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  • 1 Dipartimento di Chimica, Università degli Studi di Milano via Golgi 19 20133 Milano Italy
  • 2 Università degli Studi di Padova Dipartimento di Scienze Chimiche via Marzolo 1 35131 Padova Italy
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Metal-free stereoselective additions of activated nucleophiles to β-nitrostyrenes were investigated under continuous-flow conditions in microreactors, in the presence of a chiral bifunctional catalyst. Optimization of the experimental setup gave excellent enantioselectivities (up to 85% e.e.) and higher productivities if compared to the flask syntheses. The potential of this flow chemistry approach was demonstrated by the successful synthesis of an advanced intermediate for the preparation of the GABAB receptor agonist Baclofen.

  • Poechlauer, P; Manley, J.; Broxterman, R.; Gregertsen, B.; Ridemark, M. Org. Process Res. Dev. 2012, 16, 1586–1590.

  • (a) Benaskar, F.; Ben-Abdelmoumen, A.; Patil, N.; Rebrov, E.; Meuldijk, J.; Hulshof, L.; Hessel, V.; Krtschil, U.; Schouten, J. J. Flow Chem. 2011, 1, 74–89; (b) for a review discussing the merits of batch and micro flow reactors, see: Hartman, R. L.; McMullen, J. P.; Jensen, K. F. Angew. Chem., Int. Ed. 2011, 50, 7502–7519; see also: (c) Hartung, A.; Keane, M. A.; Kraft, A. J. Org. Chem. 2007, 72, 10235–10238; (d) Battilocchio, C.; Deadman, B. J.; Nikbin, N.; Kitching, M. O.; Baxendale, I. R.; Ley, S. V. Chem. Eur. J. 2013, 19, 7917–7930 and references cited.

  • (a) Sheldon, R. A. Green Chem. 2007, 9, 1273–1283; (b) Jimenez-Gonzalez, C.; Poechlauer, P.; Broxterman, Q. B.; Yang, B.-S.; am Ende, D.; Baird, J.; Bertsch, C.; Hannah, R. E.; Dell’Orco, P.; Noorman, H.; Yee, S.; Reintjens, R.; Wells, A.; Massonneau, V.; Manley, J. Org. Process Res. Dev. 2011, 15, 900–911; (c) Rossi, E.; Woehl, P.; Maggini, Org. Process Res. Dev. 2012, 16, 1146–1149; (d) Elvira, K. S.; Casadevall i Solvas, X.; Wootton, R. C. R.; deMello, A. J. Nat. Chem. 2013, 5, 905–915; (e) Pinho,V. D.; Gutmann, B.; Miranda, L. S. M.; de Souza, R. O. M. A.; Kappe, C. O. J. Org. Chem. 2014, 79, 1555–1562.

  • Dunne, P. J. Green Chem., 2013, 15, 3099–3104.

  • For the application of flow chemistry for multistep organic synthesis, see: (a) Wegner, J.; Ceylan, S.; Kirschning, A. Adv. Synth. Catal. 2012, 354, 17–57; (b) Baumann, M.; Baxendale, I. R.; Ley, S. V. Mol. Divers. 2011, 3, 613–630. For some recent, representative contributions, see: Chen, M.; Buchwald, S. Angew. Chem., Int. Ed. 2013, 52, 4247–4250 and Baxendale, I. R.; Ley, S. V.; Mansfield, A. C.; Smith, C. D. Angew. Chem., Int. Ed. 2009, 48, 4017–4021.

  • (a) Enantioselective Organocatalysis. Reactions and Experimental procedures; Dalko, P. I. Ed.; Wiley-VCH: Weinheim, 2007; (b) Asymmetric Organocatalysis, in Topics in Current Chemistry, List, B. Ed., Springer, 2009, vol. 291; (c) Puglisi, A.; Benaglia, M.; Chiroli, V. Green Chem. 2013, 15, 1790–1813. For very recent contributions with chiral organocatalysts not included in the review see: (d) Martín-Rapún, R.; Sayaleroa, S.; Pericàs, M. A. Green Chem. 2013, 15, 3295–3301; (e) Osorio-Planes, L.; Rodriguez-Escrich, C.; Pericas, M. A. Chem. Eur. J. 2014, 20, 2367–2372.

