Advertisement

Flow-Assisted Synthesis of Heterocycles at High Temperatures

  • Ryan J. Sullivan
  • Stephen G. NewmanEmail author
Chapter
Part of the Topics in Heterocyclic Chemistry book series (TOPICS, volume 56)

Abstract

Performing selective and high-yielding transformations on complex organic molecules at temperatures in the range of 200–450°C may at first seem counterintuitive or even impossible. However, using continuous flow systems, conditions of this sort are indeed accessible and viable for useful chemistry. This review highlights recent endeavors in heterocycle synthesis and modification enabled by high-temperature (>200°C) flow chemistry, with emphasis placed on showcasing the variety and synthetic utility of different high-temperature enabled transformations. The reviewed content naturally falls into three categories: pericyclic transformations, condensation reactions, and modification/functionalization of heterocycles. Different shortcomings and considerations necessary when planning high-temperature flow reactions have also been highlighted where applicable.

Keywords

Condensation Flow chemistry Heterocycles High-temperature high-pressure Novel process windows Pericyclic 

References

  1. 1.
    Rudnick LR, Bartz WJ (2013) Comparison of synthetic, mineral oil, and bio-based lubricant fluids. In: Rudnick LR (ed) Synthetics, mineral oils, and bio-based lubricants, 2nd edn. CRC Press, Boca Raton, pp 347–366CrossRefGoogle Scholar
  2. 2.
    Atkins P, De Paula J (2010) Atkin’s physical chemistry, 9th edn. Oxford University Press, OxfordGoogle Scholar
  3. 3.
    Kappe CO, Dallinger D, Murphree SS (2009) Practical microwave synthesis for organic chemists – strategies, instruments, and protocols. Wiley-VCH, WeinheimGoogle Scholar
  4. 4.
    Leadbeater NE (ed) (2010) Microwave heating as a tool for sustainable chemistry. CRC Press, Boca RatonGoogle Scholar
  5. 5.
    Larhed M, Olofsson K (eds) (2006) Microwave methods in organic synthesis. Springer, HeidelbergGoogle Scholar
  6. 6.
    Galema SA (1997) Microwave chemistry. Chem Soc Rev 26:233–238CrossRefGoogle Scholar
  7. 7.
    Lidström P, Tierney J, Wathey B, Westman J (2001) Microwave assisted organic synthesis – a review. Tetrahedron 57:9225–9283CrossRefGoogle Scholar
  8. 8.
    Kappe CO (2004) Controlled microwave heating in modern organic synthesis. Angew Chem Int Ed 43:6250–6284CrossRefGoogle Scholar
  9. 9.
    de la Hoz A, Diaz-Ortiz A, Prieto P (2016) Microwave-assisted green organic synthesis. In: Stefanidis G, Stankiewicz A (eds) Alternative energy sources for green chemistry. Royal Society of Chemistry, Cambridge, pp 1–33Google Scholar
  10. 10.
    Damm M, Glasnov TN, Kappe CO (2010) Translating high-temperature microwave chemistry to scalable continuous flow processes. Org Process Res Dev 14:215–224CrossRefGoogle Scholar
  11. 11.
    Glasnov TN, Kappe CO (2011) The microwave-to-flow paradigm: translating high-temperature batch microwave chemistry to scalable continuous-flow processes. Chem Eur J 17:11956–11968CrossRefPubMedGoogle Scholar
  12. 12.
    Razzaq T, Kappe CO (2010) Continuous flow organic synthesis under high-temperature/pressure conditions. Chem Asian J 5:1274–1289PubMedGoogle Scholar
  13. 13.
    Gutmann B, Cantillo D, Kappe CO (2015) Continuous-flow technology – a tool for the safe manufacturing of active pharmaceutical ingredients. Angew Chem Int Ed 54:6688–6728CrossRefGoogle Scholar
  14. 14.
