Manganese-Catalyzed Multicomponent Synthesis of Tetrasubstituted Propargylamines: System Development and Theoretical Study

The importance of multicomponent reactions as an efficient tool in organic synthesis is widely recognized, as the need for sustainable, practical, atom- and step-economic methodologies is becoming a crucial concept in contemporary research. In this context, the synthesis of propargylamines via multicomponent protocols holds great promise, because of their biological action and their potential as synthons. Ketone-derived, tetrasubstituted propargylamines are a relatively unexplored subclass of compounds, while protocols to access them have only been described in the past decade, owing to the challenging nature of ketones as multicomponent coupling partners. Herein, we report a catalytic system based on the earth-abundant manganese for the ketone, amine, alkyne (KA2) reaction. The efficiency of manganese, combined with sustainable reaction conditions, comprise a useful new method for accessing various interesting propargylamines. Additionally, the use of computational methods reveals mechanistic aspects of this reaction, for the first time, raising important points regarding the reactivity of both manganese and ketones.This work was supported by the Hellenic Foundation for Research and Innovation (H.F.R.I.) under the “First Call for H.F.R.I. Research Projects to support Faculty members and Researchers and the procurement of high-cost research equipment grant” (Project Number: 16-Acronym: SUSTAIN), as well as by European Funding: Horizon 2020-MSCA (ITN-EJD CATMEC 14/06-721223). The contribution of COST Action CA15106 (C−H Activation in Organic Synthesis - CHAOS) is also gratefully acknowledged

Zn-Catalyzed Multicomponent KA2 Coupling: One-Pot Assembly of Propargylamines Bearing Tetrasubstituted Carbon Centers

Tetrasubstituted propargylamines comprise a unique class of highly useful compounds, which can be accessed through the multicomponent coupling between ketones, amines, and alkynes (KA2 coupling), an underexplored transformation. Herein, the development of a novel, highly efficient, and user-friendly catalytic system for the KA2 coupling, based on the environmentally benign, inexpensive, and readily available zinc acetate, is described. This system is employed in the multicomponent assembly of unprecedented, tetrasubstituted propargylamines derived from structurally diverse, challenging, and even biorelevant substrates. Notable features of this protocol include the demonstration of the enhancing effect that neat conditions can have on catalytic activity, as well as the expedient functionalization of hindered, prochiral cyclohexanones, linear ketones, and interesting molecular scaffolds such as norcamphor and nornicotine. © 2019 American Chemical Society

Manganese-Catalyzed Multicomponent Synthesis of Tetrasubstituted Propargylamines: System Development and Theoretical Study

Herein, we report a catalytic system based on the earth-abundant manganese for the ketone, amine, alkyne (KA2) reaction. The efficiency of manganese manifests at relatively high temperatures, combined with sustainable reaction conditions, and provides a tool for accessing propargylamines from structurally diverse starting materials, including synthetically relevant and bioactive molecules. Our efforts were also aimed at shedding light on the catalytic mode of action of manganese in this transformation, in order to explain its temperature-related behavior. The use of computational methods reveals mechanistic aspects of this reaction indicating important points regarding the reactivity of both manganese and ketones. (Figure presented.). © 2020 Wiley-VCH Gmb

Manganese‐Catalyzed Multicomponent Synthesis of Tetrasubstituted Propargylamines: System Development and Theoretical Study

The importance of multicomponent reactions as an efficient tool in organic synthesis is widely recognized, as the need for sustainable, practical, atom- and step-economic methodologies is becoming a crucial concept in contemporary research. In this context, the synthesis of propargylamines via multicomponent protocols holds great promise, because of their biological action and their potential as synthons. Ketone-derived, tetrasubstituted propargylamines are a relatively unexplored subclass of compounds, while protocols to access them have only been described in the past decade, owing to the challenging nature of ketones as multicomponent coupling partners. Herein, we report a catalytic system based on the earth-abundant manganese for the ketone, amine, alkyne (KA2) reaction. The efficiency of manganese, combined with sustainable reaction conditions, comprise a useful new method for accessing various interesting propargylamines. Additionally, the use of computational methods reveals mechanistic aspects of this reaction, for the first time, raising important points regarding the reactivity of both manganese and ketones.This work was supported by the Hellenic Foundation for Research and Innovation (H.F.R.I.) under the “First Call for H.F.R.I. Research Projects to support Faculty members and Researchers and the procurement of high-cost research equipment grant” (Project Number: 16-Acronym: SUSTAIN), as well as by European Funding: Horizon 2020-MSCA (ITN-EJD CATMEC 14/06-721223). The contribution of COST Action CA15106 (C−H Activation in Organic Synthesis - CHAOS) is also gratefully acknowledged

Are Terminal Alkynes Necessary for MAO-A/MAO-B Inhibition? A New Scaffold Is Revealed

A versatile family of quaternary propargylamines was synthesized employing the KA2 multicomponent reaction, through the single-step coupling of a number of amines, ketones, and terminal alkynes. Sustainable synthetic procedures using transition metal catalysts were employed in all cases. The inhibitory activity of these molecules was evaluated against human monoaminoxidase (hMAO)-A and hMAO-B enzymes and was found to be significant. The IC50 values for hMAO-B range from 152.1 to 164.7 nM while the IC50 values for hMAO-A range from 765.6 to 861.6 nM. Furthermore, these compounds comply with Lipinski’s rule of five and exhibit no predicted toxicity. To understand their binding properties with the two target enzymes, key interactions were studied using molecular docking, all-atom molecular dynamics (MD) simulations, and MM/GBSA binding free energy calculations. Overall, herein, the reported family of propargylamines exhibits promise as potential treatments for neurodegenerative disorders, such as Parkinson’s disease. Interestingly, this is the first time a propargylamine scaffold bearing an internal alkyne has been reported to show activity against monoaminoxidases