Organocatalyst Efficiency in the Michael Additions of Aldehydes to Nitroalkenes in Water and in a Ball‐Mill

Abstract

The enantioselective organocatalytic Michael addition in aqueous solution was compared with the reaction performed under solvent‐free ball‐milling conditions. A range of pyrrolidine‐derived organocatalysts were tested in the addition of aldehydes to nitroalkenes. Both procedures afforded good yields, diastereoselectivities, and enantioselectivities. The best catalyst in aqueous media was O‐lauroyl‐trans‐4‐hydroxyproline, whilst the ball‐milling technique was most‐efficient with α,α‐diphenyl‐2‐pyrrolidinemethanol trimethylsilyl ether.

CHAPTER 4. Asymmetric Organocatalytic Reactions under Ball Milling

“…36 (7) in a ball-mill. 34 As already mentioned, the use of chiral thioureas as organocatalysts in asymmetric Michael additions has been highly successful. In an additional example, the reaction of a-nitrocyclohexanone with various nitrostyrenes, in the presence of 2.5 mol% of catalyst 9, resulted in efficient Michael adduct formation, in high yields (80-95%), with high diastereoselectivity (94 : 6 to 98 : 2 diastereomeric ratios), and excellent enantiomeric ratios (96 : 4 to 99 : 1) (Scheme 4.7).…”

“…34 In particular, a,a-diphenylprolinol trimethylsilyl ether (7) gave the desired Michael products in yields in the range 44-97%, and with diastereoselectivities that reached 95 : 5 diastereomeric ratios, and good enantioselectivities (62-94% ee) (Scheme 4.5). A salient observation is that by employing HSBM the yields of the reaction can be quantitative after just 1 h reaction time, which corresponds to a reduction of more than twenty times in the reaction time required under the best conditions in solution employing organocatalyst O-lauroyl-trans-4-hydroxyproline (Scheme 4.5).…”

“…A salient observation is that by employing HSBM the yields of the reaction can be quantitative after just 1 h reaction time, which corresponds to a reduction of more than twenty times in the reaction time required under the best conditions in solution employing organocatalyst O-lauroyl-trans-4-hydroxyproline (Scheme 4.5). 34 Recently, Xu and co-workers reported the use of chiral squaramide derivatives as hydrogen bonding donor catalysts for the Michael addition reaction of 1,3-dicarbonyl compounds with nitroolefins under solvent-free conditions using a planetary ball-mill. The importance of carrying out the reaction in the absence of solvents was evident as only 0.5 mol% of the organocatalyst was required to successfully perform the asymmetric reaction between 2,4-pentanedione and various aromatic b-nitrostyrenes.…”

Mechanochemistry assisted asymmetric organocatalysis: A sustainable approach

“…Recently, Sebesta and co-workers compared the enantioselective organocatalytic Michael addition of aldehydes to nitroalkenes in aqueous solution with the reaction performed under solvent-free ball-milling conditions catalysed by pyrrolidine-derived organocatalysts (Scheme 6) [45]. Both the procedures provided the product in good yield, poor to high diastereoselectivity, and moderate to high enantioselectivity.…”

Rigorous Conformational Analysis of Pyrrolidine Enamines with Relevance to Organocatalysis

“…There is a remarkable difference between the reactions of aldehydes and of ketones: no matter whether the Michael addition occurs in a catalytic or in a stoichiometric fashion, with a polymer‐bound pyrrolidine‐type catalyst, in a ball mill, microwave‐assisted, in the presence of an ionic liquid, in protic, aprotic, polar or non‐polar solvents, with acidic, basic or hydrocarbon side chains on the pyrrolidine moiety (see Scheme ), as an inter‐ or intramolecular step of so‐called domino sequences of reactions, or with acceptors other than nitroolefins (see lower part of Scheme ), a reversal of enantioselectivity between aldehydes and ketones has been observed. In the overall process the trigonal centers of the aldehyde or ketone α ‐carbonyl carbon and of the β ‐nitroolefin carbon couple with relative topicity lk in both cases, but the 1.4‐induction by the stereogenic center in the 2‐position of the pyrrolidine ring reverses: it is a [ lk , lk ‐1.4]‐process with aldehydes and a [ lk , ul ‐1.4]‐process with ketones (see Scheme ) ,…”