Screening of simple N-aryl and N-heteroaryl pyrrolidine amide organocatalysts for the enantioselective aldol reaction of acetone with isatin

We have screened a range of simple N-aryl and N-heteroaryl pyrrolidine amide organocatalysts incorporating N-pyridyl and N-quinolinyl groups in the synthetically useful aldol reaction of isatin with acetone. The ‘reverse amide’ N-pyridyl pyrrolidinylmethyl amide catalysts proved highly catalytically active but gave disappointing enantioselectivities. However, an N-3-pyridyl prolinamide catalyst gave the aldol adduct in high yields and high enantioselectivity with up to 72% ee of the (S)-isomer. Conditions were optimised for this catalyst and in particular an additive screen identified a link between the pKa of the acid additive and the yield and enantioselectivity. An N-arylsulfonamide prolinamide was also identified as a catalyst for this reaction giving the (R)-enantiomer in 68% ee.

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(S)-3-Hydroxy-3-(2-oxopropyl)indolin-2-oneC11H11NO3[α]D18=-20.0 (c 0.025, CH3OH)Source of chirality: enantioselective organocatalytic reactionAbsolute configuration: (S)

(S)-N-(Pyrrolidin-2-ylmethyl)picolinamideC11H15N3O[α]D21=+27.6 (c 0.5, CH2Cl2)Source of chirality: (S)-proline starting materialAbsolute configuration: (S)

(S)-6-Methyl-N-(pyrrolidin-2-ylmethyl)picolinamideC12H17N3O[α]D19=+26.6 (c 0.2, CH2Cl2)Source of chirality: (S)-proline starting materialAbsolute configuration: (S)

(S)-N-(Pyrrolidin-2-ylmethyl)nicotinamideC11H15N3O[α]D21=+22.6 (c 0.1, CHCl3)Source of chirality: (S)-proline starting materialAbsolute configuration: (S)

(S)-N1-(6-Methylpyridin-2-yl)-N3-(pyrrolidin-2-ylmethyl)isophthalamideC19H24N4O2[α]D14=+19.0 (c 0.1, EtOAc)Source of chirality: (S)-proline starting materialAbsolute configuration: (S)

(S)-N-(Pyridin-2-yl)pyrrolidine-2-carboxamideC10H13N3O[α]D22=-56.2 (c 0.4, EtOAc)Source of chirality: (S)-proline starting materialAbsolute configuration: (S)

C11H15N3O(S)-N-(6-Methylpyridin-2-yl)pyrrolidine-2-carboxamide[α]D22=-40.2 (c 0.4, EtOAc)Source of chirality: (S)-proline starting materialAbsolute configuration: (S)

(S)-N-(Pyridin-3-yl)pyrrolidine-2-carboxamideC10H13N3O[α]D18=-65.8 (c 0.1, CHCl3)Source of chirality: (S)-proline starting materialAbsolute configuration: (S)

(S)-N-(Pyridin-4-yl)pyrrolidine-2-carboxamideC10H13N3O[α]D18=-84.2 (c 0.2, CHCl3)Source of chirality: (S)-proline starting materialAbsolute configuration: (S)

(S)-N-(Quinolin-2-yl)pyrrolidine-2-carboxamideC14H15N3O[α]D14=+7.4 (c 0.1, CHCl3)Source of chirality: (S)-proline starting materialAbsolute configuration: (S)

(S)-N-(Quinolin-3-yl)pyrrolidine-2-carboxamideC14H15N3O[α]D17=-20.0 (c 0.05, CHCl3)Source of chirality: (S)-proline starting materialAbsolute configuration: (S)

(S)-N-(Quinolin-8-yl)pyrrolidine-2-carboxamideC14H15N3O[α]D24=+18.6 (c 0.1, CHCl3)Source of chirality: (S)-proline starting materialAbsolute configuration: (S)

(2S,2S′)-N,N′-(Pyridine-2,6-diyl)bis(pyrrolidine-2-carboxamide)C15H21N5O2[α]D20=+10.0 (c 0.1, CHCl3)Source of chirality: (S)-proline starting materialAbsolute configuration: (S)

(2S,4R)-4-(Benzyloxy)-N-(pyridin-3-yl)pyrrolidine-2-carboxamideC17H19N3O2[α]D14=-22.5 (c 0.05, CHCl3)Source of chirality: N-Boc-trans-4-hydroxy-S-proline methyl ester starting materialAbsolute configuration: (2S,4R)

(2S,4R)-4-Hydroxy-N-(pyridin-3-yl)pyrrolidine-2-carboxamideC10H13N3O2[α]D18=-1.0 (c 0.1, CHCl3)Source of chirality: (2S,4R)-4-Hydroxyproline starting materialAbsolute configuration: (2S,4R)

(S)-N-Phenylpyrrolidine-2-carboxamideC11H14N2O[α]D19=-62.0 (c 0.1, CHCl3)Source of chirality: (S)-proline starting materialAbsolute configuration: (S)

(S)-N-Methyl-N-(pyridin-4-yl)pyrrolidine-2-carboxamideC11H15N3O[α]D14=-90.0 (c 0.05, CHCl3)Source of chirality: (S)-proline starting materialAbsolute configuration: (S)

(S)-N-Methyl-N-phenylpyrrolidine-2-carboxamideC12H16N2O[α]D14=+18.2 (c 0.1, CHCl3)Source of chirality: (S)-proline starting materialAbsolute configuration: (S)

(S)-N-(3,5-Bis(trifluoromethyl)phenyl)pyrrolidine-2-carboxamideC13H12F6N2O[α]D18=-37.0 (c 0.05, CHCl3)Source of chirality: (S)-proline starting materialAbsolute configuration: (S)

(S)-N-((3,5-Bis(trifluoromethyl)phenyl)sulfonyl)pyrrolidine-2-carboxamideC13H12F6N2O3S[α]D21=-65.0 (c 0.05, CH3OH)Source of chirality: (S)-proline starting materialAbsolute configuration: (S)

(S)-1-Benzyl-3-hydroxy-3-(2-oxopropyl)indolin-2-oneC18H17NO3[α]D19=-4.0 (c 0.05, CH3OH)Source of chirality: enantioselective organocatalytic reactionAbsolute configuration: (S)

(S)-3-Hydroxy-3-(2-oxobutyl)indolin-2-oneC12H13NO3[α]D14=-40.0 (c 0.01, CH3OH)Source of chirality: enantioselective organocatalytic reactionAbsolute configuration: (S)

(R)-3-Hydroxy-3-(2-hydroxyethyl)indolin-2-oneC10H11NO3[α]D14=+19.1 (c 0.01, CHCl3)Source of chirality: enantioselective organocatalytic reactionAbsolute configuration: (S)

(R)-1-Benzyl-3-hydroxy-3-(2-hydroxyethyl)indolin-2-oneC17H17NO3[α]D14=+14.0 (c 0.01, CHCl3)Source of chirality: enantioselective organocatalytic reactionAbsolute configuration: (S)