Asymmetric Aldol Reaction Of Acetone Research Articles

On the Influence of a Camphor‐based 1,3‐Diamine Fragment in a Proline‐Based Organocatalyst

AbstractMultifunctional C1‐symmetric organocatalysts were prepared incorporating a camphor‐ and a proline‐based moiety. The new catalysts were evaluated in an asymmetric aldol reaction of acetone and aromatic aldehydes. A significant increase in the catalytic activity was found for the new proline analogue with the camphor‐based 1,3‐diamine unit. This new organocatalyst has one free primary amine group next to the secondary amine group of the proline unit. High yields of up to 97 % with good enantioselectivities (83 % ee) were obtained in the aldol reaction between various aromatic aldehydes and acetone in a shorter reaction time compared with (S)‐proline. A camphor‐based prolineamide analogue with a thiourea group was an efficient multifunctional organocatalyst for the aldol reaction of p‐nitrobenzaldehyde and cyclohexanone with 86 % yield and up to 73 % ee. Moreover, matched‐mismatched studies with opposite stereocenters in the camphor‐based 1,3‐diamine fragment revealed a significant influence of this unit on the overall performance of the new organocatalyst.

Chiral Thiazolidine based Organocatalysts: Synthesis and Application in Asymmetric Aldol Reactions

Several novel chiral organocatalysts derived from thiazolidines containing amide and thioureia functionalities were synthesized in good yields. These organocatalysts were tested in the asymmetric aldol reaction of acetone with p-nitrobenzaldehyde. Reaction parameters such as reaction time, catalyst loading and solvent were optimized. Products with conversions up to 84% and enantiomeric ratios (er) up to 84.5:15.5 (R:S) were obtained. The effect of several chiral and non-chiral additives on the reactivity and selectivity of the reaction was also evaluated. The reaction was extended to other aromatic aldehydes with the best organocatalyst and when p-bromobenzaldehyde was used, an er of 94.5:5.5 (R:S) was obtained.

Proline-based organocatalyst-mediated asymmetric aldol reaction of acetone with substituted aromatic aldehydes: an experimental and theoretical study.

This work involves a facile synthesis of three (S) -proline-based organocatalysts with C2 symmetry and their effects in enantioselective aldol reaction of acetone with substituted aromatic aldehydes. Moderate enantioselectivities (up to 61% ee) were obtained depending on the nature of the substituents on the aryl ring. Computational calculations at HF/6-31 + G(d) level were employed to underline the enantioselectivity imposed by all the organocatalysts. Higher calculations at B3LYP/6-311 ++ G(d,p) scrf=(solvent=dichloromethane)//B3LYP/6-31 + G(d) levels of theory were also performed for the aldol reaction of acetone with benzaldehyde and 4-nitrobenzaldehyde catalyzed by 1. The computational outcomes were consistent with those produced by experimental results and they were valuable to elucidate the mechanism for the observed stereoselectivity.

Synthesis and asymmetric catalytic performance of one-handed helical poly(phenylacetylene)s bearing proline dipeptide pendants

One-handed helical substituted polyacetylene has received extensive attention due to its potential in chiral stationary phases and molecular recognition. Here, three one-handed helical poly(phenylacetylene)s bearing proline or proline dipeptide as the pendants (PPA-Pro, PPA-Pro-Pro and PPA-Pro-Hyp) were synthesized. As the catalyst, the three helical polymers separately catalyzed the asymmetric aldol reaction of acetone with p-nitrobenzaldehyde in a various media. The results indicate that PPA-Pro-Pro and PPA-Pro-Hyp bearing dipeptide pendants showed the higher catalytic activity and enantioselectivity than the PPA-Pro bearing proline pendants and the corresponding monomer catalysts. This indicates the synergistic effect of the dipeptide pendants with the one-handed helical mainchain of the polymer catalyst. The polymer catalysts can be recycled and maintain the catalytic performance after four circles. When imidazole was added to the reaction system, the reaction yield could be efficiently improved without affecting the enantioselectivity.

Theoretical Study of the Histidine-catalyzed Asymmetric Aldol Reaction of Acetone and Benzaldehyde.

