Isotopic Labelling of Functionalised Arenes Catalysed by Iridium(I) Species of the [(cod)Ir(NHC)(py)]PF6 Complex Class

Paul W. C. Cross; John M. Herbert; William J. Kerr; Alan H. McNeill; Laura C. Paterson

doi:10.1055/s-0035-1560518

Synlett, Table of Contents

Synlett 2016; 27(01): 111-115
DOI: 10.1055/s-0035-1560518

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Isotopic Labelling of Functionalised Arenes Catalysed by Iridium(I) Species of the [(cod)Ir(NHC)(py)]PF₆ Complex Class

Paul W. C. Cross

^aUniversity of Strathclyde, Department of Pure & Applied Chemistry, WestCHEM, 295 Cathedral Street, Glasgow G1 1XL, UK Email: w.kerr@strath.ac.uk

,

John M. Herbert

^bDepartment of Isotope Chemistry and Metabolite, Sanofi-Synthélabo, Willowburn Avenue, Alnwick, Northumberland NE66 2JH, UK

,

William J. Kerr*

^aUniversity of Strathclyde, Department of Pure & Applied Chemistry, WestCHEM, 295 Cathedral Street, Glasgow G1 1XL, UK Email: w.kerr@strath.ac.uk

,

Alan H. McNeill

^bDepartment of Isotope Chemistry and Metabolite, Sanofi-Synthélabo, Willowburn Avenue, Alnwick, Northumberland NE66 2JH, UK

,

Laura C. Paterson

^aUniversity of Strathclyde, Department of Pure & Applied Chemistry, WestCHEM, 295 Cathedral Street, Glasgow G1 1XL, UK Email: w.kerr@strath.ac.uk

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Abstract

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Dedicated to Professor Steven V. Ley, with much gratitude and respect, on the occasion of his 70^th birthday

Abstract

Iridium(I) complexes of the type [(cod)Ir(NHC)(Py)]PF₆ have been exposed as efficient catalysts in the area of hydrogen-isotope exchange. More specifically, by an ortho-directed C–H activation process, high levels of deuterium incorporation have been achieved using low levels of catalyst over a range of functionalised aromatic compounds. Additionally, the developed protocol has been extended to include a selected pharmacological target, where chemoselective labelling is observed within such a multifunctional substrate.

Key words

iridium - C–H activation - hydrogen-isotope exchange - deuteration

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References

References and Notes
1 Present address: Isotope Chemistry and Metabolite Synthesis, Covance Laboratories Limited, Willowburn Avenue, Alnwick, Northumberland NE66 2JH, UK.

For selected reviews, see:

2a Atzrodt J, Derdau V, Fey T, Zimmermann J. Angew. Chem. Int. Ed. 2007; 46: 7744
2b Salter R. J. Labelled Compd. Radiopharm. 2010; 53: 645
2c Nilsson GN, Kerr WJ. J. Labelled Compd. Radiopharm. 2010; 53: 662
2d Allen PH, Hickey MJ, Kingston LP, Wilkinson DJ. J. Labelled Compd. Radiopharm. 2010; 53: 731
2e Lockley WJ. S, McEwen A, Cooke R. J. Labelled Compd. Radiopharm. 2012; 55: 235
2f Isin EM, Elmore CS, Nilsson GN, Thompson RA, Weidolf L. Chem. Res. Toxicol. 2012; 25: 532

For selected examples, see:

3a Lin D.-L, Chang W.-T, Kuo T.-L, Liu R.-H. J. Anal. Toxicol. 2000; 24: 275
3b Atzrodt J, Derdau V. J. Labelled Compd. Radiopharm. 2010; 53: 674

For selected examples, see:

4a Heinekey DM. J. Labelled Compd. Radiopharm. 2007; 50: 1063
4b Parkin G. J. Labelled Compd. Radiopharm. 2007; 50: 1088

For selected examples, see:

5a Miyashita M, Sasaki M, Hattori I, Sakai M, Tanino K. Science 2004; 305: 495
5b Quasdorf KW, Huters AD, Lodewyk MW, Tantillo DJ, Garg NK. J. Am. Chem. Soc. 2012; 134: 1396

6a Brown JA, Irvine S, Kennedy AR, Kerr WJ, Andersson S, Nilsson GN. Chem. Commun. 2008; 1115
6b Cochrane AR, Idziak C, Kerr WJ, Mondal B, Paterson LC, Tuttle T, Andersson S, Nilsson GN. Org. Biomol. Chem. 2014; 12: 3598
6c Kennedy AR, Kerr WJ, Moir R, Reid M. Org. Biomol. Chem. 2014; 12: 7927
6d 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
6e Atzrodt J, Derdau V, Kerr WJ, Reid M, Rojahn P. Tetrahedron 2015; 71: 1924
6f Devlin J, Kerr WJ, Lindsay DM, McCabe TJ. D, Reid M, Tuttle T. Molecules 2015; 20: 11676

For a recent disclosure of the use of complexes of the type [(cod)Ir(NHC)Cl], see:

