Journal of Flow Chemistry

, Volume 8, Issue 1, pp 35–43 | Cite as

Catalyst-free reductive amination of levulinic acid to N-substituted pyrrolidinones with formic acid in continuous-flow microreactor

  • Tengfei Ma
  • Hong-Yu Zhang
  • Guohui Yin
  • Jiquan Zhao
  • Yuecheng Zhang
Full Paper


The reductive amination of levulinic acid to N-substituted pyrrolidinones was performed in a continuous-flow microreactor (CFMR) in high yield, using formic acid as hydrogen source and acetonitrile as the reaction solvent. The developed protocol allows the avoidance of high boiling solvents such as DMSO and the additive triethylamine, more commonly associated with this synthetic transformation. As a result, the reaction products are more readily separated from the low boiling solvent.

Graphical abstract

The continuous reductive amination of levulinic acid with amines to N-substituted pyrrolidones was performed in a continuous-flow microreactor in high yield, using formic acid as hydrogen source and acetonitrile as the reaction solvent under catalyst-free conditions.


Continuous-flow microreactor Levulinic acid Amines Reductive amination N-substituted pyrrolidinones 



We thank the National Natural Science Foundation of China (Grant No. 21476057), the Natural Science Foundation of Hebei Province (CN) (Grant No. B2016202393, B2015202284), and the Program for the Top Young Innovative Talents of Hebei Province (CN) (Grant No. BJ2017010) for financial support. We thank Dr. Charlotte Wiles (Chief Executive Officer of Chemtrix BV, the Netherlands) for revising the manuscript.

Supplementary material

41981_2018_5_MOESM1_ESM.docx (702 kb)
ESM 1 (DOCX 701 kb)