  • Geyer, K.; Gustafson, T.; Seeberger, P. H. Beilstein J. Org. Chem. 2009, 5, 1–19.

  • For organocatalyzed reactions via substrate-iminium activation under continuous-flow conditions, see: (a) Chiroli, V.; Benaglia, M.; Cozzi, F.; Puglisi, A.; Annunziata, R.; Celentano, G. Org. Lett. 2013, 15, 3590–3593; (b) Porta, R.; Benaglia, M.; Chiroli, V.; Coccia, F.; Puglisi, A. Isr. J. Chem. 2014, 54, 381–394; (c) Chiroli, V.; Benaglia, M.; Puglisi, A.; Porta, R.; Jumde, R. P.; Mandoli, A. Green Chem. 2014, 16, 2798–2806.

  • For some recent selected books and reviews: (a) Microreactors in Organic Synthesis and Catalysis; Wirth, T. Ed.; Wiley-VCH: Weinheim, 2008; (b) Hessel, V. Chem. Eng. Technol. 2009, 32, 1655–1681; (c) Geyer, K.; Gustafson, T.; Seeberger, P. H. Synlett 2009, 2382–2391; (d) Wiles, C.; Watts, P. Chem. Commun. 2011, 6512–6535; (e) Wegner, J.; Ceylan, S.; Kirschning, A. Chem. Commun. 2011, 4583–4592; (f) Ceylan, S.; Coutable, L.; Wegner,V.; Kirschning, A. Chem. Eur. J. 2011, 17, 1884–1893; (g) Wiles, C.; Watts, P. Green Chem. 2012, 14, 38–54.

  • Solodenko, W.; Mennecke, K.; Kirschning, A. Chem. Eur. J. 2002, 12, 5972–5990. For achiral organocatalysts, see: (a) Rueping, M.; Bootwicha, T.; Sugiono, E. Beilstein J. Org. Chem. 2012, 8, 300–307; (b) Shen, B.; Jamison, T. F. Org. Lett. 2012, 14, 3348–3351; (c) Kleinke, A. S.; Jamison, T. F. Org. Lett. 2013, 15, 710–713.

  • Odedra, A.; Seeberger, P. H. Angew. Chem., Int. Ed. 2009, 48, 2699–2702.

  • Fritzsche, S.; Ohla, S.; Glaser, P.; Giera, D. S.; Sickert, M.; Schneider, C.; Belder, D. Angew. Chem., Int. Ed. 2009, 48, 2699–2702.

  • Carroccia, L.; Musio, B.; Degennaro, L.; Romanazzi, G.; Luisi, R. J. Flow Chem. 2013, 3, 29–33.

  • For a different approach where a catalyst precursor slowly dissolves within the streaming of reactant's solution, see: Opalka, S. M.; Longstreet, A. R.; McQuade, D.T. Beilstein J. Org. Chem. 2011, 7, 1671–1679.

  • Review: (a) Takemoto, Y. Org. Biomol. Chem. 2005, 3, 4299–4306; for other reviews on bifunctional catalysts, see: (b) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713–5743 and (c) Lu, L.-Q.; An, X.-L.; Chen, J.-R.; Xiao, W.-J. Synlett 2012, 23, 490–508; for a recent contribution on the addition of 1,3-diketones on nitroalkenes, see: (d) Baran, R.; Veverková, E; Škvorcová, R.; Šebesta, A. Org. Biomol. Chem. 2013, 11, 7705–7711 and references cited; (e) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 119–125.

  • For a discussion on possible different mechanistic pathways, see: Hamza, A.; Schubert, G.; Soós, T.; Papai, I. J. Am. Chem. Soc. 2006, 128, 13151–13160.

  • The reaction performed in flask at 70 °C (same conditions as in the flow process) in our hands afforded the product in 37% yield, with a productivity of 11100 (compared to 27300 of the reaction in flow), thus further highlighting the advantages of the reactions in microreactor devices (see Scheme 2).

  • Gotoh, H.; Ishikawa, H.; Hayashi, Y. Org. Lett., 2007, 9, 5307–5309 and references cited.