Skip to main content
SpringerLink
Log in

Continuous Flow Generation of Highly Reactive Organometallic Intermediates: A Recent Update

  • Review
  • Published:
Journal of Flow Chemistry Aims and scope Submit manuscript

Abstract

Reactive organometallic intermediates present a distinct opportunity for the creation of novel carbon-carbon and carbon-heteroatom bonds. Whereas their utility in synthesis is well-established, the thermal sensitivity of these species often imposes the requirement for stringent reaction conditions, including strict control of reaction temperatures, concentrations, and use of additives. Moreover, their strong reactivity can pose challenges in achieving the desired selectivity. Since pioneering works in the 2000s, the advent of flow microreactor technology has revolutionized this field, expanding the possibilities of reactive organometallic intermediates within synthetic chemistry. In this review, we provide an overview of the recent advancements in this dynamic area, focusing on breakthroughs that have emerged within the past four years.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Scheme 1
Scheme 2
Scheme 3
Scheme 4
Scheme 5
Scheme 6
Scheme 7
Scheme 8
Scheme 9
Scheme 10
Scheme 11
Scheme 12
Scheme 13
Scheme 14
Scheme 15
Scheme 16
Scheme 17
Scheme 18
Scheme 19
Scheme 20
Scheme 21
Scheme 22
Scheme 23
Scheme 24
Scheme 25
Scheme 26
Scheme 27
Scheme 28
Scheme 29
Scheme 30
Scheme 31
Scheme 32
Scheme 33
Scheme 34
Scheme 35
Scheme 36
Scheme 37
Scheme 38
Scheme 39
Scheme 40
Scheme 41
Scheme 42
Scheme 43
Scheme 44
Scheme 45
Scheme 46
Scheme 47
Scheme 48
Scheme 49
Scheme 50
Scheme 51
Scheme 52
Scheme 53
Scheme 54

Similar content being viewed by others

References

  1. Capaldo L, Wen Z, Noël T (2023) A field guide to flow chemistry for synthetic organic chemists. Chem Sci 14:4230–4247. https://doi.org/10.1039/D3SC00992K

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Buglioni L, Raymenants F, Slattery A, Zondag SDA, Noël T (2022) Technological innovations in photochemistry for organic synthesis: flow chemistry, high-throughput experimentation, scale-up, and photoelectrochemistry. Chem Rev 122:2752–2906. https://doi.org/10.1021/acs.chemrev.1c00332

    Article  CAS  PubMed  Google Scholar 

  3. Noël T, Cao Y, Laudadio G (2019) The fundamentals behind the use of flow reactors in electrochemistry. Acc Chem Res 52:2858–2869. https://doi.org/10.1021/acs.accounts.9b00412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Colella M, Carlucci C, Luisi R (2018) Supported catalysts for continuous flow synthesis. Top Curr Chem 376:46. https://doi.org/10.1007/s41061-018-0225-0

    Article  CAS  Google Scholar 

  5. Razzaq T, Kappe CO (2010) Continuous flow organic synthesis under high-temperature/pressure conditions. Chem Asian J. https://doi.org/10.1002/asia.201000010

    Article  PubMed  Google Scholar 

  6. Kockmann N, Thenée P, Fleischer-Trebes C, Laudadio G, Noël T (2017) Safety assessment in development and operation of modular continuous-flow processes. React Chem Eng 2:258–280. https://doi.org/10.1039/C7RE00021A

    Article  CAS  Google Scholar 

  7. Gutmann B, Kappe CO (2017) Forbidden chemistries — paths to a sustainable future engaging continuous processing. J Flow Chem 7:65–71. https://doi.org/10.1556/1846.2017.00009

    Article  CAS  Google Scholar 

  8. Gutmann B, Cantillo D, Kappe CO (2015) Continuous-flow technology—a tool for the safe manufacturing of active pharmaceutical ingredients. Angew Chem Int Ed 54:6688–6728. https://doi.org/10.1002/anie.201409318

    Article  CAS  Google Scholar 

  9. Dong Z, Wen Z, Zhao F, Kuhn S (2021) Scale-up of micro- and milli-reactors: an overview of strategies, design principles and applications. Chem Engin Sci: X 10:100097. https://doi.org/10.1016/j.cesx.2021.100097

    Article  CAS  Google Scholar 

  10. Zondag SDA, Mazzarella D, Noël T (2023) Scale-up of photochemical reactions: transitioning from lab scale to industrial production. Annu Rev Chem Biomol Eng 14:283–300. https://doi.org/10.1146/annurev-chembioeng-101121-074313

    Article  CAS  PubMed  Google Scholar 

  11. Plutschack MB, Pieber B, Gilmore K, Seeberger PH (2017) The Hitchhiker’s guide to flow chemistry. Chem Rev 117:11796–11893. https://doi.org/10.1021/acs.chemrev.7b00183

    Article  CAS  PubMed  Google Scholar 

  12. Hone C, Kappe CO (2021) Towards the standardization of flow chemistry protocols for organic reactions. Chem-Methods 1:454–467. https://doi.org/10.1002/cmtd.202100059

    Article  CAS  Google Scholar 

  13. Harenberg JH, Weidmann N, Knochel P (2020) Continuous-flow reactions mediated by main group organometallics. Synlett 31:1880–1887. https://doi.org/10.1055/s-0040-1706536

