When we see an EvoluChem PhotoRedOx Box™ used in creative ways, we feel obliged to share it as loudly as possible. Recently, we wrote about photocatalytic methods for Hot labels using HAT<\/a> for deuterium and tritium labeling that used the PhotoRedox Box TC™. This month, we have this amazing work from Veronique Gouverneur and coworkers in JACS entitled \u201cPhotoredox Nucleophilic (Radio)fluorination of Alkoxyamines<\/a>\u201d (Ref 1) developing a novel photoredox induced fluorination for radiolabeling a wide range of pharmaceutically relevant small molecules. The optimized reaction was then applied to a radiosynthesizer which incorporated a PhotoRedOx Box Flow Reactor™<\/a> and blue LED as part of a flow process ultimately affording an automated radiosynthetic platform with fast access to 18<\/sup>F labeled aliphatic fluorides. An amazing work\u2014but we\u2019re getting ahead of ourselves.<\/p>\n Why would someone make so much effort to incorporate radioactive 18<\/sup>F into a small molecule? The answer is Positron Emission Tomography (PET). PET is a sensitive non-invasive imaging technique for real time monitoring in vivo<\/em> with numerous diagnostics uses for detecting cancers, metabolic conditions, organ failure, blood flow and on and on. Because of both its decay profile (97% \u03b2+) and half-life of 109.7 min of 18<\/sup>F, radiolabeled small molecules containing F are a great source of positrons for imaging. As many drugs already contain a 19<\/sup>F, radiolabeled derivatives can be utilized in the identical manner of the unlabeled drug, although synthetic methods for incorporating the radiolabeled 18<\/sup>F can be limiting. A good synthetic method for radiolabeling with 18<\/sup>F requires a few things. An efficient mild reaction, performed quickly, with a simple purification. And the ability to be performed onsite or near an imagining site so that the labeled compound can be utilized efficiently.<\/p>\n In recent years, methods for two-electron pathways to fluorination of small molecules are quite abundant (Figure 1). However, most require complex synthesis of pre-functionalized precursors as an efficient leaving group, harsh conditions and have poor reactivity for secondary or tertiary substrates. Two recent examples of radical fluorination are also described, with limitations on accessible substrates, selectivity and purification issues (Ref 2,3). When you start to think about the requirements for synthesis on demand, with limitations on availability of labeled fluorine sources, short time frames and purification complications, the requirements for a successful radiolabeling fluorination reaction become apparent. As such the author\u2019s stated goal is as follows, \u201cto offer radiochemists a novel versatile method to prepare alkyl 18<\/sup>F-fluorides using a broader range of both starting materials and carbocations\u201d.<\/p>\n Figure 1:<\/strong> Methods for Fluorination (adapted from Ref 1-Figure1)<\/p>\n The authors selected TEMPO-derived alkoxyamines, which are suitable for photoredox induced functionalization, although fluorination with them has not been previously described. TEMPO-derived substrates are easily accessible in a single step from a diverse set of functional handles including carboxylic acids, halides, alkenes, alcohols, aldehydes, boronates and C-H bonds. For fluorine sources, the authors were only interested in fluorine reagents that would be suitable for radiolabeling and so common reagents such as SelectFluor (requiring F2<\/sub> for synthesis, not practical at a radiolabeling facility) or NEt3<\/sub>\u00b73HF (successful initial reaction of 84% but not compatible for automation) were not thoroughly investigated. Instead, the authors focused on KF and CsF two fluorine sources accessible as 18<\/sup>F that are easily handled. And so, the authors set about extensively optimizing their reaction with an eye towards every detail mattering for automation. HFIP was added as a proton source and solubilizing agent. The reaction proceeded well with low substrate loading. An ionic iridium photocatalysts was selected over other options, ultimately for suitability in purification from automated reaction by a cartridge. Also, the reaction proceeded without need for degassing with nitrogen. Ultimately a reaction was discovered that proceeds quickly, with 71% radiochemical yield in 2 minutes of irradiation time (92% at 20 minutes).