6g Cochrane AR, Irvine S, Kerr WJ, Reid M, Andersson S, Nilsson GN. J. Labelled Compd. Radiopharm. 2013; 56: 451

For examples of HIE at olefinic C–H bonds, see:

6h Kerr WJ, Mudd RJ, Paterson LC, Brown JA. Chem. Eur. J. 2014; 20: 14604

7 Kerr WJ, Reid M, Tuttle T. ACS Catal. 2015; 5: 402
8 Bennie LS, Fraser CJ, Irvine S, Kerr WJ, Andersson S, Nilsson GN. Chem. Commun. 2011; 47: 11653
9 Lee HM, Jiang T, Stevens ED, Nolan SP. Organometallics 2001; 20: 1255
10 Hillier AC, Lee HM, Stevens ED, Nolan SP. Organometallics 2001; 20: 4246
11 Crabtree RH, Morehouse SM, Quirk JM. Inorg. Synth. 1986; 24: 173
12 Typical Procedure for the Preparation of Catalysts 3a–cAn oven-dried Schlenk flask was charged with NHC salt 1 (2.49 mmol) and evacuated for 30 min. The flask was then transferred into a nitrogen-filled glove box and isolated KH (2.49 mmol) was added. The flask was then attached to a Schlenk line (argon/vacuum), evacuated once, and filled with argon. Anhydrous THF (30 mL) was added, and the slow evolution of hydrogen was observed. The resulting solution was then allowed to stir for 20 h at r.t. after which time the reaction mixture was filtered through a dry filter stick into an oven-dried Schlenk flask. The THF was evaporated, and the resulting free carbene was extracted into anhydrous toluene (30 mL). The resulting toluene solution was filtered through another dry filter stick into a previously evacuated and oven-dried Schlenk flask containing [(cod)Ir(py)₂]PF₆ (2, 1.66 mmol). The reaction was allowed to stir for 2 d at r.t. under an argon atmosphere. After this time, the mixture was filtered to yield the desired iridium complex 3.

13a Cross PW. C, Ellames GJ, Gibson JS, Herbert JM, Kerr WJ, McNeill AH, Mathers TW. Tetrahedron 2003; 59: 3349
13b Ellames GJ, Gibson JS, Herbert JM, McNeill AH. Tetrahedron 2001; 57: 9487
13c Shu AY. L, Chen W, Heys JR. J. Organomet. Chem. 1996; 524: 87
13d Heys JR, Shu AY. L, Senderoff SG, Phillips NM. J. Labelled Compd. Radiopharm. 1993; 33: 431
13e Piola L, Fernández-Salas JA, Manzini S, Nolan SP. Org. Biomol. Chem. 2014; 12: 8683

14 Representative Procedure for Isotopic Labelling: Acetophenone (4a) Using Catalyst 3c (Scheme 2)A 100 mL, three-necked round-bottom flask was fitted with two stopcock valves and a Suba-Seal and was flame-dried under vacuum. The flask was then placed under a nitrogen atmosphere and evacuated three times. The flask was then charged with catalyst 3c (34 mg, 0.042 mmol) and CH₂Cl₂ (5 mL), and then purged with nitrogen. The solution was allowed to stir under an atmosphere of nitrogen for 15 min prior to the addition of acetophenone (4a, 100 mg, 0.83 mmol). The Suba-Seal was then replaced with a greased glass stopper, and the solution was stirred whilst being cooled to –78 °C in a dry ice–acetone slurry. The flask was twice evacuated and flushed with nitrogen. Upon a third evacuation, an atmosphere of deuterium gas was introduced via a balloon. The cold bath was removed, and the flask was allowed to warm to r.t. NOTE: The glass stopper was physically restrained as the reaction mixture warms. The resulting mixture was stirred vigorously for 16 h before removing excess deuterium gas and replacing with air. The reaction mixture and washings (CH₂Cl₂) were transferred into a single-necked flask before removing the solvent under reduced pressure. The catalyst complex was then precipitated by the addition of PE–Et₂O (1:1, 10 mL) to the reaction residues. The catalyst was then removed by filtration through a plug of silica, and the resulting filtrate was concentrated under reduced pressure. The level of deuterium incorporation in the substrate was determined by ¹H NMR to be 94%. The integrals were calibrated against a peak corresponding to a position not expected to be labelled. The equation below was used to calculate the extent of labelling: % D = 100 – [(residual integral/no. of labelling sites) × 100] Acetophenone (4a)¹H NMR (400 MHz, CDCl₃): δ = 2.45 (s, 3 H), 7.32 (t, 2 H, J = 8.0 Hz), 7.41 (t, 1 H, J = 8.0 Hz), 7.81 (d, 2 H, J = 8.0 Hz) ppm. Labelling expected at δ = 7.81 ppm. Determined against integral at δ = 2.45 ppm
15 In experiments using 2.5 mol% of catalysts 3a or 3c in CH₂Cl₂ over 16 h at r.t., 81% and 90% D incorporation was obtained, respectively, in the labelling of acetophenone (4a)