    Article  CAS  Google Scholar 

  14. Nagaki A, Ashikari Y, Takumi M, Tamaki T (2021) Flash chemistry makes impossible organolithium chemistry possible. Chem Lett 50:485–492. https://doi.org/10.1246/cl.200837

    Article  CAS  Google Scholar 

  15. Yoshida J, Kim H, Nagaki A (2017) “Impossible” chemistries based on flow and micro. J Flow Chem 7:60–64. https://doi.org/10.1556/1846.2017.00017

    Article  CAS  Google Scholar 

  16. Natho P, Luisi R (2023) Flow chemistry as green technology for the genesis and use of organometallic reagents in the synthesis of key building blocks and APIs – An update. Tetrahedron Green Chem 2:100015. https://doi.org/10.1016/j.tgchem.2023.100015

    Article  Google Scholar 

  17. Scattolin T, Simoens A, Stevens CV, Nolan SP (2022) Flow chemistry of main group and transition metal complexes. Trends Chem 4:584–607. https://doi.org/10.1016/j.trechm.2022.04.001

    Article  CAS  Google Scholar 

  18. Colella M, Nagaki A, Luisi R (2020) Flow technology for the genesis and use of (highly) reactive organometallic reagents. Chem Eur J 26:19–32. https://doi.org/10.1002/chem.201903353

    Article  CAS  PubMed  Google Scholar 

  19. Inoue K, Okano K (2020) Trapping of transient organolithium compounds. Asian J Org Chem 9:1548–1561. https://doi.org/10.1002/ajoc.202000339

    Article  CAS  Google Scholar 

  20. Zhao T, Micouin L, Piccardi R (2019) Synthesis of organometallic compounds in flow. Helv Chim Acta 102:e19001. https://doi.org/10.1002/hlca.201900172

    Article  CAS  Google Scholar 

  21. Degennaro L, Carlucci C, De Angelis S, Luisi R (2016) Flow technology for organometallic-mediated synthesis. J Flow Chem 6:136–166. https://doi.org/10.1556/1846.2016.00014

    Article  CAS  Google Scholar 

  22. Kim H, Nagaki A, Yoshida JI (2011) A flow-microreactor approach to protecting-group-free synthesis using organolithium compounds. Nat Commun 2:264. https://doi.org/10.1038/ncomms1264

    Article  CAS  PubMed  Google Scholar 

  23. Yoshida J, Kim H, Nagaki A (2011) Green and sustainable chemical synthesis using flow microreactors. ChemSusChem 4:331–340. https://doi.org/10.1002/cssc.201000271

    Article  CAS  PubMed  Google Scholar 

  24. Luisi R, Degennaro L, Colella M (2022) Lithium complexes in organic synthesis. In: Comprehensive Organometallic Chemistry IV. Elsevier, pp 2–56

  25. Köbrich G, Akhtar A, Ansari F, Breckoff WE, Büttner H, Drischel W, Fischer RH, Flory K, Fröhlich H, Goyert W, Heinemann H, Hornke I, Merkle HR, Trapp H, Zündorf W (1967) Chemistry of Stable α-Halogenoorganolithium Compounds and the Mechanism of Carbenoid Reactions. Angewandte Chemie Int Edition English 6:41–52. https://doi.org/10.1002/anie.196700411

    Article  Google Scholar 

  26. Pace V, Holzer W, De Kimpe N (2016) Lithium halomethylcarbenoids: preparation and use in the homologation of carbon electrophiles. Chem Record 16:2061–2076. https://doi.org/10.1002/tcr.201600011

    Article  CAS  Google Scholar 

  27. Gioiello A, Ceccarelli G, Colella M, Luisi R (2023) Streamlining C1 homologation reactions using continuous flow technology: focus on diazomethane and methyllithium chemistry. In: Homologation Reactions. Wiley, pp 143–190

  28. Colella M, Tota A, Großjohann A, Carlucci C, Aramini A, Sheikh NS, Degennaro L, Luisi R (2019) Straightforward chemo- and stereoselective fluorocyclopropanation of allylic alcohols: exploiting the electrophilic nature of the not so elusive fluoroiodomethyllithium. Chem Commun 55:8430–8433. https://doi.org/10.1039/c9cc03394g

    Article  CAS  Google Scholar 

  29. Monticelli S, Colella M, Pillari V, Tota A, Langer T, Holzer W, Degennaro L, Luisi R, Pace V (2019) Modular and chemoselective strategy for the direct access to α-fluoroepoxides and aziridines via the addition of fluoroiodomethyllithium to carbonyl-like compounds. Org Lett 21:584–588. https://doi.org/10.1021/acs.orglett.8b04001

    Article  CAS  PubMed  Google Scholar 

  30. Parisi G, Colella M, Monticelli S, Romanazzi G, Holzer W, Langer T, Degennaro L, Pace V, Luisi R (2017) Exploiting a “beast” in carbenoid chemistry: development of a straightforward direct nucleophilic fluoromethylation strategy. J Am Chem Soc 139:13648–13651. https://doi.org/10.1021/jacs.7b07891

    Article  CAS  PubMed  Google Scholar 

  31. Colella M, Musci P, Andresini M, Spennacchio M, Degennaro L, Luisi R (2022) The synthetic versatility of fluoroiodomethane: recent applications as monofluoromethylation platform. Org Biomol Chem 20:4669–4680. https://doi.org/10.1039/D2OB00670G

