Enamine‐Based Aldol Organocatalysis in Water: Are They Really “All Wet”?

Brogan, Anita; Dickerson, Tobin J.; Janda, Kim D.

doi:10.1002/anie.200601392

Cited by 283 publications

(78 citation statements)

References 37 publications

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“…[15] Hayashi has proposed that these reactions might be better considered as carried out "in the presence of water". [16] On the other hand, Blackmond has raised doubts about the greenness of organocatalytic reactions carried out in the presence of water.…”

Section: Introductionmentioning

confidence: 99%

New Simple Hydrophobic Proline Derivatives as Highly Active and Stereoselective Catalysts for the Direct Asymmetric Aldol Reaction in Aqueous Medium

et al. 2008

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New 4-substituted acyloxyproline derivatives with different hydrophobic properties of the acyl group were easily synthesized and used as catalysts in the direct asymmetric aldol reaction between cyclic ketones (cyclohexanone and cyclopentanone) and several substituted benzaldehydes. Reactions were carried out using water, this being the best reaction medium examined. Screening of these catalysts showed that compounds bearing the most hydrophobic acyl chains [4-phenylbutanoate and 4-(pyren-1-yl)butanoate] provided better results. The latter catalysts were successfully used in only 2 mol% at room temperature without additives to give aldol products in excellent stereoselectivities. These results demonstrate that derivatization of the proline moiety with the proper simple hydrophobic substituent in the 4-position can furnish highly active and stereoselective catalysts without the need of additional chiral backbones in the molecule. Finally, an explanation of the observed stereoselectivities in the presence of water is provided.

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Section: Introductionmentioning

confidence: 99%

New Simple Hydrophobic Proline Derivatives as Highly Active and Stereoselective Catalysts for the Direct Asymmetric Aldol Reaction in Aqueous Medium

et al. 2008

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“…As a result, the reaction is not really proceeding in water and is more likely performed in "organic solvent". [9] Thus, a special design of water-solu-ble organocatalyst is required for performing these reactions in aqueous media with good stereoselection. [10] With the goal of developing a recyclable catalyst that displays high activity and enantioselectivity in aqueous media, our group has reported a water-soluble and recyclable catalyst, diarylprolinol silyl ether 1 in combination with Brønsted acid, which catalyzed the asymmetric Michael addition of aldehydes to nitroolefins in aqueous media with excellent diastereoand enantioselectivities through activation of aldehydes by an enamine mechanism [Scheme 1, Eq.…”

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confidence: 99%

Highly Active Water‐Soluble and Recyclable Organocatalyst for the Asymmetric 1,4‐Conjugate Addition of Nitroalkanes to α,β‐Unsaturated Aldehydes

Ghosh

Zheng

2010

Adv Synth Catal

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A novel strategy for the catalytic asymmetric conjugate addition of nitroalkanes to a,b-unsaturated aldehydes in aqueous media has been developed by using diarylprolinol silyl ether in combination with benzoic acid as a water-soluble organocatalyst providing the desired adducts in good to excellent enantioselectivities (up to 95% ee). This catalyst can be recycled at least five times with only a slight reduction in activity and selectivity. In addition, the synthetic procedure presented is simple, practical and environmentally benign.

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“…3,4 However, there are still some limitations on the availability of organocatalysts and the versatility of reactions that might be effective "in pure water".…”

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confidence: 99%

“…Michael donors such as ethyl 2-benzylacetoacetate (1d), ethyl 3-oxopentanoate (1e), and ethyl benzoylacetate (1f) and acceptors such as acrylonitrile (2b) ( Table 3, entries [3][4][5][6][7][8][9][10][11][12]. The decreased reactivity of the reactants 1d-1f with their increase in hydrophobicity might be accounted for by the difficulty to cause effective substrate interactions in water.…”

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confidence: 99%

Development of new DMAP-related organocatalysts for use in the Michael addition reaction of β-ketoesters in water

