Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

The flow synthesis of heterocycles for natural product and medicinal chemistry applications


This article represents an overview of recent research from the Innovative Technology Centre in the field of flow chemistry which was presented at the FROST2 meeting in Budapest in October 2009. After a short introduction of this rapidly expanding field, we discuss some of our results with a main focus on the synthesis of heterocyclic compounds which we use in various natural product and medicinal chemistry programmes.

This is a preview of subscription content, log in to check access.


  1. 1

    Anastas PT, Warner JC (1998) Green chemistry: theory and practice. Oxford University Press, New York, p 30

  2. 2

    Seeberger PH (2009) Scavengers in full flow. Nat Chem 1: 258–260. doi:10.1038/nchem.267

  3. 3

    Lombardino JG, Lowe JA III (2004) A guide to drug discovery: the role of the medicinal chemist in drug discovery—then and now. Nat Rev Drug Discov 3: 853–862. doi:10.1038/nrd1523

  4. 4

    Ley SV, Baxendale IR (2008) The changing face of organic synthesis. Chimia 62: 162–168. doi:10.2533/chimia.2008.162

  5. 5

    Seeberger PH, Blume T (2007) New avenues to efficient chemical synthesis—emerging technologies. Springer, Berlin, Heidelberg, New York

  6. 6

    Dar YL (2004) High-throughput experimentation: a powerful enabling technology for the chemicals and materials industry. Macromol Rapid Commun 25: 34–47. doi:10.1002/marc.200300166

  7. 7

    Tierney JP, Lidström P (2005) Microwave assisted organic synthesis. Blackwell Publishing, Oxford. ISBN 1-4051-1560-2

  8. 8

    Kappe OC, Stadler A (2005) Microwaves in organic and medicinal chemistry. Wiley-VCH, Weinheim

  9. 9

    Shipe WD, Wolkenberg SE, Lindsley CW (2005) Accelerating lead development by microwave-enhanced medicinal chemistry. Drug Discov Today Technol 2: 155–161. doi:10.1016/j.ddtec.2005.05.002

  10. 10

    Gedye R, Smith F, Westaway K, Ali H, Baldisera L, Laberge L, Rousell J (1986) The use of microwave ovens for rapid organic synthesis. Tetrahedron Lett 3: 279–282. doi:10.1016/S0040-4039(00)83996-9

  11. 11

    Bonander N, Bill RM (2009) Relieving the first bottleneck in the drug discovery pipeline: using array technologies to rationalize membrane protein production. Expert Rev Proteomics 6: 501–505. doi:10.1586/epr.09.65

  12. 12

    Congreve M, Murray CW (2003) In: Hillisch A, Hilgenfeld R (eds) Modern methods of drug discovery. Series: experientia supplementum, vol 93. Birkhauser Verlag, Berlin

  13. 13

    Ojima I, Thurston DE (2009) Welcome to future medicinal chemistry. Future Med Chem 1: 1–2. doi:10.4155/FMC.09.14

  14. 14

    Grabowski M, Chruszcz M, Zimmermann MD, Kirillova O, Mino W (2009) Benefits of structural genomics for drug discovery research. Infect Disord Drug Targets 9: 459–474. doi:10.2174/187152609789105704

  15. 15

    Congreve M, Murray CW, Blundell TL (2005) Structural biology and drug discovery. Drug Discov Today 10: 895–907. doi:10.1016/S1359-6446(05)03484-7

  16. 16

    Kennedy JP, Williams L, Bridges TM, Daniels RN, Weaver D, Lindsley CW (2008) Application of combinatorial chemistry science on modern drug discovery. J Comb Chem 10: 345–354. doi:10.1021/cc700187t

  17. 17

    Murray CW, Rees DC (2009) The rise of fragment based drug discovery. Nat Chem 1: 187–192. doi:10.1038/nchem.217

  18. 18

    Verdonk ML, Rees DC (2008) Group efficiency—a guideline for hits-to leads chemistry. ChemMedChem 3: 1179–1180. doi:10.1002/cmdc.200800132

  19. 19

    Tickle I, Sharff A, Vinkovic M, Yon J, Jhoti H (2004) High throughput protein crystallography and drug discovery. Chem Soc Rev 33: 558–565. doi:10.1039/B314510G