    Article  CAS  PubMed  Google Scholar 

  32. Colella M, Tota A, Takahashi Y, Higuma R, Ishikawa S, Degennaro L, Luisi R, Nagaki A (2020) Fluoro-substituted methyllithium chemistry: external quenching method using flow microreactors. Angewan Chem - Int Edition 59:10924–10928. https://doi.org/10.1002/anie.202003831

    Article  CAS  Google Scholar 

  33. Spennacchio M, Colella M, Andresini M, Dibenedetto RS, Graziano E, Aramini A, Degennaro L, Luisi R (2022) Unlocking geminal fluorohaloalkanes in nucleophilic fluoroalkylation chemistry: generation and trapping of lithiumfluorocarbenoids enabled by flow microreactors. Chem Commun 59:1373–1376. https://doi.org/10.1039/d2cc06717j

    Article  CAS  Google Scholar 

  34. Musci P, Colella M, Sivo A, Romanazzi G, Luisi R, Degennaro L (2020) Flow microreactor technology for taming highly reactive chloroiodomethyllithium carbenoid: direct and chemoselective synthesis of α-chloroaldehydes. Org Lett 22:3623–3627. https://doi.org/10.1021/acs.orglett.0c01085

    Article  CAS  PubMed  Google Scholar 

  35. Von Keutz T, Cantillo D, Kappe CO (2019) Continuous flow synthesis of terminal epoxides from ketones using in situ generated bromomethyl lithium. Org Lett 21:10094–10098. https://doi.org/10.1021/acs.orglett.9b04072

    Article  CAS  Google Scholar 

  36. Kuhwald C, Kirschning A (2021) Matteson reaction under flow conditions: iterative homologations of terpenes. Org Lett 23:4300–4304. https://doi.org/10.1021/acs.orglett.1c01222

    Article  CAS  PubMed  Google Scholar 

  37. Okamoto K, Higuma R, Muta K, Fukumoto K, Tsuchihashi Y, Ashikari Y, Nagaki A (2023) External flash generation of carbenoids enables monodeuteration of dihalomethanes. Chemistry – A European Journal. https://doi.org/10.1002/chem.202301738

  38. Hafner A, Meisenbach M, Sedelmeier J (2016) Flow Chemistry on Multigram Scale: Continuous Synthesis of Boronic Acids within 1 s. Org Lett 18:3630–3633. https://doi.org/10.1021/acs.orglett.6b01681

    Article  CAS  PubMed  Google Scholar 

  39. Hafner A, Mancino V, Meisenbach M, Schenkel B, Sedelmeier J (2017) Dichloromethyllithium: synthesis and application in continuous flow mode. Org Lett 19:786–789. https://doi.org/10.1021/acs.orglett.6b03753

    Article  CAS  PubMed  Google Scholar 

  40. Lima F, Meisenbach M, Schenkel B, Sedelmeier J (2021) Continuous flow as an enabling technology: a fast and versatile entry to functionalized glyoxal derivatives. Org Biomol Chem 19:2420–2424. https://doi.org/10.1039/d1ob00288k

    Article  CAS  PubMed  Google Scholar 

  41. Colella M, Musci P, Cannillo D, Spennacchio M, Aramini A, Degennaro L, Luisi R (2021) Development of a continuous flow synthesis of 2-substituted azetines and 3-substituted azetidines by using a common synthetic precursor. J Org Chem 86:13943–13954. https://doi.org/10.1021/acs.joc.1c01297

    Article  CAS  PubMed  Google Scholar 

  42. Tyler JL, Aggarwal VK (2023) Synthesis and applications of Bicyclo[1.1.0]butyl and azabicyclo[1.1.0]butyl organometallics. Chemistry – A European Journal 29:e202300008. https://doi.org/10.1002/chem.202300008

  43. Musci P, Colella M, Andresini M, Degennaro L, Luisi R (2022) Synthesis and strain-release reactions of 1-azabicyclo[1.1.0]butanes: an update. Arkivoc 2023:33–49. https://doi.org/10.24820/ark.5550190.p011.844

  44. Musci P, von Keutz T, Belaj F, Degennaro L, Cantillo D, Kappe CO, Luisi R (2021) Flow technology for telescoped generation, lithiation and electrophilic (C3) functionalization of highly strained 1-azabicyclo[1.1.0]butanes. Angewandte Chem - Int Edition 60:6395–6399. https://doi.org/10.1002/anie.202014881

    Article  CAS  Google Scholar 

  45. Musci P, Colella M, Andresini M, Aramini A, Degennaro L, Luisi R (2022) Flow technology enabled preparation of C3-heterosubstituted 1-azabicyclo[1.1.0]butanes and azetidines: accessing unexplored chemical space in strained heterocyclic chemistry. Chem Comm 58:6356–6359. https://doi.org/10.1039/d2cc01641a

    Article  CAS  PubMed  Google Scholar 

  46. Kwong A, Firth JD, Farmer TJ, O’Brien P (2021) Rapid “high” temperature batch and flow lithiation-trapping of N-Boc pyrrolidine. Tetrahedron 81:131899. https://doi.org/10.1016/j.tet.2020.131899

    Article  CAS  Google Scholar 

  47. Beak P, Lee W-K (1989) α-Lithioamine synthetic equivalents from dipole-stabilized carbanions: The t-Boc group as an activator for α′-lithiation of carbamates. Tetrahedron Lett 30:1197–1200. https://doi.org/10.1016/S0040-4039(00)72714-6

