Triazabicyclodecene: an Effective Isotope. Exchange Catalyst in CDCl 3

Transcription

1 Triazabicyclodecene: an Effective Isotope Exchange Catalyst in CDCl 3 Supporting Information Cyrille Sabot, Kanduluru Ananda Kumar, Cyril Antheaume, Charles Mioskowski*, Laboratoire de Synthèse Bio-rganique, UMR 7175/LC1-CNRS, and Service Commun de RMN, IFR85, Université Louis Pasteur de Strasbourg, 74 route du Rhin, B.P 60024, Illkirch cedex, France mioskow@aspirine.u-strasbg.fr Table of contents Experimental procedures General considerations....s4....s4 Representative procedure for deuteration reaction (compounds in Tables 2 and 3) 2-Acetoxyacetophenone 1i trans-2-dimethylamino-4,5-diphenylimidazoline 2 Characterization data ( 1 H/ 13 C) 2-Acetoxyacetophenone 1i S4-S S5.. S5-S6...S7...S7 S1

2 S-Methyltetramethylthiouronium iodide 2 trans-2-dimethylamino-4,5-diphenylimidazoline 2 Spectral data ( 1 H/ 2 H) TMG 4 -Methoxyacetophenone-d 3 1a-d 3 Acetophenone-d 3 1b-d 3 4 -Nitroacetophenone-d 3 1c-d 3 2-Methoxyacetophenone-d 2 1d-d 2 2-Methylacetophenone-d 2 1e-d 2 2-Chloroacetophenone-d 2 1f-d 2 2,2-Dimethylacetophenone-d 1 1g-d 1 1-Phenylpropane-1,2-dione-d 3 : 1h-d 3 2-Acetoxyacetophenone-d 2 1i-d 2 Naphthylmethylketone-d 3 1j-d 3 2-Acetylpyridine-d 3 1k-d 3 2-Acetylthiophene-d 3 1l-d 3 Benzylacetone-d 5 1m-d 5 Cyclodecanone-d 3 1n-d 4 1-Phenylacetylene-d 1 3a-d 1 4-Phenylbut-1-yne-d 1 3b-d 1 1-Phenyl-2-methylacetylene-d 3 3c 2-Ethynyl-1-methylimidazole 3d-d 1 Methyl-1-phenylacetate 4-d 2 3-Nitrofluorene 5-d 2 Indene 6-d 3... S8...S9..S10.. S10.. S11.. S12-S15..S16.. S17..S18..S19..S20..S21..S22..S23..S24..S25 S26-S28. S29-S31..S32..S33.. S34.. S35-S36.. S37.. S38 S39 S2

3 1 H NMR study References S40 S41 S3

4 Experimental procedures General considerations All substrates were commercially available and used without further purification except 2- acetoxyacetophenone 1i synthesized from commercially available 2-hydroxyacetophenone. The trans-2-dimethylamino-4,5-diphenylimidazoline 2 was obtained in two steps from commercially available tetramethylthiourea. Deuterated chloroform used for deuterium incorporation reactions, contained D, 99.80% and H 2 <0.01%. 1 H and 1 H-{ 2 H} NMR spectral data were recorded at 600 or 300 MHz, on spectrometers using a software pulse program library. CDCl 3 was used as lock and CHCl 3 as internal standard (7.27 ppm). 2 H NMR spectral data were recorded at 46 MHz and chemical shifts are reported relative to CDCl 3 (7.27 ppm). HRMS analysis was performed in positive electrospray mode. Representative procedure for deuteration reaction (compounds in Tables 2 and 3): For compound 1b: To a solution of 10 mol % of TBD (10 mg, mmol) in 3 ml of CDCl 3, was added 1b (84 µl, 0.72 mmol). The reaction mixture was stirred at room temperature for 12 hours and quenched with 1N HCl (1 ml). The organic layer was washed with water (2 x 2 ml), brine (1 ml), dried over anhydrous Na 2 S 4 and filtered. Filtrate was concentrated to afford 1b-d 3. The total incorporation yield was determined by 1 H NMR spectroscopy relative to the intensity of a non exchangeable proton in the molecule, or by GC-MS. For example, the global deuterium incorporation of compound 1b-d 3 determined by GC-MS, was calculated as follow: 1/3 x 5.3% + 2/3 x 2% + 3/3 x 65.6% = 86.4% of total incorporation. Moreover, S4