  20. 20

    Ley SV, Baxendale IR (2008) New tools for molecule makers: emerging technologies. In: Proceedings of Bozen Symposium, systems chemistry, p 65–85. ISBN 978-8325-2188-2

  21. 21

    Ceylan S, Kirschning A (2009) Organic synthesis in mini flow reactors using immobilised catalysts. In: Benaglia M (ed) Recoverable and recyclable catalysts. John Wiley & Sons, New York, pp 379–410

  22. 22

    Hessel V, Knobloch C, Löwe H (2008) Review on patents in microreactor and microprocess engineering. Recent Pat Chem Eng 1: 1–16

  23. 23

    Carter CF, Baxendale IR, O’Brien M, Pavey JBJ, Ley SV (2009) Synthesis of acetal protected building blocks using flow chemistry and flow I.R. methods: preparation of butane-2,3-diacetal tartrates. Org Biomol Chem 7: 4594–4597. doi:10.1039/b917289k

  24. 24

    Carter CF, Baxendale IR, Pavey JBJ, Ley SV (2010) The continuous flow synthesis of butane-2,3-diacetal protected building blocks using microreactors. Org Biomol Chem 8: 1588–1595. doi:10.1039/b924309g

  25. 25

    Carter CF, Lange H, Ley SV, Baxendale IR, Wittkamp B, Goode JG, Gaunt NL (2010) ReactIR flow cell: a new analytical tool for continuous flow chemical processing. Org Process Res Dev 14: 393–404. doi:10.1021/op900305v

  26. 26

    Baxendale IR, Griffiths-Jones CM, Ley SV, Tranmer GK (2006) Preparation of the neolignan natural product Grossamide by a continous-flow process. Synlett 3: 427–430. doi:10.1055/s-2006-926244

  27. 27

    Ley SV, Baxendale IR, Bream RN, Jackson PS, Leach AG, Longbottom DA, Nesi M, Scott JS, Storer RI, Taylor SJ (2000) Multi-step organic synthesis using solid-supported reagents and scavengers: a new paradigm in chemical library generation. J Chem Soc Perkin Trans 9: 3815–4196. doi:10.1039/B006588I

  28. 28

    Kirschning A, Solodenko W, Mennecke K (2006) Comining enabling techniques in organic synthesis—continuous flow processes with heterogenized catalysts. Chem Eur J 12: 5972–5990. doi:10.1002/chem.200600236

  29. 29

    Baxendale IR, Hayward JJ, Lanners S, Ley SV, Smith CD (2008) Microreactors in organic synthesis and catalysis. In: Wirth T (ed) Organic chemistry in microreactors: heterogeneous reactions, chapter 4.2. Wiley-VCH, Weinheim, pp 84–122

  30. 30

    Jönsson D, Warrington BH, Ladlow M (2004) Automated flow-through synthesis of heterocyclic thioethers. J Comb Chem 6: 584–595. doi:10.1021/cc0499486

  31. 31

    Griffiths-Jones CM, Hopkin MD, Jonsson D, Ley SV, Tapolczay DJ, Vickerstaffe E, Ladlow M (2007) A fully automated flow-through synthesis of secondary sulphonamides in a binary reactor system. J Comb Chem 9: 422–430. doi:10.1021/cc060152b

  32. 32

    Kirschning A, Altwickler C, Dräger G, Harders J, Hoffmann N, Hoffmann U, Schönfeld H, Solodenko W, Kunz U (2001) PASSflow syntheses using functionalized monolithic polymer/glass composites in flow-through microreactors. Angew Chem Int Ed 40: 3995–3998. doi:10.1002/1521-3773(20011105)

  33. 33

    Solodenko W, Kunz U, Jas G, Kirschning A (2002) polymer-assisted Horner-Emmons olefination using pass-flow reactors: pure products without purification. Bioorg Med Chem Lett 12: 1833–1835. doi:10.1016/S0960-894X(02)00265-2

  34. 34

    The H-Cube hydrogenation system and the X-Cube system are commercially available from ThalesNano. Website: http://www.thalesnano.com; Saaby S, Knudsen KR, Ladlow M, Ley SV (2005) The Use of a Continuous Flow-Reactor Employing a Mixed Hydrogen-Liquid Flow Stream for the Efficient Reduction of Imines to Amines. J Chem Soc, Chem Commun 23:2909-2911. doi:10.1039/b504854k

