One-Pot Multicomponent Synthesis of Highly Functionalized Piperidines from Substituted β-Nitrostyrenes, Meldrum’s Acid, Aromatic Aldehydes, and Ammonium Acetate

Abstract

An efficient and straightforward synthetic protocol has been developed for the diversity-oriented synthesis of highly functionalized piperidines containing a Meldrum's acid moiety via pseudo five-component reaction between aromatic aldehydes, ammonium acetate, substituted β-nitrostyrenes and Meldrum's acid for the generation of a wide range of structurally interesting and pharmacologically significant compounds.

Recent Developments on Five-Component Reactions

“…Finally, the reaction of 39 with anilines followed by cyclization and tautomerization afford products 36. Wang and co-workers developed a reaction for the synthesis of highly functionalized piperidines 40 using two equiv of aromatic aldehydes, and one equiv each of Meldrum's acid, substituted β-nitrostyrenes and ammonium acetate under basic conditions (Scheme 15) [25]. First, the Michael addition of Meldrum's acid to substituted nitrostyrenes followed by nitro-Mannich nucleophilic addition on intermediate arylimine gives amines 41.…”

[Cp*Ru]-catalyzed selective coupling/hydrogenation

“…Chromatography on silica gel using PE/Et 2 O (70:30) as eluent afforded compound 3b as colourless oil as a mixture of isomers in a 3:2 ratio due to the Boc protecting group, (76 mg, 87%) 1 H NMR (400 MHz, CD 2 Cl 2 ) δ 7.32-7.22 (m, 5H), 7.09-6.97 (2bs, 1H), 5.06 -4-(4-nitrophenyl)-1-tosyl-1,2,3 3 ]PF 6 } (1 mol%) were dissolved in methanol or ethanol (1 mL) followed by the addition of cinnamyl alcohol 1a (1.0 eq). Extraction with H 2 O and CH 2 Cl 2 x 3 followed by drying over sodium sulfate and concentration afforded a crude oil which was further purified by chromatography on silica gel using PE/Et 2 O (80:20) as eluent to afford compound 6a as yellow oil (24 mg, 76%) in a 75:19:6 stereoisomeric ratio (only the major compound is described), 1 H NMR (400 MHz, C 6 In a 20 mL reactor, containing 3-methylene-4-phenyl-1-tosyl-1,2,3,4-tetrahydropyridine 3a (30 mg, 0.09 mmol), THF (2 mL) was added followed by the addition of {Ru(Cp*)(CH 3 CN) 3 ]PF 6 } and the additive (5 mol%). After concentration in vacuo, the crude mixture was purified by short column chromatography to afford the acetal 5 as product.…”

“…[3][4][5][6] Multicomponent cascade transformations constitute new straightforward protocols for the syntheses of polysubstituted piperidines. 1,2 Traditional approaches to access polyfunctionalized piperidines usually involve alkylation, arylation of piperidone derivatives, hydrogenation of substituted pyridine or cycloadditions.…”

“…1,2 Traditional approaches for accessing polyfunctionalized piperidines usually involve alkylation, arylation of piperidone derivatives, hydrogenation of substituted pyridines or cycloadditions. [3][4][5][6] Multicomponent cascade transformations constitute new straightforward protocols for the syntheses of polysubstituted piperidines. 6 Recently, direct functionalization of piperidines has emerged as an excellent alternative to the aforementioned methodologies.…”

“…[3][4][5][6] Multicomponent cascade transformations constitute new straightforward protocols for the syntheses of polysubstituted piperidines. 6 Recently, direct functionalization of piperidines has emerged as an excellent alternative to the aforementioned methodologies. Among the latter, neutral redox processes involving the formation of transient azomethine ylides from aldehydes and amines have been efficiently used for the preparation of 2-and 2,3-IJdi)substituted piperidines.…”