L‐Prolinethioamides – Efficient Organocatalysts for the Direct Asymmetric Aldol Reaction

Abstract

Received Aldol reaction / Asymmetric organocatalysis / Water / Solvent-free reactions / Prolinethioamides ABSTRACT Organocatalysts 1, derived from L-Pro and (1S,2R)-cis-1-aminoindan-2-ol or (R)-1-aminoindane, are evaluated as promoters in the direct asymmetric aldol reaction between ketones and aromatic aldehydes in the presence of water and under solvent-free reaction conditions. L-Prolinethioamides 1c and 1d exhibited higher enantioselectivity than the corresponding prolinamides 1a and 1b in the model aldol reaction between cyclohexanone with 4-nitrobenzaldehyde in the presence of 4-nitrobenzoic acid as cocatalyst. In particular, L-prolinethioamide 1d (5 mol%), derived from L-Pro and (R)-1-aminoindane, is shown as the most efficient organocatalyst studied promoting the direct aldol reaction of cycloalkyl, alkyl, and α-functionalized ketones with aromatic aldehydes in the presence of water and under solvent-free reaction conditions employing only 2 equiv. of nucleophile. Generally, anti-aldol products are obtained in high yields and excellent diastereo-and enantioselectivities (up to >98/2 anti/syn, up to 98% ee). Solvent-free conditions give slightly higher dr and ee than using water as solvent. In addition, organocatalyst 1d can be easily recovered by extractive work-up and reused. Prolinethioamide 1d (5 mol%) in combination with 4-NO 2 C 6 H 4 CO 2 H (5 mol%) is also a very effective organocatalytic system for the asymmetric solvent-free intramolecular Hajos-Parrish-Eder-Sauer-Wiechert reaction with comparable or higher levels of enantioselectivity (up to 88% ee) to other reported catalysts in organic solvents.

Prolinethioamides versus Prolinamides in Organocatalyzed Aldol Reactions—A Comparative Study

“…We assumed that the respective thioamides, due to their higher acidity, would catalyze aldol reactions in a highly stereoselective manner. Unfortunately, the synthesis of optically pure aniline derived L-prolinethioamide with the calculated pK a = 16.7 failed, and as such we turned our attention to N-alkyl-prolinethioamides [19,20]. According to Shi's calculations aliphatic prolinethioamides are less acidic than aromatic derivatives due to lack of resonance stabilization of the conjugated anion [23].…”

“…It was assumed that the metal-free Zimmerman-Traxler-like transition state was destabilized by steric interactions thus leading to a less stereoselective reaction. [19,20]. Simple N-aryl-and N-alkyl-prolinamides as well as their thio-counterparts were ineffective in catalyzing the asymmetric aldol reaction; the products were obtained with low enantioselectivities although with good yields, but their efficacy could be slightly improved by the addition of an acid co-catalyst [28].…”

“…The use of N-Boc-protection was preferred since hydrogenolysis of the corresponding Cbz-thioamide was found to be problematic. The synthesis of these type of catalysts is short and high yielding, however, it is not suitable for the preparation of thioamides derived from aromatic amines, because of racemization occuring during the reaction of amide 3 with the sulphur reagent [19,20].…”

“…Although model studies were carried out on 4-cyanobenzaldehyde (16) instead of 4-nitro- (7) it was clear that the replacement of the amide moiety with the thioamide group had a beneficial effect on the catalytic activity of 18 ( Figure 2) [19,20,23]. …”

“…Comparison of acetamide and thioacetamide acidities suggested that thio-derivaties might be good candidates for organocatalysis in the aldol reaction. As a result, we had prepared a series of prolinethioamides and investigated their use in a direct aldol reaction [19].…”