  1. 1.
    Hooper J, Watts P (2007). J Label Compd Radiopharm 50:189–196CrossRefGoogle Scholar
  2. 2.
    Wiles C, Watts P (2014). Green Chem 16:55–62CrossRefGoogle Scholar
  3. 3.
    Plutschack MB, Pieber B, Gilmore K, Seeberger PH (2017). Chem Rev 117:11796–11893CrossRefGoogle Scholar
  4. 4.
    Tonhauser C, Natalello A, Löwe H, Frey H (2012). Macromolecules 45:9551–9570CrossRefGoogle Scholar
  5. 5.
    Hartman RL, McMullen JP, Jensen KF (2011). Angew Chem Int Ed 50:7502–7519CrossRefGoogle Scholar
  6. 6.
    Jahnisch K, Hessel V, Lowe H, Baerns M (2004). Angew Chem Int Ed 43:406–446CrossRefGoogle Scholar
  7. 7.
    Cambie D, Bottecchia C, Straathof NJ, Hessel V, Noel T (2016). Chem Rev 116:10276–10341CrossRefGoogle Scholar
  8. 8.
    Skelton V, Greenway GM, Haswell SJ, Styring P, Morgan DO, Warrington BH, Wong SYF (2001). Analyst 126:11–13CrossRefGoogle Scholar
  9. 9.
    Greenway GM, Haswell SJ, Morgan DO, Skelton V, Styring P (2000). Sensors Actuators B Chem 63:153–158CrossRefGoogle Scholar
  10. 10.
    Schwolow S, Heikenwälder B, Abahmane L, Kockmann N, Röder T (2014). Org Process Res Dev 18:1535–1544CrossRefGoogle Scholar
  11. 11.
    Sachse A, Hulea V, Finiels A, Coq B, Fajula F, Galarneau A (2012). J Catal 287:62–67CrossRefGoogle Scholar
  12. 12.
    Wiles C, Watts P (2012). ChemSusChem 5:332–338CrossRefGoogle Scholar
  13. 13.
    Newman SG, Gu L, Lesniak C, Victor G, Meschke F, Abahmane L, Jensen KF (2014). Green Chem 16:176–180CrossRefGoogle Scholar
  14. 14.
    Watts P, Wiles C, Haswell SJ, Pombo-Villar E, Styring P (2001) Chem Commun 0:990–991Google Scholar
  15. 15.
    Sadler S, Sebeika MM, Kern NL, Bell DE, Laverack CA, Wilkins DJ, Moeller AR, Nicolaysen BC, Kozlowski PN, Wiles C, Tinder RJ, Jones GB (2014). J Flow Chem 4:140–147CrossRefGoogle Scholar
  16. 16.
    Wiles C, Watts P, Haswell SJ, Pombo-Villar E (2002). Tetrahedron Lett 43:2945–2948CrossRefGoogle Scholar
  17. 17.
    Saxena RC, Adhikari DK, Goyal HB (2009). Renew Sust Energ Rev 13:167–178CrossRefGoogle Scholar
  18. 18.
    González-García S, Gullón B, Rivas S, Feijoo G, Moreira MT (2016). J Clean Prod 120:170–180CrossRefGoogle Scholar
  19. 19.
    Kuo C-H, Poyraz AS, Jin L, Meng Y, Pahalagedara L, Chen S-Y, Kriz DA, Guild C, Gudz A, Suib SL (2014). Green Chem 16:785–791CrossRefGoogle Scholar
  20. 20.
    Herbst A, Janiak C (2017). CrystEngComm 19:4092–4117CrossRefGoogle Scholar
  21. 21.
    Zhang Y, Yan X, Niu B, Zhao J (2016). Green Chem 18:3139–3151CrossRefGoogle Scholar
  22. 22.
    Zhang Y, Zhai X, Zhang H, Zhao J (2017). RSC Adv 7:23647–23656CrossRefGoogle Scholar
  23. 23.
    Kang S, Yu J (2016). Biomass Bioenergy 95:214–220CrossRefGoogle Scholar
  24. 24.
    Nhien LC, Long NVD, Lee M (2016). Chem Eng Res Des 107:126–136CrossRefGoogle Scholar
  25. 25.
    Bozell JJ, Petersen GR (2010). Green Chem 12:539–554CrossRefGoogle Scholar
  26. 26.
    Thapa I, Mullen B, Saleem A, Leibig C, Baker RT, Giorgi JB (2017). Appl Catal A Gen 539:70–79CrossRefGoogle Scholar
  27. 27.
    Liu Y, Li H, He J, Zhao W, Yang T, Yang S (2017). Catal Commun 93:20–24CrossRefGoogle Scholar
  28. 28.
    Touchy AS, Hakim Siddiki SMA, Kon K, Shimizu K-i (2014). ACS Catal 4:3045–3050CrossRefGoogle Scholar
  29. 29.
    Hengst K, Schubert M, Carvalho HWP, Lu C, Kleist W, Grunwaldt J-D (2015). Appl Catal A Gen 502:18–26CrossRefGoogle Scholar
  30. 30.
    Omoruyi U, Page S, Hallett J, Miller PW (2016). ChemSusChem 9:2037–2047CrossRefGoogle Scholar
  31. 31.
    Sonoda N, Tsutsumi S (1963). Bull Chem Soc Jpn 36:1311–1313CrossRefGoogle Scholar
  32. 32.
    Zainol MM, Amin NAS, Asmadi M (2017). Fuel Process Technol 167:431–441CrossRefGoogle Scholar
  33. 33.
    Akiyama S, Niki T, Utsunomiya T, Watanabe J, Nishioka M, Suzuki H, Hayasaka F, Kamagishi K (2000) Eur Pat 1020447Google Scholar
  34. 34.
    Matviiuk T, Madacki J, Mori G, Orena BS, Menendez C, Kysil A, Andre-Barres C, Rodriguez F, Kordulakova J, Mallet-Ladeira S, Voitenko Z, Pasca MR, Lherbet C, Baltas M (2016). Eur J Med Chem 123:462–475CrossRefGoogle Scholar
  35. 35.
    Vidal JD, Climent MJ, Corma A, Concepcion DP, Iborra S (2017). ChemSusChem 10:119–128CrossRefGoogle Scholar
  36. 36.
    Li Z, Song L, Li C (2013). J Am Chem Soc 135:4640–4643CrossRefGoogle Scholar
  37. 37.
    Yu M, Stevenson K, Zhou G (2014). Tetrahedron Lett 55:5591–5594CrossRefGoogle Scholar
  38. 38.
    Qi J, Sun C, Tian Y, Wang X, Li G, Xiao Q, Yin D (2014). Org Lett 16:190–192CrossRefGoogle Scholar
  39. 39.
    Shilling WL (1966) U.S. Patent 3235562Google Scholar
  40. 40.
    Croock LR, Jansen BA, Spencer KE, Watson DH (1966) GB Patent 1036694Google Scholar
  41. 41.
    Van der Stoel RE, Bosma MAR, Janssen PHJ, Van de Moesdijk CGM (1985) U.S. Patent 4560760Google Scholar
  42. 42.
    Manzer LE (2006) U.S. Patent 7129362Google Scholar
  43. 43.
    Manzer LE (2006) US 0247444Google Scholar
  44. 44.
    Vidal JD, Climent MJ, Concepcion P, Corma A, Iborra S, Sabater MJ (2015). ACS Catal 5:5812–5821CrossRefGoogle Scholar
  45. 45.
    Huang YB, Dai JJ, Deng XJ, Qu YC, Guo QX, Fu Y (2011). ChemSusChem 4:1578–1581CrossRefGoogle Scholar
  46. 46.
    Wei Y, Wang C, Jiang X, Xue D, Li J, Xiao J (2013). Chem Commun 49:5408–5410CrossRefGoogle Scholar
  47. 47.
    Albert J, Wölfel R, Bösmann A, Wasserscheid P (2012). Energy Environ Sci 5:7956–7962CrossRefGoogle Scholar
  48. 48.
    Fang Q, Hanna MA (2002). Bioresour Technol 81:187–192CrossRefGoogle Scholar
  49. 49.
    Flannelly T, Lopes M, Kupiainen L, Dooley S, Leahy JJ (2016). RSC Adv 6:5797–5804CrossRefGoogle Scholar
  50. 50.
    Wei Y, Wang C, Jiang X, Xue D, Liu Z-T, Xiao J (2014). Green Chem 16:1093–1096CrossRefGoogle Scholar
  51. 51.
    Ledoux A, Kuigwa LS, Framery E, Andrioletti B (2015). Green Chem 17:3251–3254CrossRefGoogle Scholar
  52. 52.
    Wu C, Luo X, Zhang H, Liu X, Ji G, Liu Z, Liu Z (2017). Green Chem 19:3525–3529CrossRefGoogle Scholar
  53. 53.
    Ortiz-Cervantes C, Flores-Alamo M, García JJ (2016). Tetrahedron Lett 57:766–771CrossRefGoogle Scholar

Copyright information

© Akadémiai Kiadó 2018

Authors and Affiliations

  1. 1.School of Chemical Engineering and TechnologyHebei University of TechnologyTianjinPeople’s Republic of China
  2. 2.National-Local Joint Engineering Laboratory for Energy Conservation of Chemical Process Integration and Resources UtilizationHebei University of TechnologyTianjinPeople’s Republic of China

Personalised recommendations