A Selenourea-Thiourea Brønsted Acid Catalyst Facilitates Asymmetric Conjugate Additions of Amines to α,β-Unsaturated Esters

Abstract

β-Amino esters are obtained with high levels of enantioselectivity via the conjugate addition of cyclic amines to unactivated α,β-unsaturated esters. A related strategy enables the kinetic resolution of racemic cyclic 2-arylamines, using benzyl acrylate as the resolving agent. Reactions are facilitated by an unprecedented selenourea-thiourea organocatalyst. As elucidated by DFT calculations and 13 C kinetic isotope effect studies, the ratelimiting and enantiodetermining step of the reaction is the protonation of a zwitterionic intermediate by the catalyst. This represents a rare case in which a thiourea compound functions as an asymmetric Brønsted acid catalyst.

Organocatalyzed C−N bond‐forming Reactions for the Synthesis of Amines and Amides

“…The catalyst used acts as an H-bond catalyst (Scheme 9). [15] Scheme 1. (A) CÀ N bond formation reaction in a biological system for the biosynthesis of retronecine.…”

Novel Access to Known and Unknown Thiourea Catalyst via a Multicomponent‐Reaction Approach

“…[14,17,31,32] Recently, a few cases reported that thioureas can also act as Brønsted acids in a catalytic fashion. [33,34] In general, electron-poor aryl moieties adjacent to the thiourea nitrogen enhance the hydrogen donor ability and thus the catalytic activity. [2,35] Most often, 3,5-bis(trifluorometh-yl) phenyl [35] or other fluoro substituted aryl moieties [1,2,19,34,36] are used at one or both sites of the thiourea group for this task.…”

“…[33,34] In general, electron-poor aryl moieties adjacent to the thiourea nitrogen enhance the hydrogen donor ability and thus the catalytic activity. [2,35] Most often, 3,5-bis(trifluorometh-yl) phenyl [35] or other fluoro substituted aryl moieties [1,2,19,34,36] are used at one or both sites of the thiourea group for this task. Nevertheless, several moieties have been reported that also lead to a significant increase of the catalytic activity of thioureas using electron-withdrawing groups, such as aromatic acetyl or sulfone [37,38] as well as sulfoxide moieties, [10] directly attached to the thiourea group.…”

“…This work has two main aims: (i) to replace the commonly used 3,5-bis(trifluoromethyl) phenyl motifs by surrogates that perform similarly or exhibit improved catalytic activity and furthermore (ii) to introduce a new and simplified synthesis strategy for thiourea catalysts. Thus, in contrast to the typically applied thiourea catalysts synthesis routes involving thiophosgene, [40][41][42] its surrogates [34,[43][44][45][46][47] or other toxic compounds, [48,49] a multicomponent reaction (MCR) approach is investigated herein in order to decrease the overall toxicological impact and at the same time provide a straightforward and structurally versatile access to the desired catalysts. Our approach is based on a report by Al-Mourabit et al, [50] who extended the synthesis protocol of Lipp et al [51] and reported the synthesis of thioureas from aliphatic amines, isocyanides and elemental sulfur in excellent yields at ambient to moderate temperature.…”

“…Their catalytic interactions arise via several mechanisms, for instance by direct activation of the electrophile by hydrogen bonding, indirect activation by anion‐binding of the substrate, or by increasing the catalysts Brønsted acidity by anion stabilization (the thiourea compound acts as co‐catalyst) . Recently, a few cases reported that thioureas can also act as Brønsted acids in a catalytic fashion …”