    Plutschack MB, Pieber B, Gilmore K, Seeberger PH (2017) The hitchhiker’s guide to flow chemistry. Chem Rev 117:11796–11893CrossRefPubMedGoogle Scholar
  15. 15.
    Porta R, Benaglia M, Puglisi A (2016) Flow chemistry: recent developments in the synthesis of pharmaceutical products. Org Process Res Dev 20:2–25CrossRefGoogle Scholar
  16. 16.
    Malet-Sanz L, Susanne F (2012) Continuous flow synthesis. A pharma perspective. J Med Chem 55:4062–4098CrossRefPubMedGoogle Scholar
  17. 17.
    Movsisyan M, Delbeke EIP, Berton JKET, Battilocchio C, Ley SV, Stevens CV (2016) Taming hazardous chemistry by continuous flow technology. Chem Soc Rev 45:4892–4928CrossRefPubMedGoogle Scholar
  18. 18.
    Britton J, Raston CL (2017) Multi-step continuous-flow synthesis. Chem Soc Rev 46:1250–1271CrossRefPubMedGoogle Scholar
  19. 19.
    Newman SG, Jensen KF (2013) The role of flow in green chemistry and engineering. Green Chem 15:1456–1472CrossRefGoogle Scholar
  20. 20.
    Vaccaro L (ed) (2017) Sustainable flow chemistry: methods and applications. Wiley-VCH, WeinheimGoogle Scholar
  21. 21.
    Lummiss JAM, Morse PD, Beingessner RL, Jamison TF (2017) Towards more efficient, greener syntheses through flow chemistry. Chem Rec 17:667–680CrossRefPubMedGoogle Scholar
  22. 22.
    Eckert CA, Knutson BL, Debenedetti PG (1996) Supercritical fluids as solvents for chemical and materials processing. Nature 383:313–318CrossRefGoogle Scholar
  23. 23.
    Jessop PG, Leitner W (eds) (1999) Chemical synthesis using supercritical fluids. Wiley-VCH, WeinheimGoogle Scholar
  24. 24.
    van Eldik R, Klärner F-G (eds) (2002) High pressure chemistry: synthetic, mechanistic, and supercritical applications. Wiley-VCH, WeinheimGoogle Scholar
  25. 25.
    Adeyemi A, Bergman J, Brånalt J, Sävmarker J, Larhed M (2017) Continuous flow synthesis under high-temperature/high-pressure conditions using a resistively heated flow reactor. Org Process Res Dev 21:947–955CrossRefGoogle Scholar
  26. 26.
    May SA, Johnson MD, Braden TM, Calvin JR, Haeberle BD, Jines AR, Miller RD, Plocharczyk EF, Rener GA, Richey RN, Schmid CR, Vaid RK, Yu H (2012) Rapid development and scale-up of a 1H-4-substituted imidazole intermediate enabled by chemistry in continuous plug flow reactors. Org Process Res Dev 16:982–1002CrossRefGoogle Scholar
  27. 27.
    Houk KN, Gonzalez J, Li Y (1995) Pericyclic reaction transition states: passions and punctilios, 1935–1995. Acc Chem Res 28:81–90CrossRefGoogle Scholar
  28. 28.
    Fleming I (2015) Pericyclic reactions, 2nd edn. Oxford University Press, OxfordGoogle Scholar
  29. 29.
    Spangler CW (1976) Thermal [1,j] sigmatropic rearrangements. Chem Rev 76:187–217CrossRefGoogle Scholar
  30. 30.
    Borukhova S, Noël T, Metten B, de Vos E, Hessel V (2013) Solvent- and catalyst-free Huisgen cycloaddition to rufinamide in flow with a greener, less expensive dipolarophile. ChemSusChem 6:2220–2225CrossRefPubMedGoogle Scholar
  31. 31.
    Gutmann B, Roduit J-P, Roberge D, Kappe CO (2010) Synthesis of 5-substituted 1H-tetrazoles from nitriles and hydrazoic acid by using a safe and scalable high-temperature microreactor approach. Angew Chem Int Ed 49:7101–7105CrossRefGoogle Scholar
  32. 32.
    Gutmann B, Obermayer D, Roduit J-P, Roberge DM, Kappe CO (2012) Safe generation and synthetic utilization of hydrazoic acid in a continuous flow reactor. J Flow Chem 2:8–19CrossRefGoogle Scholar
  33. 33.