  35. 35

    Baxendale IR, Griffiths-Jones CM, Ley SV, Tranmer GK (2006) Microwave-assisted Suzuki coupling reactions with encapsulated palladium catalyst for batch and continuous-flow transformations. Chem Eur J 12: 4407–4416. doi:10.1002/chem.200501400

  36. 36

    Solodenko W, Jas G, Kunz U, Kirschning A (2007) Continuous enantioselective kinetic resolution of terminal epoxides using immobilized chiral cobalt-salen complexes. Synthesis 5: 583–589. doi:10.1055/s-2007-965877

  37. 37

    Kamahori K, Ito K, Itsuno S (1996) Asymmetric Diels-Alder reaction of methacrolein with cyclopentadiene using polymer-supported catalysts: design of highly enantioselective polymeric catalysts. J Org Chem 61: 8321–8324. doi:10.1021/jo960518e

  38. 38

    Mandoli A, Orlandi S, Pini D, Salvadori P (2004) Insoluble polystyrene-bound bis(oxazoline): batch and continuous-flow heterogeneous enantioselective glyoxylate-ene reaction. Tetrahedron Asymmetry 15: 3233–3244. doi:10.1016/j.tetasy.2004.08.015

  39. 39

    Bonfils F, Cazaux I, Hodge P, Caze C (2006) Michael reactions carried out using a bench-top flow system. Org Biomol Chem 4: 493–497. doi:10.1039/B515241K

  40. 40

    Burguete MI, Cornejo A, Garcia-Verdugo E, Gil MJ, Luis SV, Mayoral JA, Martinez-Merino V, Sokolova M (2007) Pybox monolithic miniflow reactors for continuous asymmetric cyclopropanation reaction under conventional and supercritical conditions. J Org Chem 72: 4344–4350. doi:10.1021/jo070119r

  41. 41

    Hafez AM, Taggi AE, Dudding T, Lectka T (2001) Asymmetric catalysis on sequentially-linked columns. J Am Chem Soc 123: 10853–10859. doi:10.1021/ja016556j

  42. 42

    France S, Bernstein D, Weatherwax A, Lectka T (2005) Performing the synthesis of a complex molecule on sequentially linked columns: toward the development of a “synthesis machine”. Org Lett 7: 3009–3012. doi:10.1021/ol050980y

  43. 43

    Baxendale IR, Ley SV, Smith CD, Tranmer GK (2006) A flow reactor for the synthesis of peptides utilizing immobilised reagents, scavengers and catch and release protocols. Chem Commun 46: 4835–4837. doi:10.1039/b612197g

  44. 44

    Hopkin MD, Baxendale IR, Ley SV (2010) An automated flow-based synthesis of imatinib: the API of Gleevec. Chem Commun 46: 2450–2452. doi:10.1039/c001550d

  45. 45

    Qian Z, Baxendale IR, Ley SV (2010) A flow process using microreactors for the preparation of a quinolone derivative as a potent 5HT 1B Antagonist. Synlett 4: 505–508. doi:10.1055/s-0029-1219358

  46. 46

    Venturoni F, Nikbin N, Ley SV, Baxendale IR (2010) Application of flow chemistry microreactors in the preparation of casein kinase I inhibitors. Org Biomol Chem 8: 1798–1806. doi:10.1039/b925327k

  47. 47

    Baxendale IR, Deeley J, Griffiths-Jones CM, Ley SV, Saaby S, Tranmer GK (2006) A flow process for the multi-step synthesis of the alkaloid natural product oxomaritidine: a new paradigm for molecular assembly. Chem Commun 24: 2566–2568. doi:10.1039/b600382f

  48. 48

    The AFRICA flow system is commercially available from Syrris. Website: http://www.syrris.com

  49. 49

    The UniqsisFlowSyn system is commercially available from Uniqsis. Website: http://www.uniqsis.com

  50. 50

    The Advion NanoTek system is commercially available from Advion. Website: http://www.advion.com

  51. 51

    The Vapourtec R2+/R4 flow system is commercially available from Vapourtec. Website: http://www.vapourtec.com

