Proline-Catalyzed Ketone-Aldehyde Aldol Reactions are Accelerated by Water

Abstract

Proline-catalyzed aldol reactions between acetone or 4-thianone and different aldehydes are accelerated by addition of 1-10 equivalents of water to the reaction medium, allowing stoichiometric aldol reactions to proceed at acceptable rates.

Development of fructose-1,6-bisphosphate aldolase enzyme peptide mimics as biocatalysts in direct asymmetric aldol reactions

“…Although the use of DMSO for proline-catalysed reactions oen yields better results, 46,47 previous studies also demonstrated no reaction or longer reaction time when anhydrous DMSO was applied. 37 When the same reaction was performed in hydrous/ wet DMSO, good yields and high selectivities (with both yield and ee) were obtained as reported in literature.…”

Concentration‐Flux‐Steered Mechanism Exploration with an Organocatalysis Application

“…Therefore, we deliberately chose the concentrations for the compounds to be similar in order to facilitate the exploration of the catalytic cycle, for which we did not expect nitropropene or propanal to be required in significant excess; that is, we expected that at most one or two propanal/nitropropene molecules take part explicitly in the catalytic cycle. Furthermore, we did not consider the role of typical additives [73][74][75] , such as water, during the exploration with exception of step III, because the reaction will proceed even if no water is added (though at reduced yield).…”

A Simple and Efficient Protocol for Proline-Catalysed Asymmetric Aldol Reaction

“…However, proline scarce solubility in most organic solvents has limited its use in dimethylsulfoxide (DMSO), acetonitrile, or dimethylformamide (DMF). Moreover, proline often displays poor activity, requiring the use of high catalyst loadings and high reaction times, sometimes with unsatisfactory stereocontrol [1, [28][29][30][31][32][33][34][35][36]. Because, in several cases, proline-catalysed aldol reactions are still underdeveloped, the last 15 years have witnessed an intense effort aimed at modifying the proline scaffold, following two directions: (1) the carboxylic group is replaced by a new hydrogen-bonding donor, such as a tetrazole, or by a sterically demanding group, such as the Hayashi-Jørgensen diarylmethanol and related compounds, as exhaustively reviewed by Trost [37]; and (2) the carboxylic group is retained and a supplementary substituent is bound to the proline scaffold.…”

“…The role of the solvent in determining the aldol reaction efficiency was also addressed by other authors. Invariably, the use of unmodified proline (without additives) forced to choose polar aprotic solvents to obtain acceptable yields and selectivities [1,11,[13][14][15][28][29][30][31][32][33][34][35][36]44,45]. A peculiar case was represented by ionic liquids (ILs) [67][68][69][70][71][72], which allowed in a few cases to decrease the catalyst loading (up to 1 mol%) and, during the work-up, to confine proline in a separate phase, enabling a simple product isolation and the reuse of the catalytic system.…”

“…A number of research groups noticed that protic media were not suitable for aldol condensations promoted exclusively by native proline [15,[29][30][31][32][33]87]. However, despite a plethora of studies focused on the use and the role of water (as solvent, co-solvent, or additive) [31,32,34,87,[100][101][102][103][104][105]110,111], very few authors extended their investigations to alcohols [15,29,31,42,102,106], discouraged by the generally observed poor diastereo-and enantioselectivity. Only when proline was used in combination with metal salts as additives, the use of methanol as solvent [106] or co-solvent [102] afforded acceptable results.…”