    Gutmann B, Glasnov TN, Razzaq T, Goessler W, Roberge DM, Kappe CO (2011) Unusual behavior in the reactivity of 5-substituted-1H-tetrazoles in a resistively heated microreactor. Beilstein J Org Chem 7:503–517CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Varas AC, Noël T, Wang Q, Hessel V (2012) Copper(I)-catalyzed azide–alkyne cycloadditions in microflow: catalyst activity, high-T operation, and an integrated continuous copper scavenging unit. ChemSusChem 5:1703–1707CrossRefPubMedGoogle Scholar
  35. 35.
    Palde PB, Jamison TF (2011) Safe and efficient tetrazole synthesis in a continuous-flow microreactor. Angew Chem Int Ed 50:3525–3528CrossRefGoogle Scholar
  36. 36.
    Lengyel L, Nagy TZ, Sipos G, Jones R, Dormán G, Ürge L, Darvas F (2012) Highly efficient thermal cyclization reactions of alkylidene esters in continuous flow to give aromatic/heteroaromatic derivatives. Tetrahedron Lett 53:738–743CrossRefGoogle Scholar
  37. 37.
    Lengyel LC, Sipos G, Sipőcz T, Vágó T, Dormán G, Gerencsér J, Makara G, Darvas F (2015) Synthesis of condensed heterocycles by the Gould–Jacobs reaction in a novel three-mode pyrolysis reactor. Org Process Res Dev 19:399–409CrossRefGoogle Scholar
  38. 38.
    Tsoung J, Bogdan AR, Kantor S, Wang Y, Charaschanya M, Djuric SW (2017) Synthesis of fused pyrimidinone and quinolone derivatives in an automated high-temperature and high-pressure flow reactor. J Org Chem 82:1073–1084CrossRefPubMedGoogle Scholar
  39. 39.
    Cantillo D, Sheibani H, Kappe CO (2012) Flash flow pyrolysis: mimicking flash vacuum pyrolysis in a high-temperature/high-pressure liquid-phase microreactor environment. J Org Chem 77:2463–2473CrossRefPubMedGoogle Scholar
  40. 40.
    Bogaert-Alvarez RJ, Demena P, Kodersha G, Polomski RE, Soundararajan N, Wang SSY (2001) Continuous processing to control a potentially hazardous process: conversion of aryl 1,1-dimethylpropargyl ethers to 2,2-dimethylchromenes (2,2-dimethyl-2H-1-benzopyrans). Org Process Res Dev 5:636–645CrossRefGoogle Scholar
  41. 41.
    Martin RE, Morawitz F, Kuratli C, Alker AM, Alanine AI (2012) Synthesis of annulated pyridines by intramolecular inverse-electron-demand hetero-Diels–Alder reaction under superheated continuous flow conditions. Eur J Org Chem 2012:47–52CrossRefGoogle Scholar
  42. 42.
    Lehmann J, Alzieu T, Martin RE, Britton R (2013) The Kondrat’eva reaction in flow: direct access to annulated pyridines. Org Lett 15:3550–3553CrossRefPubMedGoogle Scholar
  43. 43.
    Tsoung J, Wang Y, Djuric SW (2017) Expedient Diels–Alder cycloadditions with ortho-quinodimethanes in a high temperature/pressure flow reactor. React Chem Eng 2:458–461CrossRefGoogle Scholar
  44. 44.
    Jouanno L-A, Chevalier A, Sekkat N, Perzo N, Castel H, Romieu A, Lange N, Sabot C, Renard P-Y (2014) Kondrat’eva ligation: Diels–Alder-based irreversible reaction for bioconjugation. J Org Chem 79:10353–10366CrossRefPubMedGoogle Scholar
  45. 45.
    Alvarez-Builla J, Vaquero JJ, Barluenga J (eds) (2011) Modern heterocyclic chemistry. Wiley-VCH, WeinheimGoogle Scholar
  46. 46.
    Joule JA, Mills K (2010) Heterocyclic chemistry, 5th edn. Wiley-Blackwell, New YorkGoogle Scholar
  47. 47.
    Herath A, Cosford NDP (2010) One-step continuous flow synthesis of highly substituted pyrrole-3-carboxylic acid derivatives via in situ hydrolysis of tert-butyl esters. Org Lett 12:5182–5185CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Obermayer D, Glasnov TN, Kappe CO (2011) Microwave-assisted and continuous flow multistep synthesis of 4-(pyrazol-1-yl)carboxanilides. J Org Chem 76:6657–6669CrossRefPubMedGoogle Scholar
