Hydrogen-Bond-Driven Electrophilic Activation for Selectivity Control: Scope and Limitations of Fluorous Alcohol-Promoted Selective Formation of 1,2-Disubstituted Benzimidazoles and Mechanistic Insight for Rationale of Selectivity

Abstract

Hydrogen-bond-driven electrophilic activation for selectivity control during competitive formation of 1,2-disubstituted and 2-substituted benzimidazoles from o-phenylenediamine and aldehydes is reported. The fluorous alcohols trifluoroethanol and hexafluoro-2-propanol efficiently promote the cyclocondensation of o-phenylenediamine with aldehydes to afford selectively the 1,2-disubstituted benzimidazoles at rt in short times. A mechanistic insight is invoked by NMR, mass spectrometry, and chemical studies to rationalize the selectivity. The ability of the fluorous alcohols in promoting the reaction and controlling the selectivity can be envisaged from their better hydrogen bond donor (HBD) abilities compared to that of the other organic solvents as well as of water. Due to the better HBD values, the fluorous alcohols efficiently promote the initial bisimine formation by electrophilic activation of the aldehyde carbonyl. Subsequently the hydrogen-bond-mediated activation of the in situ-formed bisimine triggers the rearrangement via 1,3-hydride shift to form the 1,2-disubstituted benzimidazoles.

Steric and Electronic Effect on C2‐H Arylation of Sulfonamides

“…The nature of the chemical reactions can be controlled by the influence of weak interactions or soft force . Therefore, many reactions are designed by exploring cooperative multiple non‐covalent interactions like hydrogen bonding, halogen bonding, hydrophobic effect, cation‐π, anion‐π, etc . Our research goal is encircled in understanding the reactivity of non‐prefunctionalized substrates by weak or noncovalent interactions .…”

Chemoselective synthesis of 1,2-disubstituted benzimidazoles in lactic acid without additive

“…The satisfactory results from these scale-up experiments further confirmed the advantage of this simple and "green" protocol for its potential in large-scale synthesis. a) General conditions: o-phenylenediamine (1 mmol) and Ia (2 mmol) in lactic acid (2 mL), stirred at ambient temperature for 4-6 h; b) yield of isolated product; c) values reported in literature Chebolu et al, 2012;Ahmadian et al, 2015); d) reaction at 80 • C and purified by silica gel column chromatography. From the experimental observations and literature reports on experiments carried out under similar reaction conditions , a plausible reaction mechanism for the selective formation of 1,2-substituted benzimidazoles in lactic acid was proposed (Fig.…”

“…Several methods have been reported for the selective synthesis of 1,2-disubstituted benzimidazoles using FeF 3 , Me 3 SiCl (Wan et al, 2009), ZnO-NPs (Sharma et al, 2015), HClO 4 -SiO 2 as catalyst or microwave irradiation in acetic acid (Azarifar, 2010), ultrasonic irradiation (Kumar et al, 2014). In addition, Chebolu et al (2012) reported a metal/Lewis acid-free protocol in which fluorous alcohols with better hydrogen bond donor (HBD) abilities could efficiently promote the selective formation of 1,2-disubstituted benzimidazoles.…”

A Zirconium Indazole Carboxylate Coordination Polymer as an Efficient Catalyst for Dehydrogenation‐Cyclization and Oxidative Coupling Reactions

“…[28,32] Moreover, trace amount (6 %) of imine B (2-(benzylideneamino)aniline) was found during this process in this experiment, which was somewhat different from the process with Cu or Ru as the catalysts. [29,33] Scheme 2. The oxidative coupling of benzyl cyanides with tert-butyl hydroperoxide.…”