    Article  CAS  Google Scholar 

  48. Kestemont JP, Frost JR, Jacq J, Pasau P, Perl F, Brown J, Tissot M (2022) Scale-Up and optimization of a continuous flow carboxylation of N-Boc-4,4-difluoropiperidine using s-BuLi in THF. Org Process Res Dev 26:635–639. https://doi.org/10.1021/acs.oprd.1c00092

    Article  CAS  Google Scholar 

  49. Donnelly K, Baumann M (2021) A continuous flow synthesis of [1.1.1]propellane and bicyclo[1.1.1]pentane derivatives. Chem Commun 57:2871–2874. https://doi.org/10.1039/d0cc08124h

    Article  CAS  Google Scholar 

  50. Wang S, Panayides JL, Riley D, Tighe CJ, Hellgardt K, Hii KK, Miller PW (2021) Rapid formation of 2-lithio-1-(triphenylmethyl)imidazole and substitution reactions in flow. React Chem Eng 6:2018–2023. https://doi.org/10.1039/d1re00343g

    Article  CAS  Google Scholar 

  51. Okano K, Yamane Y, Nagaki A, Mori A (2020) Trapping of transient thienyllithiums generated by deprotonation of 2,3-or 2,5-dibromothiophene in a flow microreactor. Synlett 31:1913–1918. https://doi.org/10.1055/s-0040-1706479

    Article  CAS  Google Scholar 

  52. Brégent T, Ivanova MV, Poisson T, Jubault P, Legros J (2022) Continuous-flow divergent lithiation of 2,3-dihalopyridines: deprotolithiation versus halogen dance. Chem - Europ J 28:e202202286. https://doi.org/10.1002/chem.202202286

    Article  CAS  Google Scholar 

  53. Takahashi Y, Ashikari Y, Takumi M, Shimizu Y, Jiang Y, Higuma R, Ishikawa S, Sakaue H, Shite I, Maekawa K, Aizawa Y, Yamashita H, Yonekura Y, Colella M, Luisi R, Takegawa T, Fujita C, Nagaki A (2019) Synthesis of biaryls having a piperidylmethyl group based on space integration of lithiation, borylation, and Suzuki-Miyaura coupling. Eur J Org Chem 2020:618–622. https://doi.org/10.1002/ejoc.201901729

    Article  CAS  Google Scholar 

  54. Lee HJ, Kwak C, Kim DP, Kim H (2021) Continuous-flow Si-H functionalizations of hydrosilanesviasequential organolithium reactions catalyzed by potassiumtert-butoxide. Green Chem 23:1193–1199. https://doi.org/10.1039/d0gc03213a

    Article  CAS  Google Scholar 

  55. Nagaki A, Ashikari Y, Kawaguchi T, Mandai K, Aizawa Y, Nagaki A (2020) A synthetic approach to dimetalated arenes using flow microreactors and the switchable application to chemoselective cross-coupling reactions. J Am Chem Soc 142:17039–17047. https://doi.org/10.1021/jacs.0c06370

    Article  CAS  PubMed  Google Scholar 

  56. Ichinari D, Ashikari Y, Mandai K, Aizawa Y, Yoshida J, Nagaki A (2019) A novel approach to functionalization of aryl azides through the generation and reaction of organolithium species bearing masked azides in flow microreactors. Angew Chem Int Ed 59:1567–1571

    Article  Google Scholar 

  57. Djukanovic D, Heinz B, Mandrelli F, Mostarda S, Filipponi P, Martin B, Knochel P (2021) Continuous flow acylation of (hetero)aryllithiums with polyfunctional N, N-dimethylamides and tetramethylurea in toluene. Chem - A Eur J 27:13977–13981. https://doi.org/10.1002/chem.202102805

    Article  CAS  Google Scholar 

  58. Weidmann N, Nishimura RHV, Harenberg JH, Knochel P (2021) Halogen-lithium exchange of sensitive (hetero)aromatic halides under Barbier conditions in a continuous flow set-up. Synthesis (Germany) 53:557–568. https://doi.org/10.1055/s-0040-1707259

    Article  CAS  Google Scholar 

  59. Lima F, André J, Marziale A, Greb A, Glowienke S, Meisenbach M, Schenkel B, Martin B, Sedelmeier J (2020) Continuous Flow as enabling technology: synthesis of heteroaromatic sulfinates as bench stable cross-coupling partners. Org Lett 22:6082–6085. https://doi.org/10.1021/acs.orglett.0c02155

    Article  CAS  PubMed  Google Scholar 

  60. Wong JYF, Barker G (2020) Recent advances in benzylic and heterobenzylic lithiation. Tetrahedron 76:131704. https://doi.org/10.1016/j.tet.2020.131704

    Article  CAS  Google Scholar 

  61. Ashikari Y, Tamaki T, Kawaguchi T, Furusawa M, Yonekura Y, Ishikawa S, Takahashi Y, Aizawa Y, Nagaki A (2021) Switchable chemoselectivity of reactive intermediates formation and their direct use in a flow microreactor. Chem - A Eur J 27:16107–16111. https://doi.org/10.1002/chem.202103183

    Article  CAS  Google Scholar 

  62. Jiang Y, Yorimitsu H (2022) Taming highly unstable radical anions and 1,4-organodilithiums by flow microreactors: controlled reductive dimerization of styrenes. JACS Au 2:2514–2521. https://doi.org/10.1021/jacsau.2c00375

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Wong JYF, Thomson CG, Vilela F, Barker G (2021) Flash chemistry enables high productivity metalation-substitution of 5-alkyltetrazoles. Chem Sci 12:13413–13424. https://doi.org/10.1039/d1sc04176b

