Synlett, Inhaltsverzeichnis Synlett 2024; 35(19): 2201-2206DOI: 10.1055/a-2239-6965 letter Isotopic Labeling Directing Hydrogen Isotope Exchange with Aryl Carboxylic Acids Richard J. Mudd a Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow, Scotland, UK, G1 1XL , Marc Reid a Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow, Scotland, UK, G1 1XL , Laura C. Paterson a Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow, Scotland, UK, G1 1XL , Jens Atzrodt b Sanofi Germany, R&D Operations, Industriepark Höchst, 65926 Frankfurt am Main, Germany , Volker Derdau c Sanofi Germany, R&D, Integrated Drug Discovery, Isotope Chemistry, Industriepark Höchst, 65926 Frankfurt am Main, Germany , William J. Kerr ∗ a Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow, Scotland, UK, G1 1XL› InstitutsangabenArtikel empfehlen Abstract Artikel einzeln kaufen Alle Artikel dieser Rubrik Abstract A highly effective and selective ortho-directed hydrogen isotope exchange process for aryl carboxylic acids has been achieved by using an iridium(I) N-heterocyclic carbene/phosphine complex under mild and neutral conditions. Good levels of deuterium incorporation have been delivered across a wide array of examples, including a number of biologically active drug compounds. Key words Key wordsiridium catalysis - hydrogen isotope exchange - deuteration - carboxylic acids - benzoic acids Volltext Referenzen References and Notes 1a Kopf S, Bourriquen F, Li W, Neumann H, Junge K, Beller M. Chem. Rev. 2022; 122: 6634 1b Atzrodt J, Derdau V, Kerr WJ, Reid M. Angew. Chem. Int. Ed. 2018; 57: 3022 1c Lockley WJ. S, Heys JR. J. Labelled Compd. Radiopharm. 2010; 53: 635 2a Di Martino RM. C, Maxwell BD, Pirali T. Nat. Rev. Drug Discovery 2023; 22: 562 2b Derdau V, Elmore CS, Hartung T, McKillican B, Mejuch T, Rosenbaum C, Weibe C. Angew. Chem. Int. Ed. 2023; e202306019 2c Atzrodt J, Derdau V, Kerr WJ, Reid M. Angew. Chem. Int. Ed. 2018; 57: 1758 2d Elmore CS, Bragg RA. Bioorg. Med. Chem. Lett. 2015; 25: 167 2e Lockley W, McEwen A, Cooke R. J. Labelled Compd. Radiopharm. 2012; 55: 235 3a Schellekens RC. A, Stellaard F, Woerdenbag HJ, Frijlink HW, Kosterink JG. W. Br. J. Clin. Pharmacol. 2011; 72: 879 3b Simmons EM, Hartwig JF. Angew. Chem. Int. Ed. 2012; 51: 3066 4a DeWitt SH, Maryanoff BE. Biochemistry 2018; 57: 472 4b Tung RD. Future Med. Chem. 2016; 8: 491 5 For a recent review detailing contributions to the field of iridium-catalysed hydrogen isotope exchange, see: Kerr WJ, Knox GJ, Paterson LC. J. Labelled Compd. Radiopharm. 2020; 63: 281 6 Brown JA, Cochrane AR, Irvine S, Kerr WJ, Mondal B, Parkinson JA, Paterson LC, Reid M, Tuttle T, Andersson S, Nilsson GN. Adv. Synth. Catal. 2014; 356: 3551 For selected examples, see: 7a Owens PK, Smith BI. P, Campos S, Lindsay DM, Kerr WJ. Synthesis 2023; 55: 3644 7b Kerr WJ, Knox GJ, Reid M, Tuttle T, Bergare J, Bragg RA. ACS Catal. 2020; 10: 11120 7c Kerr WJ, Lindsay DM, Owens PK, Reid M, Tuttle T, Campos S. ACS Catal. 2017; 7: 7182 7d Devlin J, Kerr WJ, Lindsay DM, McCabe TJ. D, Reid M, Tuttle T. Molecules 2015; 20: 11676 7e Atzrodt J, Derdau V, Kerr WJ, Reid M, Rojahn P, Weck R. Tetrahedron 2015; 71: 1924 7f Kerr WJ, Reid M, Tuttle T. ACS Catal. 2015; 5: 402 7g Brown JA, Irvine S, Kennedy AR, Kerr WJ, Andersson S, Nilsson GN. Chem. Commun. 2008; 1115 8 Kerr WJ, Mudd RJ, Paterson LC, Brown JA. Chem. Eur. J. 2014; 20: 14604 9 Kerr WJ, Mudd RJ, Reid M, Atzrodt J, Derdau V. ACS Catal. 2018; 8: 10895 10 Kerr WJ, Lindsay DM, Reid M, Atzrodt J, Derdau V, Rojahn P, Weck R. Chem. Commun. 2016; 52: 6669 For selected iridium-based examples, see: 11a Stork CM, Weck R, Valero M, Kramp H, Güssregen S, Waldvogel SR, Sib A, Derdau V. Angew. Chem. Int. Ed. 2023; 62: e202301512 11b Krüger J, Manmontri B, Fels G. Eur. J. Org. Chem. 2005; 1402 For a comparison of the use of Group VIII metals, see: 11c Lockley WJ. S. J. Labelled Compd. Radiopharm. 