CC BY-NC-ND 4.0 · SynOpen 2021; 05(01): 29-35
DOI: 10.1055/s-0040-1706016

Development of a Continuous Photochemical Benzyne-Forming Process

a   School of Chemistry, University College Dublin, Science Centre South, D04 N2E2, Dublin, Ireland
b   Department of Chemistry, University of Durham, South Road, DH1 3LE, Durham, UK
a   School of Chemistry, University College Dublin, Science Centre South, D04 N2E2, Dublin, Ireland
› Author Affiliations
This research has been enabled through funding by SSPC (European Regional Development Fund; 12/RC2275_P2) and instrumentation acquired through a recent Science Foundation Ireland Infrastructure Call 2018 (18/RI/5702). We gratefully acknowledge support from the School of Chemistry at UCD for a PhD scholarship (to CB). Support of our research through a RSC Research Enablement Grant (E20-2998 to MB) is acknowledged.


A continuous-flow process is presented that enables the safe generation and derivatization of benzyne under photochemical conditions. This is facilitated by a new high-power LED lamp emitting light at 365 nm. The resulting flow process effectively controls the release of gaseous by-products based on an adjustable backpressure regulator and delivers a series of heterocyclic products in a short residence time of 3 minutes. The robustness of this methodology is demonstrated for the rapid generation of benzotriazoles, 2H-indazoles and various furan-derived adducts, facilitating the preparation of these important heterocyclic scaffolds via a simple and readily scalable flow protocol.

Supporting Information

Publication History

Received: 23 December 2020

Accepted after revision: 07 January 2021

Article published online:
01 February 2021

© 2021. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes or adapted, remixed, transformed or built upon. (

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

  • References

    • 1a Gutmann B, Cantillo D, Kappe CO. Angew. Chem. Int. Ed. 2015; 54: 6688
    • 1b Movsisyan M, Delbeke EI. P, Berton JK. E. T, Battilocchio C, Ley SV, Stevens CV. Chem. Soc. Rev. 2016; 45: 4892
    • 1c Baumann M, Moody TS, Smyth M, Wharry S. Org. Process Res. Dev. 2020; 23: 1802
    • 1d Dallinger D, Gutmann B, Kappe CO. Acc. Chem. Res. 2020; 53: 1330
    • 2a Colella M, Nagaki A, Luisi R. Chem. Eur. J. 2020; 26: 19
    • 2b Baumann M, Moody TS, Smyth M, Wharry S. Eur. J. Org. Chem. 2020; 7398
    • 3a Sambiago C, Noël T. Trends Chem. 2020; 2: 92
    • 3b Di Filippo M, Bracken C, Baumann M. Molecules 2020; 25: 356
    • 3c Elliott LD, Knowles JP, Koovits PJ, Maskil KG, Ralph MJ, Lejeune G, Edwards LJ, Robinson RI, Clemens IR, Cox B, Pascoe DD, Koch G, Eberle M, Berry MB, Booker-Milburn KI. Chem. Eur. J. 2014; 20: 15226
  • 4 Rehm TH. ChemPhotoChem 2020; 4: 235

    • For selected recent examples, see:
    • 5a Steiner A, Roth PM. C, Strauss FJ, Gauron G, Tekautz G, Winter M, Williams JD, Kappe CO. Org. Process Res. Dev. 2020; 24: 2208
    • 5b Levesque F, Di Maso MJ, Narsimhan K, Wismer MK, Naber JR. Org. Process Res. Dev. 2020; 24: 2935
    • 5c Williams JD, Nakano M, Gerardy R, Rincon JA, de Frutos O, Mateos C, Monbaliu J.-CM, Kappe CO. Org. Process Res. Dev. 2019; 23: 78
    • 5d Alcazar J, Abdiaj I. Bioorg. Med. Chem. 2017; 25: 6190
    • 5e Cochran JE, Waal N. Org. Process Res. Dev. 2016; 20: 1533
    • 6a Levesque F, Seeberger PH. Angew. Chem. Int. Ed. 2012; 51: 1706
    • 6b Kopetzki D, Levesque F, Seeberger PH. Chem. Eur. J. 2013; 19: 5450
    • 6c Turconi J, Griolet F, Guevel R, Oddon G, Villa R, Geatti A, Hvala M, Rossen K, Göller R, Burgard A. Org. Process Res. Dev. 2014; 18: 417
    • 6d Triemer S, Gilmore K, Vu GT, Seeberger PH, Seidel-Morgenstern A. Angew. Chem. Int. Ed. 2018; 57: 5525