Nakano

Watanabe

et al. 2009

Tetrahedron Letters

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Abstract:A general and efficient protocol for the Michael addition reactions of β-ketoesters in pure water has been developed. The reactions are successfully catalyzed by newly designed DMAP-related organocatalysts such as 4-(didecylamino)pyridine, and the desired Michael adducts are obtained in good to high yields Keywords:Michael addition reaction; β-Ketoesters; DMAP-related organocatalyst, Aqueous media Organic reactions in water have received considerable attention from synthetic chemists, since they are environmentally clean, non-toxic and inexpensive. 1 In particular, over the past decade remarkable progress has been achieved in the field of organocatalytic transformations 2 in aqueous media as a primary contribution to "green chemistry". 3,4 However, there are still some limitations on the availability of organocatalysts and the versatility of reactions that might be effective "in pure water".In designing new water-tolerant organocatalysts, we were interested in the unique base character of 4-(dimethylamino)pyridine (DMAP, pK a 9.70 in H 2 O). There was a sharp contrast in the appearance of the reaction mixture in the respective experiments ( Figure 1). Thus, while the mixture containing 3d became an emulsion after the first 20-30 min of stirring, other compounds led to a substantially clear heterogeneous phase separation. We supposed that the attachment of two tails of an n-decyl chain to a 4-aminopyridine head should be "matched" to form a sort of hydrophobic media in water under such conditions, which allowed efficient catalysis to take place. To obtain further insight into the solvent effect of 3d-catalysis, we performed experiments using methyl cyclopentan-1-one-2-carboxylate (1b) as a Michael donor in various organic and water solvents (Table 2). In THF, CH 2 Cl 2 , and acetonitrile, the reaction proceeded very slowly and gave the adduct 4b in yields of 59-90% (Table 2, entries 1-3). The reaction in MeOH gave results that were almost comparable to those in water, 20 but the latter solvent was still advantageous with respect to its environmental friendliness and the reaction rate (Table 2, entries 4 and 5). 21< Table 2 > With these results in hand, we then investigated the general scope of this method. Thus, various β-ketoesters 1 were treated with Michael acceptors 2 in the presence of a catalytic amount of 3d under the standardized conditions. In all of the cases examined, the 3a-catalyzed reactions are also shown for comparison (Table 3).< Table 3 > When the reaction of ethyl 2-methylacetoacetate (1c) with 2a was performed in the presence of 10 mol% of 3d, the desired adduct 4c was obtained in 88% yield after stirring for 7.5 h, while the use of 3a resulted in an incomplete reaction even after 23 h, and gave 4c in only 15% yield (Table 3, entries 1 and 2). Very similar behavior was observed for otherMichael donors such as ethyl 2-benzylacetoacetate (1d), ethyl 3-oxopentanoate (1e), and ethyl benzoylacetate (1f) and acceptors such as acrylonitrile (2b) ( Table 3, entries 3-12). The decreased react...

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Enamine‐Based Aldol Organocatalysis in Water: Are They Really “All Wet”?

Abstract: Reactions with, in, or on water? Despite claims to the contrary, few examples of truly aqueous organocatalysis have been reported. Close examination of the data from recent reports reveals that these reactions likely occur in concentrated organic phases.

Cited by 283 publications

References 37 publications

New Simple Hydrophobic Proline Derivatives as Highly Active and Stereoselective Catalysts for the Direct Asymmetric Aldol Reaction in Aqueous Medium

New Simple Hydrophobic Proline Derivatives as Highly Active and Stereoselective Catalysts for the Direct Asymmetric Aldol Reaction in Aqueous Medium

Highly Active Water‐Soluble and Recyclable Organocatalyst for the Asymmetric 1,4‐Conjugate Addition of Nitroalkanes to α,β‐Unsaturated Aldehydes

Development of new DMAP-related organocatalysts for use in the Michael addition reaction of β-ketoesters in water

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