Simple, inexpensive, and facile l-prolinamide used as a recyclable organocatalyst for highly efficient large-scale asymmetric direct aldol reactions

In order to discover a simple, inexpensive, and efficient route to obtain highly enantiomerically enriched anti-aldol products for applications in industry, a series of prolinamides 1–5 with different carbocyclic rings have been synthesized from achiral cycloalkylamine, and prolinamides 6–9 have been synthesized from aniline with different substituents. The organocatalysts obtained catalyzed the asymmetric aldol reaction and showed that no matter carbocyclic rings or aromatic rings were found to play a significant role in the formation of the aldol products. Moreover, the prolinamide 6 exhibited efficient catalytic activity in the asymmetric aldol reaction only with 5 mol % catalyst loading and 4 equiv of ketone, and afforded aldol products in high diastereoselectivity (up to anti/syn 99:1) and enantioselectivity (99%) and significantly enhanced the reaction yield (99%). These results were much better than l-proline-3-nitroanilide which had the strongest electron-withdrawing group on the aromatic ring. Furthermore, catalyst 6 can be easily recovered and reused, without a significant decrease of enantioselectivity after five cycles. This inexpensive, simple, and recyclable catalyst can be efficiently used in large-scale reactions with the enantioselectivities being maintained at the same level, which offers a great possibility for application in industry.

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(S)-N-Cyclopropyl-pyrrolidine-2-carboxamideC8H14N2O[α]D20=-66.2 (c 1, CHCl3)Source of chirality: l-prolineAbsolute configuration: (2S)

(S)-N-Cyclopentyl-pyrrolidine-2-carboxamideC10H18N2O[α]D20=-53.9 (c 1, CHCl3)Source of chirality: l-prolineAbsolute configuration: (2S)

(S)-N-Cyclohexyl-pyrrolidine-2-carboxamideC11H20N2O[α]D20=-60.5 (c 1, CHCl3)Source of chirality: l-prolineAbsolute configuration: (2S)

(S)-N-Cycloheptyl-pyrrolidine-2-carboxamideC12H22N2O[α]D20=-45.6 (c 1, CHCl3)Source of chirality: l-prolineAbsolute configuration: (2S)

(S)-N-cyclooctyl-pyrrolidine-2-carboxamideC13H24N2O[α]D20=-48.3 (c 1, CHCl3)Source of chirality: l-prolineAbsolute configuration: (2S)

(S)-N-Phenyl-pyrrolidine-2-carboxamideC11H14N2O[α]D20=-44.2 (c 0.5, EtOH)Source of chirality: l-prolineAbsolute configuration: (2S)

(S)-N-(4-Methylphenyl) pyrrolidine-2-carboxamideC12H16N2O[α]D20=-58.9 (c 0.5, EtOH)Source of chirality: l-prolineAbsolute configuration: (2S)

(S)-N-(2,4-Dimethylphenyl) pyrrolidine-2-carboxamideC13H18N2O[α]D20=-62.8 (c 0.5, EtOH)Source of chirality: l-prolineAbsolute configuration: (2S)

(S)-N-(3-Nitrophenyl) pyrrolidine-2-carboxamideC11H13N3O3[α]D20=-41.1 (c 0.5, EtOH)Source of chirality: l-prolineAbsolute configuration: (2S)

(S)-N-n-Hexyl-pyrrolidine-2-carboxamideC11H22N2O[α]D20=-48.6 (c 1, CHCl3)Source of chirality: l-prolineAbsolute configuration: (2S)