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, 67401 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-S6......S5.. S5-S6...S7...S7 S1
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
1 H NMR study References S40 S41 S3
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, 0.072 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
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 1.320 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), 7.45-5 (t, J= Hz, 2H, Har), 7.60-7.70 (t, J= Hz, 1H, Har), 7.90-0 (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, 192.4. IR (KRS-5): 2936, 1751, 1705, 1598, 1450, 1421, 1375, 1220. CIMS 179 [M+H + ], 196 [M+NH + 4 ]. trans-2-dimethylamino-4,5-diphenylimidazoline 2 S5
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, 176.9. 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 202-203 C RMN 1 H (300 MHz ; CDCl 3 ) δ : 2 (s, 6H), 4.69 (s, 2H), 4.78 (bs, 1H), 7.15-7.48 (m, 10H). RMN 13 C (50 MHz ; CDCl 3 ) δ : 38.8, 7, 126.9, 127.7, 128.8, 143.8, 162.3. IR (KRS-5) ν (cm -1 ): 3028, 2866, 2827, 1667, 1609, 1485, 1451. MS (Electrospray) 266.1612 m/z (266.1657 calcd for M+H). S6
Characterization data ( 1 H/ 13 C) 1.9792 3.1002 000 3.1911 7.9366 7.9115 7.6441 7.6190 951 211 7.4960 7.4709 5.3506 2.2399 1 H NMR 300 MHz 1i 192.4176 170.6456 134.4419 134.1343 129.1088 127.9953 77.7849 77.3600 76.9351 66.2689 20.7909 13 C NMR 75 MHz 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 S7
100 431 3.3473 2.6195 1 H NMR 300 MHz S I- N + N 2' 176.9164 77.7849 77.3600 76.9351 45.3027 1639 13 C NMR 75 MHz 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 S8
9.7364 363 000 7.3266 7.3046 4.7802 4.6910 219 Ph N N 1 H NMR 300 MHz Ph N H 2 9.5 9.0 162.2905 143.7898 128.8193 127.6914 126.9004 77.9899 77.3600 76.7155 73.9470 38.7619 13 C NMR 50 MHz 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 S9
Spectral data ( 1 H/ 2 H) 741 100 4.7789 2.7120 NH N N TMG S10
000 113 492 0.0119 0.0490 0.1775 7.9572 7.9426 6.9529 6.9382 3.8826 717 553 389 717 553 389 0.0752 1 H-{ 2 H} NMR- 600 MHz 0.0119 0.0490 0.1775 2.60 6 2 2.48 CD 3 Me 1a-d 3 455 2 H NMR - 47 MHz CDCl 3 S11
7.9644 7.9627 943 923 899 827 813 800 786 000 769 697 677 310 653 397 7.4949 7.4921 7.4894 7.4795 7.4785 7.4768 7.4692 7.4665 7.4638 2.68 2.6247 2.6120 2.6083 2.6048 994 960 922 884 847 2.64 0.0030 0.0486 2.60 0.2606 6 2 2.6247 2.6120 2.6083 2.6048 994 960 922 884 847 1 H-NMR - 600 MHz 0.0030 0.0486 0.2606 1b-d 3 CD 3 0.0773 000 434 407 0.0041 0.0486 0.2607 0.0041 0.0486 0.2607 2.6247 2.6086 922 7.9805 7.9672 7.9648 923 902 800 694 677 656 7.4925 7.4795 7.4665 2.6247 2.6086 922 1 H-{ 2 H} NMR - 600 MHz 2.70 2.65 2.60 5 S12
