Brønsted Acid‐Catalyzed Four‐Component Cascade Reaction: Facile Synthesis of Hexahydroimidazo[1,2‐a]pyridines

Abstract

An efficient four-component cascade reaction for the synthesis of trisubstituted hexahydroimidazoA C H T U N G T R E N N U N G [1,2-a]pyridines starting from readily available aldehydes, ketones and ethane-1,2diamine catalyzed by p-toluenesulfonic acid is described. Two new cycles and five new bonds are constructed with all reactants being efficiently utilized in this transformation. The mechanism of the reaction was investigated and some crucial reaction intermediates were observed.

An Effect of H-bonding in Synthesis of 1, 5-Diketones via Tandem Aldol-Michael Addition Reaction Using Room Temperature Ionic Liquid (RTIL).

“…Plethora of information is available for synthesis of 1,5‐diketones . In general, 1,5‐diketones are synthesized by condensation of one mole aldehydes and two moles of ketones which have α‐hydrogen atom.…”

l-Phenylalanine Triflate as Organocatalyst for Divergent ­Approaches to Trisubstituted Hexahydroimidazo[1,2-a]pyridine and 1,4-Diazepane Derivatives

“…On the basis of reports in the literature 10,14 and experimental results, we propose a plausible mechanism for the LPAT-catalyzed multicomponent reaction shown in Scheme 2. In the first reaction mechanism, condensation of acetophenone and 1,2-ethanediamine initially gives an imine intermediate; this is followed by the formation of the enamine intermediate A 1 catalyzed by LPAT.…”

“…13 Various substituted benzaldehydes bearing methyl, fluoro, chloro, bromo, or nitro groups gave high yields (Table 2, entries 1-7), and the electronic properties of the benzaldehyde had little effect on the yield of the product (entry 8). This method was further extended to heteroaromatic aldehydes such as nicotinaldehyde, thiophene-2-carbaldehyde, and 2-butyl-4-chloro-1H-imidazole-5-carbaldehyde, and the desired products were isolated in 76, 88, and 72% yield, respectively (entries [10][11][12]. Furthermore the aliphatic aldehyde cyclohexanecarbaldehyde also reacted smoothly to yield product 4r, albeit with a lower yield (entry 18).…”

“…9 Recently, a four-component cascade reaction of an aromatic ketone, an aldehyde, and 1,2-ethanediamine was reported to give trisubstituted hexahydroimidazo[1,2-a]pyridines when 20 mol% of 4-toluenesulfonic acid was used as a catalyst. 10 Further exploration of the scope of this reaction, avoidance of the use of a toxic reagent, and the development of general and efficient methods using environmentally friendly materials are still highly desirable goals.…”

Three‐Component Synthesis of 7‐Hydroxy‐7‐polyfluoroalkylhexahydroimidazo[1,2‐a]­pyridin‐5(1H)‐ones

“…The most widely used approach is based on the reaction of heterocyclic ketene‐aminals with bis‐electrophiles 13. Other procedures involving the condensation of ethylenediamine with glutaraldehyde,14a MOM‐protected cyanohydrins,14b α‐nitro‐δ‐oxo esters,14c or with a combination of an aldehyde and a ketone14d have been reported. The intramolecular cyclization of α‐amino‐acid‐containing dipeptides,15 and reactions of chiral (2 S )‐2‐amino‐2‐substituted‐ N ‐(4‐methylphenyl)acetamides with glutaraldehyde and benzotriazole16 have been used for the synthesis of chiral hexahydroimidazo[1,2‐ a ]pyridines.…”