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Weidmann N, Harenberg JH, Knochel P (2020) Continuous flow preparation of (hetero)benzylic lithiums via iodine-lithium exchange reaction under Barbier conditions. Org Lett 22:5895–5899. https://doi.org/10.1021/acs.orglett.0c01991

    Article  CAS  PubMed  Google Scholar 

  65. Kremsmair A, Wilke HR, Harenberg JH, Bissinger BRG, Simon MM, Alandini N, Knochel P (2023) In situ quench reactions of enantioenriched secondary alkyllithium reagents in batch and continuous flow using an I/Li-Exchange. Angewandte Chemie - Int Edition 62:e202214377. https://doi.org/10.1002/anie.202214377

    Article  CAS  Google Scholar 

  66. Andresini M, Carret S, Degennaro L, Ciriaco F, Poisson J, Luisi R (2022) Multistep continuous flow synthesis of isolable NH2-sulfinamidines via nucleophilic addition to transient sulfurdiimide. Chem - Eur J 28:e202202066. https://doi.org/10.1002/chem.202202066

    Article  CAS  PubMed  Google Scholar 

  67. Mulks FF, Pinho B, Platten AWJ, Andalibi MR, Expósito AJ, Edler KJ, Hevia E, Torrente-Murciano L (2022) Continuous, stable, and safe organometallic reactions in flow at room temperature assisted by deep eutectic solvents. Chem 8:3382–3394. https://doi.org/10.1016/j.chempr.2022.11.004

    Article  CAS  Google Scholar 

  68. Nagaki A, Yamashita H, Hirose K, Tsuchihashi Y, Yoshida J (2019) Alkyllithium compounds bearing electrophilic functional groups: a flash chemistry approach. Angew Chem Int Ed 58:4027–4030. https://doi.org/10.1002/anie.201814088

    Article  CAS  Google Scholar 

  69. Nagaki A, Sasatsuki K, Ishiuchi S, Miuchi N, Takumi M, Yoshida J (2019) Synthesis of Functionalized Ketones from Acid Chlorides and Organolithiums by Extremely Fast Micromixing. Chem Eur J 25:4946–4950. https://doi.org/10.1002/chem.201900743

    Article  CAS  PubMed  Google Scholar 

  70. Seto M, Masada S, Usutani H, Cork DG, Fukuda K, Kawamoto T (2019) Application of continuous flow-flash chemistry to scale-up synthesis of 5-cyano-2-formylbenzoic acid. Org Proc Res Dev 23:1420–1428. https://doi.org/10.1021/acs.oprd.9b00180

    Article  CAS  Google Scholar 

  71. Lee HJ, Torii D, Jeon Y, Yoshida J, Kim H (2020) Integrated synthesis using isothiocyanate-substituted aryllithiums by flow chemistry. Synlett 31:1899–1902. https://doi.org/10.1055/s-0040-1707251

    Article  CAS  Google Scholar 

  72. Ashikari Y, Guan K, Nagaki A (2022) Flash functional group-tolerant biaryl-synthesis based on integration of lithiation, zincation and Negishi coupling in flow. Frontiers in Chemical Engineering 4:. https://doi.org/10.3389/fceng.2022.964767

  73. von Keutz T, Williams JD, Kappe CO (2021) Flash chemistry approach to organometallic C-glycosylation for the synthesis of remdesivir. Org Proc Res Dev 25:1015–1021. https://doi.org/10.1021/acs.oprd.1c00024

    Article  CAS  Google Scholar 

  74. Paymode DJ, Cardoso FSP, Agrawal T, Tomlin JW, Cook DW, Burns JM, Stringham RW, Sieber JD, Gupton BF, Snead DR (2020) Expanding access to remdesivir via an improved pyrrolotriazine synthesis: supply centered synthesis. Org Lett 22:7656–7661. https://doi.org/10.1021/acs.orglett.0c02848

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Siegel D, Hui HC, Doerffler E et al (2017) Discovery and synthesis of a phosphoramidate prodrug of a pyrrolo[2,1- f ][triazin-4-amino] adenine C-nucleoside (GS-5734) for the treatment of ebola and emerging viruses. J Med Chem 60:1648–1661. https://doi.org/10.1021/acs.jmedchem.6b01594

    Article  CAS  PubMed  Google Scholar 

  76. Polterauer D, Williams JD, Hone CA, Oliver Kappe C (2021) Telescoped lithiation, C-arylation and methoxylation in flow-batch hybrid toward the synthesis of canagliflozin. Tetrahedron Lett 82:153351. https://doi.org/10.1016/j.tetlet.2021.153351

    Article  CAS  Google Scholar 

  77. Ivanova M, Legros J, Poisson T, Jubault P (2022) Continuous flow synthesis of Celecoxib from 2-bromo-3,3,3-trifluoropropene. J Flow Chem 12:147–151. https://doi.org/10.1007/s41981-021-00205-x

    Article  CAS  PubMed  Google Scholar 

  78. Cole KP, Argentine MD, Conder EW, Vaid RK, Feng P, Jia M, Huang P, Liu P, Sun B, Tadayon S, Zhu C, Zhu R (2020) Development and production of an enantioselective tetrahydroisoquinoline synthesis enabled by continuous cryogenic lithium-halogen exchange. Org Proc Res Dev 24:2043–2054. https://doi.org/10.1021/acs.oprd.0c00141