  52. 52

    The Microreactor Explorer kit is commercially available from Aldrich. Website: http://www.sigmaaldrich.com/chemistry/chemical-synthesis/technology-spotlights/microreactor-explorer-kit.html

  53. 53

    The Labtrix system is commercially available from Chemtrix. Website: http://www.chemtrix.com/web/4/1/product.html

  54. 54

    The Future Chemistry is commercially available from Future Chemistry. Website: http://www.futurechemistry.com

  55. 55

    Baumann M, Baxendale IR, Ley SV, Smith CD, Tranmer GK (2006) Fully automated continuous flow synthesis of 4,5-disubstituted oxazoles. Org Lett 8: 5231–5234. doi:10.1021/ol061975c

  56. 56

    Quadrapure Benzylamine (QP-BZA), Quadrapure Sulfonic Acid (QP-SA), Quadrapure Dimethylamine (QP-DMA) and Quadrapure Thiourea (QP-TU) are high-loading scavengers commercially available from Johnson Matthey. Website: http://www.reaxa.com

  57. 57

    Baxendale IR, Ley SV, Smith CD, Tamborini L, Voica A-F (2008) A bifurcated pathway to thiazioles and imidazoles using a modular flow microreactor. J Comb Chem 10: 851–857. doi:10.1021/cc800070a

  58. 58

    Baxendale IR, Ley SV (2005) Formation of 4-aminopyrimidines via trimerisation of nitriles using focused microwave heating. J Comb Chem 7: 483–489. doi:10.1021/cc049826d

  59. 59

    Smith CJ, Iglesias-Sigüenza FJ, Baxendale IR, Ley IR (2007) Flow and batch mode focused microwave synthesis of 5-amino-4-cyanopyrazoles and their further conversion to 4-aminopyrazolopyrimidines. Org Biomol Chem 5: 2758–2761. doi:10.1039/b709043a

  60. 60

    Baxendale IR, Hayward JJ, Ley SV (2007) Microwave reactions under continuous flow conditions. Comb Chem High Throughput Screen 35: 802–836. doi:10.2174/138620707783220374

  61. 61

    Baxendale IR, Pitts MR (2006) Microwave flow chemistry: the next evolutionary step in synthetic chemistry? Chim Oggi Chem Today 24: 41–45 ISSN: 0392-839X

  62. 62

    Dressen MHCL, van de Kruijs BHP, Meuldijk J, Vekemans JAJM, Hulshof LA (2010) Flow processing of microwave-assisted (heterogeneous) organic reactions. Org Process Res Dev 14: 351–361. doi:10.1021/op900257f

  63. 63

    Glasnov TN, Kappe CO (2007) Microwave-assisted synthesis under continuous flow conditions. Macromol Rapid Commun 28: 395–410. doi:10.1002/marc.200600665

  64. 64

    Baxendale IR, Griffiths-Jones CM, Ley SV, Tranmer GK (2006) Microwave-assisted Suzuki coupling reactions with an encapsulated palladium catalyst for batch and continuous-flow transformations. Chem Eur J 12: 4407–4416. doi:10.1002/chem.200501400

  65. 65

    Saaby S, Baxendale IR, Ley SV (2005) Non-metal-catalysed intramolecular alkyne cyclotrimerisation reactions promoted by focused microwave heating in batch and flow modes. Org Biomol Chem 3: 3365–3368. doi:10.1002/chem.200501400

  66. 66

    Sedelmeier J, Ley SV, Lange H, Baxendale IR (2009) PdEnCAT TM TPP30 as a catalyst for the generation of functionalised aryl- and alkyl-substituted acetylenes via microwave-assisted Sonogashira type reactions. Eur J Org Chem 26: 4412–4420. doi:10.1002/ejoc.200900344

  67. 67

    Smith CD, Baxendale IR, Lanners S, Hayward JJ, Smith SC, Ley SV (2007) [3+2] Cycloaddition of acetylenes with azides to give 1,4-disubstituted 1,2,3-triazoles in a modular flow reactor. Org Biomol Chem 5: 1559–1561. doi:10.1039/b702995k