5 the site of deuterium incorporation in the substrate was determined by 2 H NMR spectroscopy relative to CHCl 3 (7.27 ppm). 2-Acetoxyacetophenone 1i 1i To a solution of 2-hydroxyacetophenone (1 g, 9.3 mmol) dissolved in pyridine (40 ml), dried over 3Å molecular sieves beforehand, was added acetyl chloride (667 µl, 9.3 mmol) by dropwise at 0 C. The reaction mixture was stirred at room temperature for 8 hours. The solution was filtered, and filtrate concentrated. The residue was dissolved with 1N HCl and the organic layer was extracted twice with diethylether. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated to afford a brown residue. The crude product was purified by chromatography on a silica gel column eluting with 20% ethyl acetate in cyclohexane to give g (80% yield) of 1i as a yellow oil. Analytical data were in accordance with the previous literature report. 1 R f = 0.44 (UV, Vanilline) in 30% EtAc/ Cyclohexane. 1 H NMR (CDCl 3, 300 MHz): δ 2.24 (s, 3H), 5.35 (s, 2H), (t, J= Hz, 2H, Har), (t, J= Hz, 1H, Har), (t, J= Hz, 2H, Har). 13 C NMR (CDCl 3, 75 MHz): δ 20.8, 66.3, 12, 129.1, 134.1, 134.4, 170.6, IR (KRS-5): 2936, 1751, 1705, 1598, 1450, 1421, 1375, CIMS 179 [M+H + ], 196 [M+NH + 4 ]. trans-2-dimethylamino-4,5-diphenylimidazoline 2 S5

6 N S N S Step 1 + Step 2 I - N N 99% 76% Ph Ph N N H N 2' 2 Step 1: S-Methyltetramethylthiouronium iodide 2 To a solution of tetramethylthiourea (1 g, 7 mmol) in 8 ml of dried methanol at 0 C under argon, was added methyl iodide (870 µl, 19 mmol) by dropwise. After 16 h stirring at room temperature, the solvent was removed under reduced pressure and 2,065 g (99% yield) of 2 as a yellow solid was obtained (hygroscopic). 2 RMN 1 H (300 MHz ; CDCl 3 ) δ : 2.62 (s, 3H), 3.35 (s, 12H). RMN 13 C (75 MHz ; CDCl 3 ) δ : 18.6, 45.3, Step 2: trans-2-dimethylamino-4,5-diphenylimidazoline 2 To a solution of trans-1,2-diphenylethylenediamine (1 g, 4.71 mmol) in 14 ml of dried acetonitrile, at 0 C, under argon, was added S-methyltetramethylthiouronium iodide 2 (1.808 g, 9 mmol). The solution was stirred at room temperature for 2 h and further 2 h at reflux. After cooling, the solution was diluted with 50 ml of dichloromethane and treated by a solution 5% of sodium carbonate (2 x 50 ml). The organic layer was dried over potassium carbonate, filtered and filtrate concentrated. After recrystallization (dichloromethane and a minimum of n-hexane), 953 mg (76% yield) of a white solid 2 was obtained. mp C RMN 1 H (300 MHz ; CDCl 3 ) δ : 2 (s, 6H), 4.69 (s, 2H), 4.78 (bs, 1H), (m, 10H). RMN 13 C (50 MHz ; CDCl 3 ) δ : 38.8, 7, 126.9, 127.7, 128.8, 143.8, IR (KRS-5) ν (cm -1 ): 3028, 2866, 2827, 1667, 1609, 1485, MS (Electrospray) m/z ( calcd for M+H). S6