1984; 21: 45 For a selected ruthenium-based example, see: 11d Muller V, Weck R, Derdau V, Ackermann L. ChemCatChem 2020; 12: 100 For a selected rhodium-based example, see: 11e Garreau AL, Zhou H, Young MC. Org. Lett. 2019; 21: 7044 For selected palladium-based examples, see: 11f Ma S, Villa G, Thuy-Boun PS, Homs A, Yu J.-Q. Angew. Chem. Int. Ed. 2014; 53: 734 11g Zhang Z, Jiang Z.-J, Cao Y, Chen J, Gao Z. Synthesis 2022; 54: 4907 Tetrazoles are amongst the most employed carboxylic acid isosteres; for relevant review articles, see: 12a Myznikov LV, Hrabalek A, Koldobskii GI. Chem. Heterocycl. Compd. 2007; 43: 1 12b Herr RJ. Bioorg. Med. Chem. 2002; 10: 3379 13 Kennedy AR, Kerr WJ, Moir R, Reid M. Org. Biomol. Chem. 2014; 12: 7927 14a Bennie LS, Fraser CJ, Irvine S, Kerr WJ, Andersson S, Nilsson GN. Chem. Commun. 2011; 47: 11653 14b Kerr WJ, Mudd RJ, Brown JA. Chem. Eur. J. 2016; 22: 4738 14c Crabtree RH, Felkin H, Morris GE. J. Organomet. Chem. 1977; 141: 205 14d Crabtree RH. Acc. Chem. Res. 1979; 12: 331 15 Hansch C, Leo A, Taft RW. Chem. Rev. 1991; 91: 165 16 4-Methoxy(2,6-2H2)benzoic Acid (D9a); Typical Procedure Exchange reactions were carried out on a Heidolph Synthesis 1 Liquid 16 device. The device was evacuated and filled with argon, and the water condenser was turned on. A carousel tube was charged with substrate 9a (13.1 mg, 0.086 mmol) and iridium catalyst 6 (7.6 mg, 0.0043 mmol). MTBE (1 mL) was added, rinsing the inner walls of the tube. The tube was then sealed at the screw cap, with the gas inlet left open under argon. The flask was subjected to two cycles of evacuation and refilling of deuterium from a balloon. The gas inlet tube was then closed, creating a sealed atmosphere of deuterium. The carousel shaking motion was initiated (750 rpm) and the temperature was set to 50 ℃. After starting the shaking motion and temperature controller of the device, the timer was started, and a rapid red/orange to clear/yellow colour change was observed. The reaction mixture was stirred for 2 h, then excess deuterium was removed and replaced with air. The solution was then diluted with Et2O (2 mL), basified with 2 M aq NaOH (2 mL), and separated. The aqueous layer was washed with Et2O (2 × 2 mL), acidified to pH 1 with 2 M aq HCl (~3 mL), and extracted with CH2Cl2 (2 × 2 mL). The CH2Cl2 extracts were dried (Na2SO4), filtered, and concentrated in vacuo. The level of incorporation was determined by 1H NMR spectroscopic analysis, with the integrals of the anticipated labelling positions measured against a peak corresponding to a position where labelling was not expected. The percentage deuteration was calculated by using the following equation: %Deuteration = 100 – [(residual integral/no. of labelling sites) × 100]. D incorporation; Run 1: 89%; Run 2: 90%; Average: 90%. 1H NMR (300 MHz, DMSO): δ = 12.68 (br s, 1 H, O–H), 7.93–7.84 (m, 2 H, Ar-H), 7.05-6.97 (m, 2 H, Ar-H), 3.81 (s, 3 H, O-CH3 ). Incorporation expected at δ = 7.93–7.84. Determined against integral at δ = 3.81. 17 It is predicted that the pyridine and pyridine N- oxide functionalities would outcompete carboxylic acid binding; see: Timofeeva DS, Lindsay DM, Kerr WJ, Nelson DJ. Catal. Sci. Technol. 2021; 11: 5498 18 García-Rodríguez C, Mujica P, Illanes-González J, López A, Vargas C, Sáez JC, González-Jamett A, Ardiles ÁO. Biomedicines 2023; 11: 1516 19 Vane JR, Botting RM. Thromb. Res. 2003; 110: 255 20 Srivastava R, Mishra MK, Patel AK, Singh A, Kushwaha K. GSC Biol. Pharm. Sci. 2019; 7: 52 Zusatzmaterial Zusatzmaterial Supporting Information