991 CD 3 2 H NMR - 46 MHz 1b-d 3 CDCl 3 S13
GC CH 3 1b MS S14
GC CD 3 1b-d 3 MS S15
175 000 2.6954 2.6793 2.6633 0.0264 0.0665 0.1542 8.3380 8.3236 8.1312 8.1168 2.6954 2.6793 2.6633 1 H-{ 2 H} NMR - 600 MHz 2.76 2.74 2.72 0.0264 2.70 0.0665 2.68 0.1542 2.66 2.64 2.62 2.60 CD 3 2 N 1c-d 3 2.6722 2 H NMR - 46 MHz CDCl 3 S16
000 915 379 0.0084 0.1320 0.0084 0.1320 3.1182 7.9514 7.9388 988 865 7.4969 7.4843 7.4716 7.2697 4.7278 4.7008 4.7278 4.7008 197 1 H-{ 2 H} NMR - 600 MHz Me D D 1d-d 2 4.7 4.7015 2 H NMR - 46 MHz CDCl 3 S17
000 451 424 0.1172 3.1800 7.9842 7.9716 642 519 7.4836 7.4709 7.4583 283 112 2.9992 2.9873 2.9750 1.2256 0.1172 283 112 2.9992 2.9873 2.9750 D D 1 H-{ 2 H} NMR - 600 MHz 1e-d 2 0 2.9892 2 H NMR - 46 MHz CDCl 3 S18
7.9829 7.9702 7.6364 7.6240 308 181 051 4.7353 4.7131 1 H-{ 2 H} NMR - 600 MHz 4.7353 4.7131 Cl D D 1f-d 2 000 837 259 0.0694 0.2645 0.0694 0.2645 4.7 4.7076 2 H NMR - 46 MHz CDCl 3 S19
1.9978 2.9692 0.7853 000 7.9830 7.9579 889 650 411 7.4997 7.4734 7.4508 3.6183 957 731 505 266 1.2444 1.2219 1 H-{ 2 H} NMR - 600 MHz D 1g-d 1 927 CDCl 3 2 H NMR - 46 MHz S20
000 140 1.9619 0.0433 0.2364 0.3960 0.0433 0.2364 0.3960 396 232 064 290 167 7.6668 7.6545 7.6422 239 109 7.4979 7.2697 396 232 064 0.0780 1 H-{ 2 H} NMR - 600 MHz CD 3 2.60 5 0 1h-d 3 000 3.3972 593 164 2 H NMR - 46 MHz CDCl 3 S21
5.36 000 993 1.9809 0.0948 2.9850 7.9476 7.9234 7.6561 7.6319 7.6068 346 083 7.4841 5.3425 2.2503 1 H-{ 2 H} NMR- 600 MHz 0.0097 0.0916 D D 1i-d 2 5.3395 CDCl 3 2 H NMR - 46 MHz S22
000 721 558 782 680 955 0.0182 0.0547 0.1488 0.0182 0.0547 0.1488 2.7655 2.7508 2.7357 8.7832 8.7689 201 068 7.9658 7.9538 7.8974 7.8841 7.6364 7.6234 7.6111 646 516 400 294 167 038 2.7655 2.7508 2.7357 1 H-{ 2 H} NMR - 600 MHz D 3 C 2.85 2.80 2.75 2.70 1j-d 3 9.5 9.0 7.2651 2.7404 2 H NMR - 46 MHz CDCl 3 S23
000 0.9917 527 037 0.0041 0.0638 0.2540 0.0041 0.0638 0.2540 2.7402 2.7214 2.7022 587 458 7.8561 7.8540 7.8431 7.8414 7.8305 7.8284 7.4891 7.4809 7.4781 7.4699 2.7402 2.7214 2.7022 0.0735 1 H-{ 2 H} NMR - 600 MHz 2.70 N CD 3 1k-d 3 2.7123 2 H NMR - 46 MHz CDCl 3 9.0 0.0 S24
000 0.0052 0.0557 0.2509 0.9891 0.0052 0.0557 0.2509 7.7109 7.7057 7.6534 7.6452 7.1483 7.1415 7.1336 816 655 491 816 655 491 1 H-{ 2 H} NMR - 600 MHz 2.60 S 1l-d 3 CD 3 936 519 2 H NMR - 46 MHz CDCl 3 S25
6.1599 2.6998 000 0.2482 441 7.3102 7.3052 7.2814 7.2173 7.1922 2.9065 2.1433 2.1358 2.1270 1.7303 1 H -{ 2 H} NMR - 300 MHz 2.1433 2.1358 2.1270 0.2482 441 D D CD 3 2.8 2.7 2.2 1m-d 5 2.7482 2.1170 2 H NMR - 46 MHz CDCl 3 S26
GC H H CH 3 1m MS S27
GC D D CD 3 1m-d 5 MS S28
