Synthesis 2012; 44(15): 2469-2473
DOI: 10.1055/s-0032-1316550
paper
© Georg Thieme Verlag Stuttgart · New York

Reductive Amination by Continuous-Flow Hydrogenation: Direct and Scalable Synthesis of a Benzylpiperazine

Jing Liu*
Janssen Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA, Fax: +1(858)3203354   Email: jliu30@its.jnj.com
,
Anne E. Fitzgerald
Janssen Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA, Fax: +1(858)3203354   Email: jliu30@its.jnj.com
,
Neelakandha S. Mani
Janssen Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA, Fax: +1(858)3203354   Email: jliu30@its.jnj.com
› Author Affiliations
Further Information

Publication History

Received: 19 March 2012

Accepted after revision: 18 May 2012

Publication Date:
02 July 2012 (eFirst)

Abstract

A benzylpiperazine was prepared directly from the corresponding benzaldehyde and piperazine on a continuous-flow hydrogenation apparatus. The synthesis was protecting group free, safe, and environmentally friendly. Large-scale synthesis under flow hydrogenation conditions was also demonstrated.

Supporting Information

 
  • References

  • 1 Borch RF, Bernstein MD, Durst HD. J. Am. Chem. Soc. 1971; 93: 2897
    • 2a Abdel-Magid AF, Carson KG, Harris BD, Maryanoff CA, Shah RD. J. Org. Chem. 1996; 61: 3849
    • 2b Abdel-Magid AF, Mehrman SJ. Org. Process Res. Dev. 2006; 10: 971 ; and references cited therein
  • 3 Trost BM. Science 1991; 254: 1471
  • 4 Apodaca R, Xiao W. Org. Lett. 2001; 3: 1745
  • 5 Micovic IV, Ivanovic MD, Piatak DM, Bojic VD. Synthesis 1991; 1043
  • 6 Suwa T, Sugiyama E, Shibata I, Baba A. Synlett 2000; 556

    • For select examples, see:
    • 7a Robichaud A, Ajjou AN. Tetrahedron Lett. 2006; 47: 3633
    • 7b Xing L, Cheng C, Zhu R, Zhang B, Wang X, Hu Y. Tetrahedron 2008; 64: 11783
    • 7c Erathodiyil N, Ooi S, Seayad AM, Han Y, Lee SS, Ying JY. Chem.–Eur. J. 2008; 14: 3118
    • 7d Bhor MD, Bhanushali MJ, Nandurkar NS, Bhanage BM. Tetrahedron Lett. 2008; 49: 965
    • 8a Jones RV, Godorhazy L, Varga N, Szalay D, Urge L, Darvas F. J. Comb. Chem. 2006; 8: 110
    • 8b Yoswathananont N, Nitta K, Nishiuchi Y, Sato M. Chem. Commun. 2005; 40
    • 8c O’Brien M, Taylor N, Polyzos A, Baxendale IR, Ley SV. Chem. Sci. 2011; 2: 1250

      For select examples of flow-hydrogenation applications, see:
    • 9a Irfan M, Petricci E, Glasnov TN, Taddei M, Kappe CO. Eur. J. Org. Chem. 2009; 1327
    • 9b Knudsen KR, Holden J, Ley SV, Ladlow M. Adv. Synth. Catal. 2007; 349: 535
    • 9c Franckevicius V, Knudsen KR, Ladlow M, Longbottom DA, Ley SV. Synlett 2006; 889
  • 10 Saaby S, Knudsen KR, Ladlow M, Ley SV. Chem. Commun. 2005; 2909
  • 11 At the time of manuscript preparation, another example of reductive amination with a secondary amine on a flow-hydrogenation apparatus was reported: Cooper CG. F, Lee ER, Silva RA, Bourque AJ, Clark S, Katti S, Novorozhkin V. Org. Process Res. Dev 2012; 16: 1090
  • 12 The price difference is on a per mole basis. From the same vendor (Sigma-Aldrich), N-Boc piperazine costs $335/25 g, or $2500/mol; piperazine costs $16/100 g, or $14/mol at the time the manuscript was written
  • 13 Process Mass Intensity (PMI) is the total mass of raw materials input divided by the mass of final Active Pharmaceutical Ingredient (API) output. It is one of the benchmarks to measure the environmental impact and sustainability of chemical processes. For a review of such benchmarks, see: Constable DJ. C, Curzons AD, Cunningham VL. Green Chem. 2002; 4: 521
  • 14 Reactions were conducted using a commercially available instrument, the H-Cube (manufactured by ThalesNano Nanotechnology Inc. in Budapest, Hungary)
  • 15 A preliminary NMR experiment was performed to monitor formation of intermediate (s). Equal molar of 2 and piperazine were dissolved in CD3OD and allowed to stand at r.t. for 48 h. 1H NMR showed mainly three compounds in the ratio of 1:1:0.2. The structures were tentatively assigned to aldehyde 2, piperazine hemiaminal methyl ether, and dimethyl ketal, respectively
  • 16 Cartridges for H-Cube and H-Cube Midi contain catalyst of different particle sizes. The actual difference varies based on the nature of catalyst and the batches. For an excellent analysis of various parameters that can impact cartridge performances, see: Bryan MC, Wernick D, Hein CD, Petersen JV, Eschelbach JW, Doherty EM. Beilstein J. Org. Chem. 2011; 7: 1141
  • 17 Keith JM, Liu J. PCT Int. Appl WO139951, 2011 ; Chem. Abstr. 2011, 155, 637818
  • 18 Bretherick’s Handbook of Reactive Chemical Hazards . Vol. 1, 7th ed. Urben PG. Elsevier; Amsterdam: 2007: 1980