Multicomponent Mannich reactions: General aspects, methodologies and applications

Filho, João Francisco Allochio; Lemos, Bárbara C.; Souza, Acácio S. de; Pinheiro, Sérgio; Greco, Sandro J.

doi:10.1016/j.tet.2017.10.063

Cited by 117 publications

(65 citation statements)

References 139 publications

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“…The Mannich reaction is one of the most important basic reaction types in organic chemistry for C−C and C−N bond formation . The classical Mannich product arises from the condensation reaction of a compound containing at least one active hydrogen atom with formaldehyde and a secondary amine . A special variation of this latter reaction when formaldehyde is replaced by benzaldehyde, the secondary amine by ammonia, and the C−H acid by an electron‐rich aromatic compound such as 2‐naphthol.…”

Section: Introductionmentioning

confidence: 99%

“…[1][2][3] The classical Mannich product arises from the condensation reaction of a compound containing at least one active hydrogen atom with formaldehyde and a secondary amine. [4] A special variation of this latter reaction when formaldehyde is replaced by benzaldehyde, the secondary amine by ammonia, and the CÀ H acid by an electron-rich aromatic compound such as 2-naphthol. The reaction was first developed by Mario Betti and the aminonaphthol synthesized in this way became as Betti base.…”

Section: Introductionmentioning

confidence: 99%

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Ortho‐Quinone Methide Driven Synthesis of New O,N‐ or N,N‐Heterocycles

et al. 2019

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To synthesize functionalized Mannich bases that can serve two different types of ortho ‐quinone methide ( o ‐QM) intermediates, 2‐naphthol and 6‐hydroxyquinoline were reacted with salicylic aldehyde in the presence of morpholine. The Mannich bases that can form o ‐QM and aza ‐ o ‐QM were also synthesized by mixing 2‐naphthol, 2‐nitrobenzaldehyde, and morpholine followed by reduction of the nitro group. The highly functionalized aminonaphthol derivatives were then tested in [4+2] cycloaddition with different cyclic imines. The reaction proved to be both regio‐ and diastereoselective. In all cases, only one reaction product was obtained. Detailed structural analyses of the new polyheterocycles as well as conformational studies including DFT modelling were performed. The relative stability of o ‐QMs/ aza‐o ‐QM were also calculated, and the regioselectivity of the reactions could be explained only when the cycloaddition started from aminodiol 4 . It was summarized that starting from diaminonaphthol 25 , the regioselectivity of the reaction is driven by the higher nucleophilicity of the amino group compared with the hydroxy group. 12H‐benzo[a]xanthen‐12‐one ( 11 ), formed via o ‐QM formation, was isolated as a side product. The proton NMR spectrum of 11 proved to be very unique from NMR point of view. The reason for the extreme low‐field position of proton H‐1 could be accounted for by theoretical calculation of structure and spatial magnetic properties of the compound in combination of ring current effects of the aromatic moieties and steric compression within the heavily hindered H(1)‐C(1)‐C(12b)‐C(12a)‐C(12)=O structural fragment.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ortho‐Quinone Methide Driven Synthesis of New O,N‐ or N,N‐Heterocycles

et al. 2019

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“…MCRs are a greatly potent device in pharmaceutical, agro and combinatorial chemistry . These reactions shows an extensive variety of potentials for a powerful structure of composite fragments in a one‐pot procedure, consequently evading the difficult purification processes and tolerating reserves of reagents and solvents . MCRs possess several benefits in terms of simple reaction approach, readily accessible raw constituents, shorter reaction time, higher yields, environmentally friendly, cost‐efficacy and high atom‐economy .…”

Section: Introductionmentioning

confidence: 99%

Microwave‐Assisted Multicomponent Reaction: A Green and Catalyst‐Free Method for the Synthesis of Poly‐Functionalized 1,4‐Dihydropyridines

Maddila

Kerru

Chinnam³

et al. 2019

ChemistrySelect

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A facile and an efficient procedure for the synthesis of poly‐substituted 1,4‐dihydropyridine derivatives under catalyst‐free conditions has been established by a one‐pot multi‐component reaction in EtOH solvent under microwave irradiation (150 W). The remarkable benefits of this approach are: simple operation, non‐toxic, short reaction time (< 5 min), excellent yields (93‐98%), no column chromatography, clean reaction profile and environmentally friendly reaction.

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“…Mannich bases can be easily transformed into numerous compounds due to their high reactivity. Several Mannich bases are of particular interest due to their importance as precursors of valuable pharmaceuticals products and their use as synthetic building blocks [1,2]. Mannich bases have attracted more and more attention from chemists due to their specific biological activities, such as antiviral [3,4], acetylcholinesterase inhibitory [5,6,7], antioxidant [8,9], and antiproliferative [10,11] activity.…”

Section: Introductionmentioning

confidence: 99%

Microwave-Assisted Synthesis of Mono- and Disubstituted 4-Hydroxyacetophenone Derivatives via Mannich Reaction: Synthesis, XRD and HS-Analysis

et al. 2019

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An efficient microwave-assisted one-step synthetic route toward Mannich bases is developed from 4-hydroxyacetophenone and different secondary amines in quantitative yields, via a regioselective substitution reaction. The reaction takes a short time and is non-catalyzed and reproducible on a gram scale. The environmentally benign methodology provides a novel alternative, to the conventional methodologies, for the synthesis of mono- and disubstituted Mannich bases of 4-hydroxyacetophenone. All compounds were well-characterized by FT-IR, 1H NMR, 13C NMR, and mass spectrometry. The structures of 1-{4-hydroxy-3-[(morpholin-4-yl)methyl]phenyl}ethan-1-one (2a) and 1-{4-hydroxy-3-[(pyrrolidin-1-yl)methyl]phenyl}ethan-1-one (3a) were determined by single crystal X-ray crystallography. Compound 2a and 3a crystallize in monoclinic, P21/n, and orthorhombic, Pbca, respectively. The most characteristic features of the molecular structure of 2a is that the morpholine fragment adopts a chair conformation with strong intramolecular hydrogen bonding. Compound 3a exhibits intermolecular hydrogen bonding, too. Furthermore, the computed Hirshfeld surface analysis confirms H-bonds and π–π stack interactions obtained by XRD packing analyses.

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Multicomponent Mannich reactions: General aspects, methodologies and applications

Cited by 117 publications

References 139 publications

Ortho‐Quinone Methide Driven Synthesis of New O,N‐ or N,N‐Heterocycles

Ortho‐Quinone Methide Driven Synthesis of New O,N‐ or N,N‐Heterocycles

Microwave‐Assisted Multicomponent Reaction: A Green and Catalyst‐Free Method for the Synthesis of Poly‐Functionalized 1,4‐Dihydropyridines

Microwave-Assisted Synthesis of Mono- and Disubstituted 4-Hydroxyacetophenone Derivatives via Mannich Reaction: Synthesis, XRD and HS-Analysis

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