Directing Hydrogen Isotope Exchange with Aryl Carboxylic Acids

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

iridium catalysis - hydrogen isotope exchange - deuteration - carboxylic acids - benzoic acids

Publikationsverlauf

Eingereicht: 24. November 2023

Angenommen nach Revision: 05. Januar 2024

Accepted Manuscript online:
05. Januar 2024

Artikel online veröffentlicht:
05. Februar 2024

• 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