<\/p>\n Figure 2:<\/strong> Model reaction for optimization<\/p>\n The authors then screened a broad selection of substrates containing a wide array of functional groups found in medicinal chemistry, with each TEMPO-derived version of each accessible in one step. Most of the reactions proceeded with greater than 70% conversion for labeling with 18<\/sup>F. (Check out the paper to see the full substrate scope). In addition, the reaction proceeding with unpurified TEMPO-derived substrates without loss of reactivity or labeling demonstrates a one pot method for access to radiolabeled 18<\/sup>F compounds.<\/p>\n Figure 3:<\/strong> Reaction in radio-synthesizer with PhotoRedox Box™<\/p>\n With the reaction in hand, the authors then set out to perform the photocatalytic radiofluorination reaction in an automated system. Here the\u00a0 PhotoRedOx Box Flow Reactor™ was utilized with a blue LED because it was easily incorporated in flow into a TRASIS AllinOne radio-synthesizer. The number of steps and reaction details that can be automated in the radio-synthesizer is quite impressive and we really can\u2019t do it justice in this short summary. (but check the Supporting information of the paper if you are interested). Notably, all the of the steps required are incorporated. From the loading of each reagent, drying of the 18<\/sup>F labeled fluoride source, mixing of reagents, transfer to the PhotoRedOx Box Flow Reactor™<\/a><\/strong> with 450 nm LED, back into the synthesizer for purification on a C18 cartridge followed by analysis by radio-HPLC with the entire process taking less than 90 minutes.<\/p>\n In the end, the authors successfully developed \u201cthe first redox-neutral, light-mediated nucleophilic fluorination of alkoxyamines, and demonstrate suitability for 18<\/sup>F-labeling and applications in PET imaging.\u201d The automated process takes advantage of two commercial instruments with easy operation and should be broadly applicable to other flow photoredox processes. Great work!<\/p>\n [\/et_pb_text][\/et_pb_column][\/et_pb_row][\/et_pb_section]<\/p>\n","protected":false},"excerpt":{"rendered":" Flow photochemistry in the PhotoRedOx Box™ is Hot as F! This month, we feature novel photoredox induced fluorination for radiolabeling a wide range of pharmaceutically relevant small molecules.<\/p>\n","protected":false},"author":7786,"featured_media":24787,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_et_pb_use_builder":"on","_et_pb_old_content":"We are huge fans of what could be classified as \u201ccreative photocatalysts\u201d. One of our favorite papers over the past few years was this work that we wrote about here<\/a> using Hypericum flowers as an organic dye for C-C bond formation. A few dried flower petals, a base and an LED and you have a new photochemical reaction. So, if your paper can be described as using a \u201cFenton Boat photocatalyst\u201d, well you have our attention.\r\nIf you Google \u201cFenton Boats\u201d, you get links to a boat shop in Fenton, Michigan, but we\u2019ll argue that soon you will get this recent paper in Angewandte from Zhijun Chen and coworkers entitled, \u201cA Sustainable Wood-Based Iron Photocatalyst for Multiple Uses with Sunlight: Water Treatment and Radical Photopolymerization<\/a>\u201d\r\nWhat\u2019s a Fenton Boat? Stick around and we\u2019ll explain. And show you a video of a photocatalyst boat.\r\n\r\nEmbed tweet:\r\n A Sustainable Wood-Based Iron Photocatalyst for Multiple Uses with Sunlight: Water Treatment and Radical Photopolymerization (Zhijun Chen and co-workers) https:\/\/t.co\/ayHH23uBwY<\/a> pic.twitter.com\/m4a8kJ0jet<\/a><\/p>\u2014 Angewandte Chemie (@angew_chem) May 2, 2023<\/a><\/blockquote> ![\"Photocatalytic](\"https:\/\/hepatochem.com\/wp-content\/uploads\/2024\/05\/Figure-1-1024x841.jpg\")
<\/a><\/p>\n![\"Photocatalytic](\"https:\/\/hepatochem.com\/wp-content\/uploads\/2024\/05\/Figure-2-1024x333.jpg\")
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<\/a><\/p>\nReferences<\/strong><\/h3>\n
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