7 Characterization data ( 1 H/ 13 C) H NMR 300 MHz 1i C NMR 75 MHz S7

8 H NMR 300 MHz S I- N + N 2' C NMR 75 MHz S8

9 Ph N N 1 H NMR 300 MHz Ph N H C NMR 50 MHz S9

10 Spectral data ( 1 H/ 2 H) NH N N TMG S10

11 H-{ 2 H} NMR- 600 MHz CD 3 Me 1a-d H NMR - 47 MHz CDCl 3 S11

12 H-NMR MHz b-d 3 CD H-{ 2 H} NMR MHz S12

13 991 CD 3 2 H NMR - 46 MHz 1b-d 3 CDCl 3 S13

14 GC CH 3 1b MS S14

15 GC CD 3 1b-d 3 MS S15

16 H-{ 2 H} NMR MHz CD 3 2 N 1c-d H NMR - 46 MHz CDCl 3 S16

17 H-{ 2 H} NMR MHz Me D D 1d-d H NMR - 46 MHz CDCl 3 S17

18 D D 1 H-{ 2 H} NMR MHz 1e-d H NMR - 46 MHz CDCl 3 S18

19 H-{ 2 H} NMR MHz Cl D D 1f-d H NMR - 46 MHz CDCl 3 S19

20 H-{ 2 H} NMR MHz D 1g-d CDCl 3 2 H NMR - 46 MHz S20

21 H-{ 2 H} NMR MHz CD h-d H NMR - 46 MHz CDCl 3 S21

22 H-{ 2 H} NMR- 600 MHz D D 1i-d CDCl 3 2 H NMR - 46 MHz S22

23 H-{ 2 H} NMR MHz D 3 C j-d H NMR - 46 MHz CDCl 3 S23

24 H-{ 2 H} NMR MHz 2.70 N CD 3 1k-d H NMR - 46 MHz CDCl S24

25 H-{ 2 H} NMR MHz 2.60 S 1l-d 3 CD H NMR - 46 MHz CDCl 3 S25

26 H -{ 2 H} NMR MHz D D CD m-d H NMR - 46 MHz CDCl 3 S26

27 GC H H CH 3 1m MS S27

28 GC D D CD 3 1m-d 5 MS S28

29 H -{ 2 H} NMR MHz D D D D 1n-d H NMR - 46 MHz CDCl 3 S29

30 GC H H H H 1n MS S30

31 GC D D D D 1n-d 4 MS S31

32 H NMR MHz 3a-d 1 D S32

33 H-{ 2 H} NMR MHz D 3b-d H NMR - 46 MHz CDCl 3 S33

34 H-{ 2 H} NMR MHz 793 CH 3 3c-d H NMR - 46 MHz CDCl 3 S34

35 Reaction of 2d with TBD H NMR Before work-up MHz N N D 3d-d TBD H NMR After work-up MHz S35

36 Reaction 2d with PSTBD H NMR MHz N N D d-d 1 0 S36

37 H NMR 400 MHz D D Me 4-d H NMR 46 MHz CDCl 3 S37

38 H NMR 300 MHz D D 5-d 2 N H NMR - 46 MHz CDCl 3 S38

39 H NMR 300 MHz D D D 6-d H NMR - 46 MHz CDCl 3 S39

40 Mechanistic study C/ TBD and in CDCl 2 Cl 32 (1 with éq.) 1 in equivalent CD 2 Cl 2 CDCl 3 B/ TBD in in CD CD 2 Cl 2 Cl 2 2 A/ A/ TBD in in CDCl CDCl C/ TBD and 1a (1éq.) in CD 2 Cl 2 C/ TBD in CD 2 Cl 2 with 1 equivalent 4'-Metoxyacetophenone in CD 2 Cl 2 B/ a1 in CD 2 Cl 2 B/ 4'-Metoxyacetophenone in CD 2 Cl 2 A/ Deuterated TBD in CD 2 Cl 2 A/ TBD-d in CD 2 Cl 2 S40

41 References 1 Itsuno, I.; J. Chem. Soc. Perkin Trans. I 1985, Fujisaki, S.; Fujiwara, I.; Norisue, Y.; Kajigaeshi, S. Bull. Chem. Soc. Jpn. 1985, 58, S41