A Continuous-Flow, Two-Step, Metal-Free Process for the Synthesis of Differently Substituted Chiral 1,2-Diamino Derivatives

Abstract

The enantioselective organocatalytic reduction of aryl-substituted nitroenamines was successfully performed under continuous-flow conditions. After a preliminary screening with a 10-μL microreactor, to establish the best reaction conditions, the reduction was scaled up in a 0.5-mL mesoreactor, without appreciable loss of enantioselectivity, that remained constantly higher than 90%. The in-flow nitro reduction was also accomplished, either by Raney nickel catalyzed hydrogenation or by a metal-free methodology based on the use of the very inexpensive and readily available reducing agent trichlorosilane. The final aim is to develop a two-step, continuous-flow process for the stereo­selective, metal-free, catalytic synthesis of differently functionalized chiral 1,2-diamines.

Key words

flow chemistry - chiral diamines - microreactors - nitro­enamines - organocatalysis

• References

• 1 Chiral Amine Synthesis: Methods, Developments and Applications. Nugent TC. Wiley-VCH; Weinheim: 2010

Reviews:
• 2a Lucet D. LeGall T. Mioskowski C. Angew. Chem. Int. Ed. 1998; 37: 2580
• 2b Ballini R. Petrini M. Tetrahedron 2004; 60: 1017
• 2c Kotti SR. Timmons C. Li G. Chem. Biol. Drug Des. 2006; 67: 101
• 3 Liu XW. Yan Y. Wang Y.-Q. Wang C. Sun J. Chem. Eur. J. 2012; 18: 9204
• 4 Ferraro A. Bernardi L. Fochi M. Adv. Synth. Catal. 2016; 358: 1561

For reviews on organocatalyzed enantioselective reductions see:
• 5a Benaglia M. Genoni A. Bonsignore M. Enantioselective Organocatalytic Reductions. In Stereoselective Organocatalysis: Bond Formation Methodologies and Activation Modes. Rios Torres R. Wiley; Hoboken: 2013: 559-585
• 5b Rossi S. Benaglia M. Massolo E. Raimondi L. Catal. Sci. Technol. 2014; 9: 2708
• 6 Massolo E. Benaglia M. Orlandi M. Rossi S. Celentano G. Chem. Eur. J. 2015; 21: 3589
• 7a Genoni A. Benaglia M. Massolo E. Rossi S. Chem. Commun. 2013; 49: 8365

For reviews see:
• 7b Guizzetti S. Benaglia M. Eur. J. Org. Chem. 2010; 5529
• 7c Jones S. Warner CJ. A. Org. Biomol. Chem. 2012; 10: 2189

Recent reviews:
• 8a Atodiresei I. Vila C. Rueping M. ACS Catal. 2015; 5: 1972
• 8b Puglisi A. Benaglia M. Porta R. Coccia F. Curr. Organocatal. 2015; 2: 79
• 8c Munirathinam R. Huskens J. Verboom W. Adv. Synth. Catal. 2015; 357: 1093
• 8d Rodríguez-Escrich C. Pericàs MA. Eur. J. Org. Chem. 2015; 1173

Some very recent examples of continuous-flow synthetic methods:
• 8e Poh J.-S. Tran DN. Battilocchio C. Hawkins JM. Ley SV. Angew. Chem. Int. Ed. 2015; 54: 7920
• 8f Fabry DC. Ronge MA. Rueping M. Chem Eur. J. 2015; 21: 5350
• 8g Tran DN. Battilocchio C. Lou S.-B. Hawkins JM. Ley SV. Chem. Sci. 2015; 6: 1120

Reviews on the synthesis of APIs under continuous-flow conditions:
• 8h Gutmann B. Cantillo D. Kappe CO. Angew. Chem. Int. Ed. 2015; 54: 6688
• 8i Porta R. Benaglia M. Puglisi A. Org. Process Res. Dev. 2016; 20: 2
• 9 For the detailed synthesis of nitroenamines, please see the Supporting Information.
• 10 Brenna D. Porta R. Massolo E. Raimondi L. Benaglia M. ChemCatChem 2017; 9: 941
• 11 Although different experimental conditions were investigated (flow rate, temperature, stoichiometry, solvents, use of additives like thiourea), the maximum yield was 33%; low conversion and the appearance of some side products due to starting material degradation were observed and were responsible for the disappointing results.
• 12 For a recent review on nitro reduction, see: Orlandi M. Brenna D. Harms R. Jost S. Benaglia M. Org. Process Res. Dev. 2016; DOI: 10.1021/acs.oprd.6b00205.
• 13 Review on continuous-flow hydrogenation: Cossar PJ. Hizartzidis L. Simone MI. McCluskey A. Gordon CP. Org. Biomol. Chem. 2015; 13: 7119
• 14a Orlandi M. Tosi F. Bonsignore M. Benaglia M. Org. Lett. 2015; 17: 3941
• 14b Orlandi M. Benaglia M. Tosi F. Annunziata R. Cozzi F. J. Org. Chem. 2016; 81: 3037
• 14c The methodology is described in a patent: Bonsignore M. Benaglia M. EP 2892862, 2016

For the application of flow chemistry for multistep organic synthesis, see:
• 15a Newton S. Carter CF. Pearson CM. Alves LC. Lange H. Thansandote P. Ley SV. Angew. Chem. Int. Ed. 2014; 53: 4915
• 15b Wegner J. Ceylan S. Kirschning A. Adv. Synth. Catal. 2012; 354: 17
• 15c Baumann M. Baxendale IR. Ley SV. Mol. Divers. 2011; 3: 613

For some other recent representative contributions, see:
• 15d Chen M. Buchwald S. Angew. Chem. Int. Ed. 2013; 52: 4247
• 15e Baxendale IR. Ley SV. Mansfield AC. Smith CD. Angew. Chem. Int. Ed. 2009; 48: 4017
• 16 Yan Q. Liu M. Kong D. Zi G. Hou G. Chem. Commun. 2014; 50: 12870
• 17 Wang L. Shirakawa S. Maruoka K. Angew. Chem. Int. Ed. 2011; 50: 5327
• 18 Belokon YN. Pritula LK. Tararov VI. Bakhmutov VI. Struchknov YT. Timofeeva TV. Belikov VM. J. Chem. Soc., Dalton Trans. 1990; 1867