0.2812 000 236 2.4960 2.4885 2.4809 2.4722 0.2812 2.4646 2.4546 2.4470 2.4395 9.9610 236 2.4960 2.4885 2.4809 2.4722 2.4646 2.4546 2.4470 2.4395 1.8407 1.8232 1.8018 1.4968 1.4905 1.4779 1.4679 1.4591 1.3549 1.3373 2.4 1 H -{ 2 H} NMR - 300 MHz D D D D 1n-d 4 2.4928 2 H NMR - 46 MHz CDCl 3 S29
GC H H H H 1n MS S30
GC D D D D 1n-d 4 MS S31
000 2.9159 0.0987 320 258 195 164 143 091 7.4998 7.3688 7.3594 7.3563 7.3521 7.3449 7.3376 7.3345 7.3313 925 1 H NMR - 300 MHz 3a-d 1 D S32
505 178 090 002 000 1.9882 0.0646 7.3604 7.3554 7.3466 7.3328 7.3240 7.3127 7.2814 7.2726 7.2613 7.2575 7.2487 2.9091 2.8840 2.8588 425 174 2.4923 178 090 002 1 H-{ 2 H} NMR - 600 MHz 0.0646 D 3b-d 1 1.9971 2 H NMR - 46 MHz CDCl 3 S33
7.4345 7.4207 7.4094 7.4031 7.3228 7.3115 7.3065 7.2964 7.2889 7.2826 1 H-{ 2 H} NMR - 600 MHz 793 CH 3 3c-d 3 000 947 2.9949 2 H NMR - 46 MHz CDCl 3 S34
Reaction of 2d with TBD 0.9950 2.2741 000 0.0661 0.8003 0.4172 7.4043 3.6584 3.4651 3.3233 3.3032 3.2869 3.2680 3.2479 215 014 1.9813 1.9612 1.9424 1 H NMR Before work-up - 300 MHz 3.4651 N N D 3d-d 1 0.0661 0 3.48 3.46 TBD 0.9576 118 000 0.6859 7.4228 7.2908 3.6717 3.4783 2.1724 3.4783 1 H NMR After work-up - 300.13 MHz 0.6859 S35
Reaction 2d with PSTBD 000 0.9954 3.1226 0.1648 7.4291 7.3053 3.6810 3.4814 1 H NMR - 300 MHz 3.4814 N N D 0.1648 3d-d 1 0 S36
002 000 0.1433 3.7188 3.6588 3.6474 3.6417 3.6367 7.3782 7.3744 7.3706 7.3592 7.3567 7.3529 7.3498 7.3460 7.3397 7.3314 7.3188 7.3144 7.3125 7.3062 7.3018 7.2980 7.2942 7.2860 7.2822 7.2771 3.7188 3.6588 3.6474 3.6417 3.6367 0.1023 1 H NMR 400 MHz D D Me 4-d 2 000 0.1433 3.70 3.6317 2 H NMR 46 MHz CDCl 3 S37
8.2699 7.8945 7.8810 7.8789 019 7.8727 7.8706 109 7.8633 7.8561 7.8519 7.8498 568 7.8353 7.6440 187 7.6336 7.6315 335 7.6273 7.6200 7.6138 7.6117 7.6045 7.6024 7.4932 7.4870 7.4693 7.4620 7.4506 7.4391 7.4329 7.3133 7.2738 5 0.1132 3.9676 0 3.95 3.90 3.9676 0.1132 1.6523 1 H NMR 300 MHz D D 5-d 2 N 2 116 2 H NMR - 46 MHz CDCl 3 S38
000 0.8561 0.1078 0.1078 0.8071 0.1203 0.1203 6.9290 6.9186 6.9103 3.4117 195 7.4967 7.4509 7.4260 7.3282 7.3261 7.3043 7.2461 7.2222 7.1972 6.9290 6.9186 6.9103 817 3.4117 1.6006 1 H NMR 300 MHz D D 0 6.96 6.92 3.40 D 6-d 3 000 2.1509 6.9778 3.4222 2 H NMR - 46 MHz CDCl 3 S39
Mechanistic study 000 340 209 000 163 0.4590 0.4857 000 3.9566 209 0.4857 7.2801 3.2794 3.2605 3.2417 3.1651 3.1451 3.1250 1.9500 1.9312 1.9111 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 3 3 1.9776 1.9705 0.0823 000 000 2.9184 3.9368 1.8576 1.9625 536 000 198 1.9604 112 2.9184 1.9604 4.8284 3.2015 3.1827 3.1626 3.1124 923 723 1.9161 1.8960 1.8772 1.8571 1.8383 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
References 1 Itsuno, I.; J. Chem. Soc. Perkin Trans. I 1985, 2039. 2 Fujisaki, S.; Fujiwara, I.; Norisue, Y.; Kajigaeshi, S. Bull. Chem. Soc. Jpn. 1985, 58, 2429. S41