Synthesis of [¹⁸F]-γ-Fluoro-α,β-unsaturated Esters and Ketones via Vinylogous ¹⁸F-Fluorination of α-Diazoacetates with [¹⁸F]AgF

Published as part of the Special Topic Halogenation methods (with a view towards radioimaging applications)

Abstract

This communication reports a method for the vinylogous radiofluorination of α-diazoacetates to generate [¹⁸F]-γ-fluoro-α,β-unsaturated esters and ketones in moderate to good radiochemical yields. The method uses no-carrier-added [¹⁸F]AgF and is compatible with aromatic and non-aromatic substrates and a number of different functional groups. The labeling method is showcased in the synthesis of a fluorinated cholest-5-en-3-one derivative as well as a difluorinated product pertinent to drug discovery.

Key words

fluorine-18 - late-stage fluorination - PET radiochemistry - diazo chemistry - positron emission tomography

• References

• 1 For a general overview of PET, see: Ametamey SM, Honer M, Schubiger PA. Chem. Rev. 2008; 108: 1501
• 2 For an introduction to the use of PET in drug development, see: Elsinga PH, Waarde AV, Paans AM. J, Dierckx RA. J. O. Trends on the Role of PET in Drug Development 2012

For recent reviews of new fluorine-18 radiochemistry, see:
• 3a Miller PW, Long NJ, Vilar R, Gee AD. Angew. Chem. Int. Ed. 2008; 47: 8998
• 3b Cai L, Lu S, Pike VW. Eur. J. Org. Chem. 2008; 2853
• 3c Tredwell M, Gouverneur V. Angew. Chem. Int. Ed. 2012; 51: 11426
• 3d Brooks AF, Topczewski JJ, Ichiishi N, Sanford MS, Scott PJ. H. Chem. Sci. 2014; 5: 4545
• 3e Jacobson O, Kiesewetter DO, Chen X. Bioconjugate Chem. 2015; 26: 1
• 3f Preshlock S, Tredwell M, Gouverneur V. Chem. Rev. 2016; 116: 719
• 3g Deng X, Rong J, Wang L, Vadev N, Josephson L, Liang SH. Angew. Chem. Int. Ed. 2019; 58: 2580
• 4 Sanford MS, Scott PJ. H. ACS Cent. Sci. 2016; 2: 128
• 5 For a recent example, see: Langstrom B, Blom E. WO 2008106442 A1, 2008
• 6a Scott PJ. H, Brooks AF, Ichiishi N, Sanford MS. US 20160317682 A1, 2016
• 6b Mossine AV, Brooks AF, Ichiishi N, Makaravage KJ, Sanford MS, Scott PJ. H. Sci. Rep. 2017; 7: 233
• 6c Mossine AV, Brooks AF, Bernard-Gauthier V, Bailey J, Ichiishi N, Schirrmacher R, Sanford MS, Scott PJ. H. J. Labelled Compd. Radiopharm. 2018; 61: 228
• 6d Lee SJ, Brooks AF, Ichiishi N, Makaravage KJ, Mossine AV, Sanford MS, Scott PJ. H. Chem. Commun. 2019; 55: 2976
• 6e Lee SJ, Makaravage KJ, Brooks AF, Scott PJ. H, Sanford MS. Angew. Chem. Int. Ed. 2019; 58: 3119
• 6f Verhoog S, Brooks AF, Winton WP, Viglianti BL, Sanford MS, Scott PJ. H. Chem. Commun. 2019; 55: 6361
• 7 Qin C, Davies HM. L. Org. Lett. 2013; 15: 6152
• 8 Glasspoole BW, Crudden CM. Nat. Chem. 2011; 3: 912
• 9 Gray EE, Nielsen MK, Choquette KA, Kalow JA, Graham TJ. A, Doyle AG. J. Am. Chem. Soc. 2016; 138: 10802
• 10a Hollingworth C, Hazari A, Hopkinson MN, Tredwell M, Benedetto E, Huiban M, Gee A, Brown JM, Gouverneur V. Angew. Chem. Int. Ed. 2011; 50: 2613
• 10b Topczewski JJ, Tewson TJ, Nguyen HM. J. Am. Chem. Soc. 2011; 133: 19318
• 10c Benedetto E, Tredwell M, Hollingworth C, Khotavivattana T, Brown JM, Gouverneur V. Chem. Sci. 2013; 4: 89
• 11 Carbonnel E, Poisson T, Jubault P, Pannecoucke X, Besset T. Front. Chem. 2019; 7: 111; DOI: 10.3389/fchem.2019.00111
• 12a Frost AB, Brambilla M, Exner RM, Tredwell M. Angew. Chem. Int. Ed. 2019; 58: 472
• 12b Tredwell M. Synlett 2019; 30: 1371
• 13 Radiochemical yields (RCY) are nonisolated and were calculated by % integrated area of the ¹⁸F-labelled product versus [¹⁸F]fluoride in a radio-TLC trace. Product identities were confirmed by radio-HPLC.
• 14 In addition to low RCYs, we were not able to synthesize reference standards to confirm the identity of [¹⁸F]7F and [¹⁸F]8F because of stability issues, which is consistent with Davies’ results. For example, they reported an NMR yield for the OMe product, but did not isolate it, suggesting that the compound is unstable.⁷
• 15 Winton W, Brooks AF, Wong KK, Scott PJ. H, Viglianti BL. SynOpen 2019; 3: 55
• 16 Lights in the fume hood where the reactions occurred were turned off as a general precaution. However, ambient laboratory lighting was left on and we do not believe the chemistry is light sensitive.