  68. 68

    Commercially available Omnifit glass columns with adjustable hight-end pieces (plunger) Typically, the solid-supported reagent is placed in an appropriately sized Omnifit column, usually 10- mm bore by 150- mm length, or shorter and the plungers are adjusted to relevant bed heights and the polymer swelled/washed with solvent. Website: http://www.omnifit.com

  69. 69

    Smith CJ, Baxendale IR, Nikbin N, Ley SV, Smith CD (2010) manuscript submitted

  70. 70

    Nikbin N, Ladlow M, Ley SV (2007) Continuous flow ligand-free Heck reactions using monolithic Pd[0] nanoparticles. Org Process Res Dev 11: 458–462. doi:10.1021/op7000436

  71. 71

    Baxendale IR, Ley SV, Mansfield AC, Smith CD (2009) Multistep synthesis using modular flow reactors: Bestmann-Ohira Reagent for the formation of alkynes and triazoles. Angew Chem Int Ed 48: 4017–4021. doi:10.1002/anie.200900970

  72. 72

    Roth GJ, Liepold B, Müller SG, Bestmann HJ (2004) Further improvements of the synthesis of alkynes from aldehydes. Synthesis 1: 59–62. doi:10.1055/s-2003-44346

  73. 73

    Baxendale IR, Schou SC, Sedelmeier J, Ley SV (2010) Multi-step synthesis by using modular flow reactors: the preparation of yne-ones and their use in heterocycle synthesis. Chem Eur J 16: 89–94. doi:10.1002/chem.200902906

  74. 74

    Baumann M, Baxendale IR, Ley SV (2010) Synthesis of 3-nitropyrrolidines via dipolar cycloaddition reactions using a modular flow reactor. Synlett 5: 749–752. doi:10.1055/s-0029-1219344

  75. 75

    Baumann M, Baxendale IR, Kirschning A, Ley SV, Wegner J (2010) Synthesis of highly substituted nitropyrrolidines, nitropyrrolizines and nitropyrroles via multicomponent-multistep sequences within a flow-reactor. Heterocycles (in print). doi:10.3987/COM-10-S(E)77

  76. 76

    Singh RP, Meshri DT, Shreeve JM (2006) DAST and Deoxofluor mediated nucleophilic fluorination reactions of organic compounds. Adv Org Synth 2: 291–326 ISSN:1574-0900

  77. 77

    Baumann M, Baxendale IR, Ley SV (2008) The use of diethylaminosulfur trifluoride (DAST) for fluorination in a continuous-flow microreactor. Synlett 14: 2111–2114. doi:10.1055/s-2008-1078026

  78. 78

    Baumann M, Baxendale IR, Martin LJ, Ley SV (2009) Development of fluorination methods using continuous-flow microreactors. Tetrahedron 65: 6611–6625. doi:10.1016/j.tet.2009.05.083

  79. 79

    Prakash GKS, Yudin AK (1997) Perfluoroalkylation with organosilicon reagents. Chem Rev 97: 757–786. doi:10.1021/cr9408991

  80. 80

    Baumann M, Baxendale IR, Ley SV, Nikbin N, Smith CD, Tierney JP (2008) A modular flow reactor for performing Curtius rearrangements as a continuous flow process. Org Biomol Chem 6: 1577–1586. doi:10.1039/b801631n

  81. 81

    Baumann M, Baxendale IR, Ley SV, Nikbin N, Smith CD (2008) Azide monoliths as convenient flow reactors for efficient Curtius rearrangement reactions. Org Biomol Chem 6: 1587–1593. doi:10.1039/b801634h

  82. 82

    Hornung CH, Mackley MR, Baxendale IR, Ley SV (2007) A microcapillary flow disc reactor for organic synthesis. Org Process Res Dev 11(3): 399–405. doi:10.1021/op700015f

  83. 83

    Hornung CH, Hallmark B, Baumann M, Baxendale IR, Ley SV, Hester P, Clayton P, Mackley MR (2010) A multiple microcapillary reactor for organic synthesis. Ind Eng Chem Res 49: 4576–4582. doi:10.1021/ie901674h

  84. 84

    Jun-ichi Y, Nagaki A, Yamada T (2008) Flash chemistry: fast chemical synthesis by using microreactors. Chem Eur J 14: 7450–7459. doi:10.1002/chem.200800582