    Article  CAS  Google Scholar 

  79. Alonso M, Garcia MC, McKay C, Thorp LR, Webb M, Edwards LJ (2021) Use of lithium diisopropylamide in flow: operability and safety challenges encountered on a multigram scale. Org Proc Res Dev 25:988–1000. https://doi.org/10.1021/acs.oprd.1c00015

    Article  CAS  Google Scholar 

  80. Ramanjaneyulu BT, Vidyacharan S, Ahn GN, Kim DP (2020) Ultrafast synthesis of 2-(benzhydrylthio)benzo[d]oxazole, an antimalarial drug, via an unstable lithium thiolate intermediate in a capillary microreactor. React Chem Eng 5:849–852. https://doi.org/10.1039/d0re00038h

    Article  CAS  Google Scholar 

  81. Sharma BM, Nikam AV, Lahore S, Ahn G, Kim D (2022) Cyanide‐free cyanation of sp2 and sp‐carbon atoms by an oxazole‐based masked CN source using flow microreactors. Chem Eur J 28. https://doi.org/10.1002/chem.202103777

  82. Sun M, Li J, Liang C, Shan C, Shen X, Cheng R, Ma Y, Ye J (2021) Practical and rapid construction of 2-pyridyl ketone library in continuous flow. J Flow Chem 11:91–98. https://doi.org/10.1007/s41981-020-00120-7

    Article  CAS  Google Scholar 

  83. Heinz B, Djukanovic D, Filipponi P, Martin B, Karaghiosoff K, Knochel P (2021) Regioselective difunctionalization of pyridines via 3,4-pyridynes. Chem Sci 12:6143–6147. https://doi.org/10.1039/D1SC01208H

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Huck L, de la Hoz A, Díaz-Ortiz A, Alcázar J (2017) grignard reagents on a tab: direct magnesium insertion under flow conditions. Org Lett 19:3747–3750. https://doi.org/10.1021/acs.orglett.7b01590

    Article  CAS  PubMed  Google Scholar 

  85. von Keutz T, Cantillo D, Kappe CO (2020) Organomagnesium based flash chemistry: continuous flow generation and utilization of halomethylmagnesium intermediates. Org Lett 22:7537–7541. https://doi.org/10.1021/acs.orglett.0c02725

    Article  CAS  Google Scholar 

  86. von Keutz T, Williams JD, Kappe CO (2020) Continuous Flow C-glycosylation via metal-halogen exchange: process understanding and improvements toward efficient manufacturing of remdesivir. Org Proc Res Dev 24:2362–2368. https://doi.org/10.1021/acs.oprd.0c00370

    Article  CAS  Google Scholar 

  87. Reynard G, Wimmer E, Richelet J, Fourquez J, Lebel H (2023) Chemoselective borylation of bromoiodoarene in continuous flow: synthesis of bromoarylboronic acids. J Flow Chem 13:21–29. https://doi.org/10.1007/s41981-022-00246-w

    Article  CAS  Google Scholar 

  88. Petersen TP, Becker MR, Knochel P (2014) Continuous flow magnesiation of functionalized heterocycles and acrylates with TMPMgCl⋅LiCl. Angewandte Chem Int Edition 53:7933–7937. https://doi.org/10.1002/anie.201404221

    Article  CAS  Google Scholar 

  89. Ketels M, Konrad DB, Karaghiosoff K, Trauner D, Knochel P (2017) Selective lithiation, magnesiation, and zincation of unsymmetrical azobenzenes using continuous flow. Org Lett 19:1666–1669. https://doi.org/10.1021/acs.orglett.7b00460

    Article  CAS  PubMed  Google Scholar 

  90. Ketels M, Ganiek MA, Weidmann N, Knochel P (2017) Synthesis of polyfunctional diorganomagnesium and diorganozinc reagents through in situ trapping halogen–lithium exchange of highly functionalized (hetero)aryl halides in continuous flow. Angewandte Chem Int Edition 56:12770–12773. https://doi.org/10.1002/anie.201706609

    Article  CAS  Google Scholar 

  91. Ketels M, Ziegler D, Knochel P (2017) Selective zincation of 1,2-dicyanobenzene and related benzonitriles in continuous flow using in situ trapping metalations. Synlett 28:2817–2822. https://doi.org/10.1055/s-0036-1588837

    Article  CAS  Google Scholar 

  92. Zhang H, Buchwald SL (2017) Palladium-catalyzed Negishi coupling of α-CF3 oxiranyl zincate: access to chiral CF3-substituted benzylic tertiary alcohols. J Am Chem Soc 139:11590–11594. https://doi.org/10.1021/jacs.7b06630

    Article  CAS  PubMed  Google Scholar 

  93. Roesner S, Buchwald SL (2016) Continuous-flow synthesis of biaryls by Negishi cross-coupling of fluoro- and trifluoromethyl-substituted (hetero)arenes. Angewandte Chem Int Edition 55:10463–10467. https://doi.org/10.1002/anie.201605584

    Article  CAS  Google Scholar 

  94. Herath A, Molteni V, Pan S, Loren J (2018) Generation and cross-coupling of organozinc reagents in flow. Org Lett 20:7429–7432. https://doi.org/10.1021/acs.orglett.8b03156

    Article  CAS  PubMed  Google Scholar 

  95. Kandasamy M, Huang YH, Ganesan B, Senadi GC, Lin W (2019) In situ generation of alkynylzinc and its subsequent Negishi reaction in a flow reactor. Eur J Org Chem 2019:4349–4356. https://doi.org/10.1002/ejoc.201900471