      For previous reports on generating benzynes in flow, see:
    • 7a Browne DL, Wright S, Deadman BJ, Dunnage S, Baxendale IR, Turner RM, Ley SV. Rapid Commun. Mass Spectrom. 2012; 26: 1999
    • 7b Nagaki A, Ichinari D, Yoshida J. J. Am. Chem. Soc. 2014; 136: 12245
    • 7c Susanne F, Martin B, Aubry M, Sedelmeier J, Lima F, Sevinc S, Piccioni L, Haber J, Schenkel B, Venturoni F. Org. Process Res. Dev. 2017; 21: 1779
    • 7d Tan Z, Li Z, Jin G, Yu C. Org. Process Res. Dev. 2019; 23: 31
  • 8 Himenshima Y, Sonoda T, Kobayashi H. Chem. Lett. 1983; 12: 1211
    • 9a Wenk HH, Winkler M, Sander W. Angew. Chem. Int. Ed. 2003; 42: 502
    • 9b Takikawa H, Nishii A, Sakaib T, Suzuki K. Chem. Soc. Rev. 2018; 47: 8030
    • 9c Pellissier H, Santelli M. Tetrahedron 2003; 59: 701
  • 10 Goetz AE, Garg NK. J. Org. Chem. 2014; 79: 846 ; and references therein
  • 11 Chang D, Zhu D, Shi L. J. Org. Chem. 2015; 80: 5928
    • 12a Maki Y, Furuta T, Suzuki M. J. Chem. Soc., Perkin Trans. 1979; 1: 553
    • 12b Maki Y, Furuta T, Kuzuya M, Suzuki M. J. Chem. Soc., Chem. Commun. 1975; 616
  • 13 Gann AW, Amoroso JW, Einck VJ, Rice PW, Chambers JJ, Schnarr NA. Org. Lett. 2014; 16: 2003
  • 14 CCDC 2051221 contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via

    • For recent examples, see:
    • 15a Bonciolini S, Di Filippo M, Baumann M. Org. Biomol. Chem. 2020; 18: 9428
    • 15b Di Filippo M, Baumann M. Eur. J. Org. Chem. 2020; 6199
    • 15c Laudadio G, Deng Y, van der Wal K, Ravelli D, Nuno M, Fagnoni M, Guthrie D, Sun Y, Noël T. Science 2020; 369: 92
  • 16 Briguglio I, Piras S, Corona P, Gavini E, Nieddu M, Boatto G, Carta A. Eur. J. Org. Chem. 2015; 612
    • 17a Zhang S.-G, Liang C.-G, Zhang W.-H. Molecules 2018; 23: 2738
    • 17b Cerecetto H, Gerpe A, Gonzalez M, Aran V, de Ocariz C. Mini-Rev. Med. Chem. 2005; 5: 869
    • 17c Gaikwad DD, Chapolikar AD, Devkate CG, Warad KD, Tayade AP, Pawar RP, Domb AJ. Eur. J. Med. Chem. 2015; 90: 707
    • 18a Applegate J, Turnbull K. Synthesis 1988; 1011
    • 18b Azarifar D, Ghasemnejad-Borsa H. Synthesis 2006; 1123
    • 18c Browne DL, Vivat JF, Plant A, Gomez-Bengoa E, Harrity JP. A. J. Am. Chem. Soc. 2009; 131: 7762
    • 18d Fang Y, Wu C, Larock RC, Shi F. J. Org. Chem. 2011; 76: 8840
  • 19 Larock and co-workers observed a similar outcome using 4-nitrophenyl sydnone when no 2H-indazole product was isolated, whereas monochlorinated benzene appendages were tolerated, see reference 18d.
  • 20 CCDC 2051222 contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via
  • 21 The high-power LED system used in this study is available from Vapourtec (