(Z)-Stereoselective Synthesis of Mono- and Bis-heterocyclic Benzimidazol-2-ones via Cascade Processes Coupled with the Ugi Multicomponent Reaction

Abstract

Several novel cascade reactions are herein reported that enable access to a variety of unique mono- and bis-heterocyclic scaffolds. The sequence of cascade events are mediated through acid treatment of an Ugi adduct that affords 1,5-benzodiazepines which subsequently undergo an elegant rearrangement to deliver (E)-benzimidazolones, which through acid-promoted tautomerization convert to their corresponding (Z)-isomers. Moreover, a variety of heterocycles tethered to (Z)-benzimidazole-2-ones are also accessible through similar domino-like processes, demonstrating a general strategy to access significantly new scaffold diversity, each containing four points of potential diversification. Final structures of five scaffolds have been definitively proven by X-ray crystallography.

A Decarboxylative C(sp3)−N Bond Forming Reaction to Construct 4‐Imidazolidinones via Post‐Ugi Cascade Sequence in One Pot

“…[15] In addition, it has been reported for the synthesis of nitrogen-containing heterocycles via the U-4CR with α-keto acids in many literatures. [16] Faggi et al disclosed the treatment of the Ugi-4CR adducts assembled from aliphatic ketones, anilines, α-keto acids, and isocyanides with methanolic potassium hydroxide to afford 2,5-dioxo-1,3-diphenyl-3-hydroxy-1,4-diazaspiro [5.5]undecane. [17] In order to expand the scope of this novel cascade reaction, aldehyde was replaced with aliphatic ketone in the Ugi reaction as shown in Table 3.…”

“…Elevating temperature to 200°C for 20 min, compound 9 a was isolated with 89% yield. Inorganic bases didn't give the desired product 4imidazolidinone 9 a (entries [14][15][16][17]. The 1D and 2D NMR analysis of the decarboxylative product 9 a confirmed the chemical structure of 4-imidazolidinone (see supplementary data).…”

“…Different temperatures and reaction times were next evaluated with diisopropylamine (DIPA, entries 9-13), and the yield was further improved to 88% (entry 12). Et 3 N were less effective under the similar conditions to synthesize compound (�) 6 a (entries [15][16][17] and inorganic bases gave no desired compound (�) 6 a (entries 18-21). The reaction didn't yield compound (�) 6 a in a higher yield in different solvents (DMSO, MeCN, EtOH, and dioxane) with DIPA than in DMF (entries 22-25).…”

One‐Pot Construction of Bis‐Heterocycles through Isocyanide Based Multicomponent Reactions

“…In 2015, one-pot synthesis of various BHCs containing (Z)benzimidazole-2-one (79, 83) was reported by Hulme et al [76] The scaffolds with 3 or 4-points of diversity were generated via U-4CR in combination with a theoretical 6-step cascade.…”

Microwave‐Assisted Construction of Pyrrolopyridinone Ring Systems by Using an Ugi/Indole Cyclization Reaction

“…During the past few years, we have focused our attention on the use of Ugi four‐component reactions (U‐4CRs) for the synthesis of nitrogen‐containing heterocycles . Pyrrole derivatives are an important class of heterocyclic compounds and exhibit a wide range of biological properties, including antimicrobial, antituberculous, enzyme inhibitory and anticancer activities.…”