Nucleophilic imidazole ring solvents

Another potent group of alkylators are the a-haloketones. The classic example is the alkylator TPCK (tosyl-L-phenylalanylchloromethyl ketone) which interacts specifically with one imidazole ring (histidine residue) in the enzyme a-chymotrypsin (see Section 7.2.3). These compounds are significantly more reactive in Sn2 displacements than alkyl halides. For example, nucleophilic attack by iodide will proceed 33,000 times as quickly on chlo-roacetone as on n-propyl chloride (acetone solvent, 50°C). Inductive pull of the carbonyl function would be expected to both increase the electrophilicity of the methylene function, and stabilize the approaching anionic nucleophile. a-Haloacids and amides will exhibit a similar effect, and both iodoacetic acid and iodoacetamide have found use as biochemical probes for the alkylation of purified enzymes. 

Annulation of the imidazole ring to compound 11 evidently occurs through the oxidation of the latter to imine A which can also exist as tautomers B and C. The nucleophilic attack of the N(4) atom at the carbon atom of the imine moiety in structure B leads to the closure of the imidazole ring to form dihydroimidazo-quinoxaline system D, and further oxidation of the latter under the reaction conditions leads to tricyclic compound 12a. Air oxygen or a solvent (dimethyl sulfoxide) can act as an oxidant in this case (Scheme 4.5). 

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