CC BY 4.0 · SynOpen 2023; 07(01): 69-75
DOI: 10.1055/a-1995-1859
Virtual Collection Click Chemistry and Drug Discovery

Photochemical Synthesis of Pyrazolines from Tetrazoles in Flow

Adam Burke
Silvia Spiccio
Mara Di Filippo
This research was supported by Science Foundation Ireland (12/RC2275_P2 and 18/RI/5702), the Royal Society of Chemistry (Research Enablement Grant; E20-2998), and the School of Chemistry through provision of a Sir Walter Hartley scholarship to M.D.F.


Pyrazolines and their pyrazole congeners are important heterocyclic building blocks with numerous applications in the fine chemical industries. However, traditional routes towards these entities are based on multistep syntheses generating substantial amounts of chemical waste. Here we report an alternative approach using UV-light to convert tetrazoles into pyrazolines via a reagent-free photo-click strategy. This route generates nitrile imine dipoles in situ that are trapped with different dipolarophiles rendering a selection of these heterocyclic targets in high chemical yields. A continuous flow method is ultimately realized that generates multigram quantities of product in a safe and readily scalable manner thus demonstrating the value of this photochemical approach for future exploitations in industry.

Supporting Information

Publication History

Received: 24 November 2022

Accepted after revision: 07 December 2022

Accepted Manuscript online:
08 December 2022

Article published online:
22 February 2023

© 2022. This is an open access article published by Thieme under the terms of the Creative Commons Attribution 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 Ahsan MJ, Ali A, Ali A, Thiriveedhi A, Bakht MA, Yusuf M, Salahuddin, Afzal O, Altamimi AS. A. ACS Omega 2022; 7: 38207
    • 1b Haider K, Shafeeque M, Yahya S, Yar MS. Eur. J. Med. Chem. Rep. 2022; 5: 100042
    • 1c Kumari P, Mishra VS, Narayana C, Khanna A, Chakrabarty A, Sagar R. Sci. Rep. 2020; 10: 6660
    • 2a Baumann M, Baxendale IR, Ley SV, Nikbin N. Beilstein J. Org. Chem. 2011; 7: 442
    • 2b Silver KS, Soderlund DM. Pestic. Biochem. Physiol. 2005; 82: 136
    • 2c Mertens L, Hock KJ, Koenigs RM. Chem. Eur. J. 2016; 22: 9542
    • 2d Alex K, Tillack A, Schwarz N, Beller M. Org. Lett. 2008; 10: 2377
    • 3a Vahedpour T, Hamzeh-Mivehroud M, Hemmati S, Dastmalchi S. ChemistrySelect 2021; 6: 6483
    • 3b Lévai A. Chem. Heterocycl. Compd. 1997; 33: 647
    • 3c Li Y, Wei L, Wan J.-P, Wen C. Tetrahedron 2017; 73: 2323
    • 3d Golovanov AA, Odin IS, Gusev DM, Vologzhanina AV, Sosnin IM, Grabovskiy SA. J. Org. Chem. 2021; 86: 7229
    • 4a Bégué D, Dargelos A, Wentrup C. J. Org. Chem. 2020; 85: 7952
    • 4b Bégué D, Qiao GG, Wentrup C. J. Am. Chem. Soc. 2012; 134: 5339
    • 4c Nunes CM, Reva I, Fausto R, Bégué D, Wentrup C. Chem. Commun. 2015; 51: 14712
    • 4d Deepthi A, Acharjee N, Sruthi SL, Meenakshy CB. Tetrahedron 2022; 116: 132812
    • 6a Wang Y, Rivera Vera CI, Lin Q. Org. Lett. 2007; 9: 4155
    • 6b Clovis JS, Eckell A, Huisgen R, Sustmann R. Chem. Ber. 1967; 100: 60
    • 6c Padwa A, Nahm S, Sato E. J. Org. Chem. 1978; 43: 1664
    • 7a Plutschack MB, Pieber B, Gilmore K, Seeberger PH. Chem. Rev. 2017; 117: 11796
    • 7b Gutmann B, Cantillo D, Kappe CO. Angew. Chem. Int. Ed. 2015; 54: 6688
    • 7c Colella M, Nagaki A, Luisi R. Chem. Eur. J. 2020; 26: 19
    • 8a Dallinger D, Gutmann B, Kappe CO. Acc. Chem. Res. 2020; 53: 1330
    • 8b Movsisyan M, Delbeke EI. P, Berton JK. E. T, Battilocchio C, Ley SV, Stevens CV. Chem. Soc. Rev. 2016; 45: 4892
    • 9a Fitzpatrick DE, Ley SV. Tetrahedron 2018; 74: 3087
    • 9b Adamo A, Beingessner RL, Behnam M, Chen J, Jamison TJ, Jensen KF, Monbaliu J.-CM, Myerson AS, Revalor EM, Snead DR, Stelzer T, Weeranoppanant N, Wong SY, Zhang P. Science 2016; 352: 61
    • 10a Breen CP, Nambiar AM. K, Jamison TF, Jensen KF. Trends Chem. 2021; 3: 373
    • 10b Gioiello A, Piccinno A, Lozza AM, Cerra B. J. Med. Chem. 2020; 63: 6624
    • 10c Baumann M, Moody TS, Smyth M, Wharry S. Org. Process Res. Dev. 2020; 24: 1802
    • 10d Baxendale IR, Brocken L, Mallia CJ. Green Process Synth. 2013; 2: 211
    • 11a Buglioni L, Raymenants F, Slattery A, Zondag SD. A, Noël T. Chem. Rev. 2022; 122: 2752
    • 11b Sambiago C, Noël T. Trends Chem. 2020; 2: 92
    • 11c 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: 1
    • 11d Rehm TH. ChemPhotoChem 2020; 4: 235
    • 11e Di Filippo M, Bracken C, Baumann M. Molecules 2020; 25: 356
  • 12 Ley SV, Chen Y, Fitzpatrick DE, May OS. Curr. Opin. Green Sustainable Chem. 2020; 25: 100353
  • 13 Donnelly K, Baumann M. J. Flow Chem. 2021; 11: 223
  • 14 Ramanathan M, Wang Y.-H, Liu S.-T. Org. Lett. 2015; 17: 5886
  • 15 CCDC 2221466, CCDC 2221467, and CCDC 2221468 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via
  • 18 Oligomerisation of the dipolarophile was observed when using the high-power LED emitting at 365 nm.