The mechanism of histidine-catalyzed asymmetrical aldol reaction of acetone with benzaldehyde was studied by using B3LYP method of density functional theory at the levels of 6-31G(d,p) and cc-pvdz basis sets. The calculation results showed that the reaction mechanism included four steps: (I) nucleophilic attack of histidine on acetone to form alcohol intermediate Inter-A through the transition state TS1 (considered a rate control step because the activation energy (49.95 kcal/mol) was relatively high); (II) dehydration of the alcohol intermediate to form the cis- or trans-enamine through the transition states TS3 and TS4 with the energy barriers of 36.12 and 38.15 kcal/mol; (III) electrophilic addition of cis-enamine or trans-enamine with benzaldehyde to form imine Inter-C or Inter-E through the transition states TS8, TS9, TS10, and TS11 (energy barriers 18.43, 22.34, 13.24, and 13.24 kcal/mol, respectively); (IV) after combination of the imine intermediate with water through the transition states TS12, TS13, TS14, and TS15 (energy barriers 22.79, 34.6, 28.2, 25.12 kcal/mol, respectively), removal of the histidine catalys to obtain the final S or R aldol product. Through analyzing the potential energy profile of reaction, we found that the histidine-catalyzed reaction of acetone with benzaldehyde was more energetically favorable to obtain the R-product (ee value >99%). Solvent effects computed with a polarizable continuum model (PCM) indicated that the DMSO and water can reduce the reaction energy barrier.

Mechanism and rate constant of proline-catalysed asymmetric aldol reaction of acetone and p-nitrobenzaldehyde in solution medium: Density-functional theory computation

In search of new ways to improve catalyst design, the current research focused on using quantum mechanical descriptors to investigate the effect of proline as a catalyst for mechanism and rate of asymmetric aldol reaction. A plausible mechanism of reaction between acetone and 4-nitrobenzaldehyde in acetone medium was developed using highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energies calculated via density functional theory (DFT) at the 6-31G∗/B3LYP level of theory. New mechanistic steps were proposed and found to follow, with expansion, the previously reported iminium-enamine route of typical class 1 aldolase enzymes. From the elementary steps, the first step which involves a bimolecular collision of acetone and proline was considered as the rate-determining step, having the highest activation energy of 59.07 kJ mol−1. The mechanism was used to develop the rate law from which the overall rate constant was calculated and found to be 4.04×10-8dm3mol-1s-1. The new mechanistic insights and the explicit computation of the rate constant further improve the kinetic knowledge of the reaction.

Asymmetric Aldol Synthesis: Choice of Organocatalyst and Conditions.

This is the first report of a successful asymmetric aldol reaction of acetone and 4-nitrobenzaldehyde catalyzed by only 0.01 mol % of proline tetrazole (5-pyrrolidin-2-yltetrazole). Amazingly, 3 mol % of water as an additive has significantly improved the efficiency of the aldol reaction in terms of yield and enantioselectivity, up to a 0.1-mol-scale production (up to 99 % isolated yield, 84 % ee).

ChemInform Abstract: trans‐4‐Hydroxy‐L‐prolinamide as an Efficient Catalyst for Direct Asymmetric Aldol Reaction of Acetone with Isatins.

Abstract Prolinamide (2 S ,4 R )-4-hydroxy- N -(( S )-1-phenylethyl)pyrrolidine-2-carboxamide was found to be an efficient organocatalyst (10 mol %) for the direct asymmetric aldol reactions of isatins with acetone at −35 °C in THF and afforded the product in 79% yield with 74% ee . We have generalised the methodology for the direct asymmetric aldol reaction between isatin derivatives and acetone, and the corresponding aldol products were obtained in high yields (up to 99%) and with moderate enantioselectivities (up to 80%). This method has been applied to the enantioselective synthesis of ( S )-convolutamydine.

Trans-4-Hydroxy-l-prolinamide as an efficient catalyst for direct asymmetric aldol reaction of acetone with isatins

Prolinamide (2S,4R)-4-hydroxy-N-((S)-1-phenylethyl)pyrrolidine-2-carboxamide was found to be an efficient organocatalyst (10mol%) for the direct asymmetric aldol reactions of isatins with acetone at −35°C in THF and afforded the product in 79% yield with 74% ee. We have generalised the methodology for the direct asymmetric aldol reaction between isatin derivatives and acetone, and the corresponding aldol products were obtained in high yields (up to 99%) and with moderate enantioselectivities (up to 80%). This method has been applied to the enantioselective synthesis of (S)-convolutamydine.

ChemInform Abstract: N‐Arylprolinamide as an Organocatalyst for the Direct Asymmetric Aldol Reaction of Acetone with Isatin.

Abstract N -Aryl-( S )-prolinamides act as organocatalysts for the direct asymmetric aldol reaction between isatin and acetone. N -(4-Bromophenyl)-( S )-prolinamide (20 mol %) efficiently catalysed the direct aldol reaction between isatin and acetone at −35 °C, and afforded 3-alkyl-3-hydroxyindolin-2-one in 99% yield and with 71% ee. We have generalised the methodology for the direct asymmetric aldol reaction between isatin derivatives and acetone, and the corresponding aldol products were obtained in 76–99% yields and with 42–87% ee.