    Article  CAS  Google Scholar 

  96. Sathiyalingam S, Roesner S (2022) Synthesis of α- and β-carbolines by a metalation/Negishi cross-coupling/SNAr reaction sequence. Adv Synth Catal 364:1769–1774. https://doi.org/10.1002/adsc.202200127

    Article  CAS  Google Scholar 

  97. Kwon Y, Lee S, Shin I, Kim W (2023) Regioselective ortho-arylation of polyhalo-substituted (hetero)aryl tosylates using an integrated continuous flow/batch protocol. Adv Synth Catal 365:263–268. https://doi.org/10.1002/adsc.202201194

    Article  CAS  Google Scholar 

  98. Ju E, Lee M, Song J, Kwon Y, Kim W (2023) Integrated continuous-flow/batch protocol for ortho-selective alkynylation of (hetero)aryl tosylates. Bull Korean Chem Soc 44:772–776. https://doi.org/10.1002/bkcs.12717

    Article  CAS  Google Scholar 

  99. Kelly SM, Lebl R, Malig TC et al (2023) Synthesis of a highly functionalized quinazoline organozinc toward KRAS G12C inhibitor divarasib (GDC-6036), enabled through continuous flow chemistry. Org Proc Res Dev. https://doi.org/10.1021/acs.oprd.3c00164

    Article  Google Scholar 

  100. Nova-Fernández JL, Pascual-Coca G, Cabrera S, Alemán J (2023) Rapid and safe continuous-flow Simmons-Smith cyclopropanation using a Zn/Cu couple column. Adv Synth Catal. https://doi.org/10.1002/adsc.202300665

    Article  Google Scholar 

  101. Berton M, Huck L, Alcázar J (2018) On-demand synthesis of organozinc halides under continuous flow conditions. Nat Protoc 13:324–334. https://doi.org/10.1038/nprot.2017.141

    Article  CAS  PubMed  Google Scholar 

  102. Abdiaj I, Fontana A, Gomez MV, de la Hoz A, Alcázar J (2018) Visible-light-induced nickel-catalyzed Negishi cross-couplings by exogenous-photosensitizer-free photocatalysis. Angewandte Chem Int Edition 57:8473–8477. https://doi.org/10.1002/anie.201802656

    Article  CAS  Google Scholar 

  103. Abdiaj I, Horn CR, Alcazar J (2019) Scalability of visible-light-induced nickel Negishi reactions: a combination of flow photochemistry, use of solid reagents, and in-Line NMR monitoring. J Org Chem 84:4748–4753. https://doi.org/10.1021/acs.joc.8b02358

    Article  CAS  PubMed  Google Scholar 

  104. Abdiaj I, Cañellas S, Dieguez A, Linares ML, Pijper B, Fontana A, Rodriguez R, Trabanco A, Palao E, Alcázar J (2023) End-to-end automated synthesis of C(sp3)-enriched drug-like molecules via Negishi coupling and novel, automated liquid–liquid extraction. J Med Chem 66:716–732. https://doi.org/10.1021/acs.jmedchem.2c01646

    Article  CAS  PubMed  Google Scholar 

  105. Pijper B, Martín R, Huertas-Alonso AJ, Linares ML, López E, Llaveria J, Díaz-Ortiz A, Dixon DJ, de la Hoz A, Alcázar J (2023) Fully automated flow protocol for C(sp3)–C(sp3) bond formation from tertiary amides and alkyl jalides. Org Lett. https://doi.org/10.1021/acs.orglett.3c01390

    Article  PubMed  Google Scholar 

  106. Gilman H, Wright GF (1933) The Mechanism of the Wurtz—Fittig reaction. The direct preparation of an organosodium (potassium) compound from an RX compound. J Am Chem Soc 55:2893–2896. https://doi.org/10.1021/ja01334a044

    Article  CAS  Google Scholar 

  107. Bockmühl M, Ehrhart G (1935) Sodium phenyl and its derivatives and process of preparing them. US Patent 2, 012, 372

  108. Schlosser M, Hartmann J, Staehle M et al (1986) Ring tension, hydrocarbon acidity, and new super-bases. Chimia (Aarau) 40:306–308

    CAS  Google Scholar 

  109. Gissot A, Becht J-M, Desmurs JR, Pévère V, Wagner A, Mioskowski C (2002) Directed ortho-metalation, a new insight into organosodium chemistry. Angewandte Chemie 114:350–353. https://doi.org/10.1002/1521-3757(20020118)114:2%3c350::aid-ange350%3e3.0.co;2-y

    Article  Google Scholar 

  110. Garden JA, Armstrong DR, Clegg W, García-Alvarez J, Hevia E, Kennedy AR, Mulvey RE, Robertson SD, Russo L Donor-activated lithiation and sodiation of trifluoromethylbenzene: structural, spectroscopic, and theoretical Insights. Organometallics 32:5481–5490. https://doi.org/10.1021/om4007664

  111. Ma Y, Algera RF, Collum DB (2016) Sodium diisopropylamide in N, N -dimethylethylamine: reactivity, selectivity, and synthetic utility. J Org Chem 81:11312–11315. https://doi.org/10.1021/acs.joc.6b02287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Algera RF, Ma Y, Collum DB (2017) Sodium diisopropylamide: aggregation, solvation, and stability. J Am Chem Soc 139:7921–7930. https://doi.org/10.1021/jacs.7b03061

