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.

Acid‐Promoted Chemoselective Introduction of Amide Functionality onto Aromatic Compounds Mediated by an Isocyanate Cation Generated from Carbamate

“…To shed light on the origin of the difference in reactivity, we carried out DFT calculations to evaluate the activation energies of the individual steps in the reactions of the N ‐monomethyl and N , N ‐dimethyl carbamates. In our previous work, OC bond dissociation of the carbamate group was found to be accelerated in TfOH through the formation of intramolecular hydrogen bonding between the ether oxygen and ortho ‐salicylate carbonyl oxygen atoms ( SM‐2 , see Figure 4A) 16. 22…”

“…We previously carried out a screening study of leaving groups and found that carbamates with ortho ‐salicylate as an ether group (carbamoyl salicylates) show dramatic acceleration of OC bond dissociation in strong acid, which leads to facile generation of the isocyanate cation ( N ‐protonated isocyanate; 1 c , Figure 1). 16 Herein, we describe the direct amidation of aromatic compounds with isocyanate cations generated from carbamoyl salicylates in trifluoromethanesulfonic acid (TfOH) at room temperature. We further characterized the chemoselectivity of these amidation reactions, including the compatibility with other electrophilic functionalities and the difference in reactivity for secondary and tertiary amide formation.…”

Recent Advances in Synthesis of 3,4‐Dihydroisoquinolin‐1(2H)‐one

“…[ 25] Ryo Murashige and co-workers established intramolecular Friedel-Crafts cyclization of 1-(2-iso-cyanatoethyl)benzene derivatives (15) in the presence of trifluoromethane sulfonic acid. Trifluoromethane sulfonic acid serves as an efficient catalyst for the cyclization of 1-(2-iso-cyanatoethyl)benzene 15 rather the other tested Lewis/ Bronsted acid catalyst (Scheme 3).…”

Theoretical insight to intermolecular hydrogen bond interactions between methyl N-(2-pyridyl) carbamate and acetic acid: substituent effects, cooperativity and energy decomposition analysis

“…The carbamate moiety plays a significant role in medicinal chemistry, not only because it is found in drugs but also for its attendance to many prodrugs [9]. In recent years, carbamate derivatives have motivated a large number of theoretical and experimental studies due to their application in drug design and discovery [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24].…”