  85. 85

    Goto S, Verlder J, Sheikh SE, Sakamoto Y, Mitani M, Elmas S, Adler A, Becker A, Neudörfl JM, Lex J, Schmalz H-G (2008) Butyllithium-mediated coupling of aryl bromides with ketones under in-situ-quench (ISQ) conditions: an efficient one-step protocol applicable to microreactor technology. Synlett 9: 1361–1365. doi:10.1055/s-2008-1072771

  86. 86

    Gustafsson T, Gilmour R, Seeberger PH (2008) Fluorination reactions in microreactors. Chem Commun 26: 3022–3024. doi:10.1039/B803695K

  87. 87

    Csajági C, Szatzker G, Tőke ER, Ürge L, Darvas F, Poppe L (2008) Enantiomer selective acylation of racemic alcohols by lipases in continuous-flow bioreactors. Tetrahedron Asymmetry 19: 237–246. doi:10.1016/j.tetasy.2008.01.002

  88. 88

    Gustafsson T, Pontén F, Seeberger PH (2008) Trimethylaluminium mediated amide bond formation in a continuous flow microreactor as key to the synthesis of rimonabant and efaproxial. Chem Commun 9:1100–1102. doi:10.1039/B719603B

  89. 89

    Kralj JG, Sahoo HR, Jensen KF (2007) Integrated continuous microfluidic liquid-liquid extraction. Lab Chip 7: 256–263. doi:10.1039/B610888A

  90. 90

    Murphy ER, Martinelli JR, Zaborenko N, Buchwald SL, Jensen KF (2007) Accelerating reactions with microreactors at elevated temperatures and pressures: profiling aminocarbonylation reactions. Angew Chem Int Ed 46: 1734–1737. doi:10.1002/anie.200604175

  91. 91

    Brandt JC, Wirth T (2009) Controlling hazardous chemicals in microreactors: synthesis with iodine azide. Beilstein J Org Chem 5(30) doi:10.3762/bjoc.5.30

  92. 92

    Grant D, Dahl R, Cosford NDP (2008) Rapid multistep synthesis of 1,2,4-oxadiazoles in a single continuous microreactor sequence. J Org Chem 73: 7219–7223. doi:10.1021/jo801152c

  93. 93

    Kulkami AA, Kalyani VS, Joshi RA, Joshi RR (2009) Continuous flow nitration of benzaldehyde. Org Process Res Dev 13: 999–1002. doi:10.1021/op900129w

  94. 94

    Hübner S, Bentrup U, Budde U, Lovis K, Dietrich T, Freitag A, Küpper L, Jähnisch K (2009) An ozonolysis-reduction sequence for the synthesis of pharmaceutical intermediates in microstructured devices. Org Process Res Dev 13: 952–960. doi:10.1021/op9000669

  95. 95

    Damm M, Glasnov TN, Kappe CO (2010) Translating high-temperature microwave chemistry to scalable continuous flow processes. Org Process Res Dev 14: 215–224. doi:10.1021/op900297e

  96. 96

    Sedelmeier J, Ley SV, Baxendale IR, Baumann M (2010) KMnO 4 mediated oxidation as a continuous flow process. Org Lett 12: 2618–2621. doi:10.1021/ol101345z

  97. 97

    Hornung CH, Hallmark B, Mackley MR, Baxendale IR, Ley SV (2010) A palladium wall coated microcapillary reactor for use in continuous flow transfer hydrogenation. Adv Synth Catal 352: 1736–1745. doi:10.1002/adsc.201000139

  98. 98

    Malet-Sanz L, Madrazak J, Ley SV, Baxendale IR (2010) Preparation of arylsulfonyl Chlorides by Chlorosulfonylation of in situ generated diazonium salts using a continuous flow reactor. Org Biomol Chem. doi:10.1039/c0ob00450b

Download references

Author information

Correspondence to Marcus Baumann.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Baumann, M., Baxendale, I.R. & Ley, S.V. The flow synthesis of heterocycles for natural product and medicinal chemistry applications. Mol Divers 15, 613–630 (2011). https://doi.org/10.1007/s11030-010-9282-1

Download citation


  • Flow synthesis
  • Micro-reactor
  • Meso-reactor
  • Solid-supported reagents
  • Heterocycles
  • Automated synthesis