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Algera RF, Ma Y, Collum DB (2017) Sodium diisopropylamide in tetrahydrofuran: selectivities, rates, and mechanisms of arene metalations. J Am Chem Soc 139:15197–15204. https://doi.org/10.1021/jacs.7b08734

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Huang Y, Chan GH, Chiba S (2017) Amide-directed C−H sodiation by a sodium hydride/iodide composite. Angewandte Chem Int Edition 56:6544–6547. https://doi.org/10.1002/anie.201702512

    Article  CAS  Google Scholar 

  115. Asako S, Nakajima H, Takai K (2019) Organosodium compounds for catalytic cross-coupling. Nat Catal 2:297–303. https://doi.org/10.1038/s41929-019-0250-6

    Article  CAS  Google Scholar 

  116. Davison N, McMullin CL, Zhang L, Hu S, Waddell PG, Wills C, Dixon C, Lu E (2023) Li vs Na: divergent reaction patterns between organolithium and organosodium complexes and ligand-catalyzed ketone/aldehyde methylenation. J Am Chem Soc 145:6562–6576. https://doi.org/10.1021/jacs.3c01033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Anderson DE, Tortajada A, Hevia E (2023) Highly reactive hydrocarbon soluble alkylsodium reagents for benzylic aroylation of toluenes using Weinreb amides. Angewandte Chem Int Edition 62:e202218498. https://doi.org/10.1002/anie.202218498

    Article  CAS  Google Scholar 

  118. Dilauro G, Luccarelli C, Quivelli AF, Vitale P, Perna FM, Capriati V (2023) Introducing water and deep eutectic solvents in organosodium chemistry: chemoselective nucleophilic functionalizations in air. Angewandte Chem Int Edition 62:e202304720. https://doi.org/10.1002/anie.202304720

    Article  CAS  Google Scholar 

  119. Weidmann N, Ketels M, Knochel P (2018) Sodiation of arenes and heteroarenes in continuous flow. Angewandte Chem Int Edition 57:10748–10751. https://doi.org/10.1002/anie.201803961

    Article  CAS  Google Scholar 

  120. Harenberg JH, Weidmann N, Karaghiosoff K, Knochel P (2021) Continuous flow sodiation of substituted acrylonitriles, alkenyl sulfides and acrylates. Angewandte Chem - Int Edition 60:731–735. https://doi.org/10.1002/anie.202012085

    Article  CAS  Google Scholar 

  121. Harenberg JH, Weidmann N, Wiegand AJ, Hoefer CA, Annapureddy RR, Knochel P (2021) (2-ethylhexyl)sodium: a hexane-soluble reagent for Br/Na-exchanges and directed metalations in continuous flow. Angewandte Chemie - Int Edition 60:14296–14301. https://doi.org/10.1002/anie.202103031

    Article  CAS  Google Scholar 

  122. Harenberg JH, Weidmann N, Knochel P (2020) Preparation of functionalized aryl, heteroaryl, and benzylic potassium organometallics using potassium diisopropylamide in continuous flow. Angewandte Chem - Int Edition 59:12321–12325. https://doi.org/10.1002/anie.202003392

    Article  CAS  Google Scholar 

  123. Musio B, Gala E, Ley SV (2018) Real-time spectroscopic analysis enabling quantitative and safe consumption of fluoroform during nucleophilic trifluoromethylation in flow. ACS Sustain Chem Eng 6:1489–1495. https://doi.org/10.1021/acssuschemeng.7b04012

    Article  CAS  Google Scholar 

  124. Köckinger M, Ciaglia T, Bersier M, Gutmann B, Kappe CO (2018) Utilization of fluoroform for difluoromethylation in continuous flow: a concise synthesis of α-difluoromethyl-amino acids. Green Chem 20:108–112. https://doi.org/10.1039/C7GC02913F

    Article  Google Scholar 

  125. Köckinger M, Hone CA, Gutmann B, Hanselmann P, Bersier M, Torvisco A, Kappe CO (2018) Scalable continuous flow process for the synthesis of eflornithine using fluoroform as difluoromethyl source. Org Proc Res Dev 22:1553–1563. https://doi.org/10.1021/acs.oprd.8b00318

    Article  CAS  Google Scholar 

  126. Lee H, Joo J, Yim S, Kim D, Kim H (2023) Ex-situ generation and synthetic utilization of bare trifluoromethyl anion in flow via rapid biphasic mixing. Nat Commun 14:1231. https://doi.org/10.1038/s41467-022-35611-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

M. C. acknowledges the Italian MUR for funding under the framework of the Action IV.6 PON R&I 2014–2020 – DM 1062. The authors also wish to express their gratitude to Prof. Renzo Luisi and Prof. Leonardo Degennaro for the fruitful discussions.

Author information

Authors and Affiliations

  1. Department of Pharmacy-Drug Sciences, University of Bari “A. Moro”, Via E. Orabona 4, 70125, Bari, Italy

    Mauro Spennacchio, Philipp Natho, Michael Andresini & Marco Colella

Authors
  1. Mauro Spennacchio
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Philipp Natho
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael Andresini
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marco Colella
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marco Colella.

Ethics declarations

Conflicts of interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Spennacchio, M., Natho, P., Andresini, M. et al. Continuous Flow Generation of Highly Reactive Organometallic Intermediates: A Recent Update. J Flow Chem 14, 43–83 (2024). https://doi.org/10.1007/s41981-023-00292-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s41981-023-00292-y

Keywords

Search

Navigation