title: Protonation switching to the least-basic heteroatom of carbamate through cationic hydrogen bonding promotes the formation of isocyanate cations.
abstract: We found that phenethylcarbamates that bear ortho-salicylate as an ether group (carbamoyl salicylates) dramatically accelerate OC bond dissociation in strong acid to facilitate generation of isocyanate cation (N-protonated isocyanates), which undergo subsequent intramolecular aromatic electrophilic cyclization to give dihydroisoquinolones. To generate isocyanate cations from carbamates in acidic media as electrophiles for aromatic substitution, protonation at the ether oxygen, the least basic heteroatom, is essential to promote CO bond cleavage. However, the carbonyl oxygen of carbamates, the most basic site, is protonated exclusively in strong acids. We found that the protonation site can be shifted to an alternative basic atom by linking methyl salicylate to the ether oxygen of carbamate. The methyl ester oxygen ortho to the phenolic (ether) oxygen of salicylate is as basic as the carbamate carbonyl oxygen, and we found that monoprotonation at the methyl ester oxygen in strong acid resulted in the formation of an intramolecular cationic hydrogen bond (>CO(+) H⋅⋅⋅O<) with the phenolic ether oxygen. This facilitates OC bond dissociation of phenethylcarbamates, thereby promoting isocyanate cation formation. In contrast, superacid-mediated diprotonation at the methyl ester oxygen of the salicylate and the carbonyl oxygen of the carbamate afforded a rather stable dication, which did not readily undergo CO bond dissociation. This is an unprecedented and unknown case in which the monocation has greater reactivity than the dication.
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan), Fax: (+81) 3-5841-4735.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kurouchi
authors.forename: Akinari
authors.initials: A
authors.lastname: Sumita
authors.forename: Yuko
authors.initials: Y
authors.lastname: Otani
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Ohwada
mesh_terms: D002219:Carbamates; D002412:Cations / Q000737:chemistry*; D003500:Cyclization; D017953:Isocyanates / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure
chemical_list: D002219:Carbamates; D002412:Cations; D017953:Isocyanates
keywords: aromatic substitution; bond dissociation; carbamates; cations; hydrogen bonds