  49. 49.
    Darvas F, Dorman G, Lengyel L, Kovacs I, Jones R, Urge L (2009) High pressure, high temperature reactions in continuous flow; merging discovery and process chemistry. Chim Oggi Chem Today 27:40–43Google Scholar
  50. 50.
    Nagao I, Ishizaka T, Kawanami H (2016) Rapid production of benzazole derivatives by a high-pressure and high-temperature water microflow chemical process. Green Chem 18:3494–3498CrossRefGoogle Scholar
  51. 51.
    Grant D, Dahl R, Cosford NDP (2008) Rapid multistep synthesis of 1,2,4-oxadiazoles in a single continuous microreactor sequence. J Org Chem 73:7219–7223CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Seki T, Kokubo Y, Ichikawa S, Suzuki T, Kayaki Y, Ikariya T (2009) Mesoporous silica-catalysed continuous chemical fixation of CO2 with N,N′-dimethylethylenediamine in supercritical CO2: the efficient synthesis of 1,3-dimethyl-2-imidazolidinone. Chem Commun:349–351Google Scholar
  53. 53.
    Streng ES, Lee DS, George MW, Poliakoff M (2017) Continuous N-alkylation reactions of amino alcohols using γ-Al2O3 and supercritical CO2: unexpected formation of cyclic ureas and urethanes by reaction with CO2. Beilstein J Org Chem 13:329–337CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Pagano N, Herath A, Cosford NDP (2011) An automated process for a sequential heterocycle/multicomponent reaction: multistep continuous flow synthesis of 5-(thiazol-2-yl)-3,4-dihydropyrimidin-2(1H)-ones. J Flow Chem 1:28–31CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Jin J, Guidi S, Abada Z, Amara Z, Selva M, George MW, Poliakoff M (2017) Continuous niobium phosphate catalysed Skraup reaction for quinoline synthesis from solketal. Green Chem 19:2439–2447CrossRefGoogle Scholar
  56. 56.
    Yan C, Fraga-Dubreuil J, Garcia-Verdugo E, Hamley PA, Poliakoff M, Pearson I, Coote AS (2008) The continuous synthesis of ε-caprolactam from 6-aminocapronitrile in high-temperature water. Green Chem 10:98–103CrossRefGoogle Scholar
  57. 57.
    Bunnett JF, Zahler RE (1951) Aromatic nucleophilic substitution reactions. Chem Rev 49:273–412CrossRefGoogle Scholar
  58. 58.
    Terrier F (2013) Modern nucleophilic aromatic substitution. Wiley-VCH, WeinheimCrossRefGoogle Scholar
  59. 59.
    Razzaq T, Glasnov TN, Kappe CO (2009) Continuous-flow microreactor chemistry under high-temperature/pressure conditions. Eur J Org Chem 2009:1321–1325CrossRefGoogle Scholar
  60. 60.
    Hamper BC, Tesfu E (2007) Direct uncatalyzed amination of 2-chloropyridine using a flow reactor. Synlett 2007:2257–2261CrossRefGoogle Scholar
  61. 61.
    Petersen TP, Larsen AF, Ritzén A, Ulven T (2013) Continuous flow nucleophilic aromatic substitution with dimethylamine generated in situ by decomposition of DMF. J Org Chem 78:4190–4195CrossRefPubMedGoogle Scholar
  62. 62.
    Charaschanya M, Bogdan AR, Wang Y, Djuric SW (2016) Nucleophilic aromatic substitution of heterocycles using a high-temperature and high-pressure flow reactor. Tetrahedron Lett 57:1035–1039CrossRefGoogle Scholar
  63. 63.
    Bogdan AR, Charaschanya M, Dombrowski AW, Wang Y, Djuric SW (2016) High-temperature Boc deprotection in flow and its application in multistep reaction sequences. Org Lett 18:1732–1735CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Centre for Catalysis Research and Innovation, Department of Chemistry and Biomolecular SciencesUniversity of OttawaOttawaCanada

Personalised recommendations