Asymmetric Organocatalytic Aldol Reaction in Water: Mechanistic Insights and Development of a Semi-Continuously Operating Process

Dedicated to Professor Dr. Jürgen Martens on the occasion of his 65th birthday

Abstract

A detailed study on the impact of the catalyst loading on conversion and enantioselectivity of the direct aldol reaction of an aldehyde and acetone in aqueous solvent with nonimmobilized and immobilized proline amide-based organocatalysts is described. Based on a polymer-supported catalyst, batch and semi-continuously operating processes, comprising recycling studies in the latter case, were investigated.

Key words

aldol reaction - catalysis - enantioselectivity - supported catalysis - polymers

• References

• 1a Modern Methods in Stereoselective Aldol Reactions. Mahrwald R. Wiley-VCH; Weinheim: 2013
• 1b Berkessel A, Gröger H. Asymmetric Organocatalysis . Wiley-VCH; Weinheim: 2005
• 1c Melchiorre P, Marigo M, Carlone A, Bartoli G. Angew. Chem. Int. Ed. 2008; 47: 6138 ; Angew. Chem. 2008, 120, 6232
• 2a Tang Z, Yang Z.-H, Chen X.-H, Cun L.-F, Mi A.-Q, Jiang Y.-Z, Gong L.-Z. J. Am. Chem. Soc. 2005; 127: 9285
• 2b Raj M, Singh VK. Chem. Commun. 2009; 6687
• 3a Raj M, Maya V, Ginotra SK, Singh VK. Org. Lett. 2006; 8: 4097
• 3b Maya V, Raj M, Singh VK. Org. Lett. 2007; 9: 2593
• 3c Raj M, Maya V, Singh VK. J. Org. Chem. 2009; 74: 4289
• 3d Duangdee N, Harnying W, Rulli G, Neudörfl J.-M, Gröger H, Berkessel A. J. Am. Chem. Soc. 2012; 134: 11196
• 3e Baer K, Kraußer M, Burda E, Hummel W, Berkessel A, Gröger H. Angew. Chem. Int. Ed. 2009; 48: 9355 ; Angew. Chem. 2009, 121, 9519
• 4 Rulli G, Duangdee N, Baer K, Hummel W, Berkessel A, Gröger H. Angew. Chem. Int. Ed. 2011; 50: 7944 ; Angew. Chem. 2011, 123, 8092
• 5 Berkessel A, Harnying W, Duangdee N, Neudörfl J.-M, Gröger H. Org. Process Res. Dev. 2011; 16: 123
• 6 Kristensen TE, Vestli K, Fredriksen KA, Hansen FK, Hansen T. Org. Lett. 2009; 11: 2968
• 7 Kristensen TE, Vestli K, Jakobsen MG, Hansen FK, Hansen T. J. Org. Chem. 2010; 75: 1620
• 8 Kristensen TE, Hansen T. Eur. J. Org. Chem. 2010; 3179
• 9 The overall conversions decrease slightly by applying higher catalyst loadings (e.g., 1.0 mol%: 93%; 5.0 mol%: 87%). Although no detailed explanation is as yet available, this effect might be related (at least to some extent) to an increased formation of an inactive catalyst–substrate adduct in the case of reactions conducted at higher catalyst loading (for the formation of related adducts, see ref. 3d). The differences in the product-related conversions are primarily caused by the higher impact of the side-product formation (via dehydration of aldol product 4) in the case of the reactions conducted at higher catalyst loading.
• 10a Gruttadauria M, Giacalone F, Noto R. Chem. Soc. Rev. 2008; 37: 1666
• 10b Gruttadauria M, Giacalone F, Marculescu AM, Noto R. Adv. Synth. Catal. 2008; 350: 1397
• 11 Because of the large amount of catalyst, the solvent is completely absorbed by the polymer, leading to the formation of a gel.
• 12 An example for the recycling of 2 in a batch reactor is given in the Supporting Information.

For recent applications of immobilized organocatalysts in continuous flow systems, see:
• 13a Ötvös SB, Mándity IM, Fülöp F. ChemSusChem 2012; 5: 266
• 13b Ayats C, Henseler AH, Pericàs MA. ChemSusChem 2012; 5: 320
• 13c Arakawa Y, Wennemers H. ChemSusChem 2013; 6: 242
• 14a Rulli, G.; Gröger, H., unpublished results.
• 14b For further information about the role of water as an essential component for an efficient organocatalytic aldol reaction, see ref. 2b and: Gruttadauria M, Giacalone F, Noto R. Adv. Synth. Catal. 2009; 351: 33
• 15 Li X, Li L, Tang Y, Zhong L, Cun L, Zhu J, Liao J, Deng J. J. Org. Chem. 2010; 75: 2981