N-Arylprolinamide as an organocatalyst for the direct asymmetric aldol reaction of acetone with isatin

N-Aryl-(S)-prolinamides act as organocatalysts for the direct asymmetric aldol reaction between isatin and acetone. N-(4-Bromophenyl)-(S)-prolinamide (20mol%) efficiently catalysed the direct aldol reaction between isatin and acetone at −35°C, and afforded 3-alkyl-3-hydroxyindolin-2-one in 99% yield and with 71% ee. We have generalised the methodology for the direct asymmetric aldol reaction between isatin derivatives and acetone, and the corresponding aldol products were obtained in 76–99% yields and with 42–87% ee.

The 4,5-methano-l-proline as a chiral organocatalysts in direct asymmetric aldol reactions

The 4,5-methano-l-proline was studied for the direct asymmetric aldol reaction of acetone or cyclohexanone with various aromatic and aliphaticaldehydes at −20 °C or 0 °C. A loading of only 5mol % of derivative 1a was employed in this catalytic system, and excellent enantioselectivities (up to 99% ee) and yields (up to 98% yield) could be achieved.

ChemInform Abstract: Unexpected Beneficial Effect of ortho‐Substituents on the (S)‐Proline‐Catalyzed Asymmetric Aldol Reaction of Acetone with Aromatic Aldehydes.

AbstractThe reaction can be scaled up.

Unexpected Beneficial Effect of ortho-Substituents on the (S)-Proline-Catalyzed Asymmetric Aldol Reaction of Acetone with Aromatic Aldehydes

An intriguing effect of electronegative 2,6-substituents on the stereochemical outcome of (S) -proline-catalyzed aldol reactions between benzaldehyde derivatives and acetone is reported. Remarkably high enantioselectivities can be achieved with such substrates.

ChemInform Abstract: Amino Oxazolines as a New Class of Organocatalyst for the Direct Intermolecular Asymmetric Aldol Reaction Between Acetone and Aromatic Aldehydes.

AbstractThe synthesis of chiral amino oxazolines is described and the utility of the products is demonstrated in the asymmetric aldol reaction of acetone with reactive carbonyl compounds.

(S)-5-prolylamide-triazole Organocatalyst for Direct Asymmetric Aldol Reactions

A new proline derivative of (S)-5-prolylamide-triazole was synthesized and evaluated as an organocatalyst for the direct asymmetric aldol reaction of acetone with aromatic aldehydes under no extra solvent. At room temperature and in the absence of extra solvent, 15 mol% catalyst efficiently catalyzed the direct asymmetric aldol reactions to give aldol adducts, with modest enantiomeric excess (ee) of up to 74%. The titled reactions can be carried out in an environmentally friendly manner of no extra solvent and less catalyst loading.

Synthesis of polymers bearing proline moieties in the side chains and their application as catalysts for asymmetric induction

AbstractNovel polyphenylacetylene and polystyrene derivatives carrying L‐proline moieties at the side chains were synthesized by the rhodium‐catalyzed and radical polymerizations of the corresponding monomers. The polyphenylacetylene derivatives showed Cotton effects at the absorption region of the main chain, indicating that the polymers adopt helical conformations with predominantly one‐handed screw sense. The polymers catalyzed the asymmetric aldol reactions of acetone with aromatic aldehydes, and cyclohexanone with p‐nitrobenzaldehyde. The enantioselectivities largely depended on the reaction conditions. In the asymmetric aldol reaction of acetone with aromatic aldehydes, the R‐enantiomeric products were predominantly obtained except the cases with the polymer catalyst in CHCl3. The ee of the products became higher as the reaction temperature was decreased. The polymeric catalysts were recoverable from the reaction mixture by filtration, and the recovered ones catalyzed the asymmetric aldol reaction of acetone with p‐nitrobenzaldehyde without decreasing the product yield and ee. The ee was improved using the copolymers of L‐proline‐based and nonchiral monomers as catalysts. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011

Development of an N-sulfinyl prolinamide for the asymmetric aldol reaction

A new class of organocatalysts is reported that incorporates an N-sulfinyl amide in place of the carboxylic acid of proline to serve as a hydrogen bond donor, chiral directing group, and solubilizing element. The successful application of this type of catalyst to the asymmetric aldol reaction of acetone and aryl aldehydes, for which proline performs poorly, is also described.

ChemInform Abstract: Highly Efficient Direct Asymmetric Aldol Reactions Catalyzed by a Prolinethioamide Derivative in Aqueous Media.

AbstractA new L‐prolinethioamide derivative is prepared and employed in the direct asymmetric aldol reaction of acetone with aromatic aldehydes.

Highly Enantioselective and Efficient Organocatalytic Aldol Reaction of Acetone and β,γ-Unsaturated α-Keto Ester

An effective organocatalytic asymmetric aldol reaction of acetone to β,γ-unsaturated α-keto ester has been developed. In the presence of 5 mol % of 9-amino (9-deoxy)-epicinchona alkaloid and 10 mol % of 4-nitrobenzoic acid, the aldol adducts containing a chiral tertiary alcohol moiety were obtained in excellent yields and enantioselectivities.