to further functionalize the diazirene. In these reactions, anion nucleophiles, such as tetra-n-butylammonium fluoride or methoxytetra-n-butylammonium can replace the halogen substituents yielding a fluorodiazirine or methoxydiazirine respectively.

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