An Asymmetric Organocatalytic Aldol Reaction of a Hydrophobic Aldehyde in Aqueous Medium Running in Flow Mode

Dedicated to Professor Dr. Jürgen Martens on the occasion of his 70^th birthday

Published as part of the 50 Years SYNTHESIS – Golden Anniversary Issue

Abstract

Reaction conditions have been identified to conduct a one-pot asymmetric organocatalytic aldol reaction with a hydrophobic substrate in aqueous medium via a process running in flow mode. By employing a mixture of water and 2-propanol, a hydrophobic aldehyde and 3.6 mol% of an organocatalyst, this microreactor process affords the desired aldol adduct with a conversion of 74% and an enantioselectivity of 89% after a reaction time of 60 minutes.

Key words

aldol reaction - asymmetric catalysis - continuously running processes - flow chemistry - organocatalysis - water

• References

• 1 Present address: School of Chemical Engineering, The University of Adelaide, Adelaide, South Australia 5005, Australia.

Reviews:
• 2a Rudroff F, Mihovilovic MD, Gröger H, Snajdrova R, Iding H, Bornscheuer UT. Nat. Catal. 2018; 1: 12
• 2b Schrittwieser JH, Velikogne S, Hall M, Kroutil W. Chem. Rev. 2018; 118: 270
• 2c Gröger H, Hummel W. Curr. Opin. Chem. Biol. 2014; 19: 171
• 2d Denard CA, Hartwig JF, Zhao H. ACS Catal. 2013; 3: 2856
• 3a Wirth T. Microreactors in Organic Chemistry and Catalysis . Wiley-VCH; Weinheim: 2013. 2nd Ed.
• 3b Hessel V, Kralisch D, Kockmann N, Noël T, Wang Q. ChemSusChem 2013; 6: 746
• 3c Ley SV. Chem. Rec. 2012; 12: 378
• 3d Plutschack MB, Pieber B, Gilmore K, Seeberger PH. Chem. Rev. 2017; 107: 11796
• 4a Woodcock J. Modernizing Pharmaceutical Manufacturing – Continuous Manufacturing as a Key Enabler . Lecture presented at the MIT-CMAC International Symposium on Continuous Manufacturing of Pharmaceuticals; Cambridge, MA, USA: 20.05.2014
• 4b Hernan D. Continuous Manufacturing: Challenges and Opportunities. EMA Perspective . Lecture presented at the 3rd FDA/PQRI Conference on Advancing Product Quality; Rockville, MD, USA: 22–24.03.2017
• 5a Rulli G, Duangdee N, Hummel W, Berkessel A, Gröger H. Eur. J. Org. Chem. 2017; 812
• 5b Heidlindemann M, Rulli G, Berkessel A, Hummel W, Gröger H. ACS Catal. 2014; 4: 1099
• 5c Rulli G, Duangdee N, Baer K, Hummel W, Berkessel A, Gröger H. Angew. Chem. Int. Ed. 2011; 50: 7944; Angew. Chem. 2011, 123, 8092
• 5d Baer K, Kraußer M, Burda E, Hummel W, Berkessel A, Gröger H. Angew. Chem. Int. Ed. 2009; 48: 9355 , Angew. Chem. 2009, 121, 9519
• 6a Raj M, Singh VK. Chem. Commun. 2009; 6687
• 6b Raj M, Maya V, Ginotra SK, Singh VK. Org. Lett. 2006; 8: 4097
• 6c Maya V, Raj M, Singh VK. Org. Lett. 2007; 9: 2593
• 6d Raj M, Maya V, Singh VK. J. Org. Chem. 2009; 74: 4289
• 7a Duangdee N, Harnying W, Rulli G, Neudörfl J.-M, Gröger H, Berkessel A. J. Am. Chem. Soc. 2012; 134: 11196
• 7b For a continuous asymmetric aldol reaction in organic medium with a heterogenized organocatalyst, see: Rulli G, Fredriksen KA, Duangdee N, Bonge-Hansen T, Berkessel A, Gröger H. Synthesis 2013; 45: 2512
• 8 For a practical one-pot procedure toward a multigram-scale synthesis of organocatalyst 2 (Singh’s catalyst), see: Berkessel A, Harnying W, Duangdee N, Neudörfl J.-M, Gröger H. Org. Proc. Res. Dev. 2012; 16: 123
• 9 EU-Research Project ONE-FLOW (“Catalyst Cascade Reactions in ‘One-Flow’ within a Compartmentalized, Green-Solvent ‘Digital Synthesis Machinery’ – End-to-End Green Process Design for Pharmaceuticals”), Work programme: EU proposal 737266; see: one-flow.org (accessed Nov 28, 2018).